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Transcript
J Neuropathol Exp Neurol
Copyright Ó 2007 by the American Association of Neuropathologists, Inc.
Vol. 66, No. 8
August 2007
pp. 675Y682
REVIEW ARTICLE
The Neuropathology of Manganese-Induced Parkinsonism
Daniel P. Perl, MD and C. Warren Olanow, MD
Abstract
Key Words: Etiology, Globus pallidus, Manganese, Parkinsonism,
Parkinson disease.
INTRODUCTION
The capacity of high levels of manganese to damage
the nervous system and to cause parkinsonism has been
recognized since the initial report by Couper in 1837 (1).
Over the ensuing 170 years, small numbers of cases of
occupational manganism have been reported (2). With
improvements in the workplace environment and reduced
levels of exposure to manganese, cases of manganism are
now rarely encountered. Recently, it has been proposed that
chronic exposure to manganese in welding fumes may cause
or accelerate the development of Parkinson disease (PD).
This concept is based on anecdotal case reports of PD in
welders (3, 4), reduced striatal fluorodopa uptake on positron
emission tomography (PET) in a single parkinsonian patient
thought to have manganism due to chronic liver failure (5),
and a single epidemiologic study suggesting an increased
frequency of PD in welders who were solicited by attorneys
to participate in a medical-legal screening (6). This
hypothesis has led to widespread litigation directed against
From the Departments of Pathology (DPP) and Neurology (CWO), Mount
Sinai School of Medicine, New York, New York.
Send correspondence and reprint requests to: Daniel P. Perl, MD, Department of Pathology, One Gustave L. Levy Place, Box 1134, Mount Sinai
School of Medicine, New York, NY 10029-6574; E-mail: [email protected]
mssm.edu
J Neuropathol Exp Neurol Volume 66, Number 8, August 2007
MANGANESE NEUROTOXICITY
Manganese is a paramagnetic metal that is essential for
cell survival. It is the 12th most abundant element in the
earth_s crust and is widely distributed in the environment,
being present in water, soil, and food (21). Manganese is the
fourth most widely used metal in commercial products, with
more than 8 million tons being extracted annually. More
than 90% of manganese is used in the manufacture of steel
in which it imparts hardness to the finished product.
Manganese is also used in the manufacture of batteries, in
bacteriocidal and fungicidal agents, for water purification,
and as an antiknock additive in gasoline. Manganese is also
a constituent of welding rods, and manganese-containing
fumes are produced during the welding process.
675
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Manganese is an essential trace metal that is widely used in
industry, particularly in the manufacture of steel. Exposure to high
levels of manganese can cause neurotoxicity with the development
of a form of parkinsonism known as manganism. It has recently
been hypothesized that manganese exposure might also cause or
accelerate the development of Parkinson disease (PD). This article
is a review of the pathologic studies that have been reported in
patients with manganism and in primates experimentally intoxicated with manganese. They demonstrate a consistent pattern
characterized by damage to the globus pallidus (particularly the
internal segment) with sparing of the substantia nigra pars
compacta and the absence of Lewy bodies. This finding contrasts
with what is seen in PD, in which there is preferential degeneration
of dopamine neurons in the substantia nigra pars compacta coupled
with Lewy bodies and preservation of the pallidum. These
pathologic findings do not support the notion that manganese
causes PD but rather argues that manganese-induced parkinsonism
and PD are distinct and separate disease entities.
the welding industry in the United States in an attempt to
obtain compensatory damages for welders who suffer from
PD, despite numerous epidemiologic studies that show no
evidence of increased PD incidence or prevalence among
welders (7Y12).
A large body of evidence accumulated over more than
a century has demonstrated that the pathology of PD is
characterized by degeneration of dopamine neurons in the
substantia nigra pars compacta (SNc) coupled with the
presence of intracellular Lewy bodies (13Y16). Neurodegeneration can also occur in other brain areas including the
olfactory region, locus coeruleus, nucleus basalis of Meynert, dorsal motor nucleus of the vagus, pedunculopontine
nucleus, and the cerebral cortex (17, 18). In contrast,
quantitative studies have demonstrated that the globus
pallidus pars interna and pars externa are intact in patients
with PD (19, 20).
There have only been a small number of reports
describing the neuropathologic findings in patients with
manganese intoxication. However, they demonstrate a
consistent pattern characterized by cell loss and gliosis in
the globus pallidus (especially the pars interna) and to a
lesser degree in the striatum, with sparing of the SNc and no
Lewy bodies. This pattern of pathology has been precisely
reproduced in nonhuman primates that have been experimentally intoxicated with manganese. In this article we will
review all of the published pathologic findings associated
with manganese intoxication in humans and experimental
animals. These findings support the position that manganeseinduced parkinsonism and PD have different pathologies and
are distinct and separate conditions. These findings argue
against the hypothesis that manganese intoxication causes or
accelerates the development PD.
J Neuropathol Exp Neurol Volume 66, Number 8, August 2007
Perl and Olanow
speech and gait disturbance with a tendency to fall backwards, symmetric bradykinesia, rigidity, micrographia, and
masked facies (2, 28, 30). Tremor, when present, tends to be
high frequency and postural or kinetic rather than resting as
is classically seen in PD. Dystonic features are common and
classically include facial grimacing and a distinctive gait
abnormality characterized by marked plantar flexion of the
feet known as Bcoq au pied[ or Bcock walk.[ In contrast with
PD, patients with manganese-induced parkinsonism have a
poor or unsustained response to levodopa treatment (31, 37)
and normal nigrostriatal function as illustrated by neuroimaging of the dopamine system with PET or single photon
emission computed tomography (38Y41). Psychiatric manifestations have been described with acute manganese
intoxication and include hallucinations, acute behavioral
disturbances, and frank psychosis.
NEUROPATHOLOGY OF MANGANESE
NEUROTOXICITY IN HUMANS
There have been a relatively small number of
published autopsy reports in patients with manganese
intoxication. Many of these were in the early neuropathology
literature, reflecting the scientific approaches and language
of that era and appeared in obscure journals written in
German. A total of 15 cases have been reported in which a
neuropathologic evaluation has been performed on individuals who were thought to have manganese intoxication
(Table 1). In 1 case, only a gross examination of the brain is
reported (42). In 11 cases, examination of the brain
demonstrated a consistent neuropathologic pattern of lesions
TABLE 1. Neuropathologic Findings in Autopsied Cases of Manganese Induced Parkinsonism
Case
Globus Pallidus
Substantia Nigra Pars Compacta
Parkinsonism after Exposure to Manganese-Containing Ore Dust
Casamajor, 1913 (42)
Not reported
Ashizawa, 1927 (43)
BSevere reduction in ganglion cells of pars interna and somewhat
less severe in pars externa[
Trendtel, 1933 (45)
BMarked failure of nerve cells in the putamen and pallidum[
Canavan et al, 1934 (46)
BThere was a marked reduction in the number of nerve cells, so that
whole fields of only glia occurred.[
Stadler, 1936 (47)
BThe pallidum shows a more diffuse failure of ganglia cellsIfailure
of ganglia cells affects the inner part of the pallidum. Almost no
ganglia cells remain.[
Parnitzke and Peiffer,
BThe ganglia cells of the internal limb have mostly died and in their
1954 (48)
place the macroglia and microglia have increased.[
BAtrophic and brown in color[ (gross examination); Bloss of nerve
cells, which were marked in the medial segments and moderate in
the lateral ones.[ (microscopic examination)
Parkinsonism after exposure to manganese-contaminated water
Kawamura et al, 1941
BDistinct changes I[nerve cells] were heavily injured and even
(50)
necrosed.[
Parkinsonism associated with hepatic failure
Maeda et al, 1997
BRemarkable atrophy, necrosis and deciduation of the nerve cells of
(3 cases) (51)
the globus pallidus with reactive glia and microglia.[
McKinney et al, 2004
BVacuolar change, presence of macrophages, gliosis and neuronal
(52)
loss in the pars interna of the globus pallidus and substantia nigra
pars reticulata.[
Yamada et al, 1986 (49)
676
Not reported
BNerve cells not remarkably changed[
Not reported
Not reported
BIntact[ (microscopic description)
BGood pigmentation[ (gross examination);
Binconspicuous changes[ (microscopic
examination)
BMelanic color normal (gross examination);
Bthe pigment cells of the substantia nigra were
intact[ (microscopic examination)
BNo changes grossly visible[
Not reported
Not reported
Ó 2007 American Association of Neuropathologists, Inc.
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Manganese is normally cleared by the liver and
excreted in urine (22, 23). Manganese that exceeds the
clearance capacity of the liver or that gains direct entry to
the systemic circulation through respiration has the potential
of gaining access to the brain (24). Radiotracer, magnetic
resonance imaging (MRI), and pathologic studies demonstrate that manganese preferentially accumulates in the
globus pallidus where it has the potential to cause neurotoxicity (25Y27). Manganese neurotoxicity was first
described in 5 workers who developed muscle weakness,
limb tremor, and a whispering voice after exposure to
manganese in an ore-crushing plant (1). Since that original
report, a small number of similar clinical cases have been
reported, almost exclusively among manganese miners,
millers, and smelters and more rarely in workers involved
in manufacturing dry cell batteries and fungicides (2, 28).
Perhaps the best described cases are in a cohort from Taiwan
(29Y31) in which 6 of 13 individuals working in an iron
foundry developed parkinsonism due to failure of the
ventilatory system and consequent exposure to massively
high levels of manganese. Manganese toxicity has also been
described in patients with liver failure, presumably reflecting
an inability of the liver to clear the normal dietary load of
manganese, and in patients receiving long-term parenteral
nutrition presumably due to the direct systemic administration of a high manganese-containing nutritional product
(32Y35). Manganism has also been described after ingestion
and systemic administration of potassium permanganate
(36).
Parkinsonism is the cardinal clinical feature of
manganism and typically is manifested as an early onset of
J Neuropathol Exp Neurol Volume 66, Number 8, August 2007
in the globus pallidus, particularly the globus pallidus pars
interna, with sparing of the SNc (when mentioned) and an
absence of Lewy bodies. Different neuropathologic patterns
were described in 3 cases, but in our opinion these cases
corresponded both clinically and neuropathologically with
alternative diagnoses.
Manganism After Occupational Exposure
Ó 2007 American Association of Neuropathologists, Inc.
years (46). The patient had been employed at several mills in
which he was exposed to manganese dust. At autopsy,
atrophy of the basal ganglia was specifically noted. In the
Blenticular nucleus[ [putamen and globus pallidus], they
noted, Ba marked reduction in the number of nerve cells, so
that whole fields of only glia occurred.[ There was no
mention in this report of the appearance, either on gross or
microscopic examination, of the SNc.
In 1936, Stadler reported the autopsy findings of a
patient who had been exposed to manganese while working
in a brownstone mill between the years 1910 and 1915 and
1918 and 1921 (47). He developed a variety of parkinsonian
signs and symptoms including micrographia, rigid facial
features, bent body posture, stiff movements, trembling, and
gait dysfunction with an inclination to fall forward. He died
at age 56 years. At autopsy, nothing unusual was noted on
gross examination. However, microscopically both focal and
widespread neuronal loss was observed in the globus pallidus
and striatum. The neuronal damage was described as most
extensive in the medial portion of the globus pallidus. The
report points out that almost no neurons remained in the
internal aspect of the globus pallidus and that there was
almost complete replacement of nerve cells with glial cells.
The striatum was also affected. The author specifically
comments in the microscopic notes that the Bsubstantia nigra[
was intact. He further comments: Bthe pallidum seems to be
affected by manganese poisoning with a regularity that is
elsewhere in human pathology only found in carbon monoxide poisoning.[
Parnitzke and Peiffer reported the autopsy findings of a
43-year-old man who had occupational exposure to manganesecontaining dust while working as a brownstone miller (48).
The patient first noted trembling of the right leg at age 19,
1 year after he had begun to work in the mill. Over the
following 1 or 2 years he developed generalized muscular
rigidity. Five years into his illness he had difficulty speaking,
mask-like facies, and a propulsive gait. When he was 38
years of age he was described as having an almost complete
lack of mobility and being unable to sit unassisted or to feed
himself. On gross examination of the brain, no specific
abnormalities were noted and the substantia nigra was
described as showing Bgood pigmentation.[ On microscopic
examination, it was noted that BIin the pallidum: the
ganglia cells in the internal limb have mostly died[ and Bthe
cell failure [in the globus pallidus pars externa] in no way
approaches the failure level of the internal pallidum.[ In
summarizing, the authors note: BIn our case, the ganglion
cell damage occurring in the pallidum and particularly that
located in its internal limb fits with the presentation that
neuropathologists have become familiar with.[
In 1986, Yamada et al published the last available and
most complete brain examination of a case of manganeseinduced parkinsonism due to occupational exposure (49). The
report describes a 52-year-old man who had been employed in
a manganese ore-crushing facility. Clinically, he experienced
gait disturbance with difficulty walking backwards and cock
walk, masked facies, monotonous speech, and neuropsychiatric features including loss of libido, euphoria, and emotional
incontinence. There was no improvement with levodopa.
677
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In 1913, Casamajor described a patient who died after
working in an ore-separating plant that produced manganesecontaining dust (42). The length of exposure and the clinical
manifestations that were present in this patient were not
clearly described. An autopsy was performed, and the brain
and spinal cord were reported to have a normal appearance
on gross examination. The report does not further describe
the brain specimen.
In 1927, Ashizawa reported the autopsy findings of a
man who had worked as a brownstone miller (43). He had a
3-year history of mask-like facies, slight muscular rigidity,
impairment in performing fine motor tasks, trembling of the
fingers, and micrographia. At autopsy no grossly visible
abnormalities were noted in the brain, but the appearance of
the corpus striatum and SNc were not specifically addressed.
A detailed description of the microscopic appearance of a
number of brain regions was provided. The report contains
the following description of the pallidum: BThe nerve cells
in some areas of the pars externa are significantly decreased,
and, particularly in the pars interna, are on the whole
extraordinarily severely decreased, so that only a small
number of them were visible close to the pars externa and
sometimes they were not visible at all in an entire cross
section.[ In addition, the author described the appearance of
the substantia nigra, indicating that the Bnerve cells and
myelin fibers are not remarkably changedI.[ The summary
of the findings in this report states: BThe changes in the
pallidum were quite remarkable. They consisted of a severe
reduction of the gangliocytes of the pars interna, and
somewhat less severe in the pars externaI.[ It is stated
that there were no significant changes in the cerebral cortex,
thalamus, subthalamic nucleus, red nucleus, substantia nigra,
corpora quadrigemina, dentate nucleus, inferior olive, and
spinal cord. It is further specifically indicated that the
findings observed in this case were very similar to what
had been seen in the manganese-intoxicated monkeys
described by Mella and that they are distinct from what is
seen in PD (44).
In 1933, Trendtel described the findings in a dock
worker who was exposed to manganese-containing dust
while unloading brownstone ore from ships (45). The patient
demonstrated masked facies, paucity of movement, shuffling
gait, a tendency to fall backward, and weakness. A diagnosis
of chronic manganese poisoning was made. The patient died,
but his age at death and the circumstances leading to his
death were not stated. At autopsy there was BIpathological
sclerosis and scars in the striatum. In some parts there was
extensive failure of nerve cells in putamen and pallidum.[ A
description of the SNc was not provided.
In 1934, Canavan et al reported the findings in a man
diagnosed with manganese poisoning who died at age 69
Pathology of Manganese-Induced Parkinsonism
Perl and Olanow
Manganism After Exposure to ManganeseContaminated Water
Kawamura et al reported an outbreak of manganese
poisoning related to exposure to contaminated well water
(50). The report describes 16 individuals who developed a
parkinsonian syndrome after drinking well water that had
become contaminated with manganese due to the decaying
of storage batteries buried in nearby soil. Clinical features
included lethargy, masked facies, increased muscle tone, and
an action tremor. Histologic examination in 1 autopsy case
(a 46-year-old man) revealed Bdistinct changes[ in the
globus pallidus: Bnerve cellsIwere heavily injured and
even necrosed.[ No changes were visible in the thalamus,
the caudate nucleus, or the substantia nigra. The authors
conclude: BIn this case, as to the changes in the central
nervous system, degeneration and destruction of nerve cells
in the globus pallidus were considered most importantI.[
Manganism Associated With Hepatic Failure
and Total Parenteral Nutrition
There are significant amounts of manganese in the
normal diet (daily intake is about 5 mg/kg). Normally, about
98% of dietary manganese is eliminated by the liver through
biliary excretion (22, 23). In cases of hepatic failure,
however, impaired liver clearance can lead to elevated
serum manganese levels, high signal changes in the pallidum
bilaterally on T1-weighted MRI characteristic of manganese
accumulation, and parkinsonism with symmetric rigidity and
bradykinesia with a poor or unsustained response to
levodopa (21). The neuropathologic features of 4 cases of
parkinsonism occurring in the setting of hepatic failure have
been reported.
Maeda et al described the autopsy findings of 3
patients with hepatic failure who demonstrated extrapyrami-
678
dal features on clinical examination and increased signal in
the pallidum bilaterally on T1-weighted MRI characteristic
of manganese accumulation (51). At autopsy, the authors
described Bremarkable atrophy, necrosis and deciduation of
the nerve cells of the globus pallidus with reactive glia and
microglia. Similar changes of medium severity were seen in
the putamen.[ They specifically noted the marked severity of
the nerve cell loss in the medial segment of the globus
pallidus in each case. The SNc was not described in this
report.
In 2004, McKinney et al described the autopsy
findings of a patient with hepatic failure who was also
receiving total parenteral nutrition, known to contain high
levels of manganese (52Y54). MRI showed symmetrical
hyperintensities in the globus pallidi on T1-weighted imaging, consistent with manganese accumulation. The patient
subsequently died of systemic aspergillosis. At autopsy there
was Bvacuolar change, presence of macrophages, gliosis,
and neuronal loss in the pars interna of the globus pallidus[
as well as similar changes in the substantia nigra pars
reticularis. It should be kept in mind that the substantia nigra
pars reticularis does not contribute to the dopaminergic
nigrostriatal system and is anatomically and functionally
related to the globus pallidus. No findings were described in
the SNc. This pattern of findings was considered by the
authors to be Bvery specific for manganese poisoning.[
Autopsied Cases of Patients Who Were Exposed
to Manganese but Do Not Fit the Pattern of
Neuropathologic Damage Described Above
There are 3 autopsy reports of patients who were
reported to have been exposed to manganese but with a
different pattern of neuropathology than described above. In
each case, we believe this represents an example of a
different neurologic disease entity that developed coincidentally in an individual who also happened to be exposed to
manganese. In each of the 3 cases we do not believe there is
sufficient evidence to conclude that the damage suffered by
the nervous system was related to the manganese exposure.
In 1939, Voss described a patient who had worked for
15 years in a battery factory and also had occupational
exposure to brownstone dust (55). At age 37 years he
developed difficulty swallowing, dysarthria, weakness with
atrophy of the extremities, atrophy of the tongue (with
Bfibrillary twitching[), increased deep tendon reflexes, and
sustained clonus. Eye movements and sensory examination
were intact, and cognitive function was normal. Electromyographic examination showed evidence of Bdegeneration[
in the tongue and hand muscles. The patient_s weakness
progressed over 2 years to the point at which he could not
walk, and he died of aspiration pneumonia. At autopsy, there
was pallor of the lateral and ventral corticospinal tracts in
the spinal cord, particularly in the cervical region. In
addition, there was diffuse anterior horn cell loss with
atrophy of the anterior spinal roots and preservation of
dorsal horn neurons. Neuronal loss was also seen in the
hypoglossal nucleus. Both the substantia nigra and globus
pallidus were described as being intact. The final diagnosis
was amyotrophic lateral sclerosis with no pathologic
Ó 2007 American Association of Neuropathologists, Inc.
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Manganese levels were increased in the urine (10.4 Kg/100 mL;
normal, G2.0 Kg/100 mL), and blood (3.4 Kg/100 mL;
normal, 0.4Y2.0 Kg/100 mL). Intravenous infusion of a
chelating agent (20 mg/kg EDTA) was associated with a
marked increase in the urinary excretion of manganese
(56.4 mg/100 mL), but no clinical benefit. He died 4 years
after his initial evaluation. At autopsy the brain was of
normal weight. The globus pallidus was noted to be atrophic
and brown in color and Bthe melanic color of the substantia
nigra appeared normal.[ Microscopic examination revealed
marked loss of nerve cells in the medial segment of the
globus pallidus and moderate loss in the lateral portion.
There was moderate astrocytosis and mild gliosis noted in the
globus pallidus. The pigmented neurons of the substantia
nigra were described as being intact. In summary, the brunt
of the damage described was localized to the globus pallidus,
especially its medial portion, and the SNc was specifically
noted to be of normal appearance on both gross inspection
and microscopic examination. The authors note that
Bpreferential affection of the basal ganglia, especially of the
pallidum, seems to be related to the extrapyramidal and other
characteristic manifestations of CMP [chronic manganese
poisoning][ and that Bchronic manganese poisoning appears
to be different from PD neuropathologically.[
J Neuropathol Exp Neurol Volume 66, Number 8, August 2007
J Neuropathol Exp Neurol Volume 66, Number 8, August 2007
Ó 2007 American Association of Neuropathologists, Inc.
factory and modest changes in the pallidum suggest the
possibility that she may also have had a mild form of
manganism, it is hard to imagine that all of the pathologic
features were directly related to manganese intoxication.
There is no precedent for patients developing manganism 10
years after exposure to the metal had ceased. This case
represents the one and only autopsy of an individual exposed
to manganese who showed evidence of SNc cell damage
accompanied by the appearance of Lewy bodies. It is
noteworthy that PD is a common disorder with a lifetime
risk for an individual of approximately 1% to 2%, and there
is no reason to think that exposure to manganese would
diminish the risk of an individual developing PD. We
believe that in this case the patient probably had 2 different
conditions, PD and mild manganism, but we cannot
conclude that both conditions were directly related to
manganese toxicity.
Manganese-Induced Parkinsonism
in Rhesus Monkeys
Animal models have provided additional information
on the pathology associated with manganese-induced neurotoxicity. In 1924, Mella chronically exposed monkeys to
intravenous manganese chloride for 18 months. At necropsy,
the animals showed localized degeneration in the globus
pallidus and striatum (44). Pentschew et al exposed rhesus
monkeys to multiple intramuscular injections of MnO2
(suspended in olive oil) (59). After 9 months the animals
began to show motor symptoms with gait and balance
disturbances and generalized clumsiness. One animal was
killed, and the brain was described in detail. The findings
included severe damage to the medial portion of the globus
pallidus with dramatic loss of neurons and gliosis with
Bimmature[ glia having the appearance of Alzheimer type 2
astrocytes. Similar changes were seen in the substantia nigra
pars reticularis and the subthalamic nucleus. The SNc was
intact. The authors reviewed the human pathology literature
and concluded: Bthe neuropathologic findings in the manganese monkey showed such striking similarities to those in
human cases of manganese encephalopathy that they could
be said to be identical.[
Eriksson et al described the effects of chronic subcutaneous injections of manganese oxide in rhesus monkeys
(60). The animals developed an unsteady, hypoactive gait
with an action tremor and clumsiness of the limbs. At
necropsy, there was severe nerve cell loss and astrogliosis in
the globus pallidus with preservation of the caudate and
putamen. While striatal dopamine levels were said to be low,
there was no loss of pigmented neurons in the SNc or locus
coeruleus and a 11C-L-dopa PET study was normal (61).
In 1980 Gupta et al reported the appearance of
monkeys who had oral exposure to manganese chloride,
and these authors claim to have seen evidence of damage to
the pigmented neurons of the substantia nigra in the exposed
monkeys (62). However, the data they provided do not
permit confirmation of this finding. The article contains no
quantitative assessment of damage to the SNc, and the only
evidence provided for this finding is photomicrographs of an
exposed and unexposed monkey. Specifically, Figures 3a
679
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evidence of manganism. We believe that the author is
correct and that there is no reason to think this is anything
but a case of amyotrophic lateral sclerosis in an individual
with incidental manganese exposure. We further note that no
similar pathologic picture has been described in association
with manganese intoxication in either the clinical or
experimental literature.
In 1953, Scholten described a 49-year-old man who
was exposed to manganese ore, but the duration and nature
of that exposure were not provided (56). The patient
presented with gait dysfunction (feet described as being
Bstuck to the ground[), postural instability, prominent
dysarthria with hypophonia, cerebellar signs, increased deep
tendon reflexes, stooped posture, thoracic kyphosis, anterocollis (head hung forward), and dementia. His condition
gradually worsened, and he developed marked dementia and
died at age 60 years. He was diagnosed clinically as having
manganese encephalopathy. At autopsy, the striatum, thalamus, and globus pallidus were described as well preserved.
In contrast, cell loss was described in the substantia nigra,
locus coeruleus, and cerebellum (Purkinje cells). In addition,
there was degeneration of the ventral medulla with prominent loss of neurons of the inferior olives. The author of this
report concluded that he could not be certain which, if any,
of the pathologic changes were due to manganese. We
believe that the clinical features and neuropathologic
changes in this case are most consistent with a diagnosis of
multiple system atrophy with cerebellar predominance, a
condition that was not well defined until several years after
the time of this report (57). Multiple system atrophy has
never been linked to manganese exposure, either clinically
or in experimental animals. We believe manganese exposure in this case was probably coincidental and not etiologic
in nature.
Finally, in 1973, Bernheimer et al wrote a lengthy
paper on the clinical, neuropathologic, and neurochemical
aspects of various forms of basal ganglia disorders. Included
in the study are 39 cases of PD, 12 cases of postencephalitic
parkinsonism, 7 cases of Barteriosclerotic-senile[ parkinsonism, and 10 cases referred to as unclassified and atypical
cases with parkinsonian symptomatology (58). Within this
latter group a single patient (case 69) was described by the
authors as suffering from Bchronic manganese encephalopathy.[ This was a 67-year-old woman who, in her mid30s, had been exposed to manganese dioxide while working
in a battery factory. Twenty-three years before her death,
and approximately 10 years after manganese exposure had
ceased, she developed a tremor and progressed to develop
rigidity and akinesia. Morphologic examination of this
patient_s brain revealed a mild degree of pallidal atrophy
with astrocytosis in the putamen, globus pallidus, and red
nucleus. In addition, the SNc was reported to show spotty
degeneration with occasional Lewy bodies in the remaining
nigral neurons. In this case, the development of progressive
tremor, rigidity, and bradykinesia beginning approximately
10 years after cessation of exposure to manganese and
pathologic findings of cell loss and Lewy bodies in the SNc
strongly suggest that the patient had PD. Although the
patient_s exposure to manganese while working in a battery
Pathology of Manganese-Induced Parkinsonism
J Neuropathol Exp Neurol Volume 66, Number 8, August 2007
Perl and Olanow
pallidus with sparing of the SNc (explicitly stated in some
cases and not reported in others, which we assume implies
that none were found). The animal literature precisely
confirms these findings, demonstrating a pattern of damage
after manganese intoxication that primarily affects the
globus pallidus (particularly the inner segment) and to a
lesser extent the striatum with sparing of the dopaminergic
nigrostriatal pathway. The sole exception is the brief report
of Gupta et al for which insufficient information is available
to confirm the reported findings (62).
The clinical picture, lack of response to levodopa, MRI
changes, and neuroimaging studies that have been reported in
patients and animals with manganese intoxication (2) are
consistent with the pathologic pattern of damage to the
pallidum and sparing of the SNc seen in this condition and
are distinctly different from what is found in PD (Table 2).
PD is characterized by neurodegeneration involving SNc
neurons, Lewy bodies, and reduction in striatal dopamine.
PD can also affect other regions of the nervous system,
including the dorsal motor nucleus of the vagus, nucleus
basalis of Meynert, locus coeruleus, olfactory regions, and
peripheral autonomic neurons (15, 18), but this is a very
different pattern from what is found in manganism. None of
these changes have been described in either a patient or
animal model with manganese neurotoxicity. Further, the
TABLE 2. Comparison of Manganism and Parkinson Disease
Parkinson Disease
Pathology
Degeneration of SNc
neurons
DISCUSSION
It is clear that manganese can act as a neurotoxin and
produce a parkinsonian syndrome. As reviewed here, most
of the reported morphologic studies (11 of 14) show a
consistent and characteristic pattern of damage primarily
involving the globus pallidus (especially its medial portion)
and to a lesser extent the striatum with sparing of the SNc
and no Lewy bodies (Table 1). The 3 other autopsied cases
reported to have manganese exposure are consistent with
alternate diagnoses. The case reported by Voss did not
indicate damage to the pallidum or the SNc and is almost
certainly an instance of amyotrophic lateral sclerosis in a
person who had incidental exposure to manganese (55). The
cases reports by Scholten and by Bernheimer et al did note
changes in the SNc, but the clinical picture and pathologic
findings are consistent with different conditions and do not
follow the pattern of damage described in any other clinical
or experimental case of manganism (56, 58). The patient
described by Scholten probably represents a case of multiple
system atrophy with a completely different pattern of
clinical findings and pathologic lesions than those described
in patients with manganism (56). The patient reported by
Bernheimer et al with SNc damage and Lewy body formation probably represents an example of PD that occurred
in a woman with coincidental manganese exposure many
years before the onset of parkinsonian features (58).
All other cases described in the human literature show
a specific and reproducible pattern of damage to the globus
680
Neuronal loss in olfactory
region, locus coeruleus,
nucleus basalis of
Meynert, dorsal motor
nucleus of the vagus,
peripheral autonomic
neurons
Sparing of pallidum
Lewy bodies in
residual neurons
Parkinsonism
(bradykinesia, rigidity)
Resting tremor
Clinical
Asymmetry
Response to
levodopa
MRI
Good response in
virtually all patients
Normal
Fluorodopa-PET
Reduced striatal
fluorodopa uptake
Manganism
Degeneration of pallidal
neurons (especially
internal segment), striatum
Sparing of SNc
No Lewy bodies
Parkinsonism
(bradykinesia, rigidity)
Early onset speech and
gait dysfunction
No resting tremor as in
Parkinson disease
Asymmetry not a
prominent feature
Dystonia-facial grimace,
coq au pied
Minimal or no response
High signal change in
pallidum bilaterally on
T1-weighted image
Normal
SNc, substantia nigra pars compacta; MRI, magnetic resonance imaging; PET,
positron emission tomography.
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and 3b in the Gupta et al publication (62) are said to
represent a single pigmented neuron of the substantia nigra
stained with silver diamine in a control and manganesetreated monkey. However, the diameter of the neuronal
soma in the control monkey depicted in this figure is at least
twice that of the neurons in a control monkey pictured in
Figure 1 (same reported magnification) and is well beyond
the known dimensions of such cells. Furthermore, the figures
do not provide sufficient cytologic detail (i.e. the appearance
of the nucleus or outer cell membrane of the neuron) to
permit the reader to confirm the purported finding of cellular
damage to these pigmented neurons.
Finally, Olanow et al exposed 3 adult rhesus monkeys
to weekly manganese chloride injections administered intravenously (38, 63). Two of the exposed animals developed a
severe parkinsonian syndrome characterized by gait disturbance, bradykinesia, rigidity, and facial grimacing (but not
tremor), which did not respond to levodopa treatment. MRI
revealed bilateral high signal abnormalities in the striatum
and globus pallidus on T1-weighted scans, indicative of
manganese deposition. Striatal fluorodopa uptake on the
PET scan was normal in each of the animals, as were
postmortem dopamine levels, indicating preservation of the
nigrostriatal dopaminergic system. In contrast, striatal
raclopride binding on PET was reduced, suggestive of
damage to striatal neurons. At necropsy, prominent gliosis
and Alzheimer type II astrocytes were seen in the globus
pallidus, especially its medial portion, and there was no
evidence of damage to neurons of the SNc.
J Neuropathol Exp Neurol Volume 66, Number 8, August 2007
ACKNOWLEDGMENTS
The authors indicate that they have provided legal
testimony and expert consultation to the defendants in the
welding litigation. English quotations that are included in
Ó 2007 American Association of Neuropathologists, Inc.
the text are derived from publications originally published in
foreign languages and are based on certified translations.
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and distinct disease entities and speaks strongly against the
concept that environmental exposure to manganese plays a
role in the etiology of PD.
Pathology of Manganese-Induced Parkinsonism
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