Parkinsonian Syndrome

Review Article
Diagnostic Approach to
Address correspondence to
Dr Nikolaus R. McFarland, 1149
South Newell Dr, L3-100,
PO Box 100236, Gainesville,
Atypical Parkinsonian FL 32610, nikolaus.mcfarland@

neurology. ufl.edu.
Relationship Disclosure:
Syndromes Dr McFarland is supported by

a career development grant
from the National Institutes of
Health/National Institute of
Nikolaus R. McFarland, MD, PhD Neurological Disorders and
Stroke (K09 NS067024) and
the Michael J. Fox Foundation.
ABSTRACT Unlabeled Use of
Products/Investigational
Purpose of Review: Although increasingly recognized, atypical parkinsonian syn- Use Disclosure:
dromes remain challenging to diagnose and are underrecognized due to overlap with Dr McFarland reports
no disclosure.
other parkinsonisms. This article provides a diagnostic approach to atypical parkinso-
* 2016 American Academy
nian syndromes, including progressive supranuclear palsy (PSP), multiple system atrophy of Neurology.
(MSA), corticobasal degeneration (CBD), and dementia with Lewy bodies. The goal of
this review is to aid the clinician in recognizing key clinical and pathologic features and
to raise awareness of recent advances in diagnostics and treatment.
Recent Findings: Diagnostic criteria for atypical parkinsonian syndromes are evolving
to encompass increasingly recognized heterogeneity in the presentation of these dis-
orders and information gleamed from clinicopathologic correlations. PSP and CBD in
particular now share similar pathologic clinical features and include a number of
phenotypic variants. Pathologic diagnoses are increasingly used in clinical practice, and
there is frequent reference now by clinicians to tauopathies, including PSP and CBD,
and the synucleinopathies, which include MSA and dementia with Lewy bodies (as well
as Parkinson disease). Research into biomarkers, including both tissue and imaging
modalities and genetics, has the potential to increase disease recognition and make
earlier diagnosis and treatment possible. Although novel therapeutics are being
studied for atypical parkinsonian syndromes such as PSP, no new breakthrough inter-
ventions have emerged for the treatment of PSP, CBD, and MSA. Current therapeutic
management for these disorders frequently uses a multidisciplinary team approach.
Summary: The approach to atypical parkinsonian syndromes requires recognition of
a constellation of overlapping but distinct clinical features that help with identifying
and distinguishing them from Parkinson disease and other similar disorders.
(Minneap Minn) 2016;22(4):1117–1142.
INTRODUCTION such as early dementia, frequent falls,

Parkinsonism is defined as a hypo- ocular dysmotility, prominent dysau-
kinetic syndrome and is characterized tonomia, or ataxia. These syndromes
by the presence of resting tremor, mus- typically involve multisystem degen-
cular rigidity, bradykinesia or akinesia, eration and are referred to as atypical
and postural instability. While many parkinsonian syndromes. They com-
secondary or acquired causes of parkin- monly include progressive supra- Supplemental digital content:
Videos accompanying this ar-
sonism exist, the most common pri- nuclear palsy (PSP), multiple system ticle are cited in the text as
mary or neurodegenerative cause of atrophy (MSA), corticobasal degener- Supplemental Digital Content.
Videos may be accessed by
parkinsonism is Parkinson disease ation (CBD), and dementia with Lewy clicking on links provided in the
(PD). A smaller but significant number bodies (DLB), as well as other rarer HTML, PDF, and app versions
of this article; the URLs are
of patients present with a parkinsonian causes. It is critical to distinguish these provided in the print version.
syndrome that has atypical features disorders from classic PD as disease Video legends begin on page 1139.
(Minneap Minn) 2016;22(4):1117–1142 www.ContinuumJournal.com 1117
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Atypical Parkinsonian Syndromes
progression and subsequent functional nian syndromes with PD, secondary

decline is often more rapid than in PD. parkinsonisms, and heredodegen-
In these syndromes, treatment with erative disorders makes clinical diag-
standard PD therapies frequently lacks nosis challenging (Figure 5-1). These
efficacy and is fraught with complica- issues may lead to underrecognition,
tions. Patients often have complex care delay in diagnosis, and even misdiag-
needs that necessitate a multidis- nosis. Table 5-11 includes a list of pri-
ciplinary approach. This Continuum mary causes of atypical parkinsonisms.
article focuses on the diagnostic ap- Despite the diversity of these condi-
proach to atypical parkinsonian syn- tions, there has been an evolution of
dromes and aims to help the clinician our understanding of the pathophysi-
recognize key clinical and pathologic ology of these disorders. Increasingly,
features as well as recent advances in clinicopathologic terms are being
diagnostics and treatment. used to describe atypical parkinsonian
The considerable overlap of signs syndromes in the clinic because of the
and symptoms for atypical parkinso- diagnostic uncertainty and overlap of
FIGURE 5-1 Overlap of parkinsonian syndromes. Atypical parkinsonisms have common

features with Parkinson disease, secondary parkinsonisms, and
heredodegenerative disorders with parkinsonism.
1118 www.ContinuumJournal.com August 2016

a
TABLE 5-1 Primary Causes of Atypical Parkinsonism
b Multisystem Disease
Progressive supranuclear palsy
Corticobasal syndrome
Multiple system atrophy
Dementia with Lewy bodies
ParkinsonismYdementiaYamyotrophic lateral sclerosis
b Heredodegenerative Disorders
Huntington disease
Spinocerebellar ataxias (especially types 2, 3, and 17)
Wilson disease
Hereditary ceruloplasmin deficiency
Neuronal brain iron accumulation disorders (eg, PKAN2)
X-linked dystonia-parkinsonism (Lubag disease)
Gerstmann-Sträussler-Scheinker syndrome
Neuronal ceroid lipofuscinoses
Mitochondrial cytopathies
a
Modified with permission from Jankovic J, Lang AE, Saunders.1 B 2008 Saunders, an imprint
of Elsevier.
symptoms (Figure 5-2). One common- guish atypical parkinsonian syndromes

ality among neurodegenerative disor- from PD.2 These include rapid disease
ders is the presence of abnormal progression, early gait instability and
proteinaceous deposits in pathologic falls, absence or paucity of tremor, auto-
brain tissue that have been linked to nomic failure, and poor or absent re-
disease mechanisms, giving rise to the sponse to levodopa, including pain/
term neuroproteinopathy. Table 5-2 in- dysesthesia. Additional features may
cludes examples of various proteinop- include oculomotor abnormalities, pyr-
athies and diseases linked to proteins amidal tract or cerebellar signs (ataxia),
that accumulate in intracellular inclusions prominent dysautonomia, severe dysar-
or extracellular plaques (eg, !-synuclein, thria or dysphonia, laryngeal stridor,
ubiquitin, tau, and "-amyloid). myoclonus, alien limb, apraxia, and
Despite recent research and diag- early dementia (Table 5-3). This article
nostic advances, the diagnosis of atyp- focuses on some of the most common
ical parkinsonian syndromes still relies atypical parkinsonian syndromes and
primarily on clinical evaluation. Ancil- their identifying features.
lary tests such as brain imaging can be
supportive, but there are no identified, PROGRESSIVE SUPRANUCLEAR
reliable, and specific biomarkers that PALSY
have been established as diagnostic. PSP was described over 50 years ago by
However, certain features or ‘‘red flags’’ Drs Steele, Richardson, and Olszewski.3
have been identified that help distin- It is the most common form of atypical

KEY POINT
h Key features of
progressive supranuclear
palsy include early gait
instability, unexplained
falls, supranuclear gaze
palsy, axial rigidity,
dysarthric speech,
and dementia.
FIGURE 5-2 Clinicopathologic overlap of neurodegenerative proteinopathies. Atypical

parkinsonian syndromes share abnormal accumulation of proteins such as
!-synuclein, tau, amyloid, and TDP-43.
ALS = amyotrophic lateral sclerosis; FTD = frontotemporal dementia; FTLD-U = frontotemporal
lobar degeneration with ubiquitin; MND = motor neuron disease; TDP-43 = TAR DNA binding
protein 43.
parkinsonism, comprising about 5% to Gait instability and early falls are key
6% of those patients presenting with features of PSP and distinguish it from
parkinsonism. The estimated preva- other parkinsonian syndromes. Relative
lence and annual incidence of PSP is to other parkinsonian syndromes, falls
about 5 per 100,000 in individuals be- occur early, within the first year or two,
tween the ages of 50 and 99 years, but and often lead to significant injury and
is likely higher due to misdiagnosis and fractures.4 Gait in PSP is characteristically
underrecognition. The average age of stiff, broad based, with knees extended
onset is typically in the sixties (average and arms abducted. It is often described
age of 63 to 66 years), and the mean as clumsy like a ‘‘drunken sailor’’ or
survival from diagnosis is reported be- ‘‘dancing bear,’’ and includes large
tween 5 to 8 years. Hallmarks of the dis- lateral deviations and step asymmetry.
ease include prominent, early postural When turning, persons with PSP tend
instability, unexplained falls, vertical supra- to pivot rather than turn en bloc as is
nuclear palsy, and progressive dementia. more typical in PD. The cause of falls is

KEY POINT
TABLE 5-2 Classification of Atypical Parkinsonism h The rocket sign occurs in

as Proteinopathies patients with progressive
supranuclear palsy who
Proteinopathy Disorder have lost insight into their
postural instability and
Amyloidoses Alzheimer disease
‘‘rocket’’ out of their
Ubiquitin-proteasome disorders Parkinson disease, parkin mutation chair without assistance,
Synucleinopathies Parkinson disease, dementia with Lewy bodies, resulting in a high risk
multiple system atrophy for falling.
Tauopathies Progressive supranuclear palsy, corticobasal

degeneration, Alzheimer disease,
frontotemporal dementia (with parkinsonism)
Polyglutamine expansion Huntington disease, spinocerebellar ataxias
Prion disease Creutzfeldt-Jakob disease, Gerstmann-Sträussler-
Scheinker syndrome
often multifactorial and includes axial unchecked sitting (falling into their
rigidity, bradykinesia, loss of postural chair) are also common.
reflexes, freezing, a visual-vestibular com- A key feature of PSP includes inabil-
ponent, and decreased insight. ‘‘Rocket ity to perform volitional saccades and
sign’’ occurs in patients with PSP who progressive supranuclear ophthalmo-
have lost insight into their postural paresis. Although limitation of upgaze
instability and ‘‘rocket’’ out of their is often described as a sign of PSP, it is
chair without assistance, resulting in a nonspecific and can be seen in other
high risk for falling. Retropulsion and neurodegenerative disorders as well
TABLE 5-3 Red Flags for Differentiating Atypical Parkinsonism From

Parkinson Disease
b Features Predictive of Atypical Parkinsonism

Rapid disease progression
Early gait instability, falls
Absence or paucity of tremor
Irregular jerky tremor, myoclonus
Poor/absent response to levodopa
b Additional Features of Atypical Parkinsonism (and Associated Disorder)
Abnormal eye movements (progressive supranuclear palsy)
Pyramidal tract/cerebellar signs (multiple system atrophy)
Dysautonomia (multiple system atrophy)
Severe dysarthria, dysphonia, or stridor (multiple system atrophy)
Apraxia, alien limb, myoclonus (corticobasal syndrome)
Early, prominent dementia (dementia with Lewy bodies, progressive
supranuclear palsy/corticobasal syndrome)

KEY POINTS
h Early signs of as in aging. Limitation of downgaze is thria that is often spastic or hypernasal,
supranuclear gaze most sensitive, and the syndrome hypokinetic, and monotonous. Speech
palsy in patients frequently progresses to include can be slow and can include stuttering,
with progressive upgaze and lateral gaze palsies. echolalia, and occasional involuntary
supranuclear palsy Slowed saccades and reduced optoki- vocalizations. An apraxia of phonation
include slowed vertical netic nystagmusVvertical more af- has also been reported. Most concern-
saccades and reduced fected than horizontalVare also ing, however, is progressive dysphagia
optokinetic nystagmus. frequently observed and are early pre- that can lead to aspiration, pneumonia,
Square-wave jerks, or dictors of progression to supranuclear and early death. As with other parkin-
minute saccadic eye gaze palsy. Another common finding is sonisms, mood disturbance is fre-
movements, may also
square-wave jerks, characterized by quently present and characterized by
be present, representing
rapid back and forth mini saccadic apathy, depression, or both.6 Disinhi-
fixation instability.
intrusions during fixation. Complete bition, dysphoria, anxiety, and irritabil-
h To assess for the gaze palsy and involuntary ocular ity are also possible. Emotional lability
applause sign, a clinician
fixation (as well as lack of eye blink) (also called emotional incontinence),
can demonstrate three
contribute to the classic ‘‘Mona Lisa’’ referred to as pseudobulbar affect, also
claps to the patient and
ask him or her to copy.
stare or stone face. Ability to overcome can occur and cause significant distress
The applause sign is gaze limitation with vestibular or for both the patient and caregivers.
present if the patient cervical-ocular reflex maneuvers de- PSP has the highest rate of pseudo-
claps more than fines supranuclear palsy, but can be bulbar laughing or crying across all
three times and difficult to assess in patients with PSP parkinsonian syndromes.7 Cognitive
continues (perseverates). who have significant axial rigidity. Visual decline and dementia occur with dis-
concerns are also common. Blurred ease progression. A frontal subcortical
vision occurs due to a combination of dementia is typical, with slowed pro-
factors including decreased blink and cessing, or bradyphrenia, reduced
tear production, drying of the cornea, verbal fluency, and executive dysfunc-
and ocular irritation. Diplopia is com- tion. In PSP there is often perseveration
mon not only in PSP but also in other of automatic behaviors, as exemplified
parkinsonisms and is most frequently by the three-clap test or applause sign.
due to convergence insufficiency. Read- (The clinician should demonstrate to
ing is affected and may be helped by the patient three claps and ask him or
prisms in select cases. Despite visual her to copy. The applause sign is pres-
aids, patients often continue to expe- ent if the patient claps more than three
rience blurred vision and difficulty scan- times and continues [perseverates]).
ning text due to progressive gaze palsy. Grasping, imitative behaviors may also
In addition, patients may also experience be present.
photosensitivity (wearing sunglasses
inside), decreased eye blink, blepharo- Diagnosis, Heterogeneity,
spasm, and eye-opening apraxia, leading and Progressive Supranuclear
to eyebrow furrowing (procerus con- Palsy Variants
traction), and vertical wrinkling of the In 1996 the National Institute of Neuro-
forehead, referred to as procerus sign.5 logical Disorders and Stroke (NINDS)
Additional symptoms include a char- and the Society for PSP (SPSP) inter-
acteristic facial appearance from the national workshop proposed criteria
rigid bradykinesia and dystonia in facial for the diagnosis of classic PSP
musculature. The hypertonic facial mus- (Richardson syndrome).8 The criteria
cles produce facial folds and a wor- for possible or probable PSP included
ried, astonished expression. Bulbar a progressive disorder with onset after
features include a progressive dysar- the age of 40 with postural instability,

significant falls, slowing of vertical sac- phenotypic variants have recently
cades, or vertical gaze palsy. Definite been described: PSP-parkinsonism,
PSP added the requirement of patho- PSPYpure akinesia with gait freezing,
logic evidence. Supportive findings in- PSPYcorticobasal syndrome (PSP-CBS)
cluded symmetric rigidity, diminished (or primary nonfluent aphasia), PSPY
response to levodopa, and early cogni- behavioral variant of frontotemporal
tive impairment. Factors excluding the dementia (FTD), and two other pos-
diagnosis of PSP were encephalitis, sible PSP variants with features that over-
focal brain lesion, hallucinations, dysau- lap with either primary lateral sclerosis
tonomia, and alien limb syndrome. (PLS) or cerebellar ataxia. Table 5-4 lists
Cerebellar features were also previ- the clinical and pathologic features that
ously included as exclusionary, but a best differentiate these PSP variants.
recent description of a cerebellar var- Although each PSP variant may pres-
iant of PSP has called this exclusion ent differently, they are united by later
into question.9 onset of the more typical PSP features
The diagnosis of PSP is further com- of postural instability, significant falls,
plicated by its heterogeneous presenta- and supranuclear gaze palsy. Addi-
tion, resulting in increasing recognition tionally, although the distribution of
of clinical variants or phenotypes.10 In tau pathology may differ, each variant
classic presentations, the diagnosis shares pathognomonic PSP-related tau
of Richardson syndrome is relatively pathology. The definition of PSP is con-
straightforward. However, at least five tinually undergoing revision, and new
TABLE 5-4 Progressive Supranuclear Palsy Syndromes
Progressive Supranuclear
Palsy (PSP) Syndrome Clinical Features Regional Pathology
Classic PSP Early gait instability, falls, supranuclear Dentate nucleus, globus pallidus,
(Richardson syndrome) gaze palsy, axial rigidity, dysarthria, striatum, midbrain, and superior
dysphagia, progressive dementia cerebellar peduncle
PSP-parkinsonism Tremor, rigid bradykinesia, levodopa Substantia nigra, subthalamic nucleus
responsive,a late cognitive decline,
longer life expectancy (9 years)
PSPYpure akinesia with Early gait difficulty, freezing of Motor cortex, pons, cerebellum
gait freezing gait/motor block, micrographia, speech
impairment, hypophonia, longer
disease duration (11Y15 years)
PSPYcorticobasal syndrome Dystonia, dyspraxia, cortical sensory Frontal and parietal cortex
loss, apraxia of speech
PSPYbehavioral variant of Predominant cognitive, personality Frontotemporal cortex
frontotemporal dementia change, late parkinsonism
PSPYprimary lateral sclerosis Bulbar, limb weakness, upper motor Frontal predominant, corticospinal tract
neuron signs/spasticity
PSP-cerebellar Cerebellar ataxia Deep cerebellar nuclei
a
Levodopa response for PSP-parkinsonism wanes later in disease.

criteria are likely in the near future. dominance types and atypical PSP var-
In 2014, because of the overlap in fea- iants is ongoing.
tures, Respondek and colleagues10 Progressive supranuclear palsyY
proposed a more comprehensive parkinsonism. PSP-parkinsonism is
approach to describing the pheno- the most common variant of PSP with
typic spectrum of PSP based on the features of tremor, early asymmetric
predominant clinical feature seen bradykinesia, and axial rigidity that
within the first 2 years of presenta- mimic PD.11 As illustrated in Case 5-1,
tion. Predominance types were de- a striking feature is relatively normal
fined including classic Richardson eye movements early on, although
syndrome, postural instability predom- slowed saccades and reduced optoki-
inant, oculomotor predominant, Par- netic nystagmus may be present, sug-
kinsonism, CBS, FTD, and those gesting atypical disease. Patients are
unclassified. Validation of these pre- also frequently levodopa responsive,
Case 5-1
A 65-year-old man presented with a 5-year history of reported Parkinson
disease. He was diagnosed 2 years ago, but had noticed onset of a mild
right hand resting tremor 3 years earlier and progressive slowing and
stiffness of his right arm and gait. After his initial diagnosis, he was started
on carbidopa/levodopa 25 mg/100 mg with initial positive response.
However, gait instability progressed with onset of falls, slurred speech, and
mild dysphagia. His wife also noticed a progressive change in his facial
expression. He seemed to stare more and rarely initiated conversation.
On examination (Supplemental Digital Content 5-1, links.lww.com/
CONT/A178), he was fully oriented. His speech was hypophonic and dysarthric,
but language and cognition were preserved. His facial expression was
masked, and he tended to squint. Vertical saccades (upgaze and downgaze)
were reduced, and horizontal saccades were slowed. Off levodopa he had
moderate bradykinesia of hand movements, finger tapping, and rigidity in
the limbs, on the right more than the left. Mild left hand dystonic posturing
was also noted. He had marked neck rigidity, and he found it difficult to
achieve full range of motion. He stood without assistance, and his gait was
stooped, slow, and his stance was narrowed and unstable with a tendency to
hold onto the examiner or walls. Pull test revealed minimal to no compensation.
He would have fallen if not caught. Brain MRI was notable for age-related
cerebral atrophy and mild prominence of basal cisterns. Further increase in
carbidopa/levodopa dose was unhelpful. A year later, he continued to slow
in all of his movements, his dysarthria worsened, and his vertical gaze
palsy became more apparent. A diagnosis of progressive supranuclear
palsyYparkinsonism was suspected.
Comment. This case illustrates several features suggestive of probable
progressive supranuclear palsyYparkinsonism. Early on, the patient’s
features were typical of Parkinson disease, including tremor, asymmetric
rigid bradykinesia, and response to levodopa. Later, he developed
oculomotor abnormalities, bulbar features (eg, dysarthria, mild dysphagia),
increased postural instability, and waning levodopa response. There is an
increased awareness of levodopa-responsive cases of progressive supranuclear
palsy, especially early in the disease course.

KEY POINT
and that response can be sustained cognitive issues, these patients may be h Atrophy of the midbrain
for years until the later onset of PSP misdiagnosed with FTD or another pri- and superior cerebellar
symptoms are manifest. Life expec- mary dementia.15 peduncles correlates
tancy in PSP-parkinsonism is also Progressive supranuclear palsyY with disease progression
typically longer than in Richardson primary lateral sclerosis. Several re- in progressive
syndrome, averaging 9 or more years ports have suggested possible overlap supranuclear palsy.
from diagnosis. of a PSP syndrome with PLS.16,17 In-
Pure akinesia with gait freezing. In deed, there are common features that
pure akinesia with gait freezing, pa- overlap. PLS is similarly progressive and
tients characteristically present with typically manifests bulbar symptoms,
primary freezing of gait, usually with spastic gait, and sometimes ocular dys-
initiation, and frequent falls.12 Micro- motility, although usually not supra-
graphia, masked face, and apraxia of nuclear palsy. Purported PSP-PLS cases
eyelids may also be present. However, are reported to have a tauopathy
tremor, rigidity, and ophthalmoplegia mainly in motor areas linked by the
are not typical. In 2007, diagnostic cri- corticospinal tract.18
teria were developed that require Cerebellar variant of progressive
gradual onset of freezing of gait or supranuclear palsy. Recently, a number
speech, without tremor, a lasting re- of reports have described a novel var-
sponse to levodopa, or imaging sugges- iant of PSP with features of cerebellar
tive of Binswanger disease. In the first ataxia either as the presenting or pre-
5 years, there should be no evidence dominant symptom and tau pathology
of supranuclear palsy, dementia, or in the deep cerebellar nuclei.9,19 This
limb rigidity.12 cerebellar subtype of PSP appears rare,
Progressive supranuclear palsyY but may be more prevalent in Asian
corticobasal syndrome. PSP-CBS is one populations given recent reports.
of the rarest presentations of PSP. In
Pathology
contrast to classic PSP, early gait dif-
ficulty and postural instability are not The hallmark of PSP is abnormal de-
typical.13 The clinical features of PSP- position of tau and associated pathol-
CBS include asymmetrical dyspraxia, ogy (Figure 5-3). The tufted astrocyte
alien limb phenomenon, and dystonia. is pathognomonic, but other features
Rigidity and bradykinesia are common include coiled bodies, neuropil threads,
and do not respond to levodopa. These pretangles, and neurofibrillary tangles.20
patients additionally have difficulty with Tau pathology generally spares the
saccadic eye movements, most often cortex and involves the basal ganglia,
to the side affected by apraxia, as op- dentate, pontine, and oculomotor nuclei.
posed to the typical vertical gaze palsy. There is associated gliosis and degen-
Progressive supranuclear palsyY eration that is marked by midbrain at-
frontotemporal dementia. PSP-FTD is rophy, loss of pigmented cells in the
a rare variant of PSP. These patients may substantia nigra, and atrophy of the
present with behavioral and cognitive subthalamic nucleus, superior cerebel-
dysfunction either as the only feature or lar and middle cerebellar peduncles,
as the predominant feature of disease. dentate nucleus, and frontal cortex.
Other typical symptoms of PSP follow The tauopathies (PSP, CBS, Alzheimer
later in the course, including falls, disease, and FTD) are characterized by
supranuclear gaze palsy, and levodopa- abnormal tau hyperphosphorylation and
unresponsive parkinsonism.14 Because deposition. Tau is encoded by MAPT
of the predominant behavioral and and normally functions to stabilize

FIGURE 5-3 Typical neuropathologic findings in progressive supranuclear palsy. The

macroscopic photo shows atrophy of the superior cerebellar peduncle (SCP) and
midbrain structures including the subthalamic nucleus (STN) and loss of
pigmented cells in the substantia nigra (SN) (A).The photomicrographs show classic pathologic
findings including neurofibrillary tangles (B), neuropil threads (C, arrows), coiled bodies (D),
and tufted astrocyte (E, arrow) stained with PHF1 antibody to human tau.
Panel A is reprinted with permission from Dickson DW, et al, Curr Opin Neurol.18 B 2010 Lippincott Williams &
Wilkins, Inc. journals.lww.com/co-neurology/Abstract/2010/08000/Neuropathology_of_variants_of_progressive.9.aspx.
microtubules. The protein has six Brain imaging such as MRI, however,
isoforms based on splice variants, in- remains most helpful. In PSP, atrophy
cluding three or four microtubule bind- of the midbrain and superior cerebel-
ing repeat (R) domains. In PSP the 4R:3R lar peduncles can help distinguish PSP
tau ratio in brain is increased (lower in from other neurodegenerative disor-
PSP-parkinsonism) compared to con- ders. Measurement of suprapontine an-
trols. By contrast, the opposite is ob- teroposterior diameter with MRI has
served in FTD. Although MAPT is not been used for analyzing midbrain atro-
mutated in sporadic PSP, it is closely phy, but remains controversial. Another
linked to parkinsonisms including PSP. proposed method of assessing mid-
Mutation in MAPT is most commonly brain atrophy is by measurement of
associated with FTD with parkinsonism the midsagittal area of the midbrain
linked to chromosome 17 (FTDP-17). tegmentum and ratio to area of the
A recent genome-wide association study pons, which is significantly reduced in
was performed and identified three ad- PSP compared to that in PD, MSA-
ditional putative genes associated with parkinsonism, and healthy controls.22
PSP: STX6 (encodes syntaxin 6), EIF2AK3 As a result, the brainstem is often
(PERK, which involves the endoplasmic beaked and takes on the appearance
reticulum unfolded response pathway), of a hummingbird or penguin body
and MOBP (myelin-associated oligoden-
(Figure 5-4). The width of the supe-
drocytic basic protein, which is concen-
rior versus the middle cerebral peduncle
trated in pathologic regions).21
has also been used.23 Diffusion-tensor
Diagnostics imaging (DTI) shows both gray and
To date there is no available blood, CSF, white matter reduction, with predilec-
or single imaging marker for PSP. tion for the anterior and medial thalamic

KEY POINT
h The approach to
treatment of patients
with progressive
supranuclear palsy
should include a
multidisciplinary team
and involve physical,
occupational, and speech
therapy; psychiatry;
neuropsychology; social
work; and palliative care.
FIGURE 5-4 Sagittal T1-weighted MRI of a patient with

progressive supranuclear palsyYRichardson
syndrome. Marked midbrain atrophy is
present, suggesting the appearance of a hummingbird or
penguin sign. Inset shows atrophy of the superior cerebellar
peduncles (arrows).
nuclei.24 Consistent with that found and to develop an exercise program to

pathologically, positron emission to- maintain mobility. Occupational ther-
mography (PET)/single-photon emis- apy can help patients (and caregivers)
sion computed tomography (SPECT) with activities of daily living. Speech
scans of patients with PSP reveal therapy is important early on to treat
hypometabolism of bilateral frontal dysarthria. More advanced patients may
cortex, caudate heads, thalami, cingu- need cognitive therapy for speech
late gyri, and midbrain.25 Recent tau apraxia or to discuss alternative com-
PET ligands, such as 18F-T807/8 and munication modes if markedly dys-
18 arthric or anarthric. Dysphagia and
F-THK523, that have been developed
for Alzheimer disease also show aspiration are the leading causes of
promise for detecting tau in PSP (and morbidity and mortality in PSP. The
other tau disorders), but will require author recommends early and regular
further validation.26 swallowing evaluations (6-month in-
tervals) to assess risk and to modify
Therapeutic Strategies the diet. Often in later stages of the
Currently there is no specific treatment disease, the question of a feeding tube
or cure for PSP. Treatment is focused arises. Discussion with the patient,
primarily on symptomatic improve- family/caregiver, and speech patholo-
ment and, ideally, should involve a gist regarding the benefits and risks
multidisciplinary team approach includ- of a feeding tube is recommended. A
ing physical and occupational therapy, percutaneous gastrostomy tube can
speech pathology, neuropsychology, help maintain nutrition, hydration, and
psychiatry, social work, and palliative medication administration, but does
care. Physical therapy is critical for gait not reduce the risk of aspiration. The
and postural instability, fall prevention, decision regarding gastrostomy should

KEY POINTS
h Levodopa therapy be carefully approached and discussed antidepressant, or an SSRI may be help-
should be tried in most as it raises ethical, cultural, and personal ful. Treatments for other symptoms are
progressive supranuclear considerations regarding quality of summarized in Table 5-5.
palsy cases, with a life. A social worker or case manager
levodopa dose of up to is often critical to help family and care- CORTICOBASAL DEGENERATION
1200 mg/d in divided givers plan for care needs. Palliative CBD is an atypical parkinsonian syn-
doses as tolerated. Partial care also should be considered, and drome with predominant involvement
response is possible in frank discussion of advance directives of the cortex and basal ganglia that
early progressive should be pursued. presents with varied phenotypes.
supranuclear palsy, Although no one medication treats The classic presentation with asym-
particularly in progressive
all the symptoms of PSP, specific treat- metric rigidity, dystonia, and ideomo-
supranuclear
ments may be helpful. For parkinson- tor apraxia is now referred to as CBS,
palsyYparkinsonism.
ism, a levodopa trial up to 1200 mg/d but CBD is increasingly also recognized
h The most common (up to 300 mg per dose if it can be to present with features that may over-
presenting features for
tolerated) for 1 month is recommended lap with FTD, primary progressive
corticobasal degeneration
to determine responsiveness. PSP- aphasia, Alzheimer disease, posterior
are asymmetric hand
clumsiness or apraxia
parkinsonism in particular is often levo- cortical atrophy, and PSP. Typically,
followed by early dopa responsive initially and contrasts marked asymmetry of involvement is
bradykinesia, frontal with that observed in classic Richardson the most striking feature and helps dif-
syndrome, tremor, syndrome and other variants. Dopa- ferentiate CBD from other degenerative
and rigidity. mine agonists, however, often provide disorders. The most common present-
minimal benefit. Amantadine has been ing feature is asymmetric hand clumsi-
reported to have benefit for gait and ness followed by early bradykinesia, a
dysphagia, but studies to support this frontal syndrome, tremor, and rigidity.30
treatment have been limited.27 Anticho- The mean onset of disease occurs in the
linergics should be avoided due to the sixth decade, and prognosis is generally
potential for confusion. Coenzyme Q10 poor with a mean survival of about
is a well-tolerated supplement and has 7 years from diagnosis. Typical features
recently been shown in a small ran- include marked asymmetry, focal ri-
domized clinical trial to provide mod- gidity, coarse rest/action tremor, limb
est benefit in PSP, including slight dystonia (followed by contractures),
improvement in cognitive function.28 alien limb phenomenon, hand, limb,
Painful dystonic posturing of the neck gait, or speech apraxia, myoclonus, cor-
and limbs, blepharospasm, and eye- tical sensory loss, language deficits,
opening apraxia may be treated with frontal/cortical dementia, oculomotor
botulinum toxin. For cognitive decline dysfunction (gaze palsy, impaired con-
and dementia, cholinesterase inhibi- vergence), bulbar impairment, postural
tors such as rivastigmine may provide instability, gait difficulty, hyperreflexia,
modest benefit. Mood disturbance in- and extensor plantar response. Poor
cluding depression, anxiety, and irrita- levodopa response tends to occur, but
bility should be identified and treated high-dose trials are warranted early in
with antidepressants. For apathy, acti- the disease as in PSP (levodopa dose of
vating antidepressants such as bupro- up to 1200 mg/d for 2 to 3 months as
pion, venlafaxine, sertraline, and tolerated) and sometimes provide par-
fluoxetine are preferred over other se- tial benefit. Case 5-2 illustrates a typical
lective serotonin reuptake inhibitors case of CBS.
(SSRIs), which may worsen apathy. If Ideomotor apraxia, myoclonus,
pseudobulbar affect is marked, asymmetric rigid-bradykinetic syndrome,
dextromethorphan-quinidine, a tricyclic and later-onset gait/balance disturbance

TABLE 5-5 Overlapping Symptomatic Treatment Options for Progressive Supranuclear Palsy
and Corticobasal Degeneration
Symptom Treatment Options

Parkinsonism/rigidity Levodopa trial is appropriate to determine responsiveness of motor symptoms,
especially progressive supranuclear palsyYparkinsonism3
Dopamine agonists (minimal benefit)
Amantadine (possible benefit in one study27)
Gait imbalance, falls Physical therapy and assistive devices
Dystonia, blepharospasm Botulinum toxin
Spasticity, contractures Muscle relaxants (eg, baclofen)
Dysarthria Speech therapy
Dysphagia Swallow evaluation (with fluoroscopy) and therapy; modified diet,
aspiration precautions (eg, head of bed up 45 degrees, possible percutaneous
gastrostomy tube)
Sialorrhea Anticholinergics (eg, glycopyrrolate, scopolamine); may worsen cognition
Botulinum toxin in parotid and submandibular glands; use caution as botulinum
toxin can worsen dysphagia
Atropine 1% ophthalmic drops administered sublingually (for palliative use)
Ocular symptoms Zolpidem (short-term benefit/improvement in
voluntary saccades)29
Balance and eye movement therapy to help with better control of
downward saccades
Ophthalmic lubricants for dry eyes
Sunglasses for photosensitivity
Ophthalmology referral and prisms for diplopia
Eyelid crutches or myomectomy are not recommended for eye-opening apraxia
Urinary frequency Antispasmodics; due to risk of central nervous system side effects (eg, dementia)
agents such as tolterodine, trospium, solifenacin, and darifenacin are
preferred as they are more selective and less likely to cross blood-brain barrier
Dementia Cholinesterase inhibitors (eg, rivastigmine, donepezil)
Depression and anxiety Tricyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs),
serotonin norepinephrine reuptake inhibitors (SNRIs)
Pseudobulbar affect Dextromethorphan plus quinidine
have been reported as the best pre- certain task (eg, use a screwdriver or
dictors for CBS diagnosis.31 Ideomotor cut with a pair of scissors). This type of
apraxia is defined by an inability to apraxia can be difficult to distinguish
perform a skilled motor task despite from limb-kinetic apraxia, which is
having intact language, motor, and frequently seen in parkinsonisms, but
sensory function. Examples include in- is independent of modality (imitation
ability to imitate gestures or mime a versus miming). Peculiar to CBS, alien

KEY POINT
h Ideomotor apraxia is
defined by an inability to
Case 5-2
An 80-year-old right-handed man with history of hypertension, prostatic
perform a skilled
hypertrophy, and deep venous thrombosis presented with symptoms of
motor task despite having
progressive gait difficulty, falls, increasing fatigue, tremulousness, and left
intact language, motor,
hand dysfunction that he had experienced over the past 2 years. The
and sensory function.
patient’s wife reported that his gait and movement had slowed several
Examples include inability
years prior, but had worsened further in the setting of deep venous
to imitate gestures or
thrombosis and leg edema. Recently, he had begun dragging his left leg
mime a certain task (eg,
more. The patient noted increasing stiffness in his left arm and tended to
use a screwdriver or cut
hold it flexed at his side. He felt that his symptoms were beginning to
with a pair of scissors).
spread to his right side and reported symptoms of micrographia.
This type of apraxia can
Additional symptoms included hoarse, slowed speech, a decrease in facial
be difficult to distinguish
expression, and mild difficulty swallowing. If he ate too quickly he would
from limb-kinetic apraxia,
hiccup, and swallowing pills had become difficult. The patient denied
which is frequently seen
changes in cognition, memory, or mood. He had previously been evaluated
in parkinsonisms, but is
by a local neurologist, diagnosed with parkinsonism, and treated with a
independent of modality
dopamine agonist with some subjective symptomatic benefit. The addition
(imitation versus miming).
of carbidopa/levodopa did not provide additional benefit.
On examination (Supplemental Digital Content 5-2, links.lww.com/
CONT/A204), the patient was fully oriented but displayed mild disorganized
thought processes, and his cognition and language were otherwise intact.
The patient’s speech was characterized by mild hypokinetic dysarthria.
He had slight facial hypomimia, reduced vertical saccades, and slowed
optokinetic nystagmus. His left upper extremity tone was rigid, and he tended
to hold the arm flexed at his side, but without tremor. Ideomotor apraxia
and reduced graphesthesia were noted in his left hand, but no neglect. The
patient’s gait was slow and stiff with the left arm held flexed, and his left leg
dragged. Postural reflex was reduced on pull testing. Review of his brain MRI
suggested possible asymmetric cerebral atrophy, right greater than left, and
‘‘beaking’’ of his midbrain.
After his initial presentation, the patient’s symptoms rapidly progressed
with increasing left-sided rigidity, dystonic posturing, alien limb
phenomenon, limb-kinetic apraxia, and cortical sensory deficits. He had
increasing symptoms of vertical gaze palsy, gait difficulty, falls, and he
required a wheelchair and assistance with activities of daily living. His speech
remained mildly dysarthric, but was characterized by some grandiosity and
nonsensical statements. He remained on a dopamine agonist (due to
subjective benefit over levodopa) and received botulinum toxin injections
for left upper extremity dystonia and mild antecollis.
Comment. This case demonstrates progressive asymmetric limb
dysfunction, rigid bradykinesia, dystonia, apraxia, and cortical sensory
deficits consistent with probable corticobasal syndrome. Later progression
of cognitive deficits, axial rigidity, falls, and supranuclear palsy raise the
possibility of a corticobasalYprogressive supranuclear palsy syndrome.
limb phenomenon appears as abnor- lateral limb. Dementia in CBS is actually

mal grasping, posturing, or spontane- a late feature with typically preserved
ous levitation of an arm or leg, but can semantic memory.32 Neuropsychiatric
also include pursuit or avoidance of a testing often shows a fronto-striatal-
tactile stimulus in the opposite or contra- parietal predominance with deficits in

attention, concentration, verbal fluency, sion of more than 1 year, age of onset
language, praxis, and executive and vi- of 50 years or more, with or without a
suospatial function.33 Cortical findings similar family history or known tau
such as aphasia, limb apraxia, and mutations (Table 5-6).
graphesthesia depend on the hemisphere
predominantly affected. Pathology
Given the varied presentations and Although classically defined by as a dis-
evolving clinicopathologic under- tinct clinicopathologic entity, in recent
standing of CBD, clinical criteria for di- studies CBD has increasingly been
agnosis have recently been revisited. shown to present with other distinct
Armstrong and colleagues34 proposed pathologies. Clinical diagnosis of CBD
new diagnostic criteria for four CBD correlates with CBD pathology in only
phenotypes including CBS, frontal 25% to 56% of cases.34 Pathologically,
behavioral-spatial syndrome, nonfluent/ CBD is characterized by symmetrical
agrammatic primary progressive apha- cerebral atrophy, which is typically pre-
sia, and a PSP syndrome. Probable and sent despite the asymmetric clinical
possible criteria are described and in- presentation usually seen in CBD. Neu-
clude insidious onset, gradual progres- rodegeneration is widespread and, in
a
TABLE 5-6 Corticobasal Syndrome Phenotypes
Syndrome Key Features

Corticobasal syndrome (CBS) Asymmetric limb rigidity, akinesia,
(classic corticobasal degeneration) dystonia, or myoclonus
PLUS
Orobuccal or limb apraxia, cortical sensory
deficit, or alien limb phenomenon
Probable CBS is two features in each of
the categories above; possible CBS is one
feature in each of the categories above
and may be symmetric
Frontal behavioral (frontotemporal Executive dysfunction, behavioral or
dementia) variant personality changes
Posterior cortical atrophy syndrome Visuospatial disturbance, apraxia,
myoclonus, association with Alzheimer
disease pathology
Progressive nonfluent/ Effortful, agrammatic speech; impaired
agrammatic aphasia grammar/sentence comprehension or
groping, or distorted speech production
(apraxia of speech)
Progressive supranuclear Axial or symmetric limb rigidity/akinesia,
palsy syndrome postural instability, falls, urinary
incontinence, behavioral changes,
supranuclear vertical gaze palsy
a
Modified with permission from Armstrong MJ, et al, Neurology.34 B 2013 American Academy of
Neurology. www.neurology.org/content/80/5/496.short.

addition to the cortex, includes the basal PSP, rehabilitative services and mul-
ganglia, thalamus, substantia nigra, sub- tidisciplinary approaches are critical to
thalamic nucleus, and red nucleus. Path- maintain function as long as possible
ologic diagnosis is characterized by despite progressive decline. Regular
widespread but topographic deposi- exercise and activity early in the dis-
tion of 4R-predominant, hyperpho- ease are most beneficial and may delay
sphorylated tau in neurons and glia, disability. Despite the limitations in
astrocytic plaques, and corticobasal in- treatment, a levodopa dose trial up to
clusions.35 In subcortical nuclei, such 800 mg/d to 1200 mg/d should be at-
as the substantia nigra, intranuclear in- tempted; however, dopaminergic ther-
clusions are reminiscent of globose apy rarely provides improvement and
neurofibrillary tangles, but those in may induce dyskinesia or intolerance.
cortex are granular, crescent shaped, Clonazepam or levetiracetam may im-
or globular.36 Ballooned neurons with prove myoclonus, and muscle relaxants
diffuse cytoplasmic immunoreactivity (eg, baclofen) and botulinum toxin can
to !"-crystallin and ubiquitin are com- help painful rigidity and dystonic con-
mon, but not specific to CBD. ‘‘Coiled tractures that limit function. Experi-
bodies’’ are frequent in oligodendrog- mental therapeutics have focused on
lia, but, unlike PSP, tufted astrocytes tau pathology (see previous section on
are absent. PSP therapeutics).
Diagnostics MULTIPLE SYSTEM ATROPHY

Neuroimaging is most useful in CBD. MSA is characterized by variable pre-
Asymmetric frontoparietal atrophy can sentations of parkinsonism, cerebellar
be identified on CT/MRI and can some- and pyramidal signs, and autonomic dys-
times be helpful in differentiating CBD function. It was first described in the
from other parkinsonian syndromes.37 1960s under the subheadings of Shy-
Fludeoxyglucose positron emission Drager syndrome, olivopontocerebellar
tomography (FDG-PET) similarly can atrophy, and striatonigral degeneration,
sometimes reveal asymmetric cortical depending on the predominant pre-
metabolism. Uptake on levodopaY senting symptoms.39 However, the dis-
positron emission tomography (DOPA- covery of oligodendroglial cytoplasmic
PET) likewise is reduced in the inclusions and associated multisystem
striatum and highly asymmetric in the neurodegeneration in patients with
cortex. [ 123 I]"-CIT (iodine-123-2"- MSA, regardless of the clinical pheno-
carbomethoxy-3"-[4-iodophenyl] type, suggested a common pathology
tropane) SPECT shows a similar pat- and has led to the terminology used
tern of reduced asymmetric striatal today. Two clinical phenotypes are
binding, but is nonspecific to CBD generally distinguished by predominant
(similar to dopamine transporter parkinsonism (MSAYparkinsonian type
SPECT [DAT-SPECT]). Both tau and [MSA-P]) or predominant cerebellar
"-amyloid ligand are also being ex- ataxia (MSAYcerebellar type [MSA-C])
plored for use in distinguishing CBD (Table 5-7). Median age of onset for
from other related disorders.38 MSA is 58 years of age, which is
younger than that of PSP and CBD.
Therapeutic Strategies No MSA cases have been identified
Effective pharmacologic therapies for younger than age 30, whereas for PSP
CBD are still lacking, and treatment the cutoff age is 50 years. Disease
remains mainly supportive. Similar to progression is faster than in PD and

KEY POINTS
TABLE 5-7 Multiple System Atrophy Phenotypes h Multiple system

atrophyYparkinsonian
Clinical Presentation Featuresa type may be differentiated
from Parkinson disease
Multiple system atrophyYparkinsonian Onset 940 years, duration G10 years,
by its more symmetrical
type (MSA-P) (previously referred to as progressive parkinsonism poorly
Shy-Drager syndrome or striatonigral responsive to levodopa, with autonomic appearance, atypical
degeneration) failure (including orthostatic hypotension, tremor, dystonia
impotence, bladder dysfunction) (antecollis), early
dysarthria/dysphonia,
Multiple system atrophyYcerebellar Ataxia; degeneration of ventral pons,
gait and postural
type (MSA-C) (previously referred to olives, cerebellum; mild parkinsonism
instability, dysautonomia,
as olivopontocerebellar atrophy) and cognitive decline
and rapid progression.
a
Autonomic dysfunction, respiratory symptoms, and sleep disturbance can precede motor signs by h Multiple system
months to years.
atrophyYcerebellar type
is one of the most
common causes of
sporadic, adult-onset
mean survival is approximately 6 to toms. Levodopa-induced dyskinesia is ataxia and is distinguished
9 years, consistent with more wide- also possible; the development of early by parkinsonism,
spread neurodegeneration. orofacial dystonia is a red flag for MSA-P. dysautonomia, and
There are, however, select cases of rapid progression.
Clinical Features MSA-P that respond well to levodopa
In the Western hemisphere, MSA-P is for many years. Case 5-3 illustrates
more common than MSA-C. Patients many of the features of MSA-P.
present with features of bradykinesia, In MSA-C, patients present with
rigidity, and tremor and manifest a cerebellar signs such as gait and
more symmetric appearance than in balance impairment, limb ataxia, and
PD. The pill-rolling type of tremor typ- staccato speech or dysarthria. Oculo-
ically seen in PD is uncommon in motor disturbances (nystagmus, jerky
patients with MSA-P. By contrast, trem- pursuits, and hypometric/hypermetric
or in MSA-P is often higher frequency, saccades) may be present. The gait
lower amplitude, and sometimes has a ataxia in MSA-C may be indistinguish-
jerky, stimulus-sensitive, myoclonic able from other sporadic, adult-onset
component.40 Postural instability is a cerebellar ataxias. Other clues in the
later feature in MSA-P compared to that history, such as the presence of par-
in PSP. Speech is often characterized by kinsonism, dysautonomia, or rapid
a mixed spastic, hypokinetic dysarthria progression, should point toward the
or dysphonia as opposed to that ob- diagnosis of MSA-C.40 Notably, the
served in PSP. Dysphagia is not uncom- predominant motor features of the dis-
mon, earlier, and more marked than ease can change with disease progres-
observed in PD. Some patients also sion so that patients who present with
develop respiratory or laryngeal stridor. cerebellar features may eventually also
Other suggestive features include develop parkinsonism.
hyperreflexia, Babinski signs, dystonia, Features common to both subtypes
anterocollis, and early striatal deformi- of MSA include sleep disturbance,
ties (Table 5-8). MSA-P is often poorly autonomic failure, and respiratory dys-
responsive to dopaminergic therapy. function, which can precede motor signs
Patients who do respond may do so by several months to years.41 Ortho-
transiently, and therapy can be limited static hypotension is a frequent, debil-
by exacerbation of orthostatic symp- itating symptom, often complicated by

TABLE 5-8 Differentiating Multiple System AtrophyYParkinsonian

Type and Multiple System AtrophyYCerebellar Type
from Idiopathic Parkinson Disease
b Multiple System AtrophyYParkinsonian Type (MSA-P)

Symmetrical onset
Rapid progression
Tremor (distal, myoclonic)
Frequent rigidity, hypokinesia
Dystonia (axial), anterocollis (dropped head)
Early falls
Dysarthria, dysphonia
Sleep apnea, rapid eye movement (REM) sleep behavior disorder
Respiratory/laryngeal stridor
Hyperreflexia, Babinski signs
Dysautonomia (69% versus 5% in Parkinson disease)
Poor/unsustained levodopa response (~30%)
Dyskinesia (orofacial common)
b Multiple System AtrophyYCerebellar Type (MSA-C)
Cerebellar limb and gait ataxia
Early falls
Dysarthria (scanning, ataxic)
Dysphagia
Gaze impairment (hypokinetic/hyperkinetic saccades)
Lower and upper motor neuron signs
Emotionality, depression, anxiety
Progressive dementia
treatment. Urogenital dysfunction, tory insufficiency.42 These red flags

such as incomplete bladder emptying may help to distinguish MSA from PD
or urinary incontinence, is common in (Table 5-8). Although dementia histor-
women, whereas erectile dysfunction ically has not been included as a
is common in men. Urogenital dys- feature of MSA, there is increasing
function tends to occur early in MSA recognition of cognitive dysfunction
compared to PD, in which symptoms and estimates of dementia in 14% to
present only at more advanced disease 16% of patients with MSA.43
stages. Other MSA features include Pisa
syndrome, a form of axial dystonia that Pathology
manifests as lateral bending of the MSA is characterized by oligodendrog-
trunk; camptocormia, or abnormal for- lial cytoplasmic inclusions and multi-
ward flexion of the trunk; and respira- system neurodegeneration, including

KEY POINT
Case 5-3 h Glial cytoplasmic

inclusions that are
A 66-year-old man presented with a 4-year history of progressive bilateral
enriched with
upper extremity and lower facial tremors, rare myoclonus, bradykinesia,
!-synuclein are a
and speech and gait difficulty with recent falls and freezing. Over the past
pathologic hallmark of
couple of years he had been treated with carbidopa/levodopa and
multiple system atrophy.
required a high dose (up to 500 mg every 4 hours for effect). However, on
presentation off medication, he reported little change in symptoms except
mild decrease in tremor. Additional symptoms included dysphagia,
reduced appetite, urinary frequency and urgency, erectile dysfunction,
constipation, dream enactment, depression, and anxiety.
On examination (Supplemental Digital Content 5-3, links.lww.com/CONT/
A179) while seated in a wheelchair, the patient had abnormal posture with
mild right head tilt, hypokinetic dysarthric speech with mild tremulousness,
and jaw-opening dystonia. Facial hypomimia and reduced/slowed volitional
saccades vertically were noted. Jerky tremor was apparent only with sustained
posture and intention. He had moderate axial and bilateral limb rigidity and
bradykinesia, and his gait was slow and marked by hesitation and freezing.
On pull testing he took several steps and was caught by the examiner. Brain
MRI demonstrated moderate cerebral atrophy and reduced T2 signal in the
posterior putamen bilaterally and slit hyperintensity.
Comment. This case illustrates features of multiple system atrophyY
parkinsonism including rapid progression, dysarthria, dystonia, abnormal
posture, atypical tremor, axial and limb-rigid bradykinesia that is
reasonably symmetric, early gait and postural instability, rapid eye movement
(REM) sleep behavior disorder, and dysautonomia with urinary frequency and
urgency, erectile dysfunction, and probable gastrointestinal dysmotility. Note
also the presence of a wheelchair (the ‘‘wheelchair sign’’), which can be a
red flag for atypical parkinsonism and indicate significant, early postural
instability. Symptoms were partially responsive to high-dose levodopa (500 mg
5 times daily). REM sleep behavior disorder was treated with clonazepam.
neuronal loss and gliosis involving the Diagnostics

putamen, substantia nigra, pons, inferior Although the diagnosis of MSA is pri-
olivary nucleus, cerebellum, and inter- marily based on clinical criteria, several
mediolateral cell column of the thoracic diagnostic studies may be helpful. So
and sacral spinal cord.44 The degree of far no blood test exists to distinguish
involvement (nigrostriatal system, MSA from other parkinsonian syn-
pons, cerebellum) determines the pre- dromes. Biomarkers such as !-synuclein
dominant presentation or subtype of are being explored, but remain contro-
MSA. In patients with autonomic fea- versial. Neuroimaging such as MRI is
tures, the dorsal motor nucleus of the often helpful. MRI findings supportive
vagus, locus coeruleus, and ventrolat- of the diagnosis include bilateral T2
eral medulla are affected. Oligoden- hypointensity in the posterolateral puta-
droglial cytoplasmic inclusions are men, representing iron deposition, and
argyrophilic, sickle-shaped, or oval slit hyperintensity in the lateral margin
cytoplasmic aggregates that are of the putamen (Figure 5-6). Olivo-
enriched with !-synuclein and corre- pontocerebellar atrophy is consistent
late with the severity of neuronal loss with MSA-C. Pontine atrophy and gliosis
and disease duration (Figure 5-5).45 may be apparent on T2-weighted

urinary dysfunction. If a sleep distur-

bance is suspected, polysomnogram
should be performed to identify sleep
apnea, periodic limb movements, and
rapid eye movement (REM) sleep be-
havior disorder.
Therapeutic Strategies
Treatment in MSA focuses mainly on
supportive therapy and should involve
allied health care and rehabilitation
services because of the multisystem
nature of disease. Some 30% to 60% of
patients with MSA initially respond to
dopaminergic therapy. In the absence
of other treatments, a trial of up to
1000 mg/d to 1200 mg/d of levodopa
(300 mg per dose if tolerated) for a
period of 3 months is supported and
FIGURE 5-5 Glial cytoplasmic inclusions in multiple system
atrophy. Oligodendroglial cytoplasmic inclusions is the mainstay of initial therapy for
here are stained with antibody to human parkinsonism in MSA. Dopamine ago-
!-synuclein.
nists, because of autonomic and other
issues, are generally inferior to levodopa
images in a hot cross bunYlike pattern. for MSA and have not been studied
Additionally, PET scans often show carefully in this setting. The challenge is
decreased striatal and frontal metabo- to balance the benefits of therapy with
lism. DAT (125I-ioflupane) SPECT also the development of motor complica-
typically shows asymmetric reduced tions that may appear earlier in MSA as
striatal binding.46 Autonomic testing also compared to classic PD. These MSA fea-
can be helpful and include tilt-table tures include dyskinesia, frequently in-
testing, 24-hour ambulatory blood volving the jaw and face, and orthostatic
pressure and heart rate monitoring, hypotension. Alternative therapies such
and baroreceptor sensitivity (ie, the as deep brain stimulation are not recom-
baroreflex mechanism or ability to mended due to poor response.
regulate blood pressure by controlling Autonomic symptoms such as ortho-
heart rate, contractility, and peripheral static hypotension are treated first with
resistance) for orthostatic hypotension. conservative measures including oral
In the office, testing should include hydration, increased salt intake, and
supine blood pressure with heart rate, compression stockings or abdominal
then standing blood pressure and binder. If still symptomatic, pharmaco-
heart rate after 3 minutes. A drop in logic therapy with fludrocortisone or
systolic blood pressure of more than desmopressin, which increase blood
20 mm Hg or drop in diastolic blood volume, may be helpful but are con-
pressure of more than 10 mm Hg with traindicated in patients with heart fail-
minimal rise in heart rate is diagnostic. ure. Midodrine, an !1 agonist, can also
Other tests may include sweat testing be used but has the potential to cause
(eg, quantitative sudomotor axon reflex supine hypertension. Recently, the US
test [QSART]) and gastric emptying study Food and Drug Administration (FDA)
(for gastroparesis), and urodyamics for approved the use of droxidopa for

KEY POINTS
h Pharmacologic
treatment of orthostatic
hypotension may
include enhancing
blood volume with
fludrocortisone or
desmopressin or adding
drugs that increase
vascular resistance such
as midodrine, droxidopa,
or pyridostigmine.
h Dementia with Lewy
bodies is characterized
by rapid-onset dementia,
parkinsonism (coincident
or following cognitive
decline), mental status
fluctuations, and
hallucinations.
FIGURE 5-6 Axial T2-weighted MRI of a patient with multiple system atrophyYparkinsonian type
demonstrating slitlike hyperintensity (A, arrows) at the rim of the right putamen,
fluid-attenuated inversion recovery (FLAIR) hypointensity of posterior putamen (B,
arrows), and typical hot cross bun sign representing atrophy and gliosis of the pons (C).
neurogenic orthostatic hypotension. rapidly progressive dementia that is part

Droxidopa is a synthetic amino acid pre- of the spectrum of PD. It is the second
cursor for norepinephrine and epineph- most common form of neurodegenera-
rine. Pyridostigmine is an alternative that tive dementia, after Alzheimer disease,
provides a mild boost in blood pressure and has similar features to other demen-
without supine hypertension but most tias, including PD. The clinical criteria for
of the data supportive of its use come DLB in addition to early dementia in-
from patients with neuropathy. For neu- clude: (1) parkinsonism that is coinci-
rogenic bladder, antispasmodics or bot- dent with or follows dementia onset; (2)
ulinum toxin injections are often helpful. fluctuating cognition, awareness, or alert-
Alpha-blockers for benign prostatic
ness; and (3) recurrent visual hallucina-
hypertrophy, however, have the poten-
tions.47 Additional features include gait
tial to cause hypotension. Some patients
instability, falls, syncope or transient loss
require intermittent self-catheterization
or placement of a suprapubic catheter. of consciousness, delusions/paranoia,
depression, REM sleep behavior disor-
PARKINSON DEMENTIAS: der, and neuroleptic sensitivity. A com-
DEMENTIA WITH LEWY BODIES bination of dementia and psychosis in
DLB (also known as [diffuse] Lewy body general is considered a poor prognostic
dementia or disease) is an early-onset, predictor in this population.

Pathology dementia syndromes are generally lack-

Diffuse Lewy bodies are the hallmark ing, and diagnosis remains primarily
in DLB as well as in PD dementia clinical. Imaging studies have been
(Figure 5-7). Incidental Lewy bodies, promising for development of potential
however, are also found at autopsy in biomarkers to distinguish DLB.51 Brain
individuals with no clinical signs of MRI generally shows diffuse cerebral
parkinsonism, but may indicate pre- atrophy with relative preservation of
clinical disease.48 The degree of Lewy the occipital and mesial temporal lobes
body involvement of the cortex corre- when compared to Alzheimer disease.
lates with the severity of dementia.49 SPECT studies focused on examining
Spreading Lewy body pathology, or occipital hypoperfusion have reported
synucleinopathy, from brainstem to some specificity/sensitivity in discrimi-
neocortex is described by Braak and nating DLB from Alzheimer disease.
colleagues50 and is thought to contrib- FDG-PET has also been used to exam-
ute to progressive cognitive impairment. ine occipital (and parietal) lobe changes
Coincident Alzheimer disease pathology in DLB. There is emerging evidence for
is also frequently found in cases and the cingulate island sign, or preservation
contributes to dementia. of FDG-PET metabolism in the poste-
rior cingulate relative to the cuneus and
Diagnostics precuneus, that correlates with DLB
Disease-specific biomarkers for DLB/PD versus Alzheimer pathology.52 Dopami-
dementia and related parkinsonian- nergic imaging (ie, DAT-SPECT) likewise
FIGURE 5-7 Typical Lewy bodies are found in the

pigmented cells of the substantial nigra in
both Parkinson disease and dementia with
Lewy bodies. Here Lewy bodies (arrows) are stained with an
antibody specific to the pathologic phosphorylated form
(serine 129) of !-synuclein found enriched in Lewy bodies.
They have a characteristic round appearance with lighter
core and dark halo.

may be useful if there is question re- monitoring for the risk of agranulocy-
garding the diagnosis of DLB, but is not tosis.55 Other potential side effects of
specific. Pittsburg compound B (PiB) clozapine include orthostatic hypotension
scanning also can be helpful to assess and depression. Recently pimavanserin,
amyloid burden, given the association a selective 5-hydroxytryptamine, seroto-
with DLB more than in PD dementia.53 nin receptor 2 (5-HT2) inverse agonist,
In Alzheimer disease, CSF total and phos- has been studied in phase 3 trials and
phorylated tau levels are increased and holds promise for controlling psychosis
amyloid-" level is reduced. By contrast, without exacerbating parkinsonism.56
CSF tau (and possibly also !-synuclein) Treatment of cognitive impairment
is significantly lower in DLB than in begins with formal neuropsychiatric as-
Alzheimer disease.54 sessment and cognitive therapy. Often,
comorbid depression, apathy, and anx-
Therapeutic Strategies iety are found and should be treated.
As with other atypical parkinsonian For cognitive dysfunction, cholinester-
syndromes, treatment of DLB is symp- ase inhibitors such as rivastigmine and
tomatic and involves coordination of donepezil have been used, and some
caregivers and allied health personnel. evidence supports improvements in
Treatment of dementia-related psy- cognition.57 Memantine also may pro-
chosis in parkinsonisms often requires vide mild benefit.58
balancing use of dopaminergic medi-
cations, such as levodopa, and use of CONCLUSION
antipsychotics. Levodopa is usually The approach to atypical parkinsonian
beneficial for parkinsonism but in syndromes requires careful attention to
some cases can exacerbate psychosis details of the patient’s history, such as
and hallucinations. Conversely, reduc- mode of presentation and disease pro-
tion in levodopa dose, particularly at gression, as well as identification of
night, may benefit hallucinations, agi- signs and symptoms that may provide
tation, and psychosis. Dopaminergic clues to diagnosis. Growing recognition
agonists are typically not used or are of the clinical heterogeneity, overlap,
weaned, and nondopaminergic agents and varied phenotypes of these syn-
such as monoamine oxidase inhibitors dromes may further aid in diagnosis
(MAOIs), amantadine, and anticholin- and will be particularly important as
ergics are typically avoided due to their novel therapies emerge. Our increasing
potential to worsen cognition and psy- understanding of the clinicopathologic
chosis. If not improved with medication correlates for these syndromes will aid
changes, hallucinations and psychosis in the development of diagnostic bio-
are often treated with atypical antipsy- markers and will likely bolster efforts
chotics. Of note, use of antipsychotics aimed at the development of disease-
for dementia-related psychosis carries modifying therapeutics.
risk of increased mortality (mainly car-
diovascular or infectious) and should be VIDEO LEGENDS
used judiciously. Although quetiapine is Supplemental Digital
often the drug chosen by many clinicians Content 5-1
and may be helpful in mild cases, Progressive supranuclear palsyY
studies have not supported its efficacy, parkinsonism. Video shows the 65-year-
particularly for control of hallucinations. old man in Case 5-1 demonstrating
In contrast, clozapine has proven efficacy hypophonic and dysarthric speech with
but requires frequent routine blood preserved language and cognition. His

facial expression is masked, and he tends Psychiatry 1989;(suppl):78Y89. doi:10.1136/

jnnp.52.Suppl.78.
to squint. Vertical saccades (upgaze and
3. Richardson JC, Steele J, Olszewski J.
downgaze) are reduced, and horizontal Supranuclear ophthalmoplegia, pseudobulbar
saccades are slowed. Off levodopa he palsy, nuchal dystonia and dementia. A clinical
demonstrates moderate bradykinesia report on eight cases of ‘‘heterogenous
of hand movements, finger tapping, system degeneration.’’ Trans Am Neurol Assoc
1963;88:25Y29.
and rigidity in the limbs, on the right
4. Williams DR, Watt HC, Lees AJ. Predictors of
more than the left. His gait is stooped falls and fractures in bradykinetic rigid
and slow, and his stance is narrowed syndromes: a retrospective study. J Neurol
and unstable with a tendency to hold Neurosurg Psychiatry 2006;77(4):468Y473.
doi:10.1136/jnnp.2005.074070.
onto the examiner or walls. Pull test
reveals minimal to no compensation. 5. Batla A, Nehru R, Vijay T. Vertical wrinkling
of the forehead or procerus sign in
He would have fallen if not caught. progressive supranuclear palsy. J Neurol Sci
2010;298(1-2):148Y149. doi:10.1016/
links.lww.com/CONT/A178 j.jns.2010.08.010.
B 2016 American Academy of Neurology.
6. Litvan I, Mega MS, Cummings JL, Fairbanks L.
Neuropsychiatric aspects of progressive
Supplemental Digital supranuclear palsy. Neurology 1996;
Content 5-2 47(5):1184Y1189. doi:10.1212/WNL.47.5.1184.
Corticobasal degeneration. Video 7. Strowd RE, Cartwright MS, Okun MS, et al.
Pseudobulbar affect: prevalence and quality
shows the 80-year-old man in Case 5-2 of life impact in movement disorders.
demonstrating asymmetric limb dys- J Neurol 2010;257(8):1382Y1387. doi:10.1007/
function, rigidity, bradykinesia, dysto- s00415-010-5550-3.
nia, apraxia, and cortical sensory deficits 8. Litvan I, Hauw JJ, Bartko JJ, et al. Validity
consistent with probable corticobasal and reliability of the preliminary NINDS
neuropathologic criteria for progressive
degeneration. supranuclear palsy and related disorders.
links.lww.com/CONT/A204 J Neuropathol Exp Neurol 1996;55(1):97Y105.
B 2016 American Academy of Neurology. 9. Kanazawa M, Shimohata T, Toyoshima Y,

et al. Cerebellar involvement in progressive
supranuclear palsy: a clinicopathological
Supplemental Digital study. Mov Disord 2009;24(9):1312Y1318.
Content 5-3 doi:10.1002/mds.22583.
Multiple system atrophyYparkinsonism. 10. Respondek G, Stamelou M, Kurz C, et al.
The phenotypic spectrum of progressive
Video shows the 66-year-old man in
supranuclear palsy: a retrospective multicenter
Case 5-3 demonstrating hypokinetic study of 100 definite cases. Mov Disord 2014;
dysarthric speech, jaw-opening dysto- 29(14):1758Y1766. doi:10.1002/mds.26054.
nia, atypical tremor, symmetric rigid 11. Williams DR, de Silva R, Paviour DC, et al.
bradykinesia, and early postural insta- Characteristics of two distinct clinical
bility consistent with multiple system phenotypes in pathologically proven
progressive supranuclear palsy: Richardson’s
atrophyYparkinsonism. syndrome and PSP-parkinsonism. Brain
2005;128(pt 6):1247Y1258. doi:10.1093/
links.lww.com/CONT/A179 brain/awh488.
B 2016 American Academy of Neurology.
12. Williams DR, Holton JL, Strand K, et al. Pure
akinesia with gait freezing: a third clinical
REFERENCES phenotype of progressive supranuclear
1. Jankovic J, Lang AE. Movement disorders: palsy. Mov Disord 2007;22(15):2235Y2241.
diagnosis and assessment. In: Bradley WG, doi:10.1002/mds.21698.
Daroff RB, Fenichel GM, Jankovic J, eds.
13. Williams DR, Lees AJ. Progressive
Neurology in clinical practice. 5th edition.
supranuclear palsy: clinicopathological
Philadelphia, PA: Saunders; 2008.
concepts and diagnostic challenges. Lancet
2. Quinn N. Multiple system atrophyVthe Neurol 2009;8(3):270Y279. doi:10.1016/
nature of the beast. J Neurol Neurosurg S1474-4422(09)70042-0.

14. Hassan A, Parisi JE, Josephs KA. Autopsy-proven 2010;74(14):e60. doi:10.1212/
progressive supranuclear palsy presenting as WNL.0b013e3181d7d871.
behavioral variant frontotemporal dementia.
26. Ariza M, Kolb HC, Moechars D, et al.
Neurocase 2011;18(6):478Y488. doi:10.1080/
Tau positron emission tomography (PET)
13554794.2011.627345.
imaging: past, present, and future. J Med
15. Donker Kaat L, Boon AJ, Azmani A, et al. Chem 2015;58(11):4365Y4382.
Familial aggregation of parkinsonism in doi:10.1021/jm5017544.
progressive supranuclear palsy. Neurology
27. Norris FH, Panitch HS, Denys EH, et al.
2009;73(2):98Y105. doi:10.1212/
The treatment of subacute sclerosing
WNL.0b013e3181a92bcc.
panencephalitis with interferon: a case
16. King A, Curran O, Al-Sarraj S. Atypical report. J Neurol 1986;233(2):102Y107.
progressive supranuclear palsy presenting as doi:10.1007/BF00313855.
primary lateral sclerosis. J Neurol Sci 2013;
28. Stamelou M, Reuss A, Pilatus U, et al.
329(1Y2):69. doi:10.1016/j.jns.2013.03.015.
Short-term effects of coenzyme Q10 in
17. Nagao S, Yokota O, Nanba R, et al. progressive supranuclear palsy: a randomized,
Progressive supranuclear palsy presenting as placebo-controlled trial. Mov Disord
primary lateral sclerosis but lacking 2008;23(7):942Y949. doi:10.1002/mds.22023.
parkinsonism, gaze palsy, aphasia, or
29. Cotter C, Armytage T, Crimmins D. The use
dementia. J Neurol Sci 2012;323(1Y2):147Y153.
of zolpidem in the treatment of progressive
doi:10.1016/j.jns.2012.09.005.
supranuclear palsy. J Clin Neurosci
18. Dickson DW, Ahmed Z, Algom AA, et al. 2010;17(3):385Y386. doi:10.1016/
Neuropathology of variants of progressive j.jocn.2009.05.038.
supranuclear palsy. Curr Opin Neurol
30. Wenning GK, Litvan I, Jankovic J, et al.
2010;23(4):394Y400. doi:10.1097/
Natural history and survival of 14 patients
WCO.0b013e32833be924.
with corticobasal degeneration confirmed
19. Jellinger K. Cerebellar involvement in at postmortem examination. J Neurol
progressive supranuclear palsy. Mov Disord Neurosurg Psychiatry 1998;64(2):184Y189.
2010;25(8):1104Y1105. doi:10.1002/mds.23045. doi:10.1136/jnnp.64.2.184.
20. Stamelou M, de Silva R, Arias- Carrión O, 31. Litvan I, Agid Y, Goetz C, et al. Accuracy
et al. Rational therapeutic approaches to of the clinical diagnosis of corticobasal
progressive supranuclear palsy. Brain degeneration: a clinicopathologic study.
2010;133(pt 6):1578Y1590. doi:10.1093/ Neurology 1997;48(1):119Y125. doi:10.1212/
brain/awq115. WNL.48.1.119.
21. Höglinger GU, Melhem NM, Dickson DW, 32. Graham NL, Bak TH, Hodges JR. Corticobasal
et al. Identification of common variants degeneration as a cognitive disorder. Mov
influencing risk of the tauopathy Disord 2003;18(11):1224Y1232. doi:10.1002/
progressive supranuclear palsy. Nat Genet mds.10536.
2011;43(7):699Y705. doi:10.1038/ng.859.
33. Pillon B, Gouider-Khouja N, Deweer B, et al.
22. Oba H, Yagishita A, Terada H, et al. New Neuropsychological pattern of striatonigral
and reliable MRI diagnosis for progressive degeneration: comparison with Parkinson’s
supranuclear palsy. Neurology disease and progressive supranuclear
2005;64(12):2050Y2055. doi:10.1212/ palsy. J Neurol Neurosurg Psychiatry 1995;
01.WNL.0000165960.04422.D0. 58(2):174Y179. doi:10.1136/jnnp.58.2.174.
23. Longoni G, Agosta F, Kostić VS, et al. MRI 34. Armstrong MJ, Litvan I, Lang AE, et al.
measurements of brainstem structures in Criteria for the diagnosis of corticobasal
patients with Richardson’s syndrome, degeneration. Neurology 2013;80(5):
progressive supranuclear palsy-parkinsonism, 496Y503. doi:10.1212/WNL.0b013e31827f0fd1.
and Parkinson’s disease. Mov Disord
35. Dickson DW, Bergeron C, Chin SS, et al.
2011;26(2):247Y255. doi:10.1002/mds.23293.
Office of rare diseases neuropathologic
24. Knake S, Belke M, Menzler K, et al. In vivo criteria for corticobasal degeneration.
demonstration of microstructural brain J Neuropathol Exp Neurol
pathology in progressive supranuclear palsy: 2002;61(11):935Y946.
a DTI study using TBSS. Mov Disord 2010;25(9):
36. Kouri N, Whitwell JL, Josephs KA, et al.
1232Y1238. doi:10.1002/mds.23054.
Corticobasal degeneration: a pathologically
25. Renard D, Collombier L, Castelnovo G, distinct 4R tauopathy. Nat Rev Neurol
Labauge P. Teaching NeuroImages: FDG-PET 2011;7(5):263Y272. doi:10.1038/
in progressive supranuclear palsy. Neurology nrneurol.2011.43.

37. Whitwell JL, Jack CR Jr, Boeve BF, et al. 65(8):1074Y1080. doi:10.1001/
Imaging correlates of pathology in archneur.65.8.1074.
corticobasal syndrome. Neurology
49. Hurtig HI, Trojanowski JQ, Galvin J, et al.
2010;75(21):1879Y1887. doi:10.1212/
Alpha-synuclein cortical Lewy bodies
WNL.0b013e3181feb2e8.
correlate with dementia in Parkinson’s
38. Murray ME, Kouri N, Lin WL, et al. disease. Neurology 2000;54(10):1916Y1921.
Clinicopathologic assessment and imaging doi:10.1212/WNL.54.10.1916.
of tauopathies in neurodegenerative
50. Braak H, Rüb U, Jansen Steur EN, et al.
dementias. Alzheimers Res Ther 2014;
Cognitive status correlates with
6(1):1. doi:10.1186/alzrt231.
neuropathologic stage in Parkinson disease.
39. Stefanova N, Bücke P, Duerr S, Wenning GK. Neurology 2005;64(8):1404Y1410.
Multiple system atrophy: an update. Lancet doi:10.1212/01.WNL.0000158422.41380.82.
Neurol 2009;8(12):1172Y1178. doi:10.1016/
51. Sinha N, Firbank M, O’Brien JT. Biomarkers
S1474-4422(09)70288-1.
in dementia with Lewy bodies: a review.
40. Köllensperger M, Geser F, Seppi K, et al. Int J Geriatr Psychiatry 2012;27(5):443Y453.
Red flags for multiple system atrophy. Mov doi:10.1002/gps.2749.
Disord 2008;23(8):1093Y1099. doi:10.1002/
52. Graff-Radford J, Murray ME, Lowe VJ,
mds.21992.
et al. Dementia with Lewy bodies: basis
41. Jecmenica-Lukic M, Poewe W, Tolosa E, of cingulate island sign. Neurology
Wenning GK. Premotor signs and symptoms 2014;83(9):801Y809. doi: 10.1212/
of multiple system atrophy. Lancet Neurol WNL.0000000000000734.
2012;11(4):361Y368. doi:10.1016/ 53. Gomperts SN, Rentz DM, Moran E,
S1474-4422(12)70022-4. et al. Imaging amyloid deposition in Lewy
42. Köllensperger M, Geser F, Ndayisaba JP, et al. body diseases. Neurology 2008;71(12):
Presentation, diagnosis, and management of 903Y910. doi:10.1212/01.wnl.
multiple system atrophy in Europe: final 0000326146.60732.d6.
analysis of the European multiple system 54. Mollenhauer B, Bibl M, Trenkwalder C, et al.
atrophy registry. Mov Disord 2010;25(15): Follow-up investigations in cerebrospinal
2604Y2612. doi:10.1002/mds.23192. fluid of patients with dementia with Lewy
43. Brown RG, Lacomblez L, Landwehrmeyer BG, bodies and Alzheimer’s disease. J Neural
et al. Cognitive impairment in patients with Transm (Vienna) 2005;112(7):933Y948.
multiple system atrophy and progressive doi:10.1007/s00702-004-0235-7.
supranuclear palsy. Brain 2010;133(pt 8): 55. Hack N, Fayad SM, Monari EH, et al.
2382Y2393. doi:10.1093/brain/awq158. An eight-year clinic experience with
44. Ahmed Z, Asi YT, Sailer A, et al. The clozapine use in a Parkinson’s disease
neuropathology, pathophysiology and clinic setting. PloS One 2014;9(3):e91545.
genetics of multiple system atrophy. doi:10.1371/journal.pone.0091545.
Neuropathol Appl Neurobiol 2012;38(1):
56. Cummings J, Isaacson S, Mills R, et al.
4Y24. doi:10.1111/j.1365-2990.2011.01234.x.
Pimavanserin for patients with Parkinson’s
45. Wenning GK, Jellinger KA. The role of disease psychosis: a randomised,
alpha-synuclein in the pathogenesis of placebo-controlled phase 3 trial. Lancet
multiple system atrophy. Acta Neuropathol 2014;383(9916):533Y540. doi:10.1016/
2005;109(2):129Y140. doi:10.1007/ S0140-6736(13)62106-6.
s00401-004-0935-y.
57. Rolinski M, Fox C, Maidment I, McShane R.
46. Perju-Dumbrava LD, Kovacs GG, Pirker S, Cholinesterase inhibitors for dementia with
et al. Dopamine transporter imaging in Lewy bodies, Parkinson’s disease dementia
autopsy-confirmed Parkinson’s disease and and cognitive impairment in Parkinson’s
multiple system atrophy. Mov Disord disease. Cochrane Database Syst Rev
2012;27(1):65Y71. doi:10.1002/mds.24000. 2012;3:CD006504. doi:10.1002/
14651858.CD006504.pub2.
47. McKeith IG, Dickson DW, Lowe J, et al.
Diagnosis and management of dementia with
58. Emre M, Tsolaki M, Bonuccelli U, et al.
Lewy bodies: third report of the DLB Consortium.
Memantine for patients with Parkinson’s
Neurology 2005;65(12):1863Y1872. doi:10.1212/
disease dementia or dementia with Lewy
01.wnl.0000187889.17253.b1.
bodies: a randomised, double-blind,
48. DelleDonne A, Klos KJ, Fujishiro H, et al. placebo-controlled trial. Lancet Neurol
Incidental Lewy body disease and preclinical 2010;9(10):969Y977. doi:10.1016/
Parkinson disease. Arch Neurol 2008; S1474-4422(10)70194-0.

Parkinsonian Syndrome

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Parkinsonian Syndrome

Uploaded by

Copyright:

Available Formats

Review Article

Atypical Parkinsonian FL 32610, nikolaus.mcfarland@

Syndromes Dr McFarland is supported by

(Minneap Minn) 2016;22(4):1117–1142.

INTRODUCTION such as early dementia, frequent falls,

(Minneap Minn) 2016;22(4):1117–1142 www.ContinuumJournal.com 1117

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

progression and subsequent functional nian syndromes with PD, secondary

FIGURE 5-1 Overlap of parkinsonian syndromes. Atypical parkinsonisms have common

1118 www.ContinuumJournal.com August 2016

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

symptoms (Figure 5-2). One common- guish atypical parkinsonian syndromes

(Minneap Minn) 2016;22(4):1117–1142 www.ContinuumJournal.com 1119

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

FIGURE 5-2 Clinicopathologic overlap of neurodegenerative proteinopathies. Atypical

1120 www.ContinuumJournal.com August 2016

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

TABLE 5-2 Classification of Atypical Parkinsonism h The rocket sign occurs in

Tauopathies Progressive supranuclear palsy, corticobasal

TABLE 5-3 Red Flags for Differentiating Atypical Parkinsonism From

b Features Predictive of Atypical Parkinsonism

(Minneap Minn) 2016;22(4):1117–1142 www.ContinuumJournal.com 1121

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

TABLE 5-4 Progressive Supranuclear Palsy Syndromes

(Minneap Minn) 2016;22(4):1117–1142 www.ContinuumJournal.com 1123

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

1124 www.ContinuumJournal.com August 2016

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

(Minneap Minn) 2016;22(4):1117–1142 www.ContinuumJournal.com 1125

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

FIGURE 5-3 Typical neuropathologic findings in progressive supranuclear palsy. The

1126 www.ContinuumJournal.com August 2016

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

FIGURE 5-4 Sagittal T1-weighted MRI of a patient with

nuclei.24 Consistent with that found and to develop an exercise program to

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Symptom Treatment Options

(Minneap Minn) 2016;22(4):1117–1142 www.ContinuumJournal.com 1129

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

limb phenomenon appears as abnor- lateral limb. Dementia in CBS is actually

1130 www.ContinuumJournal.com August 2016

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Syndrome Key Features

(Minneap Minn) 2016;22(4):1117–1142 www.ContinuumJournal.com 1131

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Diagnostics MULTIPLE SYSTEM ATROPHY

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

TABLE 5-7 Multiple System Atrophy Phenotypes h Multiple system

(Minneap Minn) 2016;22(4):1117–1142 www.ContinuumJournal.com 1133

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

TABLE 5-8 Differentiating Multiple System AtrophyYParkinsonian

b Multiple System AtrophyYParkinsonian Type (MSA-P)

treatment. Urogenital dysfunction, tory insufficiency.42 These red flags

1134 www.ContinuumJournal.com August 2016

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Case 5-3 h Glial cytoplasmic

neuronal loss and gliosis involving the Diagnostics

(Minneap Minn) 2016;22(4):1117–1142 www.ContinuumJournal.com 1135

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

urinary dysfunction. If a sleep distur-

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.