Classification
1
1
What is an Atypical Parkinsonian Disorder?
Irene Litvan
INTRODUCTION
A parkinsonism is a syndrome defined by akinesia associated with rigidity or rest tremor. The
akinesia can be expressed as motor slowness (bradykinesia) or as a paucity of movement (hypokinesia), i.e., difficulty in the initiation of or decreased amplitude of movements such as arm swing or
facial expression. This syndrome is usually the result of a dysfunctional nigrostriatal pallidal pathway. Impairment of postural reflexes is not included as one of the features of the parkinsonian syndrome since abnormal postural reflexes are generally the consequence of dysfunction of other motor
pathways. There are a variety of causes of parkinsonism, but Parkinson’s disease (PD) is the most
common (Fig. 1). Although there is extensive literature on PD, this is one of the few books dedicated
to the remaining atypical parkinsonian disorders.To appropriately diagnose PD, one should be aware
of when to suspect that a patient does not have PD and may be suffering from one of these atypical
disorders.
The “atypical parkinsonian disorders” (previously known as “Parkinson plus syndromes”) are
characterized by a rapidly evolving parkinsonism that has a poor or transient response to dopaminergic therapy and often associates with one or more atypical features for PD. Some of these features
include early presence of postural instability, early autonomic failure, vertical supranuclear gaze
palsy, pyramidal or cerebellar signs, alien limb syndrome, and apraxia (Table 1; see corresponding
video segments on accompanying DVD). Making the distinction between these two major groups of
disorders is critical for both clinical practice and research because the prognosis and treatment of
patients with an atypical parkinsonian disorder and those with PD differ (1–4). In the clinical setting,
although patients with PD may have an almost normal life-span if treated appropriately (4–6), those
with atypical parkinsonian disorders have a shorter survival time and more complications occur at
early stages and are frequently more severe (3,7–10) (see Table 2 for an example). Moreover, indicated therapies (particularly surgical approaches) differ significantly since some may not be indicated to treat patients with atypical parkinsonian disorders. Until recently, clinicians would “lump”
all the atypical parkinsonian disorders together and would only distinguish between this group and
PD. However, the need for early identification of the different atypical parkinsonian disorders is
becoming increasingly recognized (11), as their prognosis, complications, and survival differ
(3,7,8,12–19).
For research, this distinction is crucial; homogenous groups are a necessity for studies that lead to
firm conclusions. Genetic, analytical, epidemiological, and clinical trials require the inclusion of
accurately diagnosed patients. However, diagnosis of the atypical parkinsonian disorders can be at
times challenging (20–25) since these disorders may have similar presentations at early disease stages
From: Current Clinical Neurology: Atypical Parkinsonian Disorders
Edited by: I. Litvan © Humana Press Inc., Totowa, NJ
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Litvan
Fig. 1. PSP, progressive supranuclear palsy; CBD, corticobasal degeneration; MSA, multiple system atrophy; DLB, dementia with Lewy bodies; FTDP-17, frontotemporal dementia with parkinsonism linked to chromosome 17; SCAs, spinocerebellar atrophy; NBIA, Neurodegeneration With Brain Iron Accumulation,
previously called Hallervorden–Spatz Syndrome; HIV, human immunodeficiency virus.
Table 1
When Should an Atypical Parkinsonian Disorder be Suspected?
Features suggestive of an atypical parkinsonian disorder
Motor
Rapid disease progression
Early instability and falls
Absent, poor, or not maintained response to levodopa therapy
Myoclonus
Pyramidal signs
Cerebellar signs
Early dysarthria and/or dysphagia
Early dystonia/contractures (unrelated to treatment)
Autonomic Features
Impotence/decreased genital sensitivity in females
Early orthostatic hypotension unrelated to treatment
Early and/or severe urinary disturbances
Oculomotor
Marked slowing of saccades
Difficulty initiating saccades, gaze (oculomotor apraxia)
Supranuclear gaze palsy
Nystagmus
Cognitive and behavioral
Early and severe frontal or cortical dementia
Visual hallucinations not induced by treatment
Ideomotor apraxia
Sensory or visual neglect/cortical disturbances
Classification
3
Table 2
Progression of Various Parkinsonian Disorders
Disorder
PD
CBD
DLB
MSA
PSP
Sample
Size (N)
Median Age
at Onset
(yr)
18
13
11
15
24
60
64
65
56
65
Median HY
II Latencies
(mo)
36*
25
12
0
—
Median HY
III Latencies
(mo)
66**
42
43
3
0
Median HY
IV Latencies
(mo)
166**
55
45
56
38
Median HY Median survival
V Latencies After HY V Onset
(mo)
(mo)
179**
62
59
73
56
12
43
12
10
9
Modified from Muller et al., with permission (17).
*p < 0.05; **p < 0.001 Parkinson‘s disease (PD) vs atypical parkinsonian disorders (CBD, DLB, MSA, PSP), (Mann–
Whitney U Test). PD patients had a significantly longer latency to each Hoehn and Yahr (HY) stage than those with atypical
parkinsonian disorders, confirming the more rapid progression of motor disability in patients with atypical parkinsonian disorders. Most MSA and PSP patients developed postural instability with or without falls significantly earlier than those with CBD
and DLB. Postural instability and falls are the most common initial symptoms in PSP, and almost all PSP patients developed an
HY stage III within 1 yr of motor onset. The majority of MSA (67%), the majority of DLB (55%), and 38% of CBD patients
also reached this stage early.
(i.e., progressive falls, parkinsonism not responsive to dopaminergic therapy). Tell-tale signs may
take 2 to 4 yr after symptom onset to develop, or early features may be either disregarded or misdiagnosed by clinicians.
Misdiagnosis of these disorders is frequent, as patients exhibit a variety of symptoms that may
lead them to be initially evaluated by internists or specialists (e.g., ophthalmologists, urologists, neurologists, psychiatrists, neurosurgeons). For example, it is not unusual for a patient with progressive
supranuclear palsy (PSP) to be evaluated by several ophthalmologists (and have their glasses changed
several times) or to have multiple unnecessary studies for evaluating the cause of their falls prior to
being seen by a neurologist. Similarly, patients with corticobasal degeneration (CBD) may present
after unsuccessful carpal tunnel surgery, or those with multiple system atrophy (MSA) may present
only after failed prostate surgery; in both cases these types of surgery can worsen the patients’ symptoms. Diagnostic accuracy would greatly improve, however, if clinicians from different disciplines
would have a broader knowledge of the typical and atypical presentations of these disorders and use
proposed clinical diagnostic criteria (26).
In the absence of biological markers and known pathogenesis, current diagnosis requires the presence of certain clinical features that allow for clinical diagnosis and eventual pathologic verification.
As a result, diagnostic accuracy requires that both clinical and pathological sets of diagnostic criteria
be valid and reliable (27,28). Neuropathologic diagnostic criteria for most parkinsonian disorders
have been validated and standardized (27,29); the exceptions are those for dementia with Lewy bodies (DLB) and PD with later onset dementia (PDD). Similarly, recently the clinical diagnostic criteria
have undergone the same process of rigorous operationalization and validation for most of these
disorders (26,30–35).
Though consensus for the diagnosis of several of these disorders has been put forward (30–33),
and validation studies of diagnostic criteria have been performed for most of the atypical parkinsonian disorders (36), refinement of the criteria is still needed (36). In practice, clinicians are exposed
to patients who exhibit different parkinsonian disorders, and so validation studies should compare the
accuracy of several sets of criteria with neuropathology. The Scientific Issue Committee of the Movement Disorder Society created a task force to critically review the accuracy of different sets of diagnostic criteria for parkinsonian disorders (36). The task force analyzed how well each set of diagnostic
criteria identified all subjects with the disease as having the disease (i.e., sensitivity); identified sub-
4
Litvan
Table 3
Validity of the Clinical Diagnostic Criteria for PSP, MSA, DLB, and VaD
Disorder Criteria
PSP
MSA
Blin et al. (47)
Probable/Possible
Blin et al. (47)
Probable/Possible-1st visit
Probable/Possible-last visit
Clinician’s own criteria
First visit
Last visit
Collins et al. (51)
Probable/Possible
Golbe et al. (49)
First visit
Last visit
Golbe et al. (49)
Lees (48)
First visit
Last visit
Lees (48)
NINDS-SPSP
Probable/Possible
NINDS-SPSP
Probable/Possible
Queen Square Movement
Disorder neurologists
diagnosis
Tolosa et al. (50)
Probable/Possible
Clinician’s own criteria
First visit
Last visit
Clinician’s prospective
diagnosis in life
First visit
Last visit
Consensus Criteria (55)
Probable/Possible
Consensus Criteria (55)
Probable/Possible
Queen Square movement
disorder neurologist’s
diagnosis
Quinn (54)
Probable/Possible
Quinn (54)
Probable/Possible
Sensitivity
(%)
Specificity
(%)
Positive
Predictive
Value (%)
21/63
100/85
100/63
Litvan et al.
(29)
24/83
13/34
55/89
100/98
94/74
100/85
73/50
Litvan
(19)
24/105
72
80
93
92
76
76
25/42
100/92
100/67
Litvan et al.
(19)
Litvan et al.
(29)
49
67
50
97
94
98
85
76
92
53
78
95
87
77
65
Author
Litvan et al.
(19)
n/n
TOTAL
24/105
24/83
24/105
24/83
24/105
Litvan
(29)
Litvan et al.
(29)
Lopez
(25)
58
95
82
24/83
50/83
100/93
100/83
62/75
100/98.5
100/96
84.2
96.8
80
54/54
98/98
93/93
Hughes
(52)*
Litvan
(19)
56
69
96.6
97
75.5
80
Litvan et al.
(21)
16/105
22
100
92
86
Oaski et al.
(33)
51/59
16/28
100/93
63/92
91/86
88
86
Hughes et al.
(52)*
34/143
37/63
95/82
94/98
87/86
24/83
8/40
20/143
24/83
(continued)
Classification
5
Table 3 (continued)
Validity of the Clinical Diagnostic Criteria for PSP, MSA, DLB, and VaD
Disorder Criteria
DLB
VaD
Quinn (54)
Probable/Possible
First visit
CERAD
CDLB (30)
CDLB (30)
First visit
Last visit
CDLB(30)
CDLB(30)
CDLB (30)
Probable/Possible
CDLB (30)
Probable/Possible
CDLB (30)
Probable/Possible
CDLB (30)
Probable/Possible
CDLB (30)
Clinician’s own criteria
First visit
Last visit
Clinicians own criteria
First visit
Last visit
Queen Square movement
disorder neurologists’
diagnosis
Sensitivity
(%)
Specificity
(%)
Positive
Predictive
Value (%)
Author
n/n
TOTAL
44/53
97/79
68/30
Litvan et al.
(53)
16/105
75
75
50
79
100
Mega (56)
Mega (56)
4/24
4/24
17.8
28.6
22
57
NR
100
90
75
55.8
100
91
14/105
9/80
35/56
61/89
84/23
48/23
Litvan (62)
Holmes (57)
Luis (58)
Verghese
(59)
0/34
100/94
NA/55
8/40
83/83
95/91
96/92
Lopez (25)
McKeith
(64)
100/100
30.7
8/0
100
83/NA
Hohl (60)
Lopez (34)*
5/10
13/26
17.8
28.6
99
99
75
55.8
Litvan (61)
14/105
35
48
99.6
99.6
80
100
Litvan (62)
10/105
25
98.6
33.3
Hughes et al.
(52)*
3/143
18/94
29/50
Revised from Litvan et al. (36).
*Prospective studies. Note that all other studies are retrospective. CDLB, consensus criteria for dementia with
Lewy bodies.
jects without the disease as not having the disease (i.e., specificity); and provided reasonable estimates of disease risk (i.e., positive predictive value or PPV). See summary table (Table 3) and refer to
the actual publication (36) and specific disease-related chapters in this book for detailed comments.
Overall, most of these criteria are specific but not very sensitive. It is worth noting that a validation of
pathologic and clinical diagnostic criteria for PD is still needed. Standardization of diagnostic criteria, clinical scales, and identification of outcome measures (37,38) set the stage for conducting
appropriate clinical trials.
CLASSIFICATION OF ATYPICAL PARKINSONIAN DISORDERS
Atypical parkinsonian disorders can be caused by primary or secondary diseases (see Fig. 1). The
primary causes consist of neurodegenerative processes such as PSP, CBD, MSA, DLB, and PDD.
Interestingly, one of the earlier historical cases thought to have the typical features of PSP was recently
found to have a midbrain tumor through autopsy examination. As discussed in Chapter 23, secondary
causes also include drugs, infections, toxins, or vascular disease (21,23,39–44).
6
Litvan
Table 4
Classification of Atypical Parkinsonian Disroders
Tauopathies
Progressive supranuclear palsy
Corticobasal degeneration
Lytico-bodig disease
West-French Indies parkinsonian disorder
Frontotemporal dementias with parkinsonism
linked to chromosome 17
Synucleinopathies
Parkinson’s disease
Multiple system atrophy
Dementia with Lewy bodies
Parkinson disease and dementia
Neurodegeneration with brain iron
accumulation
An alternative classification (mostly helpful for research and future therapeutic approaches rather
than for clinical use) considers the type of aggregated proteins in the brain lesions and classifies these
disorders as tauopathies and synucleinopathies (Table 4; see also Chapters 4 and 8). Commonalities
in clinical, biological, or genetic findings question the nosological classification of some of these
disorders; for further information the reader is referred to Chapters 8 and 9.
PSP and DLB/PDD are the most frequent neurodegenerative primary cause of an atypical parkinsonian disorders (31,45–47). A good history and physical examination will rule out drug-induced
atypical parkinsonian disorders and supports the diagnosis of these specific disorders (Chapter 10).
Each disorder is specifically covered in Chapters 18–23. The role of ancillary and laboratory tools to
assist in the diagnosis of these disorders is discussed in Chapters 11–16 and 24–27. Ancillary tests
(e.g., neuroradiologic or cerebrospinal studies) also help with the diagnosis of disorders caused by
vascular diseases, tumors, or infection (e.g., Whipple’s disease, Creutzfeldt–Jakob disease, human
immunodeficiency virus). Specific therapeutic and rehabilitation approaches for all of these disorders are provided in each disease chapter and an overview of future biologic and rehabilitation approaches is provided in Chapters 28 and 29.
It is our expectation that this book will continue to improve the accuracy of the diagnosis of these
disorders by raising awareness of their different presentations and by increasing diagnosticians’
index of suspicion. An early and accurate diagnosis will allow better management of these patients
and increase research potential.
There has been a tremendous increase in our knowledge concerning the proteins that characterize
and aggregate in the brain in each of these disorders. Moreover, animal models are now available to
help test potential new therapies (see Chapters 5 and 6). Hence, in addition to serving as a reference
source, it is hoped that this book will stimulate new investigators to join us in the search for answers
to the multiple questions raised throughout the book and in the battle against these disorders. It is
anticipated that a better understanding of these diseases, their nosology, and etiopathogenesis (see
Chapters 3–9) will lead to better management, quality of life (see Chapter 17), and treatment for
patients who suffer them. We anticipate that the eradication of these devastating diseases from the
face of the earth will occur in not such a remote future.
VIDEOTAPE
Postural Instability: Video segment shows a patient with a history of falls and an impaired postural
reflex with the backward pull test. The patient would have fallen, unless aided by the examiner. The
gait is stable but slightly wide-based.
Supranuclear gaze palsy: This patient shows a severe limitation in the range of ocular motor movements observed, which affects more upward than downward voluntary and pursuit gaze. As observed,
the oculocephalic reflex is preserved when the the doll’s head maneuver is performed.
Slowing of vertical saccades: Patient shows markedly slow vertical saccades and relatively preserved horizontal saccades.
Classification
7
Ocular motor apraxia: The patient shows difficulty initiating the voluntary gaze and saccades but
exhibits a preserved pursuit and optokinetic nystagmus. Once the saccades are initiated their speed is
normal.
Corticosensory deficits: This patient shows right sensory neglect and agraphesthesia. These lateralized cognitive features in conjunction with the progressive development of a right ideomotor
apraxia, dystonia, and stimulus sensitive myoclonus led to the diagnosis of corticobasal degeneration
(corticobasal syndrome).
Limb kinetic apraxia: The performance of this patient does not improve with imitation. Movements are coarse and do not represent the intended action.
Blepharospasm: Difficulty opening the eyes because of inhibition of eyelid opening, which is
followed by blepharospasm.
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