Degenerative Disorder of the CNS Flashcards
In regards to ALS
What is amyotrophy?
What is lateral?
What is sclerosis?
- Amyotrophy: Muscle atrophy
- Lateral: involving lateral (and anterior) corticospinal tracts
- Sclerosis: glial cell proliferation and hardening
What does ALS stand for?
Amyotrophic Lateral Sclerosis
T/F: ALS is most physically devastating of the neurodegenerative diseases
True
What is the etiology of ALS?
- Sporadic (90%)
- Familial (10%)
T/F: Currently, there is only one gene for ALS
False
- Over 30
When ALS is developed due to familial cause it is a (Autosomal Dominant or Autosomal recessive) disorder. Also it is associated with (Early or Late) onset.
- Autosomal Dominant
- Early Onset
What are the known risk factors of ALS?
- Males > Female
- Age: 50’s
- Race: white, non-hispanic
- Geographical area: Europe, North America, New Zealand
What are some possible risk factors for ALS?
- History of vigorous physical activity
- Chronic environmental exposure (lead, mercury, pesticides or solvents)
- Lifestyle factors (cigarette smoking, alcohol, diet)
Clear mechanism not established
T/F: Bulbar onset of ALS is more common in males
False- Females
What is the pathogenesis of ALS in regards to:
UMN?
LMN?
- Destruction of Upper Motor Neurons in the cerebral cortex affecting the corticospinal and corticobulbar tract
- Destruction of Lower Motor Neurons, the alpha motor neurons in the anterior horn of spinal cord and cranial nerve nuclei in brainstem
In regards to the pathogenesis of ALS, what are some possible causes of destruction of UMN & LMN?
- Excitotoxicity (excess glutamate)
- Oxidative damage (free radicals)
What other areas can be impacted by neuronal loss in ALS?
- Frontotemporal cortex
- Thalamus
- Substantia Nigra
- Spinocerebellar tracts
- Dorsal columns
In ALS what are the lower motor neuron symptoms?
- Asymmetric, usually distal weakness
- Extensors weaker than flexors
- Cervical extensor weakness (Head droop)
- Bulbar signs
- Hyporeflexia
- Hypotonicity
- Atrophy
- Muscle cramps
- Fasciculations
In ALS what are the Upper Motor Neuron symptoms?
- Spasticity
- Hyperreflexia/Clonus
- Pathological reflexes (Babinski, Hoffman)
- Muscle weakness (UE extensors & LE flexors)
- Pseudobulbar palsy
As ALS progresses (LMN or UMN) sign may decrease.
UMN
In ALS what are the Bulbar symptoms?
- Pseudobulbar Palsy (spastic & UMN = corticobulbar tract)
- Bulbar palsy (flaccid & LMN = cell body in CN nuclei)
What is the Bulbar presentation in ALS?
- Dysarthria
- Dysphagia
- Sialorrhea
- Pseudobulbar affect (UMN)
In ALS what are the preserved areas?
- Eye movements
- Bowel & bladder
- Sensory system
- Cognition (50%)
ALS has a variable presentation what are some early signs?
- Insidious asymmetrical weakness of distal aspect of one limb
- Cramping with volitional movement (early morning stiffness)
- Muscle fasciculations (spontaneous twitching of muscle fiber)
ALS has a variable presentation what are some late manifestations?
- Respiratory complications (respiratory failure)
- Oral motor complications (chewing, tongue mobility, swallowing) at risk for aspiration
How is ALS diagnosed?
- Clinical presentation
- EMG (Fibrillations, Fasciculation, Low amplitude polyphasic potentials)
- Muscle biopsy (Denervation atrophy)
- Muscle enzyme (CPK levels elevated)
- Normal CSF & no changes on myelogram
What is the definitive diagnostic criteria for ALS?
- UMN + LMN signs in 3 or more regions
- Exclude structural lesions
What is the time frame for obtaining an ALS diagnosis?
- May take 15-21 months from first presenting symptoms to definitive diagnosis
- EMG changes may not be seen for 6-12 months
T/F: there is no known cure for ALS
True
What is the mechanism and how is Riluzole used in managing ALS?
- Mechanism: inhibits glutamate
- May have neuroprotective effect, but not cure
- Slows progression by 10-15%
- Increases survival by 3 month
What is the con to RIluzole when managing ALS?
- Side effects common
What are some ways to manage the symptoms of ALS?
- Anticholinergic (drooling)
- Baclofen/diazepam (spasticity)
- PEG tube
- Invasive & non-invasive ventilation
What is the prognosis of ALS?
- Onset before 50 may have slower progression
- Survival 2-5 yrs
- Respiratory compromise
- Bulbar onset more rapidly progressive
- NG/PEG and ventilation may prolong life
What is dementia?
Clinical syndrome of global cognitive decline, memory deficits + one other area of cognition that has significant effect on day-to-day function
What is Alzheimer disease (AD)?
- Brain disease characterized by plaques, tangle & neuronal loss
- Progressive disease process typically causing dementia
What is Alzheimer dementia?
- Dementia that has gradual onset & slow progression
- Caused by Alzheimer disease
Alzheimer Disease is characterized by slow decline/change in what?
- Memory
- Language
- Visuospatial skills
- Personality
- Cognition
T/F: Alzheimer Disease is most common cause of dementia
True
With each decade of life Alzheimer Disease prevalence (increases or decreases)
Increases
What is risk factors for Alzheimer Disease?
- Age (older)
- Female (>80)
- Family history
- Genetic markers
- Linked to HTN, DM, obesity & increase cholesterol, depression & head injury
What are some possible protection factors from developing Alzheimer Disease?
- Diet
- High level of education
- Regular exercise
- Cognition activities
- Adequate vitamins (C, E, B6, B12, folate)
What is the genetic marker for Alzheimer Disease?
APOE4
Why is there is no single definitive cause of Alzheimer Disease?
breakdown in several processes necessary to sustain brain cells
What are the neuropathological hallmarks for Alzheimer Disease?
- Amyloid plaques
- Neurofibrillary techniques
- decrease acetylcholine activity and receptors
- Increase NMDA stimulation which increase calcium & cell death
- Target corticocortical & hippocampal cells
What are the early clinical manifestations of Alzheimer Disease?
- Mild memory loss
- Mild cognitive impairments
- Subtle personality changes (indifferent, irritable)
- Diminished judgement/ decision making/ safety (driving)
- Visuospatial deficits (navigation, manipulation of objects, 3D drawing)
What are the later clinical manifestations of Alzheimer Disease?
- Impaired recall of current events/ more recent memories
- Language deficits
- Motor changes
- Disorders of sleep, eating & sexual behavior
- May become mute & bedridden
What are the motor changes in patients with Alzheimer Disease?
- Slow movements
- Halting gait
- Generalized weakness
- Increased risk of falls (diminished postural response, reduced awareness of self in space, reduced ability to move around obstacles)
What are the 10 warning signs of Alzheimer Disease?
- Recent memory loss which affects daily life
- Difficulty completing familiar tasks
- Confusion with time/place
- Visuospatial challenges
- Problems with speaking/writing
- Challenges with planning/problem solving
- Misplacing things
- Poor judgement
- Withdrawal from social activities
- Changes in mood & personality
In order to diagnosis someone with Alzheimer Disease what must first be ruled out?
Reversible cause of dementia through:
- Blood count
- chest radiography
- general neuro exam
- medication
How is the history of progression used to diagnosis someone with Alzheimer Disease?
- Continuous gradual decline without abrupt changes
- Mini mental state examination (MMSE)
- Clock drawing test
What information from a MRI & CT can be obtained when diagnosing someone with Alzheimer Disease?
- Atrophy (can occur with normal aging)
- Neurofibrillary tangles/amyloid plaques not well imaged (found on autopsy later)
Vascular Dementia is a differential diagnosis for Alzheimer Disease. What is Vascular Dementia and what is the presentation?
- Multiple small infarcts or stroke affect deep brain structure
- Presentation of symptoms is more step -wise or variable
Lewy Body Dementia is a differential diagnosis for Alzheimer Disease. What is Lewy body Dementia present with and what is it unresponsive to?
- Present with parkinsonism
- Unresponsive to standard medications for dementia
Frontotemporal Dementia is a differential diagnosis for Alzheimer Disease. What is Frontotemporal Dementia and what are the impairments?
- Describes various progressive disorders
- Impairments in executive function & behavior
What does each set scores on the Mini- Mental State Examination indicate:
24-30
18-23
0-17
- 24-30: Normal
- 18-23: Mild cognitive impairments
- 0-17: Severe cognitive impairments
T/F: there is a cure for Alzheimer Disease
False
T/F: There is a medication that can modify Alzheimer Disease
False- No disease modifying treatment only symptoms
What are some medications used in managing Alzheimer Disease?
- Cholinesterase inhibitor
- NMDA- receptor target therapy
What are some non- pharmacological ways to delay development of cognitive decline associated with Alzheimer Disease?
- Physical activity
- Social engagement
- Intellectual activity
What is the prognosis of AD?
- Onset to death 7 - 11 years
- Death is often secondary to dehydration or infection
What is Parkinson’s Disease (PD)?
- Chronic, progressive neurodegenerative disorder
- Loss of midbrain dopamine neurons
- Presence of Lewy body inclusion
What are the cardinal features of PD?
- Rigidity
- Tremor
- Bradykinesia
- Postural Instability
The prevalence of PD commonly increases with what?
age
What is the etiology of PD?
- Idiopathic
- Genetic link (5%) (usually younger onset)
What are the risk factors for PD?
- Toxic exposure
- Precipitating infection
- Exercise may decrease risk
- Smoking and caffeine may decrease risk
- Higher education may increase risk
Describe the pathogenesis of PD
- Degradation of the substantia nigra of basal ganglia
- 70-80% loss before clinical symptoms
How does dopamine play a role in motor output in healthy individuals?
Dopamine acts on both the direct & indirect pathways of the basal ganglia to reduce inhibitory outflow of the basal ganglia to thalamus
In PD dopamine is absent what impact does this have on movement?
- More inhibition of the thalamus and thus less activation of the cortex
- Decrease dopamine = decrease movement generation
What it signal from the cortex to the striatum in the direct and indirect pathway?
- Direct: Decrease tonic inhibition and allow movement
- Indirect: Increase inhibitory flow from basal ganglia
What is the signals from the SNc to the striatum (dopamine) on direct and indirect pathways?
- Direct: Decrease inhibitory outflow from the basal ganglia & allow movement (D1= excitatory)
- Indirect: Decrease inhibitory outflow from the basal ganglia and allow movement (D2 = inhibitory)
In PD why is there poverty of movement?
- Inhibitory outflow from the basal ganglia is abnormally high
- Thalamic activation of upper motor neurons in the cortex is less likely to occur
What are some other features of PD? (not including the cardinal features)
- Stooped/kyphotic posture
- Festinating gait
- akinesia/ freezing
- dual task
- altered sense of smell
- weakness
- fatigue
- dementia
- depression
- orthostatic hypotension
T/F: there is no single definitive test of PD
True
One way diagnosis of PD can be made is through basis of history and clinical exam. What information gathered indicates a PD diagnosis?
- Classic triad of symptoms (tremor, rigidity & akinesia)
- Impaired olfaction
- Differentiate from Parkinsonism (asymmetrical, resting tremor, good response to L-dopa, impaired olfaction)
How can imaging be used in diagnosing PD?
- CT/MRI may rule out pathologies
- DaTSCAN detects levels of dopamine transporters in brain, but not disease specific
T/F: The only conclusive diagnosis of PD is autopsy
True
What is the presentation of Multisystem Atrophy (Shy-Drager Syndrome, Striatonigral Degeneration, Olivopontocereberllar Atrophy)?
- Orthostatic hypotension
- Cerebellar Dysfunction
- May initially respond to L-Dopa
What is the presentation of Progressive Supranuclear palsy?
- Vertical eye movement dysfunction
- Early falls
- axial/neck rigidity
- Speech-swallowing dysfunction
- Frontal lobe dysfunction
- Poor response to L-Dopa
What is the presentation of Corticobasal Degeneration?
- Apraxia
- Alien limb
- myoclonus
- Dystonia
- Poor response to L-Dopa
What is the presentation of Dementia with Lewy bodies?
- Early dementia/ hallucination
- Rigidity
- Fluctuating cognition
- Falls
- Motor symptoms only
- May show some response to L-Dopa
When should you consider a differential diagnosis of PD?
- Severe, early dementia
- Severe early autonomic dysfunction (orthostatic hypotension)
- Vertical gaze difficulty
- UMN signs
- Cerebellar signs
- Cortical sensory loss
- Aphasia
- Apraxia
- early falls
- Poor response to Levodopa
What are some medications that can be taken to manage PD?
- Levodopa
- Carbidopa
- COMT inhibitors
- MAO - B inhibitors
- Dopamine agonists
- Amantadine
- Anticholinergic agents
What are some examples of surgical management for PD?
- Stereotactic Surgery
- Deep Brain stimulation
Where can deep brain stimulators be placed?
- Thalamus
- Globus pallidus internal segment
- sub thalamic nucleus
What is the prognosis of PD?
- Clinical manifestations progressively worse
- L- Dopa looses effectiveness with time
- Poorer prognosis if postural instability is an early sign
- Does not significantly reduce lifespan if develop in 50s/60s
- Death usually due to infection or complication of immobility
What is Huntington’s Disease?
Progressive hereditary disorder characterized by:
- Movement abnormalities (chorea, brief, purposeless, involuntary movements)
- Personality disturbances
- Dementia
T/F: There is no cure for Huntington disease
true
What is the prevalence of Huntington Disease?
- Usually starts in midlife
- 25% late onset after 50 yrs
What is the etiology of Huntington Disease?
- Autosomal dominant transmission
- Genetic marker on Chromosome 4
- 50% chance of developing if parent has it
T/F: Not all who inherit the gene for on Chromosome 4 will develop Huntington Disease
False
- All will develop the disease if they inherit the gene
In juvenile onset of Huntington’s Disease the gene is typically inherited from?
Father
In Huntington’s Disease there is a repeat of what sequence in the genetic code?
Repeats of CAG sequence in the genetic code for Huntingtons protein
Repeats of the CAG genes tend to (increase or decrease) in number as the gene is passed on
Increase
What is the pathogenesis of Huntington’s Disease?
- Atrophy of neurons in the striatum (caudate & putamen) of the basal ganglia
- Ventricles enlarged
- White matter degeneration in frontal cortex
- Brain volume decrease by up to 20%
- exact mechanism of neuronal loss not known
What does the caudate and putamen correlate with?
- Caudate: Correlated with dementia
- Putamen: correlated with neurological symptoms
What impact does Huntington’s Disease have on indirect pathway?
- Early
- Blocks indirect pathway
- Hyperkinetic
What impact does Huntington’s Disease have on indirect & direct pathway?
- Late
- Blocks both indirect & direct pathway
- Hypokinetic (rigid, slow)
In Huntington Disease what are some movement disorders that can be present?
- Chorea
- Gaze fixation abnormalities
- Dysarthria/dysphagia
- Sleep disorders
- Urinary incontinence
What are some psychiatric disorder that can manifest in Huntington’s Disease?
- Personality changes
- Depression
What are some cognitive disorders that can manifest in Huntington’s Disease?
- Memory deficits
- Executive dysfunction
How can Huntington’s Disease be diagnosed?
- Clinical signs
- Family history
- Genetic testing
In advanced Huntington’s Disease what can be present on MRI/PET?
- Atrophy and enlarged ventricles
- Not disease specific
What are some ways to treat Huntington’s Disease?
- Counseling (genetic, psychological, social)
- Symptom management
- Experimental surgeries (mixed results)
What are some medications to manage symptoms of Huntington’s Disease?
- Tetrabenazine & Deutetrabenazine
- Can block dopamine
- Side effects: Pseudoparkinsonism, depression
What research is underway for treatment of Huntington’s Disease?
- On possible disease modifying medication
- Reduce production of disease causing mRNA/protein
What is the prognosis of Huntington’s Disease?
- Slow progression
- More severe if onset before 40
- Death 15-20 years after onset
T/F: Patient with Huntington’s Disease may survive into 90’s but with disability
True
What is Multiple Sclerosis (MS)?
- Chronic, demyelinating autoimmune disease of the CNS
- Major cause of disability in young adults
- Named for sclerotic plaques found throughout the CNS
- Variable course
Describe Relapsing-remitting MS (RRMS)
- Periods of neurologic dysfunction (>24 hours)
- Followed by full or partial recovery
- Stable periods between attacks
Describe secondary progressive MS
- 60% of individual with RRMS go on to develop within 2 decades
- Steady progressive decline
- May still have relapses
Describe primary progressive MS
Steady decline from onset with minimal recovery
Describe progressive - relapsing MS
Progressive decline from onset with clear exacerbation
What is the prevalence of MS?
- Caucasians of Northern European descent
- Females to males (3:1)
- Geographical distribution (temperate climate)
T?F: Males tend to have an earlier onset and less severe symptoms of Huntington’s Disease
False
- Later onset and more severe
When is MS typically diagnosed?
20-50 y/o
What is etiology of MS?
- Genetic component
- Coexisting autoimmune disorders
- Viral infections
- Vitamin D may provide risk reduction
What is the pathogenesis of MS?
- T cell (and possible B cell) mediated inflammatory disorder
- Demyelination by inflammatory cells & extracellular environment
- Loss of myelin causes neurons to be susceptible to apoptosis
In regards to pathogenesis of MS:
- Replaces = (Demyelination or Long-term disability)
- Axon loss & cell death = (Demyelination or Long-term disability)
- Replaces = Demyelination
- Axon loss & cell death = Long-term disability
What is Lhermitte’s sign? and what is it associated with?
- Momentary electric sensation evoked by neck flexion or cough indicating a sign of posterior column damage
- Can be seen in patients with MS
Name some common symptoms of MS
- optic neuritis
- sensory changes (paresthesia,hypothesia)
- Fatigue
- Spaticity
- Weakness (heat related conduction block)
- Cranial nerve involvement (trigeminal neuralgia, dysarthria, gaze palsies, vertigo)
- Ataxia
- Pain (Lhermitte’s sign)
- Depression
- Cognitive decline (50%)
- Bowel & bladder symptoms
What does a definitive diagnosis of MS require evidence of?
- 2 separate clinical attacks at least 1 month apart or changes in MRI over time (Dissemination in time)
- Damage in at least 2 separate areas of CNS (Dissemination in anatomical space)
What are the diagnostic tests for MS?
- Clinical syndrome
- MRI changes
- CSF (oligoclomal bands & elevated immunoglobulins)
- Abnormal evoked potentials (visual, auditory, sensory & motor)
What is the term clinically isolated syndrome?
Term used after the first demyelinating attack
What are some disease modifying agents that reduce attacks of MS by 1/3?
- Interferon drugs (Slows immune response)
- Immunomodulators (blocks immune cells)
- Immunosuppressants (Decrease T cells)
T/F: There is only one drug approved to treat secondary progressive MS and only one drug approved to treat primary progressive
True
- Secondary progressive (Mitoxantrone)
- Primary progressive (Ocrelizumab)
What benefit does corticosteroids have on MS management?
Shorten duration of acute attack
What are some other symptom managements used for MS?
- Anti spasticity
- Antidepressants
- Sleep aids
What happens in 15 & 20 years after onset of MS if it is untreated?
- 15 years: 50% use AD to walk
- 20 years: 50% wheel chair bound
What are poor prognostic indicators of MS?
- Early motor or cerebellar symptoms
- Disability after the 1st attack
- Multiple attacks in 1st year
What is the prognosis of MS?
- average 1 attack per year
- 20% benign MS
- Modest impact on life expectancy
What is the most common form of hereditary ataxia?
Friedrich’s ataxia (FA)
What is Friedrich’s ataxia?
- Inherited, recessive disease causes nervous system damage
- Characterized by degeneration of ascending & descending fibers of the spinal cord including spinocerebellar tracts
When does FA manifest?
age 5-15
What type of genetic disorder is FA? What is the percent chance of developing it?
- Autosomal recessive linked to long arm of chromosome 9
- Hereditary: 25% of offspring of affected parents develop the disorder
Describe the pathogenesis of FA including what occurs in:
- Peripheral
- Central
- Cerebellum
- Disrupts normal production of frataxin so certain cells (nerves. heart) can’t produce energy effectively & there is a build up of toxic byproduct
- Cell loss in dorsal root ganglia (peripheral)
- Secondary degeneration in posterior columns, dorsal & central spinocerebellar tracts (central)
- Later degeneration of corticospinal tracts & dentate nucleus (cerebellum)
In regards to the pathogenesis of FA what is spared?
- Corticobulbar tracts
- Cerebrum
What are the clinical manifestations of FA?
- Ataxic gait (most common)
- Staggering/lurching gait
- Clumsiness, tremor in limbs
- sensory impairments (stocking & glove)
- Loss DTR (knees & ankles)
- Muscle tone (normal at rest, flexor spasms common later)
- Progressive weakness of limbs
- Cardiomyopathy
- Dysarthria, nystagmus
In FA there musculoskeletal deformities as a result of secondary complications. What are those?
- Scoliosis
- Kyphoscoliosis
- Pes cavus
What is usually preserved in FA even though individuals can get dementia & decreased intelligence during the course of disease?
Mentation
T/F: DM is found in 10% of individuals and another 20% are found with impaired glucose tolerance
True
What is the clinical criteria needed to diagnosis FA ?
- onset ataxia before 25
- progressive course
- loss DTRs
In an individual with FA what may a CT & MRI show?
May be normal or show atrophy in cerebellum or spinal cord
What are some differentials of FA that must first be ruled out in order to diagnose FA?
Demyelinating forms of hereditary & sensory neuropathies
What testing can be done that provides conclusive diagnosis of FA?
genetic testing
What is the prognosis of FA?
- Variable
- 95% patients are using w/c by age 45
- on average lose ability to walk 15 years after onset of symptoms
- Mean age death mid 30s but can survive into 50s & 60s
On average when do individuals with FA lose ability to walk?
15 years after onset of symptoms
What is the mean age of death for individuals with FA?
Mean age death mid 30s but can survive into 50s & 60s
