Original Paper
Received: February 24, 2003
Accepted: June 4, 2003

Eur Neurol 2003;50:220–224
DOI: 10.1159/000073863

Diffuse White Matter Lesions in
Carbon Disulfide Intoxication:
Microangiopathy or Demyelination
Mei-Chuan Ku a Chin-Chang Huang a Hung-Chou Kuo a Tzu-Chen Yen b
Chi-Jen Chen c Tung-Sheng Shih d Ho-Yuan Chang e
Departments of a Neurology, b Nuclear Medicine, and c Neuroradiology, Chang Gung Memorial Hospital and
University, d Institute of Occupational Safety and Health, Council of Labor Affairs, Executive Yuan, Taipei, and
e Graduate Institutes of Environmental and Occupational Health, National Cheng Kung University Medical College,
Tainan, Taiwan, ROC

Key Words
Neurotoxic disease W Demyelination W Microangiopathy W
Carbon disulfide W Magnetic resonance imaging W
Dopamine transporter W TRODAT-1 single photon
emission computed tomography

Abstract
Long-term exposure to carbon disulfide (CS2) may induce diffuse encephalopathy with parkinsonism, pyramidal signs, cerebellar ataxia, and cognitive impairments,
as well as axonal polyneuropathy. The pathogenic mechanisms of diffuse encephalopathy are unclear, although
vasculopathy and toxic demyelination have been proposed. Recently, we have encountered a patient who
developed headache, limb tremors, gait disturbance,
dysarthria, memory impairment, and emotional lability
after long-term exposure to CS2. The brain magnetic resonance images (MRI) showed diffuse hyperintensity lesions in T2-weighted images in the subcortical white
matter, basal ganglia, and brain stem. The brain computed tomography perfusion study revealed a diffusely
decreased regional cerebral blood flow and prolonged
regional mean transit time in the subcortical white matter and basal ganglion. To our knowledge, there have
been few reports demonstrating diffuse white matter

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lesions in chronic CS2 encephalopathy using brain MRI.
In addition, the 99mTc-TRODAT-1 single photon emission
computed tomography showed a normal uptake of the
dopamine transporter, indicating a normal presynaptic
dopaminergic pathway. We conclude that diffuse white
matter lesions may develop after chronic exposure to
CS2, possibly through microangiopathy. In addition, CS2
poisoning can be considered as one of the causes of
chronic leukoencephalopathy.
Copyright © 2003 S. Karger AG, Basel

Introduction

Carbon disulfide (CS2), a volatile organic solvent used
in viscose rayon plants, can easily be absorbed and distributed into the lipid-rich tissues [1]. Clinical and experimental studies have shown that many organs are damaged
after chronic exposure to CS2 [2–7]. The central toxicity
of CS2 can be characterized by cognitive dysfunction,
emotional lability, parkinsonian features, cerebellar dysfunction, acute stroke-like symptoms, and atherosclerosis
with dyslipidemia [8–12]. Brain computed tomography
(CT) and magnetic resonance images (MRI) show focal or
diffuse brain atrophy, and multiple brain lesions in the
basal ganglia and subcortical white matter [8, 11, 12]. The

Chin-Chang Huang, MD
Department of Neurology, Chang Gung Memorial Hospital and University
199, Tung Hwa North Road
Taipei, Taiwan (ROC)
Tel. +886 3 3281200, ext. 8413, Fax +886 3 3287226, E-Mail cch0537@adm.cgmh.org.tw

data may indicate a small vessel disease. However, central
demyelination may also occur in some MRI studies [13,
14]. The relationship between small vessel disease and
central demyelination is still unknown. In addition, some
patients may develop parkinsonian features similar to
Parkinson’s disease (PD) [2, 3, 13]. The difference between CS2-induced parkinsonism and PD is still not fully
understood.
Recently, we have encountered a patient with an occupational exposure to CS2, who developed progressive limb
tremor, gait ataxia, dysarthria, rigidity, bradykinesia,
memory impairment, and emotional lability. The brain
MRI showed diffuse white matter lesions, particularly in
the periventricular areas and the basal ganglia, as well as
the pons. In order to understand the basic mechanisms of
CS2 encephalopathy, a brain CT perfusion scan and CT
angiography were performed. In addition, in order to differentiate between CS2-induced parkinsonism and PD,
we also performed a TRODAT-1 single photon emission
computed tomography (SPECT) of the brain to evaluate
the dopamine transporter (DAT) function in this patient.

Case Report
A 56-year-old man, an employee of a viscose rayon plant for
about 27 years, developed progressive limb tremors with a right-side
predominance, resulting in writing difficulty for 10 years. The symptoms got worse in the month before admission. In reviewing his history, we found he had also demonstrated progressive numbness and
muscle weakness in all distal limbs for 8 years and intermittent headache for 6 years. Gait disturbance and frequent falling when going
upstairs or down were also experienced. An insidious onset of dysarthria and dysphagia had also been noted by his family in the most
recent year. In September 2001, he noticed memory impairment, a
dull response with less facial expression, a depressive mood, and
emotional lability. These symptoms had rendered him unable to
work since December 2001. He was then admitted to the Department of Neurology at Chang Gung Memorial Hospital. From the past
and occupational histories, any exposure to carbon monoxide or other organic solvents except for CS2 was not observed. No risk factors
for stroke, including hypertension, diabetes, heart disease, transient
ischemic attacks, nor smoking and alcohol consumption histories,
were found. There was no family history of demyelinating or dysmyelinating diseases.
The neurological examination showed clear consciousness, but
monotonous speech, mild dysphagia, particularly to water, mild left
hemiparesis, obvious dysmetria in both hands with action tremor,
and ataxia with a wide-based gait. There were parkinsonian features
including bradykinesia, rigidity with decreased swing over the right
arm, axial rigidity with difficulty in standing from the sitting position, and postural instability. In addition, hypoesthesia with glove
and stocking-like sensory impairments in the distal limbs, and hyporeflexia in knee jerks and areflexia in ankle jerks were also noted.

White Matter Lesions in CS2 Poisoning

Neuropsychological tests showed prominent impairments, particularly in orientation to time, short-term memory, naming, language
expression, and construction ability. In the Mini-Mental State Examination, a score of 20 was noted (total score 30).
Laboratory studies revealed normal results, including blood
counts, blood sugar, glycohemoglobin, and liver, renal, thyroid and
adrenal functions, except for low high-density lipoprotein (39 mg/dl,
normal 1 40 mg/dl) and the presence of serum cryoglobulin (IgG).
The studies for malignancy revealed negative results.
Nerve Conduction Studies
Motor nerve conduction studies showed prolonged distal latencies
and decreased amplitudes of compound motor action potentials over
the bilateral median, ulnar, peroneal, and tibial nerves tested. The
motor nerve conduction velocities were decreased in the bilateral
ulnar, peroneal, and right tibial nerves. In sensory nerve conduction
studies, no pickup of the response was noted in the bilateral median
and ulnar nerves, and decreased amplitudes of sensory nerve action
potentials were found in the bilateral sural nerves. Electromyography
showed fibrillations and positive waves in the right flexor digitorum
index and tibialis anterior muscles, and increased amplitudes of
motor unit potentials in the right flexor digitorum index muscle. The
data indicated axonal and demyelinating polyneuropathy involving
both motor and sensory nerves with active denervation.
Evoked Potential Studies
Somatosensory evoked potentials disclosed the delayed latencies
of N9 and N13 from right median nerve stimulation, and the delayed
latencies of N9 and N20 from left median nerve stimulation. The
central conduction time of N13–N20 was prolonged in the left side.
In addition, a prolongation of the latencies of N22 and P40, and central conduction time of N22–P40 were noted on both sides with tibial
nerve stimulation. The somatosensory evoked potential data suggested diffuse peripheral and central conduction defects. Pattern reversal
visual evoked potentials also revealed a mild prolongation of P100
latencies, indicating bilateral visual conduction defects. However,
the results of the brain stem auditory evoked potentials were still
within normal limits.
Neuroimaging Studies
The initial brain CT scan in November 2001 showed multiple
hypodensity lesions in the bilateral periventricular areas, and cortical
atrophy. The brain MRI also revealed diffuse signal hyperintensities
in the bilateral corona radiata, basal ganglia and the pons, as well as
cerebral cortical atrophy, dilated sulci, and ventricular enlargement
on T2-weighted images (fig. 1). In brain magnetic resonance angiography, no major occlusion of the intracranial vessels was noted. In
December 2001, a carotid Doppler scan revealed mild heterogeneous
plaques with ! 20% stenosis at the bifurcation of the bilateral internal
carotid arteries. The flows of the bilateral ophthalmic arteries were
normal. The data indicated mild atheromatous changes in the bilateral carotid arteries.
99mTc-TRODAT-1 Brain SPECT

Brain 99mTc-TRODAT-1 SPECT was performed as previously
described [15–17]. The brain 99mTc-TRODAT-1 SPECT study
showed normal DAT functioning at the dopaminergic pathway in the
brain parenchyma. Figure 2 shows the normal uptake of a brain
99mTc-TRODAT-1 SPECT as compared with the results in a PD
patient and a normal control.

Eur Neurol 2003;50:220–224

221

Clinical Course
The patient was discharged under the impression of CS2-induced
encephalopathy with parkinsonism due to diffuse white matter
lesions after long-term exposure to CS2. He was followed up in our
outpatient clinic monthly for more than 1 year, and was treated with
L-dopa 600 mg daily and antiplatelet therapy for about 1 year. There
was no definite improvement in the parkinsonian features after Ldopa treatment. His cognitive functioning such as the memory
impairment had improved mildly 3 months later, but the other neurological deficits, including the parkinsonian features, dysarthria,
cerebellar signs with ataxia, dysmetria, and dyssynergia, still persisted. The repeated brain MRIs in March and August 2002 showed
diffuse hyperintensity lesions in the periventricular white matter,
basal ganglia, and brain stem, respectively. In September 2002, the
neurological deficits were still present.

Fig. 1. The brain MRI in T2-weighted

images showed multiple increased signal intensity lesions in the tegmentum and basis
pontis of the pons (A), the basal ganglia (B),
the paraventricular area (C), and the subcortical white matter (D).

Fig. 2. The brain 99mTc-TRODAT-1 SPECT showed a normal
uptake in the putamen and the caudate of this patient (B) as compared with those in a normal control (A), and a PD patient (C). There

was a reduction of the uptake in the corpus striatum, particularly in
the left side of the PD patient.

Environmental Investigations
We investigated the work environment of the viscose rayon plant
[18]. The concentrations of CS2 in fixed-point air samples at the cutting machine, where the patient had worked, were about 100–
200 ppm in 1992–1995. The 8-h time-weighted average concentrations of personal air samples at the cutting machine were between 20
and 40 ppm [19].

222

Eur Neurol 2003;50:220–224

Brain CT Perfusion
A brain CT perfusion scan was performed in September 2002,
which showed a diffusely decreased regional cerebral blood flow
(rCBF) and prolonged regional mean transit time (rMTT) in the
brain, especially in the subcortical white matter and the basal ganglia
(fig. 3). However, the brain CT angiography revealed no significant
stenosis or occlusion of the intracranial large vessels. The data indicated a diffuse microangiopathy.

Discussion

The present patient showed multiple lesions in the centrum semiovale, the basal ganglion, and the brain stem in
the brain MRI indicating a diffuse white matter lesion.
Clinically, the patient had cognitive impairments, parkinsonian features, pyramidal signs, and cerebellar signs, as
well as polyneuropathy. The electrophysiological studies
confirmed central and peripheral conduction defects, and
the field studies revealed a high air concentration of CS2
(20–40 ppm) in the work environment [18–20]. The current threshold limit value for the 8-h time-weighted average concentration is 10 ppm according to American Conference of Government Industrial Hygienists. The current
permissible exposure limit is even lower (4 ppm) according to the Occupational Safety and Health Administration
in the United States, but is 10 ppm in Taiwan. The data
support the notion that central white matter changes may
occur in patients with long-term CS2 exposure.
In neuroimaging studies, only a few brain CT and/or
MRI scans have shown diffuse or focal brain atrophy, and
abnormal signal intensity lesions in the caudate, putamen,
globus pallidus, and even the subcortical white matter [8–
10, 21, 22]. Peters et al. [13] suggested a central demyelination; however, the important MRI studies were not
shown. In the study by Hageman et al. [14], the brain MRI
showed diffuse white matter hyperintensities, cerebral
cortical atrophy, and mild enlargement of the ventricular

Ku/Huang/Kuo/Yen/Chen/Shih/Chang

Fig. 3. The brain CT (upper row) and rMTT
map (lower row) of the patient (A) and an
age-matched control subject (B) showed a
dilated ventricular size with periventricular
lucency and prolonged rMTT in the patient.
The rMTT of the cerebral hemisphere in the
patient is 4.13 B 2.47 s as compared with
2.66 B 1.59 s in the control subject. The
rMTT of the putamen in the patient is 3.23
B 1.57 s as compared with 2.09 B 0.90 s in
the control subject.

system in 1 patient with long-term CS2 exposure. In our
previous studies [11, 12], multiple lacunar infarcts were
noted in the subcortical white matter, basal ganglion, and
even in the brain stem. Therefore, chronic encephalopathy with a small vessel disease was suggested [12]. In the
present patient, diffuse white matter lesions were found in
the pons and subcortical white matter. In addition, the
brain CT perfusion scan showed a diffusely decreased perfusion, particularly in the subcortical white matter and
basal ganglia, and the CT angiography indicated a relatively normal caliber of the intracranial vessels. The data
are compatible with changes of cerebral microangiopathy
[23].
Previous clinical studies have suggested that CS2 might
cause vascular changes, including those in the smaller vessels of the brain, such as the arterioles and precapillaries
[3, 24]. Aaserud et al. [10] also reported a tendency
towards focal blood flow disturbances in workers with
long-term exposure to CS2, by using brain SPECT with
xenon-133 studies. Thus, the reduced rCBF in the brain
CT perfusion scan might represent a microangiopathy,
which may subsequently induce central demyelination in
the brain MRI. Clinical and experimental studies have
shown that CS2 exposure may accelerate atherosclerosis,
particularly of the aorta, and the cerebral, renal and coronary arteries [3, 9, 10, 24–27]. In addition, demyelination
changes have been found in the globus pallidus, and perivascular demyelination has been observed in the subcortical areas in some experimental animals [3, 22, 28].

The fact that chronic exposure to CS2 may induce parkinsonian features has been extensively reported [1–7].
However, the difference between CS2-induced parkinsonism and PD has rarely been reported [14]. In this patient,
we found a normal uptake of the DAT with the brain
99mTc-TRODAT-1 SPECT, suggesting a different pathophysiological mechanism than that of PD. The data are
also compatible with the ineffectiveness of L-dopa treatment during our patient’s follow-up period.
Patients with CS2 intoxication may present cerebral
white matter lesions, and acute stroke-like episodes. Clinically, some patients may also have cognitive dysfunction.
Therefore, the diagnosis of CS2 intoxication should be differentiated from Binswanger’s disease [29] and nonhypertensive small vessel disease such as cerebral autosomal
dominant arteriopathy with subcortical infarcts, and leukoencephalopathy [30]. In conclusion, CS2 poisoning may
induce diffuse white matter lesions possibly through microangiopathy. Brain CT perfusion studies with rCBF and
rMTT may provide a useful clinical tool. Furthermore,
CS2 poisoning can be considered as a cause of chronic leukoencephalopathy.

White Matter Lesions in CS2 Poisoning

Eur Neurol 2003;50:220–224

Acknowledgements
The study was supported by a grant from the National Science
Council (NSC 91-2314-B-182A-038). The authors are grateful to Ms.
Y.-C. Hsieh for typing the manuscript.

223

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