Term
|
Definition
| INvoluntary rhythmic oscillation of a body part |
|
|
Term
|
Definition
rest tremor
postural tremor
kinetic tremor |
|
|
Term
|
Definition
when the tremor is most prominent when the body part is in complete repose and fully supported against gravity
tremor is less prominent with movement or maintenance of a posture |
|
|
Term
|
Definition
tremor that is most prominent when the body part is maintained in a non-resting posture
"Action tremor" |
|
|
Term
|
Definition
tremor that is accentuated with goal directed movement of a limb
"action tremor" |
|
|
Term
essential tremor
clinical features |
|
Definition
postural/kinetic tremor (NOT rest)
often asymmetric or unilateral at onset, but eventually becomes bilateral (can also be of voice)
often hereditary
exacerbated by stress and may improve transiently with alcohol |
|
|
Term
essential tremor
differential diagnosis |
|
Definition
important to make sure there are no other possible causes of tremor
drug-induced tremors are common - esp in some common bipolar meds (lithium, valproate); cyclosporine; caffeine; many others!; withdrawal from drug (alcohol, BZDs)
medical conditions: hyperthyroidism; with neuro disease; Cushing's... |
|
|
Term
essential tremor
treatment |
|
Definition
often not wanted once patient has been reassured condition is not more serious (a la Parkinson's)
if tremor is severely interfereing:
-meds: beta-blockers, AED, topiramate
-surgical: deep brain stim, VIM thalamotomy |
|
|
Term
Parkinson's disease
cardinal clinical features |
|
Definition
rest tremor (better when using their limbs)
bradykinesia
rigidity
asymmetric onset
substantial improvement with levodopa |
|
|
Term
|
Definition
slowing of movement
reduced VELOCITY, not reduced frequency (frequency often increased) |
|
|
Term
| parkinsonism / parkinsonian features |
|
Definition
the hallmark of hypokinetic movement disorders
bradykinesia, rigidity, rest tremor |
|
|
Term
Parkinson's disease
manifestations of cardinal clinical features |
|
Definition
masked face, no expression
soft, expressionless voice
fenistration
micrographia |
|
|
Term
|
Definition
a tendency for repetitive movements to increase in frequency and decrease in amplitude (in PD: gait, speech, finger tapping)
-gait: stooped, shuffling (reduced amplitude of steps), "en bloc" turning, reduced are swing |
|
|
Term
Parkinson's disease
comorbidities (non-motor related) |
|
Definition
dementia in 25-40% (may confuse with DLB, AD)
depression in 5-40%
hallucinations in 20% of treated pts
pain
abnormal olfaction, sleep disorders, constipation (all may proceed other sx by may years) |
|
|
Term
Parkinson's disease
mimics |
|
Definition
drug-induced (anti-psychotics, anti-emetics)
other movement disorders
DLB, AD
vascular disease (getting strokes in "all the right places") |
|
|
Term
Parkinson's disease
diagnosis |
|
Definition
no reliable diagnostic test exists
clinical diagnosis (~75% confirmed on autopsy) |
|
|
Term
Parkinson's disease
macroscopic pathology |
|
Definition
| loss of pigment in the substantia nigra and locus coeruleus (may see asymmetric depigmentation0 |
|
|
Term
Parkinson's disease
microscopic pathology |
|
Definition
cell loss in: SN and other brainstem nuclei, nucleus basalis of Meynert, hypothalamus, symp ganglia, olfactory bulb
Lewy bodies and Lewy neurites
Lewy bodies-->alpha-synuclein, ubiquitin, other proteins |
|
|
Term
basal ganglia circuitry
direct pathway |
|
Definition
GOOD
pathway to cortical stimulation through the thalamus that originates in the substania nigra compacta
release of DA from sub nig: ultimately results in increased cortical stimulation
(via the striatum inhibiting medial globus pallidus, and thus removing its inhibition on the thalamus) |
|
|
Term
Parkinson's disease
pathogenesis |
|
Definition
less activation of the cortex
mutations in Lewy body proteins identified in some hereditary forms of PD
accumulations of misfolded proteins
oxidative stress
mitochondrial dysfunction
excitotoxicity |
|
|
Term
Parkinson's disease
Lewy body proteins |
|
Definition
|
|
Term
|
Definition
protein involved in proteasome system
major pathway for degrading and eliminating misfolded proteins |
|
|
Term
|
Definition
function unknown
thought to participate in maturation of pre-synaptic vesicles and the regulation of NT release
assumes alpha-helical structure in lipid-containing vesicles and form oligomers that can fibrillize into beta sheets at high concentration
dopaminergic neurons are selectively vulnerable to the toxic effects of alpha-synuclein accumulation |
|
|
Term
Parkinson's disease
hereditary forms |
|
Definition
alpha-synuclein and ubiquitin mutations found
however, most PD patients in general do not have these mutations, so must be several pathways to disease |
|
|
Term
Parkinson's disease
oxidative stress |
|
Definition
autopsy shows decreased glutathione levels and increased iron in SN
glutathione is free radical scavenger
iron helps facilitate oxidation
dopamine metabolism can produce free radicals |
|
|
Term
Parkinson's disease
mitochondrial dysfunction |
|
Definition
| idiopathic PD patients found to have decrease in mitochondrial complex I activity in the SN pars compacta |
|
|
Term
Parkinson's disease
management |
|
Definition
levodopa
L-DOPA/carbidopa
dopamine agonists
COMT inhibitors
MAO-B inhibitors
muscarinic ACh receptor agonists |
|
|
Term
|
Definition
rapidly absorbed, but competes with large neutral amino acids for GI uptake and for crossing into BBB
cross BBB and then converted to DA in brain
SE occur from peripheral conversion to DA in GI tract and liver by dopa decarboxylase |
|
|
Term
|
Definition
reduces peripheral side effects of l-dopa administered alone
increases l-dopa bioavailability
carbidopa acts to inhibit dopa decarboxylase in the periphery (it can't cross the BBB) |
|
|
Term
|
Definition
early: nausea, vomitting, orthostatic hypotension
later: dyskinesias, motor fluctuations, hallucinations
-managing dosing becomes very difficult
-on/off phases |
|
|
Term
| l-dopa vs. dopamine agonist |
|
Definition
l-dopa provides a "naturally regulated" effect because it is acting presynaptically so the cell releases DA as needed and D1/D2 DA receptors get activated appropriately
VS.
DA ags that do not give equal D1/D2 activation
l-dopa must be taken up by presynaptic dopaminergic cells and convertd to DA and released; problematic when these are the cells that are degenerating in PD
VS.
DA ags are not dependent on dopaminergic cell uptake |
|
|
Term
|
Definition
Periphery:
metabolizes l-dopa; present in the gut
CNS:
major pathway for clearing Da from the synpase |
|
|
Term
|
Definition
work in the periphery to make levodopa more available for absorption by prolonging l-dopa halflife
tolcapone - significant hepatotoxicty
entacapone - also has central effects |
|
|
Term
|
Definition
inhibit DA degradation so that there is more DA available for release (prolonged DA effect)
improves symptoms - unproven if slows disease progression |
|
|
Term
|
Definition
the striatal cells the receive DAergic inhibition also receive excitatory input from choinergic interneurons
ACh effects exacerbate parkinsonism
(effectively does the opposite of DA) |
|
|
Term
|
Definition
show modest benefits and may be useful in patients in whom tremor is the predominant symptom
SE: sedation, dry mouth, confusion, constipation, impotence, wt gain |
|
|
Term
| surgical management of Parkinson's disease |
|
Definition
thalamotomy
pallidotomy
deep brain stim of MGP, STN
fetal midbrain transplant
adrenal medullary autograft |
|
|
Term
| other Parkinsonian syndromes |
|
Definition
dementia with Lewy bodies (DLB)
progressive supranuclear palsy (PSP)
contricobasal degeneration (CBD)
multiple system atrophy (MSA) |
|
|
Term
progressive supranuclear palsy (PSP)
clinical features |
|
Definition
*parkinsonism
*supranuclear gaze palsy
-prominent truncal rigidity (gait disturbance is EARLY in course)
-dysarthria, dysphagi early on
-"frontal lobe features"
-progressive |
|
|
Term
|
Definition
lesion is in a cortical gaze center (lesion is above the brainstem nuclei), so only voluntary gaze in impaired - cannot voluntarily move their eyes in a certain direction
vestibulo-ocular reflex preserved |
|
|
Term
progressive supranuclear palsy (PSP)
macroscopic pathology |
|
Definition
atrophy & depigmentation
atrophy: pontine tegmentum, midbrain, globus pallidus
depig: substantia nigra, locus coeruleus |
|
|
Term
progressive supranuclear palsy (PSP)
microscopic pathology |
|
Definition
neuronal loss: globus pallidus, subthalamic nucleus, substantia nigra
neurofibrillary tangles and other tau deposits |
|
|
Term
progressive supranuclear palsy (PSP)
pathophysiology |
|
Definition
tau protein accumulation - abnormalities in tau may lead to dysfunctional MTs and abnormal cellular transport
signs of oxidative stress on autopsy
4-repeat isoform of tau (FTD: 3; AD: 3&4) |
|
|
Term
progressive supranuclear palsy (PSP)
diagnosis |
|
Definition
based on clinical features
no reliable radiologic or serologic findings |
|
|
Term
corticobasal degeneration (CBD)
clinical features |
|
Definition
-clumsiness, stiffness
-jerking of one arm, then same leg, then cross to other side of body
-"alien limb" that seems to move on its own accord
-dystonia
-dysarthria, dysphagia
-hemispatial neglect when left body is affected
-"frontal lobe" features |
|
|
Term
corticobasal degeneration (CBD)
macroscopic pathology |
|
Definition
atrophy: frontal, parietal cortex (often asymmetric)
depigmentation: SN, LC |
|
|
Term
corticobasal degeneration (CBD)
microscopic pathology |
|
Definition
swollen ("ballooned") neurons - resemble those of Pick's disease
tau inclusions
tau-positive threads |
|
|
Term
corticobasal degeneration (CBD)
pathophysiology |
|
Definition
| 4-repeat isoform of tau protein (same as PSP - but different immunblot patterns of tau fragments) |
|
|
Term
corticobasal degeneration (CBD)
diagnosis |
|
Definition
diagnosis is provisional during life
based primarily on clinical features |
|
|
Term
corticobasal degeneration (CBD)
management |
|
Definition
parkinsonisms sometime respond to levodopa or dopamine agonists
primarily symptomatic treatment |
|
|
Term
multiple system atrophy (MSA)
clinical features |
|
Definition
any combo of: parkinsonism, cerebellar dysfuntion, autonomic insufficiency
parkinsonism and cerebellar subtypes (named for predominant symptom) |
|
|
Term
multiple system atrophy (MSA)
comorbidities |
|
Definition
autonomic dysfunction (most)
at least 2/3 have REM sleep behavior disorder
peripheral neuropathy |
|
|
Term
multiple system atrophy (MSA)
diagnosis |
|
Definition
based on history an exam findings
MRI and functional scans may help to differentiate MSA from PD, PSP, CBD |
|
|
Term
|
Definition
cerebellar conditions
-Friedreich's ataxia
-Ataxia Telangiectasia
-Spinocerebella ataxias (SCAs) |
|
|
Term
Friedreick's ataxia
clinical features |
|
Definition
-the most common inherited ataxia
-present in early adolescence with progressive gait abnormalities leading to arm involvement
-profound loss of vib/post sense
-areflexia, ataxic gait, speech
-bilateral babinskis
-systemic manifestations of cardiomyopathy and skeletal deformities in 50-60% |
|
|
Term
Friedreick's ataxia
macroscopic pathology |
|
Definition
atrophic spinal cord and dorsal roots
(macroscopic brain is usually unremarkable) |
|
|
Term
Friedreick's ataxia
microscopic pathology |
|
Definition
degeneration and actrocytosis of the posterior columns (esp fasciculus gracilis)
loss of Clarke's column neurons
distal degen of pyramidal and spinocerebellar tracts
cell loss in dentate nuclei
atrophy of superior cerebellar peduncles |
|
|
Term
Friedreick's ataxia
pathophysiology |
|
Definition
unstable expansion of GAA trinucleotide repeat in frataxin gene (mitochondrial protein) coding region
frataxin - make iron available for several mitochondria processes
mitochondrial iron overload, decreased mitochondrial respiration, increased production of free radicals |
|
|
Term
Friedreick's ataxia
diagnosis |
|
Definition
| commercially available genetic test |
|
|
Term
Friedreick's ataxia
management |
|
Definition
|
|
Term
ataxia telangiectasia
clinical presenation |
|
Definition
symptomatic in first decade, after learning to walk
ataxic gat-->UE ataxia, ataxic speech
choreoathetosis or dystonia, oculomotor apraxia, hyporeflexia, hypotonia
telangiectasias after ataxia onset
immunodeficiency and increased risk of malignancy |
|
|
Term
|
Definition
| the occurrence of involuntary movements in a combination of chorea (irregular migrating contractions) and athetosis (twisting and writhing). |
|
|
Term
|
Definition
| difficulty initiating saccadic eye movements without thrusting head in the intended direction and turning head back |
|
|
Term
ataxia telangiectasia
macroscopic pathology |
|
Definition
| marked atrophy in cerebellar cortex, especially vermis |
|
|
Term
ataxia telangiectasia
microscopic pathology |
|
Definition
extensive loss of Purkinje cells and granule cells; retrograde loss from inferior olives
degeneration of posterior columns (fasic gracilis) and lateral columns
atrophy of anterior horn |
|
|
Term
ataxia telangiectasia
pathophysiology |
|
Definition
mutations in a gene of the phosphoinositol 3-kinase family (involved in multiple aspects of cell cycle control and DNA damage surveillance)
increased sensitivity to radiation damage --> chromosomal breakage, telomere shortening, increased intrachormosomal recombination |
|
|
Term
ataxia telangiectasia
diagnosis |
|
Definition
elevated levels of alpha-fetoprotein
clinical features are diagnostic once telangiectasias appear
(so many mutations of the gene, so genetic testing not realistic) |
|
|
Term
ataxia telangiectasia
management |
|
Definition
supportive/symptomatic therapy
treatment of infections and malignancies |
|
|
Term
spinocerebellar ataxia (SCAs)
clinical presentation |
|
Definition
dominantly ineritid ataxia with adolescence or later onset
progressive (slow) ataxia of gait, limbs, speech
various associated features |
|
|
Term
spinocerebellar ataxia (SCAs)
macroscopic pathology |
|
Definition
atrophy in cerebellar cortex, pontine nuclei, inferior olivary nuclei
variable involvement in other areas |
|
|
Term
spinocerebellar ataxia (SCAs)
microscopic pathology |
|
Definition
neuronal loss in cerebellar cortex, pontine nuclei, inferior olivary nuclei
nuclear (and sometimes cytoplasmic) aggregates of the abnormal gene product |
|
|
Term
spinocerebellar ataxia (SCAs)
pathophysiology |
|
Definition
3 types of mutations:
-expanded CAG repeat in coding region
-CAG repeats in non coding region
-conventional mutations
-ion channel dysfunction |
|
|
Term
spinocerebellar ataxia (SCAs)
diagnosis |
|
Definition
clinical and radiologic
genetic testing available for some specific SCAs |
|
|
Term
spinocerebellar ataxia (SCAs)
managemetn |
|
Definition
|
|
Term
Huntington's disease
clinical presentation |
|
Definition
-onset 30-50 years
-personality change often initial symptom
-chorea; hyperkinesia
-gradual evolution of global cognitive deficits and dementia
-slowed saccadic eye movements
-dysathria, dysphagia
-abnormal gait
-depression
-varying: athetosis, dystonia, parknsonism |
|
|
Term
|
Definition
| rapid, jerky involuntary movements appearing irregularly and unpredictably in various body parts |
|
|
Term
Huntington's disease
macroscopic pathology |
|
Definition
generalized cortical atrophy
-most marked in the head of the caudate and putamen |
|
|
Term
Huntington's disease
microscopic pathology |
|
Definition
neuronal loss and astrocytic gliosis in basal ganglia
preferential loss of medium spiny nerves that project from striatum to LGP
intrneuronal inclusions of huntingtin and ubiquitin in striatal and cortical neurons |
|
|
Term
Huntington's disease
contributors to pathophysiology |
|
Definition
mutation - expanded CAG trinucleotide repeat, huntingtin protein (function unknown)
protein aggregates: mutant huntingtin, ubiquitin in cytoplasm and nucelus
mictochondrial dysfunction, free radical toxicity, glutamate excitotoxicity, capsase-mediated apoptosis |
|
|
Term
Huntington's disease
pathophysiology |
|
Definition
selective damage to medium spin neurons of striatum ultimately leads to to much increased thalamic and cortical activity
more activation of cortex = hyperkinetic state
(opposite of Parkinson's) |
|
|
Term
Huntington's disease
diagnosis |
|
Definition
can be made clinical with clear family hx and typical manifestations
genetic testing when no family hx or unclear presentation |
|
|
Term
Huntington's disease
management |
|
Definition
symptomatic
tetradenazine approved for chorea, but can exacerbate or cause depression |
|
|
Term
Wilson's disease
clinical features |
|
Definition
autosomal recessive
hepatic and neurologic manifestations
-hepatic usually with childhood onset
-neuro usually with adult/adol onset |
|
|
Term
Wilson's disease
neruologic manifestations |
|
Definition
temor (post/kin), dysarthria/dysphagia, rigidity, personality chagnes, anxiety disorder, dystonia, chorea, cognitive deficits, depression, psychosis
*Kayser-Fleischer rings in ~100% of patients with neuro manifestations*
*this is a treatable condition!* |
|
|
Term
|
Definition
| copper deposits in cornea present in almost 100% of patients with neurologic manifestations of Wilson's disease |
|
|
Term
Wilson's disease
macroscopic pathology |
|
Definition
putamen and caudate brown and shrunken (may see copper deposits)
putamen may be centrally cavitated |
|
|
Term
Wilson's disease
microscopic pathology |
|
Definition
neuronal loss, pigment-laden macrophages, fibrillary astrocytes
Alzheimer type II asctrocytes |
|
|
Term
Wilson's disease
pathophysiology |
|
Definition
mutations in gene for ATP7B results in copper not getting packaged into vesicular compartment for excretion in bile
accumulation of copper in hepatocyte, spills over into blood and other organs - brain! |
|
|
Term
Wilson's disease
diagnosis |
|
Definition
-keep a high index of suspicion, esp in new onset psychiatric patients
-slit lamp (opthy) for Kayser-F rings
-decreased serum ceruloplasmin
-increased 24-hour urinary copper
-increased free serum copper
-liver biopsy (single most reliable test) |
|
|
Term
Wilson's disease
management |
|
Definition
decrease copper intake
zinc or tetrathiomolybdate for decreased GI absorption of copper
increase urinary clearance via chelation
liver transplant in cases of hepatic failure |
|
|
Term
|
Definition
sustained involuntary posture
-focal
-generalized |
|
|
Term
|
Definition
torticollis (neck, painful, may be spastic)
blepharospasm (sustained contraction of eyelids)
writer's cramp - task induced dystonia
-most adult onset |
|
|
Term
|
Definition
50% of childhood onset dystonias are generalized
2 genetic types - dominantly inherited |
|
|
Term
Tourette's syndrome
clinical features |
|
Definition
TICS
autosomal dominant with incomplete and sex-specific penetrance (M>F)
symptoms between ages 2-5 y
-often go through phases of tics
gradual improvement over time
cause unknown |
|
|
Term
|
Definition
| abrupt, transient, stereotypical, coordinated movements or vocalizations that can often be voluntarily suppressed, but at the expense of a buildup of inner tension that is relieved when the suppression ends |
|
|
Term
Tourette's syndrome
comorbidities |
|
Definition
|
|
Term
Tourette's syndrome
management |
|
Definition
often unnecessary in mild
variety of meds can be used |
|
|
