NPch. 22-23 Huntington's Disease & Multiple Sclerosis Flashcards
1
Q
Huntington’s Disease
A
2
Q
Huntington’s Disease
Introduction
1- what is it characterized by?
2- what is the progression in life?
A
1- progressive motor impairments, cognitive decline and mood and behavioural changes
2- symptoms noticeable during 30-50 y.o.
- Juvenile Huntington’s disease if symptoms visible during childhood
- duration is average 15-20 years (till death)
- cannot be prevented, cured or delayed but multidisciplinary approach for relief of symptoms
3
Q
Huntington’s Disease
Statistics
A
- genetic testing is available
- positive test predicts disease onset in 10-18 years
- chance of inheritance: 50%
- no cures or treatments to prevent disease progression
4
Q
Huntington’s Disease
Historical Context
A
- first medical documentation in 1872 by George Huntington (22yo)
- known for description of Huntington’s
- highlighted motor dysfunction, cognitive decline, psychiatric symptoms as core aspects of disease
- noted tendency of disease to run in families (inheritance)
- 1993 genetic mutation that causes HD was discovered
5
Q
Huntington’s Disease
Diagnosis
A
- clinical evaluation (description of symptoms - motor impairments), family history and genetic testing for CAG expansion in HTT gene
- MRI and CT not required (can help to see extent of damage)
- increasing focus on cognitive factors for diagnosis to determine onset
> motor impairments sometimes absent in beginning (“pre-manifest mutation carrier”)
6
Q
Huntington’s Disease
Differential Diagnosis
A
- autosomal dominant genetic conditions (similar; genetic testing to see whether it’s HD)
- non-progressive extrapyramidal disorders (not caused by single gene mutation)
7
Q
Huntington’s Disease
Prevalence & Epidemiology
A
- 1 in 7,300 affected in western populations (2015)
- 1-7 per million in Taiwan, Hong Kong and Japan
> difference in ethnicities probably due to variations in normal distributions of CAG repeats - higher rates in populations of european descent (endemic to all populations but related to genetic lineage)
8
Q
Huntington’s Disease
Inheritance
A
- autosomal dominant disorder
- can be inherited from either parent
> independently from sex (autosomal)
> one defective copy is enough (dominant)
> passed on even if one parent - every son/daughter has 50% chance of developing HD
- DNA test to determine whether patient is mutation carrier
> impossible to predict age of onset and initial symptoms
9
Q
Huntington’s Disease
Genetics - mutations
A
- mutation: excess of repeats of basis CAG on chromosome 4
- DNA → mRNA → aminoacid = CAG → glutamine
- HD: abnormal huntingtin protein (mHtt) with more than 36 glutamine residues
- <36 repeats: healthy individual
- 27-35 repeats: possible de novo HD
- 36-39 repeats: mild symptoms (maybe healthy until old)
- > 40 repeats: clinical HD
! the more CAG repeats, the lower the age of onset
! number of repeats linked to severity/course
10
Q
Huntington’s Disease
What is the role of Huntingtin?
A
- HTT gene encodes for the protein Huntingtin
- huntingtin important for:
> nervous system
> BDNF production (brain-derived neurotrophic factor - important for brain growth and development)
> cell adhesion
! normal function not completely understood
!! regulates glial cells and neurons’ typical functioning
11
Q
Huntington’s Disease
what type of disease is HD?
A
- toxic gain-of-function disease
> focus on conformational changes in protein structure
> if mutation happens, new function it didn’t have before
> change shape and accumulation in cells (Htt)
> (different pathways of dysfunction) - expanded poly-Q huntingtin can form large, visible inclusions
12
Q
Huntington’s Disease
Neurodegenerative patterns
A
- higher expression of HTT in neurons compared to glia
- earliest and most severe neural loss (atrophy) in striatum (caudate nucleus and putamen) → higher expression of HD
- progressive thinning and loss of neurons in cerebral cortex
- overall reduction in brain volume as disease progresses (shrinkage)
! prodromal HD: before motor symptoms
13
Q
Huntington’s disease
what are the most common neurological changes in HD?
A
- basal ganglia → striatum → caudate nucleus and putamen
- subcortical and cortical atrophy
- fewer dopamine receptors in striatum
- changes in glucose metabolism
- later stages→ damage in other brain areas (cerebral cortex, hippocampus, cerebellum, hypothalamus, thalamus)
14
Q
Huntington’s Disease
Clinical Features - how do the impairments progress?
A
(see graph!)
- 45 y.o.: medium onset for motor diagnosis
- motor diagnosis: when symptoms are severe enough
- if no motor diagnosis → “carrier”
1. from presyntomatic to advanced
> functional abilities: constant decline
2. from prodromal to advanced
> motor impairment: rapid increase
> cognitive impairment/dementia: less steep increase
> chorea (involuntary movements): slower and less steep increase
! death: complications in motor impairments (e.g. breathing)
15
Q
Huntington’s Disease
Motor symptoms
A
- Chorea (involuntary movements; start in extremities)
> not repetitive or rhythmic; “dance”-like - Hypokinesia (decrease in spontaneous movements)
+ slowness of movement, impaired muscle tension, rigidity, eye movement, difficulty swallowing, balance problems - walking becomes difficult
- severe motor impairments in later stages (no more walking)
16
Q
Huntington’s Disease
implications for motor symptoms
A
- striatal degeneration (coordination) and impaired motor neurons
→ involuntary movements, tremors (shaking) and poor coordination
17
Q
Huntington’s Disease
Cognitive symptoms
A
- cognitive difficulties can manifest years before motor symptoms
- cognitive decline is gradual (severe in later stages)
- can remain mild until later stages or rapidly transform into dementia
- attention, mental flexibility, planning and emotion recognition (! also changes in emotion regulation)
- similar symptoms to Alzheimer’s disease in later stages
18
Q
Huntington’s Disease
Implications for cognitive symptoms
A
- cortical atrophy and selective vulnerability for specific neurons
→ impaired memory, reasoning, executive functions
+ emotional and behavioral control
19
Q
Huntington’s disease
what are general cognitive symptoms?
A
- intelligence
> usually not until later stages
> earlier deterioration in nonverbal performance - memory
> even at early stages
> problems with encoding and retrieving new information
> seem to be linked to attention impairment - speed of information processing
> slow thinking in early stages - attention and executive functioning
> less self-control and inhibition
> problems with initiating activities and discussions
> focusing and dividing attention
> inflexibility and perseverance of thouhgts - (no) disease awareness
> bc of executive impairments, coping mechanism or no subjective experience of motor impairments - perception and spatial recognition
> difficulty in distinguishing and matching different shapes - language and speech
> deterioration in loudness of speech (hypophonia)
> problems with articulation (dysarthria) - emotion and social cognition
> difficulty recognizing negative emotions
> worse theory of mind
20
Q
Huntington’s Disease
TRACK-HD study findings
A
- longitudinal observational study to identify earliest detectable changes
- 10/12 cognitive outcomes showed deterioration early on
- pronounced differences compared to controls
> through Symbol digit modalities test, Circle tracing test, Stroop word-reading test - tests most affected had significant motor or psychomotor component (imagining movements)
→ shows link between motor and cognitive issues in Huntington’s disease
21
Q
Huntington’s Disease
Psychiatric features
A
- Depression (50% of HD patients)
- Frontal Lobe Syndrome (premanifest stage)
> inappropriate remarks, lack of insight on behavior, overeating, … - Irritability and Apathy (late stages)
- Psychosis or Delusions (less common)
22
Q
Huntington’s disease
what are the most common neuropsychiatric changes?
A
- affective disorders
> depression (diagnostic overlap with other symptoms; increased rates of suicide)
> anxiety - apathy
> loss of initiative, motivation and interest - irritability
> sharp reactions to provocations (→ aggressive behavior) - disinhibition
> in eating, speaking, drinking or sexual behavior - compulsiveness
- psychotic symptoms
> hallucinations and delusions (not common)
23
Q
Huntington’s Disease
implications for psychiatric symptoms
A
- disruptions in dopaminergic and other neurotransmmitter systems
→ depression, anxiety, irritability, other psychiatric symptoms
24
Q
Huntington’s disease
Physical problems
A
- weight loss
- fatigue
- sleep disorders
- autonomic nervous system dysfunction
25
Q
Huntington’s disease
Diagnosis
A
- pre-manifest stage
> actual onset cannot be predicted
> dilemma on whether to get tested if parent with HD - disease diagnostics
> Unified Huntington’s Disease Rating Scale
> heteroamnesis
26
Q
Huntington’s Disease
Quality of life
A
- disruption starts with parent’s diagnosis
- concerns over emotional, social, physical, cognitive and end-of-life issues
- interference with everyday tasks
- motor and cognitive features predict long-term care placement (not psychiatric features)
- importance of discussing end-of-life plans (even physician-assisted suicide)
27
Q
Huntington’s Disease
Family History - why is it important?
A
- genetic predisposition (qualitative variability in progression and intensity of symptoms)
- early intervention
- diagnostic confidence
- treatment planning (what interventions and at what stage)
- psychological preparedness
28
Q
Huntington’s Disease
Pharmacological Management
A
- Tetrabenazine
> only approved drug for managing chorea in HD
> only reduces movements - Antipsychotics (halperidol, risperidone)
> to treat involuntary movements
> target dopamine system (where degeneration happen) - Anxiolytics and Antidepressants (SSRIs and NSRIs)
> treat anxiety or depression
29
Q
Huntington’s Disease
Interventions
A
- Physical Therapy (maintain mobility and reduce rigidity)
- Occupational Therapy (improve or adapt daily living)
- Speech and Language Therapy (improve communication and when swallowing becomes difficult)
- Palliative Care (later stages)
30
Q
Huntington’s Disease
Emerging approaches
A
- Gene Silencing Strategies
> Antisense oliogonucleotides (ASOs)
> to reduce mutant huntingtin protein (drug would kill messenger that creates damaged protein)
> impact not yet known - trials for neuroprotective agents (e.g. coenzyme Q10)
> to keep neurons healthy and alive for longer
> efficacy not proven - targeting of molecular pathways implicated in pathogenesis
31
Q
Huntington’s Disease
Current Research and Future Directions
A
- multimodal prediction of onset
- identifying disease modifiers (slow down process)
- improving quality of life
- understanding comorbidities
- global registries for research
!! HD comorbid with somatic symptoms
> e.g. diabetes and heart disease
> genes or lifestyle?
32
Q
Huntington’s Disease
Summary of Huntington’s Disease
A
- Genetic Basis and Inheritance: Autosomal dominant conditionwith a 50% chance of inheritance. Diagnosis with genetic testing for CAG expansion in the HTT gene
- Core Symptoms: Triad of motor dysfunction, cognitive decline, and psychiatric issues, connected to neurodegenerative changes in areas (striatum and cortex)
- Epidemiology and Prevalence: More prevalent in Western populations. Prevalence varies (0.6–13.7 individuals per 100,000 in Western countries)
- Treatment Limitations: No curative treatments; existing therapies are aimed at symptom management.
- Future Directions: Current research on gene-silencing strategies, identifying disease modifiers, and improving the quality of life for patients
33
Q
Multiple Sclerosis
A
34
Q
Introduction
A
- chronic disorder of central nervous system (inflammation and demyelination)
- onset between 20-40 years
- earliest mention in the 1800s
35
Q
History
A
36
Q
Clinical Picture
A
- inflammation of white matter can occur anywhere in CNS, but most in optic nerve, spinal cord, brainstem and cerebellum
- starts with impairment of sensory perception in limbs, temporary problems with vision
- optic neuritis is first symptom in 1/3 cases (loss of vision in one eye)
+ decreased strength and coordination, functional disorders of bladder and intestines, speech impairments and dysphagia, sexual dysfunction, spasticity, pain and fatigue
37
Q
Multiple Sclerosis
Epidemiology
A
- most prevalent neurological disorder in young adults
- western countries: 1-2/1000
- African and Asian countries: 2-10/100,000
- twice more common in women (books says 3:1)
- prevalence of disease increases with distance from equator
- general onset: young-middle adulthood
- only small percentage of patients die because of MS
38
Q
Multiple Sclerosis
Etiology
A
- genetics
> 20-30% heritability (twin studies)
> 10-15 times higher risk if parent has MS - inflammation
> increased risk with viral infection (Epstein-Barr virus) - lifestyle (not predictive but increases likelihood)
> vitamin-D deficiency
> smoking
> obesity in childhood and adolescence
39
Q
Multiple Sclerosis
Neuropathology
- what happens at the neuronal level?
A
- Demyelination (loss of myelin sheath around neurons)
> shwann cells → myelin sheat
> important for communication between brain and muscles - Inflammation (demyelination triggers autoimmune response)
- Neurodegeneration (loss of grey and white matter - 30% decrease in cortical thickness)
(see photo)
40
Q
Multiple Sclerosis
imaging markers
A
(see picture)
- ventricles → bigger
- sulci and gyri → more pronounced
- white matter → less
! anomalies in cerebrospinal fluid in 90% of cases
! inflammation in CNS: defined by amount and properties of lymphocytes, plasma cella, IGG
! EPT to assess conducting along optic nerve
41
Q
Multiple Sclerosis
Disease Course - what are the different types?
A
- Relapsing-remitting
> 85%
> loss of function, followed by recovery - Secondary progressive
> 10-30%
> Relapsing-remitting followed by period without relapse, but gradual decline - Primary Progressive
> 12%
> No relapses, but gradual decline - Progressive Relapsing
> less common
> relapse and gradual decline
! benign MS: mild and few complaints, few or no limitations
(see graphs)
42
Q
Multiple Sclerosis
Clinical presentation - symptoms
A
- Visual impairment (e.g. double vision, involuntary eye movements)
- Sensory impairment (e.g. tingling sensations)
- Motor impairment, problems with bladder or bowel control, sexual dysfunction
- (mild) Cognitive impairment, fatigue
43
Q
Multiple Sclerosis
Diagnostic criteria
- general overview
A
- “McDonald” criteria
- updated in 2017 by panel of experts
- Clinical + imaging + laboratory findings
44
Q
What are the diagnostic criteria of MS?
A
- 2 attacks for definitive diagnosis (two spikes on graph)
- 1 attack with evidence of dissemination in space and time (if gradual without spikes)
- at least two periods with clinical symptoms and symptoms accounted for lesions in white matter
- complaints not attributable to another cause
45
Q
Multiple Sclerosis
Dissemination in space and time
A
- Space: evidence of lesions in at least two occasions
- Time: Evidence of new lesions at follow-up assessment
! MRI or cerebrospinal fluid markers are used
46
Q
Multiple Sclerosis
Phrmacological treatment
A
- MS cannot be cured
- anti-inflammatory drugs reduce relapse in relapsing forms of MS
- two other drugs currently available to slow down neurodegeneration in non-relapsing MS
- pharmacological treatments to manage fatigue, sleep problems, sensorimotor complaints
- corticosteroids help alliviate symptoms
- optimal care: multidiscipliary approach (neurologist + urologist + rehabilitation specialist + paramedics + …)
47
Q
Multiple Sclerosis
Cognitive Consequences
A
1- slowed information processing (very common; PASAT test)
2- deficits in specific attention and executive functions
- memory retrieval
- aphasia (language - less common)
- agnosia (vision - less common)
48
Q
Cognitive + emotional impairments
A
- behavioural changes + deficits in emotion perception and theory of mind
- comorbidity with depression, anxiery, bipolar, psychotic disorders, pathological laughter and crying
! depression not related to severity of symptoms
! depression has effects on cognitive functions (especially on executive tasks)
49
Q
cognitive consequences
- overview
A
- SPMS: most severe cognitive impairments
- cognitive impairments in 43-70% cases
- type of dementia in 5-10% cases
50
Q
PASAT test
A
- Paced auditory serial addition test
- to test information-processing (+ working memory and specific attention)
- multimodal test → very useful but not very specific
- adding up continuous series of numbers under time pressure
! MS patients have poorer performance as task increases in difficulty (no problems in simple attention task)
51
Q
Multiple Sclerosis
course of cognitive consequences
A
- cognitive impairments are relatively stable in first phase and more pronounced in secondary phase
- deterioration is more rapid and cognitive impairments are more severe in men
- most studies carried out in non-relapse period
→ during exacerbation period, patient’s performance on attention and memory tasks was very poor
→ six weeks after exacerbation period, attention deficits no longer present, but still deficits in recall
= deficits during exacerbation due to temporary inflammatory changes, and therefore reversible
52
Q
Multiple Sclerosis
other complaints
A
- fatigue (80%) and impairing
- anxiety and/or depression (20-30%)
- pain (26-86%)
> they also explain impairments in cognition
53
Q
Multiple Sclerosis
Quality of life
A
- 65% unable to work within 5 years of diagnosis
- disease progression influences QoL (qualitatively and prospectively)
- QoL of carers also affected
54
Q
Multiple Sclerosis
Summary
A
- Most common neurological disorders in young adults
- Caused by demyelination, inflammation, and neurodegeneration; genes and lifestyle influence risk and progression
- Different forms: relapsing-remitting, secondary progressive, primary progressive, and progressive relapsing
- Diagnosed if: at least two separate lesions (dissemination in space) and if lesions’ extent increases over time (dissemination in time)
- Cognitive complaints: slowed information processing
and executive dysfunction (most common) - Fatigue and reduced quality of life
