DIFFERENTIAL DIAGNOSIS OF PARKINSON'S DISEASE
                          AND THE
                PARKINSONISM PLUS SYNDROMES
Authors: Mark Stacy, MD & J. Jankovic, MD
Posted here with permission from Mark Stacy, MD
April 7, 1995
 
  Parkinson's disease is an idiopathic, relentlessly progressive,
neurologic disorder manifested clinically by tremor, bradykinesia, rigidity,
and postural instability. In addition to these four cardinal signs, there
are many motor and nonmotor manifestations of Parkinson's disease, including
cognitive, sensory, and autonomic disturbances. Within Parkinson's disease,
there are different subgroups with relatively specific clinical patterns.
For example, several studies have now demonstrated that patients with tremor
as the dominant parkinsonian symptom generally have less bradykinesia and
slower progression of the disease than those with postural instability and
gait difficulty (PlGD) as the dominant features.{54} The PIGD group generally
is older, is more likely to be cognitively impaired, and has a more rapidly
progressive course than the tremor group. One of the intriguing questions
is whether the different subgroups represent variations of the same disease,
namely Parkinson's disease, or whether they are etiologically distinct
entities. Other still unresolved issues regarding the variable expression
of Parkinson's disease include the following questions:
(1)Do juvenile (onset before age 21), young-onset (betw'een 21 and 39), and
the typical form of Parkinson's disease share common etiology', and
(2) is the tremor-dominant form of Parkinson's disease etiologically related
to essential tremor?{71}
  Pathologically Parkinson's disease is defined as a neurodegenerative
disorder characterized chiefly by depigmentation of the substantia nigra
and by the presence of Lewy bodies. These criteria, however, are too
restrictive and
 
----------------------------------------------------------------------------
>From the Department of Neurology (MS), University' of Missouri, School of
 Medicine,
 Columbia, Missouri; and Department of Neurology (JJ), Parkinson's
 Disease Center and Movement Disorders Clinic, Baylor University College of
 Medicine, Houston,Texas
simple, and they do not take into account the heterogeneous clinical and
pathologic presentation of Parkinson's disease and the overlap with other
parkinsonian disorders, each with presumably distinct etiology. In the
absence of a specific biologic marker for Parkinson's disease, the
differentiation of Parkinson's disease from other parkinsonian disorders
rests on clinicopathologic criteria that have yet to be rigorously tested
and validated.  Recent studies have shown that certain populations of
neurons are more vulnerable than others and the neuronal loss in
Parkinson's disease is not uniform. For example, the ventrolateral part
of ihe substantia nigra that projects chiefly to the putamen is more
affected than the dorsal part.{29} Although pigmented neurons in the
substantia nigra degenerate more than the non pigmented neurons,{86} the
other brain stem catecholaminergic neurons seem to degenerate regardless
of the degree of melanin pigmentation.{99} Lewy bodies, eosinophilic
cytoplasmic inclusions with an unstained halo, represent the typical
histologic hallmark of Parkinson's disease. Recent pathologic studies have
identified another characteristic, although less specific, inclusion
frequently found in the substantia nigra and the locus ceruleus of
brains of patients with Parkinson's disease termed 'the pale body'.{33}
Because these inclusions are typically found in Parkinson's disease and
they are usually absent in the other neuronal degenerations, they are
useful in differentiating Parkinson's disease from other parkinsonian
disorders. In contrast to Parkinson's disease, brains of patients
with pathologically proved multiple system atrophy (MSA){94} were found to
have distinct glial cytoplasmic inclusions.{58,82,87} It remains to he proved,
however, whether these pathologic hallmarks will be sufficiently specific
to differentiate PD, MSA, and the other atypical parkinsonian disorders
reliably. Until parkinsonian subgroups can be differentiated either by
disease-specific histologic criteria or laboratory tests, the most
practical method for separating the different parkinsonian disorders
still has to depend largely on previously described clinicopathologic
correlations.
 The vast majority (77.7%) of patients referred to the Baylor College
of Medicine Movement Disorders Clinic (BCMMDC) with hypokinetic movement
disorders have presumed Parkinson's disease (Table 1). Secondary parkinson-
 
 
Table 1. ETlOLOGIC CATEGORIES OF PARKINSONISM*
                                      Number ot
                                       PatIents      Percentage
     Parkinson's disease                1595           77.7
     Parkinsonism plus                   250           12.2
       PSP                               154            7.5
       SDS                                35            1.7
       OPCA                               23            1.1
       CBGD                               18            0.9
       SND                                 9            0.4
       PD/AD                               8            0.4
       PD/ALS                              3            0.1
     Secondary parkinsonism              168            8.2
     Heredodegenerative parkinsonism      12            0.6
     Unknown                              27            1.3
 
  *Baylor College of Medicine. Parkinson's Disease Center and Movement
   Disorders Clinic (N =2052)
   CBGD = Corticobasal ganglionic degeneration; OPCA = olivopontocerebellar
   atrophy; PD/AD parkinsonism wilh seveie dementia; PD/ALS = Parkinson's
   disease with motor neuron disease; PSP = progressive supranuclear palsy;
   SDS = Shy-Drager syndrome; SND = strialonigral degeneralion
ism is thought to represent 8.2% of all our parkinsonian patients. The causes
include environmental exposure (e.g., drugs or toxins) and other factors
(trauma, metabolic derangement, infection, stroke, brain tumor). 'Lower body'
parkinsonism, a condition in which upper body motor function is relatively
preserved while gait is markedly impaired, is often associated with multipte
lacunar infarctions and may represent one form of vascular parkinsonism.{23}
Hemiparkinsonism-hemiatrophy syndrome occurs in a younger population and
is associated with early-onset dystonia, slow progression, and poor response
to levodopa. Contralateral cortical hemiatrophy is usually present, and there
is often a history of perinatal asphyxia.{34} Medications known to cause
parkinsonism include dopamine receptor blocking drugs, such as antipsychotics
and antiemetics (e.g., meloclopramide); dopamine depleting drugs, such as
reserpine, tetrabenazine, and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
(MPTP); and alpha-methyldopa. Drug-induced parkinsonism was noted in 4% of
all our parkinsonian patients. Rare causes of parkinsonism include
hewdodegenerative diseases, such as Huntington's disease, Wilson's disease,
Hallervorden-Spatz disease, and familial basal ganglia calcification
(Table 2). These heredodegenerations account for 0.6% of our patients.
  The second largest group of parkinsonian disorders (12% of all
parkinsonian patients seen at the BCMMDC) is classified clinically as
'parkinsonism plus syndromes' and pathologically as 'multiple system
degenerations'.{49,50} Patients with these hypokinetic movement disorders
share some similarities with patients with Parkinson's disease, but
besides the parkinsonian findings, these patients exhibit additional
neurologic abnormalities, such as supranuclear ophthalmo-
 
 
Table 2. CLASSIFICATION OF PARKINSONISM
--------------------------------------------------------------------------
Primary (idiopathic) parkinsonism
 Parkinson's disease
 Juvenile parkinsonism
Secondary (acquired,symptomatic) parkinsonism
 infectious: postencephalitic, slow virus
 Drugs:dopamine receptor blocking drugs (antipsychotic. antiemetic drugs),
  reserpine,  tetrabenazine, alpha-methyl-dopa, lithium. flunarizine,
  cinnarizine
 Toxins:MPTP, CO, Mn, Hg. CS2, methanol, ethanol
 Vascular:multi-infarct
Trauma:pugilistic encephalopathy
Other:parathyroid abnormalities, hypothyroidism. hepatocerebral degeneration.
brain
  tumor, normal pressure hydrocephalus. syringomesencephatia
Heredodegenerative parkinsonism
 Huntington's disease
 Wilson's disease
 Hallervorden-Spatz disease
 Olivopontocerebellar and spinocerebellar degenerations
 Familial basal ganglia calcification
 Familial parkinsonism with peripheral neuropathy
 Neuroacanthocytosis
Multiple system degenerations (parkinsonism plus)
 Progressive supranuclear palsy
 Shy-Drager syndrome
 Striatonigral degeneration
 Parkinsonism-dementia-ALS complex
 Corticobasat ganglionic degeneration
 Autosomal dominant Lewy body disease
 Alzheimer's disease
 
paresis (progressive supranuclear palsy); dysautonomia (Shy-Drager syn-
drome); ataxia (olivopontocerebellar atrophy); laryngeal stridor
(striatonigral degeneration); combination of apraxia, cortical myoclonus,
and 'alien hand' (corticobasal ganglionic degeneration (CBGD); dementia
(Alzheimer's disease with parkinsonism (ADP) or diffuse Lewy body disease
(DLBD); and dementia coupled with motor neuron disease (parkinsonism-
dementia-amyotrophic lateral sclerosis complex of Guam) (Tables 2 and 3).
Other features useful in differentiating these disorders from Parkinson's
disease include absence or paucity of tremor, early gait abnormality such
as freezing, postural instability, pyramidal findings, and poor response
to levodopa. The lack of improvement with levodopa or dopamine agonists
may be partly explained by fundamental differences in the density of
postsynaptic dopamine receptors. These receptors are preserved in
Parkinson's disease, but they are usually decreased in the other
parkinsonian disorders. This article focuses only on the sporadic
(non-genetic) forms of multiple system degenerations.
 
 
PROGRESSIVE SUPRANUCLEAR PALSY
 
Clinical Aspects
 
        First described by Steele, Richardson, and Olszewski,{107,108}  the
diagnosis of progressive supranuclear palsy (PSP) should be considered in
any patient with progressive parkinsonism and ocular motility
disturbance. {48,52,72} At BCMMDC, 7.5% of patients with parkinsonism
fulfill the clinical criteria for PSP. In a
 
Table 3. DIFFERENTIAL DIAGNOSIS OF PARkINSONISM
         PLUS SYNDROMES
 
                                                                   PDCG/
                 PD    PSP     SDS    SND     OPCA    CBGD   ADP    ALS
 
Bradykinesia      +     +       +       +      +-       +     +-      +
Rigidity          +     +       +       +      +        +     +-      +
Gait disturbance  +     +       +       +      +        +     +-      +
Tremor            +     -       -       -      +-       +-    +       +
Ataxta            -     -       +-      -      +        -     +-      +-
Dysautonomia      +-    +-      +       +-     +-       -     -       +-
Dementia          +-    +       +-      -      -        +-    +       +
 
Dysarthria/
dysphagia         +-    +       +-      +      +        +     +-      +
Dystonia          +-    +-      -       +-     -        +     -       -
Eyelid apraxia    -     +       -       +-     -        +-    -       -
Limb apraxia      -     -       -       -      -        +     +-      -
Motor neuron
disease           -     -       +-      +-      -       -     -       +
Myoclonus         +-    -       -       -       -       +     +-      -
Neuropathy        -     -       +-      -       +-      -     -       -
Oculomotility
disturbance       -     +       +-      -       +       +     +-      -
Orthostatic
hypotension       +-    +-      +       +-      +-      -     -       -
Sleep abnormal    +-    +-      +       +-      +-      -     -       -
Asymmetric find   +     -       -       -       -       +     -       -
Levodopa response +     +-      +-      +-      -       -     -       -
ADP = Alzheimer's disease with parkinsonism; CBGD = corticobasal gangtionlc
degeneralion; OPCA = olivopontocerebellar atrophy; PO = Parkinson's disease;
PDCG/ALS = parkinsonism-dementia-amyotrophic laleral sclerosis complex of
Guam; PSP = progressive supranuclear palsy; SDS = Shy-Drager syndrome;
SND = strialonigral degeneration.
 
 
review of 126 patients with PSP, we found unsteadiness of gait, frequent
falling, monotonous speech, loss of eye contact, slowness of movement and
of mentation, sloppy eating habits, and nonspecific visual difficulty to
be the most typical presenting features.{52} Similar to Parkinson's disease,
PSP occurs more often in men, but its mean age of onset of 63 years is
about 1O years later than the onset of Parkinson's disease. Although no
well-designed epidemiologic studies have been performed in patients with
PSP, one case-control study found that patients with PSP were more likely
to live in areas of low population.{15}
 The earliest and most disabling symptom of PSP usually relates to gait and
balance impairment, as a result of which patients frequently fall and
sustain injuries. The marked instability is a result of visual-vestibular
impairment, axial rigidity, and bradykinesia.{52} In contrast to short and
shuffling steps, stooped posture, narrow base, and flexed knees, typically
seen in patients with Parkinson's disease, patients with PSP tend to have
their knees (and trunk) extended; their gait is stiff and broad based; and
instead of turning en bloc, they tend to pivot, which further compromises
their balance. Although some patients with PSP appear ataxic, they usually
do not exhibit prominent cerebellar findings; hence their ataxia is thought
to be of vestibular origin.
 Pseudobulbar symptoms in patients with PSP arc characterized chiefly by
dysarthria, dysphagia, and emotional incontinence. Rigidity, bradykinesia,
and hypertonicity of the facial muscles produce deep facial folds and
typical worried or astonished facial expression.{48} Speech in patients with
PSP is characterized by a spastic, hypernasal, monotonous, low-pitched
dysarthria. The speech rate may be slow or fast, and some patients have
severe palilalia and stuttering. An 'apraxia of phonation' was previously
reported in one patient who was aphonic except during periods of excitement
or during sleep.{47} In contrast, some patients have almost continuous,
involuntary vocalizations, including loud, groaning, moaning, humming,
and grunting sounds.{52} Progressive dysphagia causes most patients to
modify their diet, and some eventually need a feeding gastrostomy to
maintain adequate nutrition. As a result of chewing difficulties, inability
to look down, and poor hand coordination, patients with PSP are often
described as "sloppy eaters.
 Supranuclear ophthalmoparesis, typically manifested by paralysis of
down-gaze, is the most important distinguishing feature of PSP. About one
third of patients with PSP complain of blurred vision, diplopia, and eye
discomfort, but most eventually lose their ability to read or maintain eye
contact.{52} Involuntary persistence of ocular fixation is a typical,
although rarely mentioned, feature of PSP. In early stages of PSP, patients
may have only mild limitation of voluntary down-gaze, inability to converge,
and impaired vertical optokinetic nystagmus. Later, limitation of vertical
and then lateral eye movements develops. The ophthalmoparesis can be
overcome by oculocephalic (doll's eye) maneuver, but with disease
progression and brain stem involvement, vestibuloocular reflexes may be
lost, suggesting additional nuclear involvement.{45} Pathologically
documented cases of PSP without ophthalmoparesis have been reported.{14}
Other atypical cases of pathologically documented PSP include patients with
'pure akinesia'.{76}
 In a recent review of dystonia in Parkinson's disease, MSA, and PSP,
Rivest et al {98} found limb dystonia in pathologically proved cases of
PSP to be an uncommon feature, and they regard the 'dystonic' neck extension,
a frequently noted sign in patients with PSP, as a form of axial rigidity.
Patients with PSP frequently exhibit blepharospasm, with or without
'apraxia' of eyelid opening. In one study, 29% of patients had
involuntary orbicularis oculi contractions
 
John Cottingham                     [log in to unmask]