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Over the last 60 years an abnormally high prevalence of atypical Parkinsonism has been reported in 5 different geographic isolates. It was first described on Guam, later in New Guinea and in the Kii peninsula, on Guadeloupe, and in New Caledonia. We investigated the phenotype of atypical Parkinsonism in three of these foci and observed several similarities with dementia in most and amyotrophic lateral sclerosis in some. This disappearance of this disease in two places--Guam and New Guinea--suggested an environmental origin which has not been clarified before the disease ended. The exposure to annonaceae acetogenins and/or rotenone has been documented in four of these places, and experimental studies in animals demonstrated annonaceae acetogenins neurotoxicity, which is similar to rotenone neurotoxicity. Simultaneous exposure to acetogenins and rotenone could produce a synergistic toxicity on neurons.

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We characterize the clinical features of Parkinson's syndrome on Guadeloupe and describe possible environmental causes. Consecutive patients who were referred to the University Hospital at Pointe a Pitre with parkinsonism from September 1996 to May 2002 were included. All cases were examined in a standardized manner by a neurologist with a special interest in movement disorders and independently by 3 external movement disorders specialists, using standard operational clinical diagnostic criteria. The subjects were 265 patients with Parkinson's syndrome living on Guadeloupe, four fifths of whom had been referred by primary care physicians and one fifth by neurologists. The levodopa response was assessed after a minimum period of 1 month of continuous treatment. All patients had brain computed tomography or brain magnetic resonance imaging scans and detailed neuropsychological examinations. Of 265 patients, only 66 were classified as Parkinson's disease, whereas 58 fulfilled the National Institute of Neurological Disorders and Stroke (NINDS) and Society for Progressive Supranuclear Palsy (SPSP) criteria for progressive supranuclear palsy, 100 had unclassifiable parkinsonism, characterized by dopa-unresponsiveness, marked axial rigidity, relative symmetry of parkinsonian features, early dysarthria, and frontolimbic cognitive impairment. Within this group, early postural instability, dysarthria, a frontal behavior disorder, cortical or subcortical atrophy, pyramidal signs, axial rigidity, and family history of neurodegenerative disorders were associated with poorer prognosis. A very large number of unclassifiable cases of atypical parkinsonism that do not fulfill operational criteria for Parkinson's disease or other defined motor neurodegenerations has been observed on Guadeloupe. Most patients closely resemble descriptions of bodig from Guam. In both geographic isolates, an environmental cause has been discussed. Annonaceae fruits and herbal teas are consumed on both islands. These plants contain several neurotoxins, particularly acetogenins, which induce dopaminergic neuron loss in animals. Neuronal death involves cholinergic and dopaminergic cells of the substantia nigra and GABAergic neurons of the striatum, associated with microglial proliferation. The development of atypical parkinsonism in Guadeloupe and probably elsewhere, could result from synergistic toxicity, but acetogenins are probably the most potent neurotoxin, acting as mitochondrial complex I inhibitor.

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INTRODUCTION: : On Guadeloupe, atypical parkinsonism is abnormally frequent, and represents 75% of progressive parkinsonism while Parkinson's disease (PD) accounts for only 25%, which is an inversed percentage in comparison with Europe. Herbal tea made with Annonaceae leaves (containing benzyltetrahydroisoquinolines (Be-TIQ), tetrahydroprotoberberines (THPB) and acetogenins (potent mitochondrial complex I inhibitors) are commonly used on Guadeloupe. CLINICAL STUDY: : Of 265 patients studied on Guadeloupe, 66 (25%) had PD, and 199 (75%) had atypical parkinsonism. This latter group includes 58 patients (29%) with progressive supranuclear palsy (PSP), and 100 patients (50%) with unclassifiable parkinsonism (UP). This focus resembles the parkinsonism-dementia complex (PDC) described on Guam, where a very high prevalence of atypical parkinsonism has been reported since the second World War, including one-third of PSP. A preliminary case-control study on Guadeloupe showed a significant higher consumption of fruits and herbal tea of Annonaceae in atypical parkinsonian cases (PSP and unclassifiable parkinsonism, UP), compared to hospital controls and to idiopathic PD. DISCUSSION: : The overrepresentation of atypical parkinsonism on Guadeloupe and Guam could be related to the consumption of plants containing (simultaneously) isoquinoline derivates which are toxic for dopaminergic neurons and inhibitors of the mitochondrial respiratory chain such as acetogenins. This hypothesis is in keeping with epidemiologic data and experimental studies showing neuronal loss after exposure to isoquinolines or acetogenins.

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Steele, Richardson and Olszweski in 1964 described a distinctive clinical and pathological entity they called progressive supranuclear palsy (PSP). Now on Guadeloupe in the Carribbean French West Indies, Caparros-Lefebvre is identifying many patients with similar clinical and histological features. Others have a clinical syndrome of atypical parkinsonism that resembles the parkinsonism-dementia complex (PDC) of Guam and the Kii peninsula of Japan (PDC). But in those Pacific foci the histology is different and the abnormal tau is of Alzheimer's type rather than the PSP type of Guadeloupe. In both locales, neurotoxins of local foods are implicated in etiology. Future studies will confirm if Guadeloupean parkinsonism is truly a geographic focus of PSP, and if dietary factors account for both.

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Behçet's disease (BD) is a chronic relapsing multisystem disorder. While most frequently occurring around the Mediterranean and in Japan, isolated cases of BD have been reported in Africa south of the Sahara and in the Caribbean. The aim of this study was to describe our experience of BD in Guadeloupe (French West Indies) where the presence of the disease has not been reported previously. We analysed retrospectively the charts, and clinical and imaging features of patients native to Guadeloupe who were diagnosed with neurological manifestations of BD between 1989 and 1999. In our series of 13 cases, seven had neurological involvement. Neurological manifestations included meningoencephalitis or meningoencephalomyelitis in four cases, cerebral venous thrombosis in one case and peripheral neuropathy in two cases associated with myositis in one. Patients received treatment with colchicine (n=7), corticosteroids (n=6), immunosuppressive therapy (azathioprine and/or cyclophosphamide; n=4), acetylsalicylic acid (n=2) and oral anticoagulation for venous thrombosis (n=1). Long-term sequelae occurred only in patients with recurrent neurological disease. This study suggests that the frequency of BD in this Afro-Caribbean population is higher than this reported in Caucasian populations. Meningoencephalitis is associated with a poor prognosis while other patients achieved recovery.

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An unusually high frequency of atypical Parkinson syndrome has been delineated over the last 5 years in the French West Indies. Postural instability with early falls, prominent frontal lobe dysfunction and pseudo-bulbar palsy were common and three-quarters of the patients were L-dopa unresponsive. One-third of all patients seen had probable progressive supranuclear palsy (PSP). This new focus of atypical parkinsonism is reminiscent of the one described in Guam and may be linked to exposure to tropical plants containing mitochondrial complex I inhibitors (quinolines, acetogenins, rotenoids). Two hundred and twenty consecutive patients with Parkinson's syndrome seen by the neurology service at Pointe à Pitre, Guadeloupe University Hospital were studied. Currently accepted operational clinical criteria for Parkinson's syndromes were applied. The pathological findings of three patients who came to autopsy are reported. Fifty-eight patients had probable PSP, 96 had undetermined parkinsonism and 50 had Parkinson's disease, 15 had amyotrophic lateral sclerosis with parkinsonism and one had probable multiple system atrophy. All three PSP patients in whom post-mortem study was performed had early postural instability, gaze palsy and parkinsonian symptoms, followed by a frontolimbic dementia and corticobulbar signs. Neuropathological examination showed an accumulation of tau proteins, predominating in the midbrain. There was an exceptionally large accumulation of neuropil threads in Case 1. Biochemical studies detected a major doublet of pathological tau at 64 and 69 kDa in brain tissue homogenates. All cases were homozygous for the H1 tau haplotype, but no mutation of the tau gene was observed. Clinical, neuropathological and biochemical features were compatible with the diagnosis of PSP, although some unusual pathological features were noted in Case 1. A cluster of cases presenting with atypical parkinsonism is reported. Guadeloupean parkinsonism may prove to be a tauopathy identical or closely related to PSP.

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In the French West Indies there is an abnormally high frequency of levodopa-resistant parkinsonism, suggested to be caused by consumption of fruit and infusions of tropical plants, especially Annona muricata (corossol, soursop). To determine whether toxic substances from this plant can cause the neuronal degeneration or dysfunction underlying the syndrome, we exposed mesencephalic dopaminergic neurons in culture to the total extract (totum) of alkaloids from Annona muricata root bark and to two of the most abundant subfractions, coreximine and reticuline. After 24 hours, 50% of dopaminergic neurons degenerated with 18 microg/ml totum, 4.3 microg/ml (13 microM) coreximine, or 100 microg/ml (304 microM) reticuline. The effects of the alkaloid totum were not restricted to the population of dopaminergic cells since GABAergic neurons were also affected by the treatment. Nuclei in dying neurons showed DNA condensation or fragmentation, suggesting that neuronal death occurred by apoptosis. Cell death was not excitotoxic and did not require toxin uptake by the dopamine transporter. Neurodegeneration was attenuated by increasing the concentration of glucose in the culture medium, which also reduced the effect of the dopaminergic neurotoxin MPP+, a mitochondrial respiratory chain inhibitor. Toxin withdrawal after short-term exposure arrested cell death. Acute treatment with totum, coreximine, or reticuline reversibly inhibited dopamine uptake by a mechanism that was distinct from that causing neuronal death. GABA uptake was not reduced under the same conditions. This study suggests that alkaloids from A. muricata can modulate the function and the survival of dopaminergic nerve cells in vitro. It is therefore conceivable that repeated consumption could cause the neuronal dysfunction and degeneration underlying the West Indian parkinsonian syndrome.

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