Download Parkinson`s Plus Syndromes

Parkinson’s Plus Syndromes
-So named because they have parkinsonism PLUS something else that occurs early, and tends to be
the presenting/early symptom (MSA is autonomic problems or ataxia, PSP is gait problems, LBD is
dementia/hallucinations; CBD is dementia or asymmetric clumsiness/dexterity problems).
-Parkinsonism: PD (75%), vascular/PSP/MSA (each 8%), LBD, CBD.
-Alpha-synucleinopathies/lewy body pathology: PD, LBD, MSA
-Tauopathy: PSP, CBD
A) Multiple Systems Atrophy (MSA) Cerebellar vs. Parkinsonism
Pathophysiology:
-Synucleinopathy
-Mean onset age 60; survival 7-9 years, mainly 2/2 sudden death or PNA.
-Poor prognostic signs: older age of onset, early autonomic symptoms.
-Formally called Shy-Drager or Olivopontocerebellar atrophy
Signs/symptoms:
-Prominent early autonomic failure + parkinsonism (80%) and/or cerebellar features (20%).
-NOTE that the predominant motor subtype can change as the disease progresses.
-Definition:
-Autonomic features: Urinary retention OR incontinence, orthostasis, erectile dysfunction, OSA,
stridor (SCARY sign, could suggest impending respiratory failure), constipation, trouble with sweating,
gastroparesis, early satiety.
-Supportive features: Early instability (within 5 years), rapid progression, abnormal postures (leaning
laterally or frontally, anterocollis), bulbar dysfunction (dysphagia, high pitched dysarthria and
dysphonia), respiratory dysfunction (sighing/stridor), pseudobulbar affect, myoclonic jerky action
tremor/stimulus induced myoclonus, Raynaud’s, RBD, OSA, poor response levodopa (1/3
respond to it; many get early dyskinesia), oro-facial dystonia. Can sometimes get executive
dysfuntion.
-NOT supportive: dementia, family history, rest tremor
Dx:
-Clinical diagnosis
-Sweat test/autonomic testing showing no sweating can be helpful.
-Urodynamic studies to document urinary retention.
-MRI brain: “hot cross bun” sign on T2 (hyperintensity in pons/midbrain and middle cerebellar
peduncle). Also can see strip of hyperintensity along striatum on T2 imaging.
-FDG PET: reduced glucose metabolism in putamen, cerebellum, thalamus, brainstem.
-Pathology: Glial cytoplasmic inclusions are classic.
-DDx: Neuropathy/peripheral cause of autonomic failure (ie, POTS or severe neuropathy, Meige
Syndrome, etc)
Tx:
-Orthostasis: fluids/salt, avoid anti-HTNs, compression stockings, elevate head of bed (wedge pillow),
take time getting up, midodrine (7.5mg divided TID, uptitrated to max of 10mg TID daily with last dose
no later than 6PM), or fiorinef (0.1mg daily increased by 0.1mg per week until max of 0.5 mg per day,
titrated to trace pedal edema) or maybe droxidopa (200-2000mg daily). If get supine HTN, do reverse
trenbelenburg, nighttime nitro, clonidine patches, pyridostigmine.
-Constipation: Miralax, senna, etc.
-Urinary retention: Tamsulosin, ? straight cath, consider urology referral.
-CPAP for OSA; trach if stridor can reduce risk of sudden death.
-Most patients dead by 10 years after diagnosis
-30% respond to sinemet, though start slow and watch for worsening orthostasis.
Review article: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2676993/
B) Progressive Supranuclear Palsy (PSP)
Pathophysiology:
-Tau-opathy
-Pathology: Tufted astrocytes
-Onset age >40, average around 65.
Signs/symptoms:
-Early postural instability (falls within 5 years of onset, freezing, stiff gait, knees extended, pivots
WITHOUT en bloc turning, slump into the chair, toe walking, lack of insight)
- Vertical gaze palsy (namely downgaze; supranuclear, in that it can be overcome with oculocephalics,
though later becomes nuclear late in disease; can ALSO only lose vertical saccades early on). Can
present as diplopia.
-Axial rigidity
-eyelid opening apraxia
-Dysarthria (growling, pallialia, moaning, monotonous, sometimes ataxic)/dysphonia
-Dysphagia
-Square wave jerks
-frontal subcortical dementia (apathy, executive dysfunction)
-Lack of any real response to levodopa
-Astonished/worried facial expression
-frontal signs (grasp, motor persistence, perseveration with hand clapping 3 times, head lags behind
body, pseudobulbar affect, personality changes)
-Cervical dystonia (retrocollis), assymetric limb dystonia
-No rest tremor
DDx:
-Corticobasilar Degeneration
-Chronic progressive external ophthalmoplegia (eye movement problems only)
-Niemann-Pick Type C
Dx:
Imaging:
-MRI brain: midbrain atrophy, dilatation of aquaduct with normal pons (on saggital view; called
“hummingbird sign”). Measure anterior/posterior distance of pons and midbrain.
-FDG PET: hypometabolism in brainstem and midline frontal cortex.
Tx:
-Symptomatic (PT, opthy eval for prisms if diplopia, SLP).
-Consider Gtube if significant aspirations, or significant weight loss.
-Poorer prognosis: older age at onset (>63), early dysphagia or cognitive decline. Death is usually
from aspiration/pneumonia.
C) Lewy Body Dementia:
1) Signs/symptoms:
-Dementia starting before or around the same time (ie, within a year or so) as parkinsonism.
Classically with early formed visual hallucinations (usually people/children) and fluctuations in
attention.
-50% have RBD; almost no patients with AD have RBD.
-Fluctuations in attention may be mistaken for seizures, symptoms of OSA, result of poor sleep, or
medication effects/delerium.
-It is likely that PD and LBD are the same alpha- synuclein disease, just on a spectrum: with PD the
pathology starts subcortically and spreads cortically (thus early parkinsonism with late dementia),
while LBD the pathology starts cortically and spreads subcortically (early dementia with later
parkinsonism).
2) Diagnostic criteria:
-Probable LBD: Progressive cognitive decline + 2 of the following MAJOR criteria: fluctuating
attention/alertness, visual hallucinations, motor parkinsonism.
OR
Progressive cognitive decline + 1 of the MAJOR criteria + one of the following MINOR criteria: REM
sleep behavior disorder, severe neuroleptic sensitivity, or suggestive PET scan.
3) Tx:
-Cognitive: Aricept significant improvements lasting at least 12 weeks and reducing caregiver burden.
Anecdotally, it can be quite helpful.
-Avoid antipsychotics and sedative-hypnotics if possible; if needed, prefer quetiapine or clozapine as
less likely to worsen parkinsonism or cause paradoxical confusion. LBD patients are often “more
sensitive” to medication side effects.
-Parkinsonism: Sinemet can often be effective, but need to balance with risk of worsening cognitive
symptoms. Avoid dopamine agonists due to high risk of side effects in this population.
4) Prognosis:
-Average survival from time of diagnosis is 8 years.
D) Corticobasilar Degeneration:
-Tauopathy
-Pathology: Astrocytic plaques
-Mean age of onset in 60’s (none <45 have been pathologically confirmed)
-CLASSIC SYMPTOMS: “Persistent asymmetric neurologic findings” is the classic feature. Also get
limb apraxia, UMN signs, painful asymmetric rigidity and atrophy, stimulus-induced myoclonus,
primary progressive aphasia, alien hand/limb, visuospatial dysfunction, graphesia/cortical sensory
problems, high amplitude action and rest tremor, “holding hands”, insidiously progressive
parkinsonism.
-90% will have bradykinesia, rigidity, and apraxia in first 3 years.
-Dementia is the most common initial symptom; first motor symptom is limb clumsiness/dexterity
problems.
-Can often have overlap with PSP, FTD.
-Diagnostic criteria:
1) All of the following: insidious onset, gradual progression for >1 year, age of onset >50, no response
to sinemet
AND 2 of the following:
2) Akinetic rigidity syndrome, limb apraxia, or speech and language impairment.
AND 2 of the following:
3) Myoclonus, assyemtric dystonia, alien limb phenomenon, cortical sensory loss (graphesia) or
dyscalculia, frontal executive dysfunction, or visuospatial defects
-MRI brain: Asymmetric volume loss/atrophy is classic; most useful with serial studies. -PET will show
assymetric global reduction in metabolism, correlating with body areas most affected.
-DAT scan abnormal most of time.
Tx:
-DOES NOT respond to sinemet (25% response at best), other PD drugs tend to make symptoms
worse.
-Symptomatic (klonopin for myoclonus/tremor, etc)
-Prognosis: Worse if bilateral parkinsonism or frontal lobe syndrome. Death is usually 5-10 years after
symptom onset.
E) Miscellaneous genetic PD mimics:
-SCA2: AD; Usually presents as an ataxia, but can have prominent parkinsonism, or even look like
PSP.
-SCA3: AD; CAG repeat-based; wide range of age of onset, though parkinsonism form tends to be
lower repeats and later age of onset. Can also have some dysautonomia.
-DYT-3 (X-linked recessive dystonia-parkinsonism): Focal dystonia in adulthood that later shows
parkinsonism that is not very responsive to levodopa.
-DYT-5 (Dopa-responsive parkinsonism): AD, reduced penetrance; GTPCH1 gene mutation inhibiting
production of dopamine. Early onset limb onset dystonia with diurnal variation. Exquisitely and
permanently responsive to levodopa.
-Rapid Onset Dystonia-Parkinsonism (DYT-12): AD, reduced penetrance; Abrupt onset of dystonia
and parkinsonism over hours to weeks, symptoms triggered by physical or emotional stress, onset
often teens-twenties, face>arm>leg involvement.
-Wilson’s Disease
-Neurodegeneration with brain iron accumulation (NBIA)
-Huntington’s Disease
-Inborn errors of manganese metabolism
-Neuroacanthocytosis
-Mitochondrial Disorders: Example includes POLG mutations (onset 60’s, with deafness, ataxia,
cognitive changes, LMN signs, vertical supranuclear gaze palsy, responsiveness to sinemet).
-Niemann-Pick Type C: AR lysosomal storage disorder of NPC1 and NPC2 genes; onset 20-30’s;
supranuclear gaze palsy, ataxia, dysphagia/dysarthria, cognitive dysfunction, psych symptoms. Treat
early with miglustat.
-C9ORF72, MAPT, or PGRN: FTD phenotype, sometimes with parkinsonism or PSP/CBD features.
-Adult-onset Gaucher’s: AR; head thrusting, eye movement problems, ataxia, seizures, spasticity,
systemic features of storage disorder
-FXTAS (Fragile X tremor-ataxia syndrome): X-linked dominant; Onset >50, CGG repeat in FMR1
gene; presents with ataxia and tremor, but also cognitive/psychiatric and autonomic issues can be
seen.
-Prior disease