HYPOKINETIC MOVEMENT DISORDERS

PARKINSON DISEASE (PD)

Introduction: Most common neurodegenerative movement disorder. Men:women 3:2

predominance (unclear why), mean onset 60 yo (range: 40-70). Course variable.
Primarily sporadic disease, but several familial forms identified (13 PARK genes to
date associated with parkinsonism) genetic forms associated with earlier onset
PD (<50 yo).

Pathophysiology: Pathologic hallmark: Degeneration of dopaminergic nigrostriatal

projection neurons. Loss of pigmented neurons in substantia nigra & other pigment
nuclei (more widespread pathology identified). Lewy bodies (eosinophilic
cytoplasmic inclusions) composed of alpha-synuclein (normally found in unfolded
form, but in Lewy bodies high concentrations aggregate as filaments) and ubiquitin.

Clinical features/diagnosis

Diagnostic criteria: Cardinal features are bradykinesia, rest tremor, rigidity,

asymmetric onset. Features pointing to an alternate diagnosis are early (<3yrs)
prominent instability/falls, early (<3yrs) freezing, early (<3yrs) hallucinations,
dementia preceding motor symptoms or in 1st yr; supranuclear gaze palsy; severe,
symptomatic dysautonomia; documented condition known to cause parkinsonism,
e.g., drugs. Definite diagnosis only with autopsy.

Other features: 40% develop dementia see chapter Dementia for dementia with
Lewy bodies. ANS bowel/bladder dysfxn, orthostatic hypotension.

Features

Early signs

blinking (nl blink rate 15-20/min, PD 5-10). facial expression (hypomimia).

smell sensitivity.

Bradykinesia

Most characteristic feature of PD and most disabling. Slow mvmts, first noted w/ fine
motor tasks; micrographia (small handwriting). Difficulty turning in bed late
finding. Gait slow, reduced arm swing, shuffling, freezing, turning en bloc.
Monotone, hypophonic dysarthria. Sialorrhea (failure to swallow).
Postural instability

Worsening balance falls; tested via pull test. Festinationchasing center of

gravity. Retropulsion/propulsion.

Tremor

Resting 3-5 Hz pill rolling. Can involve lips, chin, but head/neck unusual. First sx in
70% pts. Usually asymmetric at dz onset. w/ anxiety, contralateral mvmt,
ambulation. Can also have action tremor (8 Hz). Postural tremor most disabling;
need to differentiate from ET. Not always alleviated with L-dopa or dopamine
agonists.

Rigidity

Increased muscle tone, cogwheeling. w/ contralateral motor mvt/mental activity

(Froment sign). Significant cause of disability, pain. Postural deformities (striatal
hands), camptocormia (flexed posture), head drop.

Differential diagnosis: (1) Parkinson-plus syndromes: eventually diagnosed in about

25% of pts w/ original dx of PD; poor response to dopaminergic therapy; worse
prognosis; more rapid progression. Other notable features are: rapid onset, early
dementia, prominent autonomic symptoms, early frequent falls. (2) Structural
(tumor, hydrocephalus, hematoma, trauma), vascular (stroke, vasculitis), infectious,
(postencephalitic, prion disease, AIDS, SSPE), toxic (carbon monoxide, manganese,
MPTP, rotenone, paraquat), metabolic [hepatocerebral degeneration, hypoxia,
hypocalcemia (Fahr's)]. (3) Drug-induced or tardive Parkinsonism: reversible (may
take months), found to cause 20% of PD in one study; consider this if rapid onset of
PD sx occurs; drugs that cause it antipsychotics, antiemetics, amiodarone,
valproate, lithium, Ca+ channel blockers.

Treatment

L-dopacarbidopa: Most effective med, active within 30 min of med ingestion, doesn't
help all sxs. Starting med early in dz doesn't long-term efficacy. Start 25/100 mg
tid. Med trial for 3 mo titrate to at least 1 g/day if no improvement, consider
atypical PD or other d/o (only 10% of path proven PD have no response to med). If
d/c, taper slowly as abrupt cessation can cause hyperpyrexia/rigidity or neuroleptic
malignant syndrome (NMS).

P.106

L-dopa side-effects: Dyskinesias, vivid dreams, sleep disturbance, visual

hallucinations, hypotension, constipation, compulsive behavior (e.g., gambling).
Nausea give med w/ meal or crackers (but high protein meal decreases med
absorption).

Carbidopa: peripheral side effects of L-dopa (nausea/hypotension). Daily dose of

75 mg needed; can increase as needed.

Dopamine agonists: Slightly less efficacious than L-dopa but still first-line
alternative. Thought to risk (by 34) of dyskinesias/motor fluctuations in first 5
yr of tx vs. L-dopa. In elderly can cause confusion, delirium, hallucinations. Ergot
derivatives (pergolide) associated with valvular disease, nonergots preferred (e.g.,
pramipexole & ropinirole). Side effects decreased impulse control (less common
w/ L-dopa) gambling, hypersexuality, hypomanic states.

Other meds: (1) Rest tremor consider amantadine, anticholinergic (limited by side
effects), beta blocker, or primidone. (2) Psychosis quetiapine or clozapine
(atypicals less chance of worsening PD)

Dopamine agonist vs. L-dopa: (Which to start?) (1) Head to head comparisons
motor complications (i.e., dyskinesia, mtr fluctuations) but worse motor fxn in
agonist group at 5 yr f/u (NEJM 2000;342:1484; J Neurol Neurosurg Psych
1994;57:1034). (2) Large 14 yr f/u UK trial agonist vs. L-dopa outcome/motor
complication similar, but still L-dopa group shows better motor fxn (Neurology
2008;71:474). (3) Agonist motor complications (at expense of worse motor fxn)
at 5 yr; eventually this adv is lost. (4) Either considered first line, even in younger
pts. (5) Eventually those treated with agonist will require adjunctive L-dopa.

Neuroprotection: Coenzyme Q10 may be protective (currently in trial).

Controversional evidence for disease modification exists for rasagiline (TEMPO
study), but much less clear evidence for L-dopa (DATATOP study), and no evidence
for riluzole and agonists.

Surgery: Indicated in pts who are L-dopa-responsive but developed motor

fluctuations/dyskinesias (increaseson time), intractable tremor, dystonia. Benefits
of surgery rarely exceed original drug effect. Ablation (such as pallidotomy or
thalamotomy) used in 50s, currently less preferred than DBS (unless DBS
contraindicated). Two major targets for DBS: globus pallidus interna (GPi) and
subthalamic nucleus (STN).

Long-term complications

Motor fluctuations: Delayed onset of L-dopa or wearing off between doses, often
predictable. Linked to low plasma levels of meds. Tx: (1) Advise pt to avoid taking L-
dopa with highprotein meals; tighten dose interval (more frequent doses of L-dopa
at same dose); consider controlled-release levodopa/carbidopa (not effective in later
stages). (2) Add COMT inhibitors: half-life of L-dopa, e.g., entacapone (give w/
each dose of L-dopa). Avoid use of tolcapone given liver toxicity, needs LFT
monitoring. (3) MAO-B inhibitors: dopamine breakdown in CNS (selegiline,
rasagiline); avoid w/ SSRI or TCA; avoid tyramine-rich foods (sausage, aged cheese,
salami) that can cause HTN crisis. (4) DBS if above fails.

Dyskinesia: Involuntary choreiform mvmts, often linked to high plasma dopamine

levels. As PD progresses, dyskinesia occurs at lower & lower L-dopa/agonist doses.
Cause unclear, but exogenous dopaminergic stimulation in denervated striatum
contributes. At 5 yr, 11% risk of dyskinesia, 10 yr 33%, >10 yr 90%. Tx:
Reduce L-dopa dose, switch from controlled-release to immediate-release if
dyskinesias in late afternoon or evening, switch to Dopa agonist monotherapy, or
add amantadine (NMDA receptor antagonist) or clozapine (Neurology 2004;62:381).

MULTIPLE SYSTEMS ATROPHY (MSA)

Introduction

Alpha-synucleinopathy parkinsonism, cerebellar, autonomic, & pyramidal sx's.

Sporadic dz, 3/100 K, onset 60 yo, mean survival 6 yr, M > F. 33% pts w/ late
onset cerebellar ataxia & 8% w/ parkinsonism develop MSA. Rapid sx progression.
Early functional disability. Dementia uncommon.

Pathology: Glial cytoplasmic inclusions (alpha-synuclein-rich). MSA-P striatonigral

system atrophy. MSA-C olivopontocerebellar atrophy. ANS sx cell loss in
brainstem (PRF, dorsal motor vagus nucleus) + spinal cord (parasympathetic
preganglionic for bladder/sexual, intermediolateral column for hypotension).

Clinical manifestations

MSA-P (Parkinsonism, prev. known as striatonigral degeneration, or SND):

Parkinsonism main feature, in 80% of pts. Progressive akinesia/rigidity. Irregular,
myoclonic (jerky) tremor > rest tremor. Orofacial or craniocervical dystonia
anterocollis and laryngeal stridor common, w/ quivering high pitched dysarthria.

MSA-C (Cerebellar, prev. known as olivopontocerebellar atrophy, or OPCA): Gait/limb

ataxia, scanning dysarthria, in 20%. Cerebellar oculomotor problems. If +FH
consider SCA & not MSA
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Autonomic: Urogenital sxs: Urinary retention or incontinence; early erectile dysfxn in

approx. all pts. Orthostatic hypotension: symptomatic in 68%; recurrent syncope in
15%; L-dopa may worsen it.

Imaging: (MRI) putaminal, olivopontocerebellar atrophy. T2 hyperintensities in pons,

mid-cerebellar peduncles.Hot cross bun signal due to cruciform degeneration of
pontocerebellar fibers. GRE (gradient echo) hypointensity in putamen slit-like
hyperintense rim around putamen (latter related to gliosis). ADC signal in
putamen (due to degeneration), not seen in PD, but seen w/ PSP.

Treatment

Parkinsonism: 30% initially responsive to L-dopa, but declines over years;

dopamineinduced confusion can ensue.

Orthostatic hypotension: Avoid large meals, increase salt intake, avoid straining
during urination/defecation, no EtOH/drugs, elastic stockings, head up tilted bed.
Fludrocortisone or midodrine first-line. Supine HTN (sometimes associated w/ severe
orthostatic hypotension) treat only if SBP > 200, start nighttime short-acting
Ca2+ antagonist. Impotence penile injections (prostaglandin), sildanefil (but can
worsen hypotension).

Speech/bulbar dysfxn: Inspiratory stridor can develop; monitor sleep apnea.

PROGRESSIVE SUPRANUCLEAR PALSY (PSP)

Introduction: Progressive dz w/ vertical gaze difficulties & falls/gait instability within

first year of onset. 5% of pts in mvmt d/o clinic have PSP; no gender difference;
onset 60s (age < 40 yo unlike PSP). Cause unknown; pathology: neurofibrillary
tangles in brainstem & basal ganglia, tau deposition, sparing of cerebral cortex.
Definitive dx via autopsy. MRI: Atrophy of midbrain may be seen; Mickey Mouse
sign demonstrates atrophy on axial midbrain cuts; beaked hummingbird
appearance of midbrain on midsagittal view.

Clinical features

Parkinsonism (symmetric unlike PD): Bradykinesia, rigidity (axial > appendicular,

unlike PD), rarely pill rolling rest tremor. Frequent falls & gait difficulty (common
presenting complaints).

Visual: Slowing of vertical saccades initially downgaze limitation, convergence,

slowing horizontal/vertical saccades (overcome by VOR). Bell phenomena (closing
eyelids causes eyes to roll up) & convergence eventually lost. Nontargeted
saccades (look left/right) affected first over targeted (look at my finger, then my
nose). Optokinetic nystagmus; square-wave jerks; eyelid apraxia.

Bulbar sxs: Dysarthria (growling speech). Pseudobulbar sx: emotional

incontinence apathy > disinhibition > dysphoria, anxiety > irritability.

Other features: Open, unblinking eyes (surprised look), masked facies, or

blepharospasm & involuntary eye closure. Neck extension (in PD usually flexed);
Dystonia of extremities.Applause sign preservation of automatic behavior
(perseverative clapping).

Treatment: L-dopa: Up to half of PSP pts have short-lived moderate benefit.

Amantadine: 100 mg bid; about 15% have modest benefit. Multidisciplinary
approach: PT/OT/social services.