Movement Disorders Flashcards
hypoactive movement disorders
due to reduced activity of the DIRECT pathway
primary receptor in the direct pathway
D1 dopamine receptors are the main dopamine receptor
D2 receptor locations
preferentially located in the mesolimbic and mesocortical pathways
Parkinson’s disease presentation
unilateral resting tremor, cogwheel rigidity, bradykinesia, and hypomimia
PD years prior may present with
REM sleep behavior disorder, constipation, and anosmia
REM sleep disorder
complex nocturnal behavior involving vocalizations, hitting, punching, or gesturing
psych component of PD
major depression seen in half of patients
non-motor features of PD
autonomic dysfunction and hallucinations
PD with dementia
diagnosis of PD for at least 1 year before the onset of dementia symptoms
familial form of PD
10-15%
LRRK2 mutations (autosomal dominant)
PARK1 gene (alpha-synuclein) and PARK2 (Parkin)
LRRK2 mutations
autosomal dominant
lead to 10% of familial and 5% of sporadic PD cases
North African Arabs
PARK1 gene
alpha-synuclein
PARK2 gene
parkin mutations
PD pathology
alpha-synuclein inclusions/Lewy bodies primarily within the substantia nigra and locus coeruleus
PD diagnostic studies
most often made based on clinical history and examination
in some cases, dopamine transporter (DAT-SPECT) scans may be done which measures the availability of striatal dopamine
- would be normal in patients with essential or drug-induced tremors
PET scans for 11F or 11C dopa measure dopa decarboxylase activity while PET scans for 11C DTBZ assess vesicular monoamine transporter-2 activity
Parkinson’s therapies aim
at increasing intracranial dopamine effects by stimulating its production (dopamine precursors), mimicking its action at receptors (direct agonists), or blocking its peripheral conversion (carbidopa), preventing inactivation (COMT inhibitors), or decreasing its breakdown (MAO-B inhibitors)
dopamine precursor
levodopa
levodopa mechanism of action
levodopa is converted into dopamine after it crosses the blood-brain barrier thus increasing intraparenchymal levels of dopamine
levodopa side effects
nausea/vomiting, dyskinesias, orthostatic hypotension
why is carbidopa given
concurrently with levodopoa to reduce GI side effects and reduce levodopa’s peripheral plasma breakdown
levodopa half life
short
can lead to motor fluctuations and peak-dose dyskinesia
levodopa in pregnancy
safe
COMT inhibitors
tolcapone and entacapone
tolcapone/entacapone mechanism of action
reduces methylation of levodopa and dopamine, which increases levodopa’s half life
tolcapone/entacapone effectiveness
ineffective when given alone but can prolong the duration of clinical response of levodopa when given together
tolcapone montioring
liver enzymes
tolcapone/entacapone side effects
severe diarrhea and discoloration of urine
MAO-B inhibitors
rasagiline and selegiline
rasagiline/selegiline mechanism of action
decreases the catabolism of dopamine, resulting in a greater peak effect and less wearing off when used in combintaion with levodopa
rasagiline/selegiline monotherapy or adjunct?
can be used as monotherapy in early PD
rasagiline/selegiline side effects
ingestion of tyramine heavy foods (aged cheeses, cured meats) can result in severe tachycardia and hypertensive crisis which at times can be fatal
concurrent use of SSRIs can lead to serotonin syndrome
decongestant medications and some narcotics may also interact with MAO-B inhibitors
direct dopamine agonists
bromocriptine, pramipexole, ropinirole, rotigotine, apomorphine
bromocriptine/pramipexole/ropinirole/rotigotine/apomorphine side effects
impulse-control disorder, hallucinations, nausea, orthostatic hypotension, peripheral edema
can worsen dyskinesias when added to levodopa
less likely to cause augmentation than levodopa
pramipexole and ropinirole side effects
excessive drowsiness and falling asleep while driving
partial dopamine agonist and partial NMDA receptor antagonist
amantadine
amantadine mechanism of action
has an anti-dyskinetic effect by reducing the frequency of abnormal involuntary movements due to levodopa
amantadine side effects
livedo reticularis
anticholinergics
trihexyphenidyl and benztropine
trihexyphenidyl/benztropine uses
can be used in younger patients (under 60) with tremor-predominant dysfunction, bradykinesia, postural instability, and/or rigidity
trihexyphenidyl/benztropine side effects
cognitive dysfunction, urinary retention, dry mouth, and GI disturbance
psychosis related therapies for PD
atypical antipsychotics
pimavanserin
clozapine
antipsychotic of choice for PD-related psychosis
clozapine mechanism of action
preferential inhibition of dopamine receptors in the frontal lobe and not the basal ganglia
clozapine side effects
bone marrow suppression
requires blood count monitoring
quetiapine use in PD
doesn’t have risk of bone marrow suppression like clozapine, but is likely not as efficacious
pimavanserin
only FDA approved medication specifically for Parkinson’s disease psychosis
pimavanserin mechanism of action
serotonin 5-HT2A receptor inverse agonist and antagonist
deep brain stimulation
used to treat the motor symptoms of PD but has no effect on its non-motor symptoms
deep brain stimulation implantation
can be implanted into the contralateral side of major symptoms, or bilaterally
deep brain stimulation contraindication
significant cognitive dysfunction
deep brain stimulation location placement
ventral intermediate nucleus (VIM) of the thalamus
globus pallidus interna (GPi) or subthalamic nucleus (STN)
ventral intermediate nucleus (VIM) of the thalamus placement for DBS use
improves tremor
globus pallidus interna (GPi) or subthalamic nucleus (STN)
improves tremor, bradykinesia, and rigidity
drug-induced parkinsonism presentation
can present with either symmetric or asymmetric symptoms, making it difficult to differentiate from Parkinson’s disease
drug-induced parkinsonism drugs
antipsychotics (chlorpromazine, prochlorpromazine, risperidone, clozapine)
antiemetics (metoclopramide)
lithium
SSRIs
valproic acid
phenytoin
drug-induced parkinsonism resolution
often but not always improve in the following weeks to months after discontinuation of the offending drug
Tauopathies
progressive supranuclear palsy (PSP)
corticobasal degeneration (CBD)
frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17)
Synucleinopathies
idiopathic PD
Lewy Body Dementia (LBD)
multiple systems atrophy (MSA)
progressive supranuclear palsy (PSP) presentation
presents with parkinsonism, early falls, vertical gaze palsy, and impaired smooth oculomotor pursuit
PSP imaging
atrophy of the midbrain tegmentum (hummingbird/penguin sign), corpus callosum, and anterior cingulate gyrus
PSP pathology
globose neurofibrillary tangles in the brainstem and ganglia
Tufted astrocytes (tau-positive astrocytic inclusions) are also present
PSP treatment
rarely respond to levodopa
corticobasal degeneration presentation
presents with early limb apraxia due to focal frontal and parietal lobe dysfunction
apraxia is usually asymmetric
associated symptoms include rigidity, agraphesthesia, and aphasia
corticobasal degeneration imaging
atrophy of the perisylvian region and asymmetrical metabolism between hemispheres
corticobasal degeneration pathology
ballooned neurons and astrocytic plaques
FTDP-17
Parkinsonism with early behavioral and personality changes and cognitive impairment
FTDP-17 genetics
linked to chromosome 17 (MAPT gene)
autosomal dominant
LBD presentation
triad of cognitive decline, symmetric parkinsonism, and visual hallucinations
other potential clinical features include REM behavior disorder, neuroleptic sensitivity, falls, syncope, and depression
LBD imaging
occipital hypometabolism on PET imaging
LBD pathology
eosinophilic cytoplasmic inclusions composed of alpha-synuclein inclusions/Lewy bodies
spongiform changes in the temporal lobes may also be present
LBD treatment
usually patients with parkinsonian symptoms will respond to levodopa but dosing is limited to psychiatric side effects
MSA presentation
presents with parkinsonism, cerebellar dysfunction, pyramidal tract signs, and autonomic dysfunction (typically beginning with bladder and erectile dysfunction, with prominent orthostasis on examination)
MSA imgaging
“hot cross bun” sign in the pons showing loss of pontocerebellar fibers
MSA pathology
alpha-synuclein inclusions/Lewy bodies, glial intracytoplasmic inclusions (gliosis) within oligodendroglia, and neuronal loss
MSA treatment
tends to be refractory to L-DOPA
autonomic symptoms can be treated with fludrocortisone or midodrine
- midodrine can cause supine hypertension
MSA variants
MSA-A: autonomic feature predominant
MSA-P: parkinson’s feature predominant
MSA-C: cerebellar ataxia predominant
hyperactive movement disorders
due to reduced activity of the indirect pathway
indirect pathway receptors
D2 receptors main dopamine receptor
chorea
Huntington’s disease
Sydenham chorea
Huntington’s disease presentation
presents with choreiform movements, psychiatric problems, and neurocognitive deficits
patients often develop depression as well
Huntington’s disease genetics
autosomal dominant
HD gene location 4p16.3
trinucleotide repeats >40 CAG leads to full penetrance of the disease
anticipation
trinucleotide repeats expand with subsequent generation
family members of those with HD who wish to pursue genetic evaluation for the trinucleotide repeat should have genetic counseling prior to and after the result is available
testing shouldn’t be performed prior to age 18
huntington’s disease imaging
caudate atrophy
Huntington’s disease pathology
selective loss of spine neurons (GABAergic inhibitory cells) in the caudate nucleus and intranuclear inclusions of huntingtin and ubiquitin
Huntington’s disease treatment
tetrabenazine
deutetrabenazine
tetrabenazine mechanism of action
reversible inhibition of vesicular monoamine transporter 2 (VMAT2), which leads to the decreased uptake of monoamines (dopamine, serotonin, norepinephrine, histamine) into synaptic vesicles, as well as depletion of monoamine storage from nerve terminals
deutetrabenazine
deuterated form of tetrabenazine
newly approved medication for chorea in HD that has better side effect profile
rule of 4s for HD
4p gene
>40 trinucleotide repeats
around 40 years of age of onset
TETRAbenazine
Sydenham chorea aka
St Vitus dance
Sydenham chorea age of presentation
occurs in children ages 5 to 18, one to eight months after having streptococcal pharyngitis
- seen in 40% of patients who develop rheumatic fever
Sydenham chorea presentation
presents with asymmetric but often bilateral choreiform movements, emotional lability, and hypotonia
Sydenham chorea treatment
antibiotics and dopaminergic blocking agents if symptomatic therapy is needed
Sydenham chorea recovery
most patients typically recover within 12-15 weeks
Sydenham chorea risk in females
females who develope Sydenham chorea are at risk of developing recurrent chorea in the setting of hormone therapy or pregnancy (chorea gravidarum)
general (primary generalized) dystonia description
sustained, slow contraction of muscles which can be focal, multifocal, segmental, hemidystonia, or generalized
general dystonia genetics
most common primary dystonia is a mutation in the Torsin A gene (DYT1) on chromosome 9
symptoms start as action-induced dystonia in early childhood
general dystonia exam findings
Geste antagoniste/sensory trick: a voluntary maneuver, such as touching the face, neck, or limb which can temporarily reduce the severity of dystonic posture
writers cramp is an example of a focal dystonia that is induced by a specific activity
generalized dystonia treatment
anticholinergics, benzodiazepines, baclofen (GABA-B agonist), gabapentin, tetrabenazine, DBS
focal dystonia treatment
botox injections
botox mechanism of action
botulinum neurotoxin cleaves synaptosomal/SNARE proteins (SNAP/VAMP) which consequently prevents exocytosis and the release of acetylcholine at neuromuscular junctions
serotype variability of botox injections
serotypes A and E cleave synaptosomal-associated protein (SNAP)-25
serotypes B, D, F, and G cleave vesicle-associated membrane protein (VAMP)
serotype C cleaves both syntaxin and SNAP-25
serotype mnemonic
serotypes associated with voels (i.e. A and E) cleave SNAP
the rest cleave VAMP
dopa-responsive dystonia presentation
presents in childhood as progressive dystonia of the lower extremities without any other significant comorbidities
symptoms are usually mild in the morning and worse at the end of the day (“diurnal”)
dopa-responsive dystonia genetics
mutation of the GTP cyclohydrolase I (GCH1)
associated with the enzyme guanosine triphaosphate cyclohydrase
typically presents as an autosomal dominant disorder
dopa-responsive dystonia treatment
low doses of levodopa
acute dystonic reaction
characterized by involuntary contractions of major muscle groups, such as cervical and limb dystonia or oculogyric crisis and opsithotonos
usually seen in younger patients after exposure to a triggering medication
acute dystonic reaction triggers
dopamine antagonists (metoclopramide, prochlorperazine)
acute dystonic reaction treatment
benztropine (anticholinergic) or diphenhydramine (antihistamine)
Lesch-Nyhan syndrome
occurs due to hypoxanthine-guanine phosphoribosyltransferase deficiency, which leads to increased serum and urine uric acid levels
Lesch-Nyhan syndrome presentation
hypotonia and developmental delay are appreciated at 4 months of age
dystonia starts around 8-12 months of age
self-injurious behavior (lip/tongue biting, headbanging, etc) is often seen
essential tremor on exam
mid to high frequency postural and action tremor of the hand or forearms
it can also involve the head or vocal cords
patients often complain of difficulties with writing, brushing their teeth/hair, or using utensils
essential tremor familial
strong family history present
essential tremor improvement with
transient benefit is appreciated with alcohol intake
essential tremor treatment
propranolol and primidone (level A evidence)
topiramate, gabapentin, atenolol, levetiracetam, alprazolam (level B evidence)
DBS if medically refractory
contraindications for beta blockers
bronchoconstriction or congestive heart failure
enhanced physiologic tremor on exam
low-amplitude, high frequency (6-12 Hz) tremor at rest and action
enhanced physiologic tremor worsens by
enhanced by anxiety or stress and usually does not require extensive workup or treatment
drug-induced tremor
variable presentations (postural vs intention vs resting tremor) based on the particular drug exposure
drug-induced tremor caused by
amiodarone, lithium, selective serotonin reuptake inhibitors, caffeine, valproic acid, immunosuppressants (tacrolimus, cyclosporine), and dopamine antagonists (haloperidol, thioridazine)
orthostatic tremor
presents with high-frequency (14-16 Hz) postural tremor in the legs only appreciated while standing
seen primarily in older adults
Tourette’s syndrome diagnostic criteria
two or more motor and one or more vocal tics, though not necessarily concurrently
for >1 year before the age of 18
coprolalia not required for diagnosis but can be present
provisional (transient) tic disorder
symptoms of tic present for less than a year then self-resolve
concurrent presentations of Tourette’s syndrome
ADHD, OCD, and other mood disorders
childhood tic disorder
diagnosed in children with tics that don’t meet the diagnostic criteria of Tourette’s syndrome
treatment of tic disorders
pharmacotherapy
behavioral therapy known as comprehensive behavioral interventions for tics (CBIT)
pharmacotherapy for tic disorders
typical/atypical dopamine antagonists: haloperidol, pimozide, aripiprazole
alpha-2 agonists: guanfacine and clonidine can also be used to treat comorbid ADHD if present
ADHD and tic disorders
can be seen together
if patient needs ADHD medication, methylphenidate should be avoided as it will make tics worse
atomoxetine can be used without worsening tics
hemiballismus
characterized by sudden, violent, involuntary, flinging movements involving the arm and/or leg
hemiballismus causes
classically seen secondary to a lesion of the contralateral subthalamic nucleus
genetic ataxias
episodic ataxia
Friedrich ataxia (FA)
Ataxia Telangiectasia (ATM)
Fragile X Tremor Ataxia Syndrome (FXTAS)
Autosomal Dominant Spinocerebellar Ataxias (SCA)
chorea-acanthocytosis
dentatorubral-pallidoluysian atrophy
benign hereditary chorea
episodic ataxia
presents with episodic ataxia, gait instability, and nystagmus
episodic ataxia genetics
autosomal dominant
episodic ataxia type I genetics
mutation to the voltage-gated potassium channel (KCNA1)
episodic ataxia type I presentation
episodes last minutes
triggered by startle and exercise
episodic ataxia type 1 treatment
carbamazepine
episodic ataxia type II genetics
due to point mutations to the voltage-gated calcium channel (CACNA1a)
episodic ataxia type II presentation
episodes last hours to days
triggered by fatigue, stress, and alcohol
episodic ataxia type II treatment
acetazolamide
episodic ataxia type III
attacks of ataxia plus tinnitus
episodic ataxia type IV
attacks of ataxia with quick head turn
CACNA1a can cause
familial hemiplegic migraine
spinocerebellar ataxia type 6
Friedrich Ataxia presentation
presents in teenage years with progressive ataxia, dysarthria/dysphagia, sensory loss due to axonal neuropathy, high-arched feet, and weakness with relatively intact cognition
- cardiomyopathy most common cause of death
Friedrich Ataxia treatment
synthetic coenzyme Q analogue: idebenone
Friedrich Ataxia treatment
autosomal recessive
due to loss of function of the frataxin (FXN) gene caused by trinucleotide repeat of GAA (>66)
Friedrich Ataxia imaging
atrophy of the cervical cord and medulla, with some minimal cerebellar atrophy
ataxia telangiectasia presentation
presents in children between 1-2 years old with progressive cerebellar ataxia, telangiectasias, and recurrent sinopulmonary infections
ataxia telangiectasia labs
elevated serum alpha-fetoprotein
ataxia telangiectasia higher risk
higher risk of cancer, particularly lymphomas
ataxia telangiectasia genetics
autosomal recessive mutation of the ATM gene
mnemonic for ataxia telangiectasia
ATM
Ataxia
Telangiectasia
Mucus/Malignancy
fragile X tremor ataxia syndrome (FXTAS) presentation
presents only in men with late-onset ataxia and postural tremor
fragile X tremor ataxia syndrome (FXTAS) genetics
premutation of the same FMR1 gene that causes Fragile X syndrome
Fragile X requires >20 CGG-trinucleotide repeats
FXTAS have repeats between 50 and 200 and thus considered a premutation
next generation would have full Fragile X due to anticipation
SCA
multiple different types with variable phenotypes but uniformally presents with progressive truncal/limb ataxia and spasticity
SCA genetics
often related to pathologic trinucleotide CAG expansions
SCA type 3
Machado-Joseph
most common SCA type
SCA type 3 presentation
presents ages 30-50 years with progressive ataxia and atrophy of the face and tongue
SCA type 6 gene
expansion in the CACNA1A gene
SCA type 6 presentation
presents in adulthood with slowly progressive ataxia
