The Lancet: Volume 354, Number 9175  24 July 1999

Possible relation of atypical parkinsonism in the French West Indies with
consumption of tropical plants: a case-control study

Dominique Caparros-Lefebvre, Alexis Elbaz, and the Caribbean Parkinsonism
Study Group*

*Members listed at end of paper
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Department of Neurology, Centre Hospitalier Universitaire (CHU) des Antilles
et de la Guyane, Route de Chauvel, 97159 Pointe à Pitre, Guadeloupe, French
West Indies (D Caparros-Lefebvre MD); and Inserm U360, Hôpital de la
Salpêtrière, Boulevard de l'Hopital, 75013 Paris, France (A Elbaz MD)
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Correspondence to: Dr Dominique Caparros-Lefebvre (e-mail: [log in to unmask])


Summary
Background In Europe and North America, Parkinson's disease is the major
form of parkinsonism; less than 4% of cases are progressive supranuclear
palsy (PSP) and about 20% are atypical parkinsonism. The distribution of
these subgroups is different in the French West Indies. We aimed to define
the clinical and demographic specificity of these disorders in Guadeloupe
and to investigate a postulated link with consumption of herbal tea and
fruits from the Annonaceae family (Annona muricata and Annona squamosa),
which contain neurotoxic benzyltetrahydroisoquinoline alkaloids.

Methods Between September, 1996, and August, 1998, 87 consecutive patients
with parkinsonism were referred to the single neurological department in
Guadeloupe. After detailed clinical, neurophysiological, cognitive, and
neuroradiological assessment, they were classified by generally accepted
criteria as having Parkinson's disease, PSP, or atypical parkinsonism. We
compared the amount of tropical fruits and herbal tea consumed by the
various parkinsonian subgroups and by frequency-matched controls (patients
with benign symptoms and no neurodegenerative disease).

Findings Of the 87 patients, 22 had Parkinson's disease, 31 had PSP, 30 had
atypical parkinsonism, and four had atypical parkinsonism associated with
motor neuron disease, 44 of the patients with PSP or atypical parkinsonism
were male. The patients with atypical parkinsonism had symmetrical rigidity
and bradykinesia, and no levodopa peak-dose dyskinesias. Patients with PSP
differed from those with atypical parkinsonism because they had supranuclear
vertical down-gaze palsy, severe gait and balance problems, and frontal-lobe
syndrome. 29 patients with PSP reported regular consumption of pawpaw fruit,
and 26 drank herbal tea. 30 patients with atypical parkinsonism reported
regular consumption of pawpaw fruit, and 24 drank herbal tea. Both of these
groups consumed significantly more fruit and herbal tea than patients with
Parkinson's disease (fruit: odds ratio 23·6; herbal tea: 28·2); and controls
(fruit: 20·7; herbal tea: 6·48).

Interpretation Our study confirms the over-representation of atypical
parkinsonism and PSP in patients with parkinsonism in the French West
Indies. Chronic exposure to neurotoxic alkaloids could be an important
aetiological factor because these compounds induce parkinsonism in animals.
A larger epidemiological study, to clarify the link between these fruits
with atypical parkinsonism and PSP, is proposed.

Lancet 1999; 354: 281-86


Introduction
In Europe and North America, idiopathic Parkinson's disease is the main
cause of parkinsonism, and atypical parkinsonian syndromes account for only
20-30%.1 Clinical and pathological studies have led to the development of
operational clinical diagnostic criteria to distinguish between these
diseases.2 Classic fully established progressive supranuclear palsy (PSP)
accounts for less than 4% of all parkinsonism cases,3 although atypical and
incomplete presentations, many labelled provisionally as parkinsonism or
atypical parkinsonism, are now well known.4 Sporadic cases of parkinsonism
with amyotrophic lateral sclerosis, or combined Parkinson's and Alzheimer's
disease are recognised, but remain infrequent except in Guam.5

A 1-year clinical study (August, 1995, to August, 1996) in Guadeloupe,
French West Indies, showed that there was an unexpectedly high percentage of
atypical parkinsonism unresponsive to levodopa. This island has 420 000
inhabitants and only one department of neurology, where the study was done.
Some patients presented with fully established classic PSP, whereas others
showed features of Parkinson's disease but with many atypical features. The
range of cases closely resembled the descriptions from another study done on
the Mariana islands.6 In the French West Indies, PSP and atypical
parkinsonism predominated in patients who consumed herbal tea and fruits of
the Annonaceae (custard apple or pawpaw family), containing alkaloids that
have insecticidal activity.7,8 The herbal tea is used in traditional
medicine mainly for its sedative and hypnotic effects.
Benzyltetrahydroisoquinolines, present in Annonaceae alkaloids, are
neurotoxic to the basal ganglia in animals.9,10 The water-soluble substance
reticuline, extracted from leaves, seeds, and bark of these plants, is a
major component is a 1
(39-hydroxy-4-methoxybenzyl)-6-methoxy-7-hydroxy-1,2,3,4-tetrahydroisoquinol
ine.8 In prospective analysis of all referred parkinsonian patients in
Guadeloupe, we assessed the link between ingestion of tropical herbal tea or
tropical fruits and the occurrence of atypical parkinsonism and PSP.

Methods
Patients
87 patients with parkinsonism were referred to the Department of Neurology
of the French West Indies University Hospital between September, 1996, and
August, 1998. Two-thirds of them were referred by primary-care physicians,
and the remainder by neurologists. Exclusion criteria were previous stroke,
untreated risk factors for stroke (such as a severe hypertension or
diabetes), treatment during the previous 2 years with neuroleptics, history
of severe head trauma, or encephalitis. Parkinson's disease was diagnosed by
the UK Parkinson's Disease Society Brain Bank criteria.2 The diagnosis of
PSP was made with the US National Institute of Neurological Disorders and
Stroke (NINDS) consensus criteria, which have nine main requirements:4 a
progressive non-familial levodopa-resistant parkinsonism occurring after age
40 years, leading to death within 10 years; postural instability;
ophthalmoplegia; pseudobulbar palsy; and frontal-lobe signs. Other clinical
features not typical of Parkinson's disease11 were: symmetry of parkinsonian
features; predominance of axial rigidity; blepharospasm; eyelid apraxia;
palmomental reflex; autonomic failure; bladder incontinence; cerebellar
signs; pyramidal signs with brisk tendon reflexes; amyotrophy; and
fasciculations. The principal investigator (DCL) examined all patients, and
neurologists of the Carribean Parkinsonism study group (PP, ET, AL, GD, MC)
examined 52 patients (60% of the cases). An acute levodopa test with 200-400
mg levodopa (or an acute apomorphine test) was done after at least 1 month
of treatment with levodopa in line with previous reports.12 Long-term
response to levodopa was also assessed. Parkinsonian signs were rated
according to the unified Parkinson's disease rating scale.13

Procedures
Serum caeruloplasmin and copper studies were done in all patients with
atypical parkinsonism, and cerebrospinal fluid was examined for cells
staining with periodic acid/Schiff, which suggests Whipple's disease in
patients with PSP.14 Electromyography was done to assess involvement of the
spinal anterior horn in patients with amyotrophy, and all patients had brain
computed tomography or magnetic resonance imaging. Patients underwent
cognitive assessment, which included: mini-mental-state examination; Mattis
scale; fluency (animals, and "P"); digit span; and the assessment of frontal
behaviour (apathy or euphoria, imitation, utilisation behaviour, and
grasping reflex).

Controls (n=65) were frequency matched for age and sex to the 65 cases with
atypical parkinsonism or PSP. Controls were selected from patients admitted
for benign symptoms without any neurodegenerative disorder (16 had
cardiovascular disease, 16 had trauma, 13 had headache or vertigo, nine had
asthma, and 11 had other disorders). All controls were examined by a general
practitioner (GM) who was not aware of the specific hypothesis being tested
in this study. Reasons for exclusion were signs of parkinsonism or dementia
(even minor signs), falls, and hypotension.

Patients and controls were asked about their birthplace, place of residence,
educational attainment (years of schooling), and consumption of herbal tea
and fruits from tropical plants. They were classified into two groups,
according to the amount of fruit or herbal tea consumed; those who had eaten
fruits or drank herbal tea once a month or more frequently for at least 2
years, and those who had rarely (less than once a month) or never did. More
accurate information about frequency and duration of use could not be
determined in a comparable way for cases and controls. We assessed
consumption of fruits and herbal tea of the Annonaceae; Annona squamosa
(common names: pomme cannelle, sweetsop, sugar apple, and cherimoya), Annona
muricata (corossol, soursop, guanabana, and graviola), Annona reticulata
(cachiman, custard-apple, and mamon).

Statistical analysis
Basic characteristics of cases and controls were compared with a
non-parametric test (Kruskal-Wallis or Wilcoxon test) for comparison of
means, and 2 analysis for comparison of proportions. Comparison of fruit or
herbal-tea consumption between groups, and calculation of odds ratios and
95% CI was done by logistic-regression analysis, with adjustment for age and
sex. Further adjustments for educational attainment did not modify our
findings and are therefore not reported. In some cases, logistic-regression
models failed to estimate the odds ratio and its CI due to small sample
sizes. In such cases, we used the Mantel-Haenszel analysis with adjustment
for age (four strata defined by age quartiles) and sex, with a continuity
correction of 0·5 in empty cells. This solution is conservative because it
underestimates the odds ratio. First, we compared consumption of fruit and
herbal tea between cases with aytypical parkinsonism or PSP and cases with
Parkinson's disease. Then we compared consumption between cases with
atypical parkinsonism or PSP and controls. Comparisons were made for the
whole group (atypical parkinsonism and PSP) versus controls, and separate
analyses were subsequently done for cases with atypical parkinsonism or PSP.
Statistical testing was at the two-tailed level of 0·05. Data were analysed
with the SAS package (version 6.12).

Results
Participants
There were 22 (25%) patients with Parkinson's disease, 31 (36%) PSP
patients, 30 (35%) patients with atypical parkinsonism, and four (4%)
patients with atypical parkinsonism and motor neuron disease (table 1). On
average, patients with Parkison's disease were younger than those with
atypical parkisonism and PSP; their disease had started at a younger age,
and they had a higher mini-mental-state score. Disease duration was not
significantly different for both groups. The sex distribution differed
slightly but not significantly, among the subgroups. Most of the
participants were of Afro-Caribbean or mixed ethnic origin; the remainder
were white (two Parkinson's disease, one atypical parkinsonism) or of Indian
origin (four Parkinson's disease, six atypical parkinsonism or PSP). A
higher proportion of cases with atypical parkinsonism or PSP than of
Parkinson's disease cases were of Afro-Caribbean or of mixed ethnic origin.
Cases with PSP and atypical parkinsonism were similar to controls in terms
of age, sex, educational attainment, and ethnic origin.

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<SNIP>   Table 1: Characteristics of cases and controls
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Characteristics of subgroups
Parkinson's disease--Only 22 patients met the criteria for Parkinson's
disease,2 with a definite response to levodopa during acute test and over
the long term (table 2). The improvement after levodopa therapy varied from
35 to 80%. The median Hoehn and Yahr stage was 2·5 (range 1·5-4). A
short-duration levodopa response with fluctuations was noted in all cases
and 50% had peak-dose dyskinesias. 17 had a predominant asymmetrical rest
tremor, which had been the first symptom.

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<SNIP>  Table 2: The clinical signs and symptoms seen in each subgroup
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PSP--31 patients had a probable or possible diagnosis of PSP.4 The median
Hoehn and Yahr stage was 3·5 (2·5-5). 22 met diagnostic criteria for
probable PSP.4 Nine had possible PSP with one major feature missing (absence
of gaze palsy in eight cases, presence of familial dementia with
parkinsonism in one case). Some of the probable PSP cases had unusual
clinical features, particularly a marked mid-brain tremor. Three patients
died (two after 6 years, one after 4 years); the cause may have been
respiratory failure related to the pseudobulbar syndrome. Bradykinesia and
rigidity occurred in all patients, symmetrically in most. All had a
predominant axial rigidity, but limb rigidity was variable. Six had
additional neck hyperextension. Ten patients had a transient improvement
with levodopa therapy, but no sustained response with emergence of motor
fluctuations was seen and the acute levodopa test was negative in all.
Cognitive testing was possible in 25 patients. Electromyography showed
abnormal spontaneous activities in all patients, with polyphasic potentials
seen in five patients, and signs of chronic partial denervation, suggesting
motor neuron disease. Results of brain imaging were normal in 24 patients
and showed moderate subcortical atrophy in seven. Serum copper studies and
cerebrospinal fluid were normal in all cases.

Atypical parkinsonism--30 patients could not be classified as having
Parkinson's disease or PSP (no improvement with levodopa and no supranuclear
down-gaze palsy). Rapid progression, a predominantly bradykinetic-rigid
syndrome with early balance problems, and little or no response to levodopa
without dyskinesias, meant that Parkinson's disease was unlikely.15 The mean
duration of levodopa therapy was 2 years (SD 2; range 3 months to 5 years).
The median Hoehn and Yahr stage was 3·5 (range 2-5). Four patients had a
family history of parkinsonism. Four had dystonia that worsened with
levodopa, and involved the limbs in three patients and the neck in one. All
but two patients had postural instability that occurred 1-2 years after
disease onset, but falls were uncommon during the first year. Eight patients
had hypometric saccades. Six patients had an initial positive response to
levodopa challenge but the response diminished over time. One had cerebellar
signs with ataxia and hypotonia, and cerebellar atrophy indicating a
diagnosis of multiple system atrophy. One had severe postural hypotension,
which occurred 3 years before parkinsonism, also indicating a diagnosis of
multiple system atrophy. During the follow-up, none of the 28 other patients
developed typical signs of multiple system atrophy. Cognitive tests were
done on 20 patients. Electromyography, done on patients with suspected motor
neuron disease, showed moderate to severe denervation and polyphasic
potentials. Biological and cerebrospinal-fluid studies were normal. Brain
imaging showed bilateral calcifications of internal pallidum in four
patients. These calcifications are frequent in people from Guadeloupe and
are incidental findings in most cases. Five patients had subcortical
atrophy. One patient died after 4 years.

Atypical parkinsonism with motor neuron disease--Four patients had
associated motor neuron disease suggesting amyotrophic lateral sclerosis,
which occurred before onset of parkinsonism. The Hoehn and Yahr stage was 5
in all cases. The parkinsonian features were similar to those in the
atypical parkinsonism group. The severity of motor neuron disease masked the
akinesia and rigidity at disease onset. Cognitive tests were possible in
only two patients. No patients responded to levodopa, and cerebrospinal
fluid was normal in all patients. Brain imaging showed frontal atrophy in
one patient and was normal in three. Three patients died (one after 4 years
and two after 9 months). In one of these patients, neuropathological
examination showed predominant changes in the medulla and upper cervical
spinal cord, including severe neuronal loss and consequent gliosis in the
anterior horns (of the upper cervical spinal cord), nucleus of the XIIth
cranial nerve, and nucleus ambiguus. In the remaining neurons of these
nuclei there were a few Hirano bodies and many skein-inclusion bodies that
were argentophilic and ubiquitin positive. There were no Lewy bodies, and no
true neurofibrillary tangles. There was pallor of the pyrimidal tracts more
marked in the medullary pyramids and spongiosis of the second layer of the
prefrontal cerebral cortex. Occasional skein-inclusion bodies were also
found in the nuclei of the reticular formation, locus coeruleus, substantia
nigra, and frontal and temporal cortex. In the locus coeruleus and
substantia nigra, there was extracellular pigment consistent with mild
neuronal loss. These neuropathological findings were similar to those
observed in patients with amyotrophic lateral sclerosis or ALS syndrome of
Guam.16,17

Follow-up
Follow-up ranged from 8 months to 2·5 years. In six patients with PSP and
ten patients with atypical parkinsonism, the clinical follow-up suggested an
overlap between Parkinson's disease, atypical parkinsonism, and PSP. Indeed,
during the first 6 months of treatment, a 25-45% functional improvement with
levodopa suggested a diagnosis of Parkinson's disease, even when axial
rigidity was prominent and the parkinsonism symptoms were symmetrical in the
limbs. After 1-2 years, parkinsonism more closely resembled atypical
parkinsonism with a loss of levodopa responsiveness, and later resembled PSP
with the emergence of a supranuclear down-gaze palsy.

Consumption of tropical fruits and herbal tea
Consumption of tropical fruits, herbal tea, or both was reported by higher
proportions of patients with PSP or atypical parkinsonism than of those with
Parkinson's disease or controls (tables 3 and 4). In separate comparisons
with the Parkinson's disease group, the strength of the association with
fruits or herbal tea was similar for PSP (odds ratio 5·98 [95% CI
1·05-34·22]) and atypical parkinsonism (6·02 [1·05-34·5]). Adjustment for
mini-mental-state examination did not affect these findings. Similarly, in
separate comparisons with the control group, the strength of the association
with consumption of fruit or herbal tea was similar for PSP (4·35
[1·25-15·2]) and atypical parkinsonism (4·27 [1·22-14·91]). When the two
variables fruit consumption and herbal-tea consumption were introduced into
the models, the association remained with both of them (fruits 14·0
[3·03-64·8]; herbal tea 4·37 [1·80-10·62]). Conversely, Parkinson's disease
was not associated with an increase in consumption of fruit or herbal tea
compared with controls (1·20 [0·39-3·75]). Analyses restricted to
individuals of Afro-Caribbean origin gave similar results (data not shown).

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<SNIP>    Table 3: Consumption of fruit and herbal tea in cases and controls
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All patients were asked to stop the consumption of herbal tea and fruits. In
two patients with PSP and four patients with atypical parkinsonism, several
symptoms improved progressively after they stopped drinking herbal tea,
particularly the gait disorder, bradykinesia, and rigidity. All six of these
patients were younger than 65 years. In the youngest patient with probable
PSP, gait impairment and postural instability were so severe that he was
unable to work. Symptoms improved progressively after he stopped daily
consumption of herbal tea from Annona muricata, and he was able to return to
work after 2 years. The 3-year follow-up showed that 29 patients with
atypical parkinsonism or PSP were stable after having been advised to stop
consumption of Annonaceae. Of the three patients with atypical parkinsonism
and motor neuron disease who died within 1 year, one drank five to ten cups
of various herbal teas per day (particularly those from Annonaceae), and two
ate two or more fruits of Annona squamosa.

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<SNIP>    Table 4: Odds ratio associated with consumption of fruit and
herbal tea
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Discussion
According to generally accepted operational diagnostic criteria,2,4,15 75%
of the patients in this study did not have Parkinson's disease. In these
atypical cases, many of which resembled PSP, there was a male preponderance.
One of the most striking symptoms was the predominance of swallowing and
breathing difficulties in patients with atypical parkinsonism, even when
amyotrophy and weakness of the limbs were mild. Neuropathological
examination was done in only one patient; the findings were similar to those
in patients with amyotrophic lateral sclerosis or in the amyotrophic lateral
sclerosis subgroup of Guam syndrome, with Hirano bodies and lamellar
intracytoplasmic inclusions resembling Bunina bodies.16-18

The frequency of atypical parkinsonism and PSP is higher in Guadeloupe than
Europe or USA; these disorders were present in 75% of our parkinsonian
patients. We believe that the patients examined provide a reliable picture
of the range of parkinsonism in Guadeloupe because most of the island cases
are referred at some point to the only department of neurology.

We found a strong association between consumption of fruit or herbal tea and
PSP or atypical parkinsonism when these patients were compared with cases of
Parkinson's disease or with controls. However, our analyses are based on
small numbers of cases. The replication of these results on a larger sample
of patients is needed. The exposure assessment was mainly qualitative, so we
were not able to investigate dose-response relations. The questionnaire
evaluated only the 2 years of exposure prior to the diagnosis assessment. A
bias cannot be excluded in patients with a longer disease duration who
changed their fruit and herbal-tea intake as a consequence of the disease.
However, we do not believe that this possibility is likely, because most of
the patients had eaten tropical fruits or drunk herbal tea all of their
lives and because large differences were observed between Parkinson's
disease cases and PSP or atypical parkinsonism cases: there is no obvious
reason why PSP or atypical parkinsonism cases would increase their
consumption of herbal tea or fruit and Parkinson's disease cases would not,
especially since most of PSP or atypical parkinsonism cases had a diagnosis
of Parkinson's disease when they were referred to our clinic. The controls
were asked about their fruit and tea consumption by a general practitioner
who was not aware of the hypothesis under investigation, and cases were
interviewed by the neurologist who led the project; however, both
investigators attempted to collect information as objectively as possible.
These cases bear a close similarity to lytico-bodig of Guam (Andrew Lees
personal communication). The overlap between PSP, atypical parkinsonism, and
dementia is probably the most characteristic feature, common to Caribbean
and Guam syndromes,18 and both have been attributed to a "slow toxin" from
certain traditional food.19 Excessive consumption of the sago palm Cycas
circinalis has been proposed as a cause of lytico-bodig of Guam.20,21 The
possible toxin in these seeds is believed to be ß-N-methylamino-L-alanine.22
Several experimental studies failed to reproduce an animal model of
parkinsonism with this compound,23 and the cause of this disorder is
unknown. The Annonaceae fruits are commonly used in Guam for their sedative
properties.24 A high prevalence of atypical parkinsonism has been also
observed in Afro-Caribbean and Indian populations living in England.25

The neurotoxins tetrahydroisoquinolines and
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine have structural similarity and
similar physiological properties.26 They are substrates and inhibitors of
monoamine oxidase, and inhibitors of mitochondrial complex I.27 The herbal
tea from Annonaceae is used daily or weekly by many people in the French
West Indies, and it has sedative or hypnotic effects.7,8 These effects could
be produced by reticuline (the major component of
benzyltetrahydroisoquinolines) which is an opioid precursor,28 and has
shown, both in vitro and in vivo, several pharmacological activities
including dopaminergic antagonism29,30 and serotoninergic agonism,
associated with antidepressive properties.31 The herbal tea of Annona
squamosa is consumed mainly by old men, which could explain the male
predominance of the disease. This herbal tea is considered to be purgative
by some patients, and aphrodisiac by others. The herbal tea of Annona
muricata is mainly used as a sedative. None of these plants has been used as
antiparkinsonian or antidepressive drugs.7 Quinoline alkaloids have been
isolated from tropical plants and also plants that can cause motor neuron
disease.32 High concentrations of endogenous benzyltetrahydroisoquinolines
have been detected in the cerebrospinal fluid of some parkinsonian
patients;33 these substances could be more potent neurotoxins than the
methyl derivatives of isoquinoline.34 The cytotoxicity of
benzyltetrahydroisoquinolines could be mediated by glutamate35 or free
radicals.36 The genetic susceptibility of some individuals to such toxins
has been seen previously in the polymorphism of cytochrome P450 activity,
which catalyses most oxidative processes.27 In our study, five patients had
a family history of neuro-degenerative disorder, which could suggest genetic
susceptibility to an exogenous toxin.

We suggest that the atypical Parkinsonism seen in many patients in
Guadeloupe could be linked to chronic exposure to
benzyltetrahydroisoquinolines from tropical herbal teas and fruits. To
confirm these findings we are planning a larger case-control study to
investigate dose-response relation and the role of specific fruits.

Contributors
D Caparros-Lefebvre examined all patients, coordinated the linked studies
with colleagues, and wrote the paper. A Elbaz did the epidemiological study,
the statistical analysis, and wrote the results.

The Caribbean Parkinsonism Study Group:
Jacqueline Abaul (Faculté Antilles-Guyane), Annick Alpérovitch (INSERM U360,
Paris), Alim-Louis Benabid (INSERM U318, Grenoble, France), Valérie Bolivar
(CHU Antilles-Guyane), Dominique Charpentier (Department of Ophthalmology,
CHU, Pointe à Pitre), Maurice Collard (CHU Strasbourg, France), Gérard
Dordain (CHU Clermont-Ferrand, France), Alexis Elbaz (INSERM U360, Paris),
Françoise Gray (CHU Paris-Ouest), Reynald Hocquemiller (Laboratoire
Pharmacognosie, Châtenay-Malabry, France), Henri Joseph (TRAMIL group),
Annie Lannuzel (CHU, Pointe à Pitre), Andrew Lees (National Hospital for
Neurology, London, UK), Gwen Mevel (CHU Antilles-Guyane), Charles
Pierrot-Deseilligny (CHU Salpêtrière and INSERM U289, Paris), Pierre Pollak
(CHU, Grenoble), Sophie Rivaud (INSERM U289, Paris), Catherine Sengler
(Pharmaco-Toxicologic Unit, CHU Pointe à Pitre), Eduardo Tolosa (Hopital
Clinici Provincial, Barcelona, Spain).

<SNIP>    References