Handbook of Clinical Neurology, Vol.

84 (3rd series)
Parkinson’s disease and related disorders, Part II
W. C. Koller, E. Melamed, Editors
# 2007 Elsevier B. V. All rights reserved

Chapter 52

Vascular parkinsonism

YACOV BALASH1 AND AMOS D. KORCZYN2*

1
Movement Disorders Unit, Department of Neurology, Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel
2
Sieratzki Chair of Neurology, Tel-Aviv University Medical School, Ramat-Aviv, Israel

Parkinson’s disease (PD) is a degenerative brain
disease consisting of a progressive loss of dopaminer-
gic neurons in the substantia nigra (SN) and other neu-
ronal systems in certain brain areas. A loss of 60–70%
of the nearly 450 000 dopamine-producing neurons of
the SN pars compacta and related decrease of the
dopamine level at the striatum must occur before PD
symptoms will take place. Several other diseases share
some clinical features of PD, like tremor, muscle rigid-
ity, hypokinesia and bradykinesia, gait instability and
freezing of gait. These disorders, collectively called
parkinsonian, can sometimes be clearly distinguished
from PD, although on other occasions the distinction
is difficult. Neuroimaging data (e.g. single-photon
emission computed tomography, SPECT), drug
response or the pathological demonstration of specific
changes in the SN or elsewhere can help in such cases.
The present review will discuss one of these entities,
called vascular parkinsonism (VP).
In 1929 Critchley, after analysis of the literature,
described five types of parkinsonism induced, accord-
ing to his opinion, by cerebrovascular diseases in
elderly patients. He identified the first (commonest)
type as ‘rigidity, fixed facies and short-stepping gait’
with absence of rest tremor; the second type is similar
but with the addition of pseudobulbar manifestations;
the third type has the addition of dementia and incon-
tinence; the fourth type shows signs of pyramidal dis-
ease; and the fifth has superimposition of a cerebellar
syndrome.
Critchley suggested that VP is a spectrum of hetero-
geneous syndromes resulting from multiple vascular
(arteriosclerotic or syphilitic) lesions in the basal
ganglia (BG), rather than a certain idiopathic disease.
This concept was criticized by Schwab and England
(1968) and Parkes et al. (1974), who claimed that a coin-
cidence or superposition of vascular changes in some
patients with PD could account for this overlap. Many
years later Critchley himself corrected his basic idea
of arteriosclerosis as a possible cause of PD and termed
the condition ‘arteriosclerotic pseudoparkinsonism’,
considered as alien to PD both clinically and pathogen-
etically (Critchley, 1981). Nevertheless, the neurologi-
cal entity of VP remains a matter of debate ever since.
Up to now, VP and PD are not clearly separated clini-
cally and for example are lumped together in the Ninth
Revision of the International Classification of Diseases
(ICD-9) as item 332.0 without any differentiation
between arteriosclerotic and idiopathic, primary
parkinsonism (ICD-9-CM International Classification
of Diseases, 2005).
Until recently, VP remained a poorly defined
clinicopathological entity, which overlaps with other
diagnoses. There are few pathologically verified
cases with suitable clinical correlation. The clinical
diagnosis of VP may be difficult and sometimes its
confirmation is only possible by neuropathological
examination, which is still considered the gold
standard for making the definite diagnosis of VP
(Jellinger, 2002). However, pathological diagnosis of
VP is non-specific and the changes are largely those
of small-vessel disease. Because of this fact there are
doubts whether VP should be regarded as a clinical
entity or, more correctly, whether VP is a variant of
small-vessel brain disease, manifested neurologically
by parkinsonian-like features, usually accompanied
by additional neurological signs (Zijlmans et al.,
2004).

*Correspondence to: Professor Amos D. Korczyn, Tel-Aviv University Medical School, Sieratzki Chair of Neurology,
Ramat-Aviv 69978, Israel. Email: amosk@tasmc.health.gov.il, Tel: þ972-3-697-4229, Fax: þ972-3-640-9113.
418 Y. BALASH AND A. D. KORCZYN
52.1. Parkinsonism associated with
brainstem lesions
Vascular lesions to the brain can cause almost any con-
stellation of neurological symptoms, depending on the
site of the lesions and other factors, and parkinsonism
cannot be assumed to be as exception. Thus, focal hemor-
rhagic and ischemic brainstem strokes were shown to
produce contralateral parkinsonian signs. To illustrate
the point we can discuss a case of a patient in whom right
hemiparkinsonism was diagnosed following hemorrhage
into the left SN. Technetium-99m hexamethylpropylene
amine oxime (99mTc-HMPAO) single photon emission
computed tomography (SPECT) showed reduced uptake
in the left putamen, globus pallidus (GP) and thalamus
(Abe and Yanagihara, 1996). The SPECT abnormalities
were assumed to be the result of the stroke, rather than
a coincidental abnormality.
In another report, a patient developed right-sided
cogwheel rigidity and resting tremor. In this case the
magnetic resonance imaging (MRI) scan showed a
contralateral midbrain hemorrhage affecting the SN
and n-isopropyl-p-123I iodoamphetamine (123I-IMP)
SPECT images showed reduced radioisotope uptake
in the left striatum, thalamus and frontal lobe (Inoue
et al., 1997).
These cases had in common an apoplectic appearance
of unilateral parkinsonian signs, which are the logical
result of an ischemic or hemorrhagic lesion of the SN
or the nigrostriatal tract and therefore constitute the most
straightforward examples of VP. Such cases should have
an acute onset, be non-progressive and even improve
spontaneously over time and respond to levodopa. How-
ever, such cases are extremely rare. Microscopically
such cases should not contain Lewy bodies.
The etiology of vascular damage should not
necessarily be atherosclerotic. Unilateral rest tremor
associated with bilateral extrapyramidal syndrome
responsive to levodopa was seen in a 25-year-old
man 7 months after subarachnoid hemorrhage due to
rupture of a peduncular subthalamic arteriovenous
malformation (Defer et al., 1994).
Parkinsonism has been described in patients with
central nervous system vasculitis (Fabiani et al.,
2002), rheumatoid arthritis (Ertan et al., 1999; Hrycaj
et al., 2003), systemic lupus erythematosus (Tan
et al., 2001; Garcia-Moreno and Chacon, 2002), anti-
phospholipid syndrome (Milanov and Bogdanova,
2001; Adhiyaman et al., 2002; Huang et al., 2002),
disseminated intravascular coagulation (Yoritaka
et al., 1997) and some neuroinfections like syphilis
(Critchley, 1929; Sandyk, 1983; Pineda et al., 2000).
Not unexpectedly, most patients had additional
manifestations, consistent with the damaged area. Of
course, more extensive lesions due to basilar occlusion
will also affect the SN but the extrapyramidal signs
will be overshadowed by other manifestations of
brainstem dysfunction.
Acute or subacute parkinsonism was also observed
as a result of tentorial herniations with brainstem
compression in patients with subdural hematomas of
traumatic or hypertensive etiology or as a result of
rupture of arterial aneurysms (Cosi and Tonali, 1964;
Pau et al., 1989; Trosch and Ransom, 1990; Turjanski
et al., 1997). In some of these cases parkinsonism
improved following removal of the hematoma (Sunada
et al., 1996), but in others it persisted and usually
responded to levodopa (Trosch and Ransom, 1990).
Sudden onset of small-stepping gait with stooped pos-
ture, severe akinesia and freezing of gait and increased
muscle tone with bilateral cogwheel phenomenon in
the arms was seen in a patient with a small high-
density lesion in the medial side of the right cerebral
peduncle and a lens-shaped low-density lesion in
the left putamen. On T1- and T2-weighted MRI
images a low signal was seen in a right peduncular
lesion extending to the SN, which was also partially
destroyed. The parkinsonism rapidly improved and
completely disappeared within 2 weeks. The high-
density lesion of the right peduncle also disappeared
on CT (Miyagi et al., 1992). Interestingly, destruc-
tion of the left subthalamic nucleus by hematoma
can improve contralateral parkinsonian rigidity after
extinction of the ballistic movement phase (Yamada
et al., 1992).
Kim (2001) reported patients with (hemi)parkinson-
ism after infarction in the territory of the anterior cer-
ebral artery. Parkinsonism was usually related to large
lesions involving the supplementary motor area and
observed after the motor dysfunction improved in
patients with initially severe limb weakness.
In patients with clinically suspected VP, the com-
parison of levodopa response with the pathologically
confirmed presence of macroscopic vascular damage
in the nigrostriatal pathway and cell loss in the SN
showed that the majority of patients with good or
excellent response to levodopa had infarcts or lacunae
in the SN in the absence of Lewy bodies (Zijlmans
et al., 2004).
These anecdotal cases of vascular lesions of the SN
or nigrostriatal pathway had features resembling PD,
including responsiveness to levodopa. However, the
follow-up, long-term prognosis and special features
of the dopaminergic treatment in relation to PD are
unknown. Motor fluctuations, so common in advanced
PD (Korczyn, 1972), have not so far been described in
cases such as these. Neither had a gradual increase in
dose over the years been documented. These cases
 VASCULAR PARKINSONISM
then typically consist of a non-progressive, levodopa-
responsive (hemi)parkinsonism of acute onset.
52.2. Parkinsonism associated with basal
ganglia lesions
Ischemic infarcts in the territory of the lenticulostriate
arteries were said to be the most frequent cause of
unilateral parkinsonism (Friedman et al., 1986;
Kulisevsky et al., 1996; Fenelon and Houeto, 1997;
Sibon et al., 2004a). In these cases, there was an acute
onset of the disorder with supportive imaging data to
suggest the vascular etiology.
A lateralized subacute parkinsonism with CT evi-
dence of a single lacunar infarct in the contralateral
BG was described by Lazzarino et al. (1990). A clini-
cal syndrome indistinguishable from PD, in which
postmortem examination revealed extensive lacunar
infarctions of the BG without evidence of coexistent
PD, was also reported (Murrow et al., 1990). However,
subdivision of parkinsonian patients with lacunar
infarcts in the BG into those with lacunes in the caudate
nucleus, lentiform nucleus or both did not correlate with
the clinical presentation (Reider-Groswasser et al.,
1995). Lacunar infarctions in the BG are frequently
observed in patients without parkinsonism and even in
completely asymptomatic cases. The extrapyramidal
signs, if present, can be asymmetrical without consis-
tent relationship to the side of the lacuna (Inzelberg
et al., 1994).
Specific regions of the brain, such as central white
matter, GP and hippocampus, are selectively vulnerable
to carbon monoxide (CO) (Koehler and Traystman,
2002). Parkinsonism after CO poisoning could be seen
in 10% of sufferers from CO encephalopathy (Choi,
2002). The most frequent signs are symmetric rigidity,
hypokinesia, masked face, glabellar sign, grasping,
short-step gait and retropulsion. Rest tremor has not
been observed but intentional tremor may occasionally
be found. The latency before the appearance of parkin-
sonism varies from 2 weeks to 6 months, but most
frequently occurs within 1 month of CO exposure.
Together with the parkinsonism, all patients have mild
to severely impaired cognitive functions. Other com-
mon symptoms are mutism, gait disturbances and
urinary incontinence. Extreme cases manifest a general
akinetic-mute state up to bed-bound (Lee and Marsden,
1994). Neither levodopa nor anticholinergic drugs were
shown to be effective. However, nearly 80% of patients
improved or recovered spontaneously within 6 months
(Choi, 2002).
Abnormally high signal bilaterally in the GP on T1-
weighted MRI images was observed in patients
419
following short terms after exposure to CO (Silverman
et al., 1993). MRI abnormalities augmented with CT
findings that revealed bilateral lucencies of the GP
suggested that their damage is of vascular origin, prob-
ably hemorrhagic infarction (Bianco and Floris, 1996).
Old necrotic lesions of the GP were earlier found on CT
scans (Klawans et al., 1982). No correlation between
the neuroimaging findings and the development of
parkinsonism has, however, been demonstrated (Choi,
2002). The damage in CO poisoning, however, is not
restricted to the BG and the direct role of the BG
damage is unknown in these cases.
52.3. Parkinsonism with white-matter lesions
A more common picture is that of short-stepped gait
with or without freezing (Giladi et al., 1997), lead-pipe
rigidity, no or mild upper-limb involvement, absence
of rest tremor, which develops insidiously, and nega-
tive response to levodopa (FitzGerald and Jankovic,
1989; Chang et al., 1992; Yamanouchi and Nagura,
1995; van Zagten et al., 1998; Winikates and Jankovic,
1999). Pseudobulbar palsy is observed in nearly half
of the patients (Yamanouchi and Nagura, 1995). The
patients frequently have cognitive decline and detrusor
overactivity (Cummings, 1994; Holstein et al., 1994).
Long tract signs in the limbs, indicating damage to
the corticospinal tracts, are found in more then half
of patients (Yamanouchi and Nagura, 1997). Many of
these patients have vascular risk factors and particu-
larly hypertension. The evolution of this disease is
typically slow, occurring over several month or even
years (Inzelberg et al., 1994), an evolution similar to
that seen in PD. Brain imaging shows diffuse subcortical
white-matter damage, not unlike that seen in patients
with Binswanger’s disease, sometimes accompanied by
unilateral or bilateral BG infarcts (Demirkiran et al.,
2001). Loss of postural reflexes and gait abnormalities
seen in these cases may indicate extrapyramidal features,
but are difficult to disassociate from coexisting spasticity
and the slowness may also reflect pyramidal, rather than
extrapyramidal, damage.
Comparing the brain pathology in these patients
with that in matched patients with Binswanger’s dis-
ease who had no parkinsonism according to clinical
records failed to reveal any significant differences in
the extent of BG damage (Yamanouchi and Nagura,
1997), thus pointing to the central role of white-matter
damage. The number of oligodendrocytes in the fron-
tal white matter of VP patients was significantly less
than in age-matched normal control subjects, but
significantly more than in those with Binswanger’s
disease. Widespread lesions in the frontal white matter
420 Y. BALASH AND A. D. KORCZYN
with only meager lesions in the BG were the main
pathological features of VP. The extent of frontal
white-matter pallor tended to be less broad in VP
than in Binswanger’s disease without parkinsonism
(Yamanouchi and Nagura, 1997). Marked atrophy in
the frontal cortex as well as lacunar lesions around
the lateral ventricles in VP were previously shown by
Grundl et al. (1991). The exact pathogenesis of these
white-matter changes is debated and likely heteroge-
neous, but generally thought to represent areas of
chronic or recurrent partial ischemia. Although
patients with BG lacunar infarct could recover sponta-
neously, those with frontal lobe infarcts could remain
static and those with periventricular and deep subcorti-
cal white-matter lesions usually had progressive
deterioration (Chang et al., 1992).
From the clinical and pathological data presented so
far, it seems that VP can occur as an acute syndrome,
resulting from lesions of the SN or the nigrostriatal
tract. These cases would be unilateral, non-progressive
and respond well to levodopa.
Diffuse white-matter damage, resulting from micro-
vascular lesions, typically manifests as a combination
of extrapyramidal, pyramidal and sometimes vascular
changes, frequently with cognitive decline
(Fig. 52.1). These cases would not typically respond
to levodopa, because the lesions involve the ascending
loop of the BG–thalamic–cortical loop (Bergman and
Deuschl, 2002), distal to the striatal site of action of
dopamine. Such cases are best described as pseudopar-
kinsonian because the extrapyramidal features are only
part of a more extensive clinical picture and because
of a lack of response to dopaminergic drugs.
BG lacunae are quite common in the elderly, fre-
quently without parkinsonian signs. If parkinsonian
signs do exist they do not bear a clear relationship to
the side of the lesion. The etiology of most BG lesions
is microvascular and in fact many, perhaps most, cases
with BG lacunae also have white-matter lesions and it
is best to look at these cases as reflecting an incidental
manifestation of BG lesions, whereas the principal
changes responsible for the motor dysfunction occur
in the white matter.
52.3.1. Brain imaging
The integrity of the nigrostriatal pathway can be
inferred from radioligand studies, in which the chemi-
cals used have affinity to the dopamine transporter
molecules at the terminals of the dopaminergic
synapses in the BG.
Small studies failed to find specific changes in VP
patients and indeed were not significantly different from
those in healthy individuals. The characteristic reduc-
tion of the uptake is pronounced in the contralateral
putamen of PD patients with unilateral symptoms, but
not in VP (Tzen et al., 2001). Normal striatal 123I-FP-
CIT binding with no significant differences in striatal
or subregional binding ratios compared with those of
the controls was seen in patients with VP. PD patients
had significantly diminished striatal binding compared
with that of controls (Lorberboym et al., 2004). As
compared to normal controls, patients with VP had sig-
nificant reduction of the ratio between N-acetylaspartate
and creatine plus phosphocreatine in the frontal cortex

Fig. 52.1. T1 and T2 magnetic resonance images of a 73-year-old patient with severe parkinsonism resistant to levodopa, gait
disorders, freezing of gait, recurrent falls and urinary urgency. Multiple infarcts are seen in the basal ganglia and brain white
matter as well as periventricular white-matter changes (own observation).
 VASCULAR PARKINSONISM
(Abe et al., 2000), suggesting a lesion beyond the clas-
sical extrapyramidal system.
52.3.2. Transcranial ultrasonography
The structurally normal SN could be visualized using
ultrasound waves delivered through a cranial
‘window’, similar to that when flow in the middle
cerebral arteries is examined (Fig 52.2).
This method can distinguish between lesions affect-
ing the SN directly, such as PD and other disorders
causing extrapyramidal features (Berg et al., 1999). This
effect is based on the high iron level in the SN, thought to
promote generation of reactive oxygen species (Berg
et al., 2002) and has been shown to be specific to PD
(Berg et al., 2005). Thus, if all PD patients show a
bilateral SN hyperechogenicity, a low echogenic SN,
particularly combined with hyperechogenic lentiform
nuclei, could suggest other kinds of parkinsonism
(Walter et al., 2002; Behnke et al., 2005).
52.3.3. Additional methods of diagnosis of vascular
parkinsonism
Non-motor differences between VP and PD could be
used in the differential diagnosis:
1. Measurement of myocardial innervation may contri-
bute to the differential diagnosis of parkinsonism
421
(Berding et al., 2003; Goldstein, 2004). In patients
with PD, even without clinical evidence of autonomic
failure, reduction in iodine-123-metaiodobenzylgua-
nidine (123I-MIBG) uptake on scintigraphy occurs in
the heart. This is considered to be a specific finding
for PD and useful for the differential diagnosis from
other parkinsonian syndromes, occurring even in the
earliest stage of the disease (Taki et al., 2000). Parkin-
sonian syndromes other than PD did not demonstrate
reduction in MIBG uptake.
2. Testing olfactory function could be helpful in
differentiating VP from PD (Katzenschlager
et al., 2004). For example, olfactory function,
diagnosed according to the Pennsylvania smell
identification test, was significantly better in VP
patients than in PD and did not differ from normal
controls.
3. Colonic transit time measured in VP patients was
normal (about 59 hours), as opposed to PD
(Hardoff et al., 2001), where markedly slow transit
is observed (Jost et al., 1994).
52.3.4. Parkinson’s disease versus vascular
parkinsonism: comparison of pathophysiology
PD results from the slowly progressive death of
selected populations of neurons, including the neuro-
melanin-containing dopaminergic neurons of the pars

Fig. 52.2. Sonographic image of the midbrain axial section in a patient with PD. The butterfly-shaped midbrain section of
low echogenicity is surrounded by the hyperchogenic basal cisterns (encircled area, centre of fig.). Note the marked hyperecho-
genicity of the left SN. This area is encircled for computerized measurement. Courtesy of Prof. Heinz Reichmann from the
Department of Neurology, Technical University of Dresden, Germany.
422 Y. BALASH AND A. D. KORCZYN
compacta of the SN, some other catecholaminergic
and serotoninergic brainstem nuclei, the cholinergic
nucleus basalis of Meynert, hypothalamic neurons
and small cortical neurons (particularly in the cingu-
late gyrus and entorhinal cortex), as well as the olfac-
tory bulb, sympathetic ganglia and parasympathetic
neurons in the gut (Korczyn, 1993; Braak and Braak,
2000).
According to the accepted model, dopamine loss
increases the activity of the indirect pathway and
reduces the activity of the direct pathway (Wich-
mann and DeLong, 2003). The final result of these
changes is an overexcitation of the main output
nuclei of the BG, GP interna and SN pars reticulata,
leading to inhibition of the thalamocortical motor
system. If the latter is essentially important in the
pathogenesis of rigidity, bradykinesia and loss of
postural reflexes, the white-matter lesions affecting
the latter pathway should result in a similar pheno-
type. However, these should not respond to levodopa
since there is no dopamine loss and in any case the
site of action of dopamine, the BG, is disconnected
from the motor cortex. Thompson and Marsden
(1987) suggested that the gait disorder of Binswan-
ger’s disease is probably due to diffuse vascular
lesions disrupting the interconnecting fiber tracts
between the BG and the motor cortex. Multiple lacu-
nar subcortical infarcts interrupting thalamocortical
drive are critical for the development of VP (Bhatia
and Marsden, 1994; van Zagten et al., 1998; Peralta
et al., 2004).
Three characteristic features of presynaptic process
affecting the dopaminergic system in PD are:
1. A major reduction of striatal levodopa uptake
of the nigrostriatal pathways (Leenders, 1997;
Broussolle et al., 1999; Brooks, 2004; Thobois
et al., 2004) which is correlated with degeneration
of the SN neurons found by pathological studies
(Jellinger, 2002; Snow, 2003). This process may be
accompanied by increased raclopride binding of
postsynaptic dopamine receptors in the putamen as
a sign of postsynaptic hypersensitivity in de novo,
drug-naive PD patients (Antonini et al., 1994; Kaasi-
nen et al., 2000).
2. An obvious effect of levodopa, which can be
seen particularly at the early stages of PD
(Hornykiewicz, 2002).
3. Presence of pathologic hallmarks – degenerating
ubiquitin-positive neuronal processes or neurites
(Lewy neurites), which have been found in all
affected brainstem regions and especially at the
dorsal motor nucleus of the vagus and later in
the SN (Braak et al., 1999; Gai et al., 2000).
Thus, PD is a neurodegenerative disease, which
selectively affects certain categories of neurons,
chiefly manifests as a progressive diminution of
dopamine level in the nigrostriatal system, induces an
overactivation of the output nuclei of the BG and
STN and inhibits the thalamocortical motor system.
VP is a clinical syndrome that may have similarities
to the cardinal motor manifestations of PD. Approxi-
mately 10% of cases of parkinsonism clinically recog-
nized as PD could pathologically be the result of
cerebrovascular disease and, in contrast, the emer-
gence of one or more clinical signs of parkinsonism
was revealed in 30% patients after stroke (Sibon
et al., 2004b). As distinct from PD, however, VP is
the result of endothelial dysfunction and arteriolo-
sclerosis causing lacunar strokes or punctate hemor-
rhages, disseminated mainly in the centrum
semiovale and/or BG. Risk factors of cerebrovascular
disease, like hypertension, diabetes mellitus type 2,
hyper-/dyslipidemia, hyperhomocysteinemia, previous
stroke history and genetic predisposition are usually
present (Keskin and Yurdakul, 1996; Ekinci et al.,
2004).
In the pathogenesis of VP without a direct lesion
affecting the SN, the dopamine level and its
metabolites in the cerebrospinal fluid should be normal
(Loeffler et al., 1995). Thus, the accepted explanation
is that the clinical symptoms in VP are related to post-
synaptic lesions of the nigrostriatal system mainly as a
result of a patchy destruction of neurons or axons at
the putamen, GP and probably the cerebral white
matter.
52.4. Conclusions
VP is not a homogenous syndrome. Its etiology may
be atherosclerotic in many cases, but it could result
from embolic, arteritic or hemorrhagic processes.
Pathophysiologically, two forms of VP should be con-
sidered: the first affects the nigrostriatal system unilat-
erally. A discrete lesion of the SN or the nigrostriatal
pathway should be seen in imaging. These patients
should have an acute onset, should not progress and
should respond to levodopa. The other, much more
common group, consists of patients presenting at more
advanced age and with predominantly lower-body
involvement and gait abnormalities rather than tremor.
A history of stroke, heart disease, arterial hypertension
and other risk factors for stroke support a vascular ori-
gin of these symptoms. Usually, these patients do not
have the typical parkinsonian rest tremor. In these
cases imaging demonstrates an extensive white-matter
disease.
 VASCULAR PARKINSONISM
BG lesions are frequently seen in patients with
parkinsonian symptoms, but their relationship to the
pathology is unclear since the onset of parkinsonism
is rarely acute and not strictly contralateral to the
damage (typically, a small lacuna). Moreover, some
people with similar lacunae do not demonstrate any
clinical manifestations. Probably, this VP syndrome
is the result of coexistent white-matter changes.
These cases are most likely to represent the entity of
‘pseudoparkinsonism’, as defined by Critchley. The
extensive damage ensures that a patient suffers not
only from increased muscle tone and bradykinesia,
but typically also from cognitive decline, pseudobulbar
syndrome, posture and gait instability and urinary
incontinence. Obviously these patients will respond
poorly to levodopa and there is an urgent need to
develop drugs that could help these patients.
References
Abe K, Yanagihara T (1996). Hemiparkinsonism following
haemorrhage in the contralateral substantia nigra.
Neuroradiology 38 (Suppl 1): S67–S69.
Abe K, Terakawa H, Takanashi M et al. (2000). Proton
magnetic resonance spectroscopy of patients with
parkinsonism. Brain Res Bull 52: 589–595.
Adhiyaman V, Meara RJ, Bhowmick BK (2002). Anti-
phospholipid syndrome and dystonia-parkinsonism: need
for anticoagulation. Parkinsonism Relat Disord 8: 215.
Antonini A, Schwarz J, Oertel WH et al. (1994). [11C]raclo-
pride and positron emission tomography in previously
untreated patients with Parkinson’s disease: influence of
L-dopa and lisuride therapy on striatal dopamine
D2-receptors. Neurology 44: 1325–1329.
Behnke S, Berg D, Naumann M et al. (2005). Differentiation
of Parkinson’s disease and atypical parkinsonian syn-
dromes by transcranial ultrasound. J Neurol Neurosurg
Psychiatry 76: 423–425.
Berg D, Becker G, Zeiler B et al. (1999). Vulnerability of the
nigrostriatal system as detected by transcranial ultrasound.
Neurology 53: 1026–1031.
Berg D, Roggendorf W, Schroder U et al. (2002). Echogeni-
city of the substantia nigra: association with increased iron
content and marker for susceptibility to nigrostriatal
injury. Arch Neurol 59: 999–1005.
Berg D, Merz B, Reiners K et al. (2005). Five-year follow-up
study of hyperechogenicity of the substantia nigra in
Parkinson’s disease. Mov Disord 20: 383–385.
Berding G, Schrader CH, Peschel T et al. (2003). [N-methyl
11C]meta-Hydroxyephedrine positron emission tomogra-
phy in Parkinson’s disease and multiple system atrophy.
Eur J Nucl Med Mol Imaging 30: 127–131.
Bergman H, Deuschl G (2002). Pathophysiology of
Parkinson’s disease: from clinical neurology to basic
neuroscience and back. Mov Disord 17 (Suppl 3):
S28–S40.
423
Bhatia KP, Marsden CD (1994). The behavioural and motor
consequences of focal lesions of the basal ganglia in man.
Brain 117: 859–876.
Bianco F, Floris R (1996). MRI appearances consistent with
haemorrhagic infarction as an early manifestation of car-
bon monoxide poisoning. Neuroradiology 38 (Suppl 1):
S70–S72.
Braak H, Braak E (2000). Pathoanatomy of Parkinson’s dis-
ease. J Neurol 247 (Suppl 2): II3–II10.
Braak H, Sandmann-Keil D, Gai W et al. (1999). Extensive
axonal Lewy neurites in Parkinson’s disease: a novel
pathological feature revealed by alpha-synuclein immuno-
cytochemistry. Neurosci Lett 265: 67–69.
Brooks DJ (2004). Neuroimaging in Parkinson’s Disease.
Neurorx 1: 243–254.
Broussolle E, Dentresangle C, Landais P et al. (1999). The
relation of putamen and caudate nucleus 18F-Dopa uptake
to motor and cognitive performances in Parkinson’s dis-
ease. J Neurol Sci 166: 141–151.
Chang CM, Yu YL, Ng HK et al. (1992). Vascular pseudo-
parkinsonism. Acta Neurol Scand 86: 588–592.
Choi IS (2002). Parkinsonism after carbon monoxide poison-
ing. Eur Neurol 48: 30–33.
Cosi V, Tonali P (1964). Acute Parkinson syndrome follow-
ing subarachnoid hemorrhage in a schizophrenic subject.
Riv Patol Nerv Ment 85: 287–301.
Critchley M (1929). Arteriosclerotic parkinsonism. Brain 52:
23–83.
Critchley M (1981). Arteriosclerotic pseudoparkinsonism.
In: FC Rose, R Capildeo (Eds.), 74: Pitman, London, pp.
745–752.
Cummings JL (1994). Vascular subcortical dementias: clini-
cal aspects. Dementia 5: 177–180.
Defer GL, Remy P, Malapert D et al. (1994). Rest tremor
and extrapyramidal symptoms after midbrain haemor-
rhage: clinical and 18F-dopa PET evaluation. J Neurol
Neurosurg Psychiatry 57: 987–989.
Demirkiran M, Bozdemir H, Sarica Y (2001). Vascular par-
kinsonism: a distinct, heterogeneous clinical entity. Acta
Neurol Scand 104 (2): 63–67.
Ekinci B, Apaydin H, Vural M et al. (2004). Two siblings
with homocystinuria presenting with dystonia and parkin-
sonism. Mov Disord 19: 962–964.
Ertan S, Fresko I, Apaydin H et al. (1999). Extrapyramidal
type rigidity in rheumatoid arthritis. Rheumatology
(Oxford) 38: 627–630.
Fabiani G, Teive HA, Germiniani FM et al. (2002). Reversi-
ble parkinsonian syndrome in systemic and brain vasculi-
tis. Mov Disord 17: 601–604.
Fenelon G, Houeto JL (1997). Unilateral parkinsonism fol-
lowing a large infarct in the territory of the lenticulostriate
arteries. Mov Disord 12: 1086–1090.
FitzGerald PM, Jankovic J (1989). Lower body parkinsonism:
evidence for vascular etiology. Mov Disord 4: 249–260.
Friedman A, Kang UJ, Tatemichi TK et al. (1986). A case
of parkinsonism following striatal lacunar infarction.
J Neurol Neurosurg Psychiatry 49: 1087–1088.
424 Y. BALASH AND A. D. KORCZYN
Gai WP, Yuan HX, Li XQ et al. (2000). In situ and in vitro
study of colocalization and segregation of alpha-synuclein,
ubiquitin, and lipids in Lewy bodies. Exp Neurol 166:
324–333.
Garcia-Moreno JM, Chacon J (2002). Juvenile parkinsonism
as a manifestation of systemic lupus erythematosus: case
report and review of the literature. Mov Disord 17:
1329–1335.
Giladi N, Kao R, Fahn S (1997). Freezing phenomenon in
patients with parkinsonian syndromes. Mov Disord 12:
302–305.
Goldstein DS (2004). Functional neuroimaging of sympa-
thetic innervation of the heart. Ann NY Acad Sci 1018:
231–243.
Grundl W, Ziegler R, Westphal KP et al. (1991). Parkinson’s
syndrome: cranial computed-tomography findings.
Their dependence on sex and age. Acta Med Hung 48:
127–136.
Hardoff R, Sula M, Tamir A et al. (2001). Gastric emptying
time and gastric motility in patients with Parkinson’s
disease. Mov Disord 16: 1041–1047.
Holstein J, Chatellier G, Piette F et al. (1994). Prevalence of
associated diseases in different types of dementia among
elderly institutionalized patients: analysis of 3447 records.
J Am Geriatr Soc 42: 972–977.
Hornykiewicz O (2002). L-DOPA: from a biologically inac-
tive amino acid to a successful therapeutic agent. Amino
Acids 23: 65–70.
Hrycaj P, Korczowska I, Lacki JK (2003). Severe Parkin-
son’s disease in rheumatoid arthritis patient treated with
infliximab. Rheumatology (Oxford) 42: 702–703.
Huang Z, Jacewicz M, Pfeiffer RF (2002). Anticardiolipin
antibody in vascular parkinsonism. Mov Disord 17:
992–997.
ICD-9-CM International Classification of Diseases (2005),
9th Rev: Clinical Modification Vol. 1. Practice Manage-
ment Information Corporation.
Inoue H, Udaka F, Takahashi M et al. (1997). Secondary
parkinsonism following midbrain hemorrhage. Rinsho
Shinkeigaku 37: 266–269.
Inzelberg R, Bornstein NM, Reider I et al. (1994). Basal
ganglia lacunes and parkinsonism. Neuroepidemiology
13: 108–112.
Jellinger KA (2002). Vascular parkinsonism—neuropathological
findings. Acta Neurol Scand 105: 414–415.
Jost WH, Jung G, Schimrigk K (1994). Colonic transit time
in non-idiopathic Parkinson’s syndrome. Eur Neurol 34:
329–331.
Kaasinen V, Ruottinen HM, Nagren K et al. (2000). Upregu-
lation of putaminal dopamine D2 receptors in early
Parkinson’s disease: a comparative PET study with
[11C] raclopride and [11C] N-methylspiperone. J Nucl
Med 41: 65–70.
Katzenschlager R, Zijlmans J, Evans A et al. (2004). Olfac-
tory function distinguishes vascular parkinsonism from
Parkinson’s disease. J Neurol Neurosurg Psychiatry 75:
1749–1752.
Keskin S, Yurdakul F (1996). Parkinsonian manifestations in
a patient with homocystinuria. Parkinsonian manifesta-
tions in a patient with homocystinuria. Child Neurol 11:
235–236.
Kim JS (2001). Involuntary movements after anterior cere-
bral artery territory infarction. Stroke 32: 258–261.
Klawans HL, Stein RW, Tanner CM et al. (1982). A pure
parkinsonian syndrome following acute carbon monoxide
intoxication. Arch Neurol 39: 302–304.
Koehler RC, Traystman RJ (2002). Cerebrovascular effects
of carbon monoxide. Antioxid Redox Signal 4: 279–290.
Korczyn AD (1972). Pathophysiology of drug-induced dys-
kinesias. Neuropharmacology 11: 601–607.
Korczyn AD (1993). The gut in PD. Neurology 43: 629–630.
Kulisevsky J, Berthier ML, Avila A et al. (1996). Unilateral
parkinsonism and stereotyped movements following a
right lenticular infarction. Mov Disord 11: 752–754.
Lazzarino LG, Nicolai A, Toppani D (1990). Subacute par-
kinsonism from a single lacunar infarct in the basal gang-
lia. Acta Neurol (Napoli) 12: 292–295.
Loeffler DA, LeWitt PA, DeMaggio AJ et al. (1995). Mar-
kers of dopamine depletion and compensatory response
in striatum and cerebrospinal fluid. J Neural Transm Park
Dis Dement Sect 9: 45–53.
Lorberboym M, Djaldetti R, Melamed E et al. (2004).
123I-FP-CIT SPECT imaging of dopamine transporters
in patients with cerebrovascular disease and clinical diag-
nosis of vascular parkinsonism. J Nucl Med 45:
1688–1693.
Lee MS, Marsden CD (1994). Neurological sequelae follow-
ing carbon monoxide poisoning clinical course and out-
come according to the clinical types and brain computed
tomography scan findings. Mov Disord 9: 550–558.
Leenders KL (1997). Pathophysiology of movement disor-
ders studied using PET. J Neural Transm Suppl 50: 39–46.
Milanov I, Bogdanova D (2001). Antiphospholipid syndrome
and dystonia-parkinsonism. A case report. Parkinsonism
Relat Disord 7: 139–141.
Miyagi K, Imaizumi T, Nagura H et al. (1992). A case of
transient parkinsonism due to mesencephalic hemorrhage.
Rinsho Shinkeigaku 32: 743–746.
Murrow RW, Schweiger GD, Kepes JJ et al. (1990). Parkin-
sonism due to a basal ganglia lacunar state: clinicopatho-
logic correlation. Neurology 40: 897–900.
Parkes JD, Marsden CD, Rees JE et al. (1974). Parkinson’s
disease, cerebroarteriosclerosis, and senile dementia. Q J
Med 43: 49–61.
Pau A, Brambilla M, Cossu M et al. (1989). Parkinsonism in
the presence of intracranial extracerebral haematomas.
Acta Neurochir (Wien) 96: 159–160.
Peralta C, Werner P, Holl B et al. (2004). Parkinsonism fol-
lowing striatal infarcts: incidence in a prospective stroke
unit cohort. J Neural Transm 111: 1473–1483.
 VASCULAR PARKINSONISM
Pineda DA, Buritica O, Sanchez JL et al. (2000). Parkinso-
nian syndromes in Medellin (Colombia). Rev Neurol 31:
936–943.
Reider-Groswasser I, Bornstein NM, Korczyn AD (1995).
Parkinsonism in patients with lucanar infarcts of the basal
ganglia. Eur Neurol 35: 46–49.
Sandyk R (1983). Parkinsonism secondary to neurosyphilis.
A case report. S Afr Med J 63: 665–666.
Schwab RS, England AC (1968). Parkinson syndromes due
to various specific causes. In: PJ Vinken, GW Bruyn
(Eds.), Vol. 6, North-Holland Publishing Co, Amsterdam,
pp. 227–247.
Sibon I, Guyot M, Allard M et al. (2004a). Parkinsonism
following anterior choroidal artery stroke. Eur J Neurol
11: 283–284.
Sibon I, Fenelon G, Quinn NP et al. (2004b). Vascular par-
kinsonism. J Neurol 251: 513–524.
Silverman CS, Brenner J, Murtagh FR (1993). Hemorrhagic
necrosis and vascular injury in carbon monoxide poison-
ing: MR demonstration. AJNR Am J Neuroradiol 14:
168–170.
Snow B (2003). Objective measures for the progression of
Parkinson’s disease. J Neurol Neurosurg Psychiatry 74:
287.
Sunada I, Inoue T, Tamura K et al. (1996). Parkinsonism due
to chronic subdural hematoma. Neurol Med Chir (Tokyo)
36: 99–101.
Taki J, Nakajima K, Hwang EH et al. (2000). Peripheral
sympathetic dysfunction in patients with Parkinson’s
disease without autonomic failure is heart selective and
disease specific. Eur J Nucl Med 27: 566–573.
Tan EK, Chan LL, Auchus AP (2001). Reversible parkinsonism
in systemic lupus erythematosus. J Neurol Sci 193: 53–57.
Thobois S, Jahanshahi M, Pinto S et al. (2004). PET and
SPECT functional imaging studies in Parkinsonian syn-
dromes: from the lesion to its consequences. Neuroimage
23: 1–16.
Thompson PD, Marsden CD (1987). Gait disorder of subcor-
tical arteriosclerotic encephalopathy: Binswanger’s
disease. Mov Disord 2: 1–8.
425
Trosch RM, Ransom BR (1990). Levodopa-responsive par-
kinsonism following central herniation due to bilateral
subdural hematomas. Neurology 40: 376–377.
Turjanski N, Pentland B, Lees AJ et al. (1997). Parkinsonism
associated with acute intracranial hematomas: an [18F]
dopa positron-emission tomography study. Mov Disord
12: 1035–1038.
Tzen KY, Lu CS, Yen TC et al. (2001). Differential diagno-
sis of Parkinson’s disease and vascular parkinsonism by
(99m)Tc-TRODAT-1. J Nucl Med 42: 408–413.
Van Zagten M, Lodder J, Kessels F (1998). Gait disorder and
parkinsonian signs in patients with stroke related to small
deep infarcts and white matter lesions. Mov Disord 13:
89–95.
Walter U, Wittstock M, Benecke R et al. (2002). Substantia
nigra echogenicity is normal in non-extrapyramidal cere-
bral disorders but increased in Parkinson’s disease.
J Neural Transm 109: 191–196.
Wichmann T, DeLong MR (2003). Pathophysiology of Par-
kinson’s disease: the MPTP primate model of the human
disorder. Ann NY Acad Sci 991: 199–213.
Winikates J, Jankovic J (1999). Clinical correlates of vascu-
lar parkinsonism. Arch Neurol 56: 98–102.
Yamada A, Takeuchi H, Miki H (1992). Unilateral abolition
of parkinsonian rigidity after subthalamic nucleus hemor-
rhage. Rinsho Shinkeigaku 32: 887–889.
Yamanouchi H, Nagura H (1995). Cerebrovascular parkin-
sonism—clinicopathologic study. Rinsho Shinkeigaku
35: 1457–1458.
Yamanouchi H, Nagura H (1997). Neurological signs and
frontal white matter lesions in vascular parkinsonism.
A clinicopathologic study. Stroke 28: 965–969.
Yoritaka A, Hattori T, Hattori Y, Mori H, Matsuoka S, Shirai
T, Kondo T, Mizuno Y (1997). A 85-year-old woman with
the onset of progressive gait disturbance at 80 years of the
age. No To Shinkei 49: 379–389.
Zijlmans JC, Daniel SE, Hughes AJ, Revesz T, Lees AJ (2004).
Clinicopathological investigation of vascular parkinsonism,
including clinical criteria for diagnosis. Mov Disord 19:
630–640.