Endemic parkinsonism: clusters, biology and clinical features.

The term 'endemic parkinsonism' refers to diseases that manifest with a dominant parkinsonian syndrome, which can be typical or atypical, and are present only in a particular geographically defined location or population. Ten phenotypes of endemic parkinsonism are currently known: three in the Western Pacific region; two in the Asian-Oceanic region; one in the Caribbean islands of Guadeloupe and Martinique; and four in Europe. Some of these disease entities seem to be disappearing over time and therefore are probably triggered by unique environmental factors. By contrast, other types persist because they are exclusively genetically determined. Given the geographical clustering and potential overlap in biological and clinical features of these exceptionally interesting diseases, this Review provides a historical reference text and offers current perspectives on each of the 10 phenotypes of endemic parkinsonism. Knowledge obtained from the study of these disease entities supports the hypothesis that both genetic and environmental factors contribute to the development of neurodegenerative diseases, not only in endemic parkinsonism but also in general. At the same time, this understanding suggests useful directions for further research in this area.

Lathyrism in Spain: Lessons from 68 publications following the 1936-39 Civil War.

After the end of the Spanish Civil War (1936-1939), an estimated 1,000 patients presented with lathyrism due to their excessive and prolonged consumption of grasspea (Lathyrus sativus L.) against the backdrop of poverty, drought, and famine. Based on 68 scientific communications between 1941 and 1962 by qualified medical professionals, the disease emerged in different geographical locations involving selective populations: (1) farmers from extensive areas of central Spain, traditionally producers and consumers of grasspea; (2) immigrants in the industrial belt of Catalonia and in the Basque Country, areas with little or no production of grasspea, which was imported from producing areas; (3) workers in Galicia, an area where the legume is neither produced nor consumed, who were seasonally displaced to high-production areas of grasspea in Castille; and (4) inmates of overcrowded postwar Spanish prisons. Original reports included failed attempts by Carlos Jiménez Díaz (1898-1967) to induce experimental lathyrism, the neuropathology of lathyrism in early stages of the disease in two patients, as reported by Carlos Oliveras de la Riva (1914-2007), and the special susceptibility of children to develop a severe form of lathyrism after relatively brief periods of consumption of the neurotoxic seed of L. sativus. In the Spanish Basque Country, L. cicera L. (aizkol) was cultivated exclusively as animal fodder. Patients who were forced to feed on this plant developed unusual manifestations of lathyrism, such as axial myoclonus and severe neuropsychiatric disorders, unknown in other regions of the country and previously unreported. The postwar epidemic of lathyrism in Spain represents the most extensively studied outbreak of this self-limiting but crippling upper motor neuron disease.

Lytico-bodig in Guam: Historical links between diet and illness during and after Spanish colonization.

This paper analyses documents on health and disease among Chamorro people during and after 333 years (1565-1898) of the Spanish claim to and occupation of Guam. Here, a complex neurodegenerative disease-known locally as lytico-bodig and medically as amyotrophic lateral sclerosis and Parkinsonism-dementia complex (ALS/PDC)-reached hyperendemic proportions in the mid-twentieth century but then declined and is now disappearing. A tau-dominated polyproteinopathy, clinical phenotypes included amyotrophic lateral sclerosis (ALS or lytico), atypical parkinsonism with dementia (P-D or bodig), and dementia alone. A plausible etiology for lytico-bodig is consumption of flour derived from the incompletely detoxified seed of Cycas micronesica (fadang in Chamorro; Federico in Spanish), a poisonous gymnosperm that survives climatic extremes that can affect the island. Traditional methods for safe consumption appear to have been lost over the course of time since governors Francisco de Villalobos (1796-1862) and Felipe de la Corte (1855-1866) proposed banning consumption in view of its acute toxic effects. A death certificate issued in 1823 might suggest ALS/PDC in people dying with disability or impedidos, and premature aging and a short life was linked to food use of fadang in the mid-1850s (Guam Vital Statistics Report, 1823). During the Japanese occupation of Guam (1941-1944), Chamorro people took refuge in the jungle for months, where they relied on insufficiently processed fadang as a staple food. After World War II, traditional foods and medicines were subsequently replaced as islanders rapidly acculturated to North American life.

Historical setting and neuropathology of lathyrism: Insights from the neglected 1944 report by Oliveras de la Riva.

Lathyrism is a central motor system disorder recognized since antiquity resulting from prolonged dietary dependence on the grasspea (Lathyrus sativus). The neuropathology underlying the characteristic spastic paraparesis of lathyrism is sketchy. Described here is a landmark but little-known Spanish-language neuropathological study of two patients with lathyrism of recent onset. Due to erroneous interpretations of Filimonov's influential work in 1926, it was assumed that spastic paraparesis of lathyrism was explained by destruction of Betz's pyramidal cells in the motor cortex. Contrary to present understanding, Betz cells and anterior horn cells were preserved, and pathological findings dominated by myelin loss were largely limited to pyramidal tracts in the lumbar cord. Thickening of the adventitia of capillaries and arterioles, together with proliferation of perivascular astrocytes, was found along the length of the spinal cord. Oliveras de la Riva proposed that the segmental spinal pathology arose because distal regions of elongate pyramidal tract axons are distant from their trophic center in the motor cortex, a view not far from the current distal axonopathy concept of lathyrism. In addition, we review the historical circumstances of Filimonov's work in Russia, a summary of the epidemic of lathyrism in Spain following its Civil War (1936-1939), and some historical aspects of the Cajal Institute in Madrid, where Oliveras de la Riva's work was carried out under the supervision of Fernando de Castro, one of Cajal's favorite students.

Paul Broca's search for Basque skulls: The full story.

Paul Broca surmised that the short and broad-brachycephalic-skulls of the earliest European settlers had become longer and narrower-dolichocephalic-in modern populations due to the blending of different races. Swedish anatomist Anders Retzius had two brachycephalic skulls said to be from contemporary Basque individuals, a claim suited to test Broca's hypothesis. Broca worked with fellow anatomist and surgeon Pedro González Velasco, the founding father of Spanish anthropology, to gather a large number of Basque skulls. In its time, this was the most fascinating collection owned by the Anthropological Society of Paris. This article explains how Broca and Velasco were able to gather such a sizeable array of specimens, which they had collected at a location known at first by the code name of "Z." Although Broca finally concluded that the origin of the Retzius skulls could not be determined, his research was to spark anthropologists' interest in the language and origins of the Basque people.

Corticobasal Syndrome in a Family with Early-Onset Alzheimer's Disease Linked to a Presenilin-1 Gene Mutation.

BACKGROUND: Alzheimer's disease (AD) is the second-most frequent cause underlying corticobasal syndrome (CBS). However, a reliable diagnosis using clinical, neuropsychological, or neuroimaging approaches has not yet been achieved. METHODS: Clinical, neuropsychological, imaging, and neuropathology studies were undertaken in a large Spanish family with early-onset familial AD (EOFAD) carrying a Met233Leu mutation linked to presenilin-1 gene (PSEN-1). RESULTS: Two of three examined members of this family presented with the usual amnestic pattern. At the age of 47 years, a third family member, in whom pathology was later confirmed, developed prominent CBS combined with severe neuropsychiatric and behavioral disturbances resembling those often found in EOFAD. CONCLUSION: Although CBS in EOFAD appears to be rare, demonstration of a linkage to PSEN-1 gene mutations may permit in vivo diagnosis.

Short and long term outcome of bilateral pallidal stimulation in chorea-acanthocytosis.

BACKGROUND: Chorea-acanthocytosis (ChAc) is a neuroacanthocytosis syndrome presenting with severe movement disorders poorly responsive to drug therapy. Case reports suggest that bilateral deep brain stimulation (DBS) of the ventro-postero-lateral internal globus pallidus (GPi) may benefit these patients. To explore this issue, the present multicentre (n=12) retrospective study collected the short and long term outcome of 15 patients who underwent DBS. METHODS: Data were collected in a standardized way 2-6 months preoperatively, 1-5 months (early) and 6 months or more (late) after surgery at the last follow-up visit (mean follow-up: 29.5 months). RESULTS: Motor severity, assessed by the Unified Huntington's Disease Rating Scale-Motor Score, UHDRS-MS), was significantly reduced at both early and late post-surgery time points (mean improvement 54.3% and 44.1%, respectively). Functional capacity (UHDRS-Functional Capacity Score) was also significantly improved at both post-surgery time points (mean 75.5% and 73.3%, respectively), whereas incapacity (UHDRS-Independence Score) improvement reached significance at early post-surgery only (mean 37.3%). Long term significant improvement of motor symptom severity (≥ 20 % from baseline) was observed in 61.5 % of the patients. Chorea and dystonia improved, whereas effects on dysarthria and swallowing were variable. Parkinsonism did not improve. Linear regression analysis showed that preoperative motor severity predicted motor improvement at both post-surgery time points. The most serious adverse event was device infection and cerebral abscess, and one patient died suddenly of unclear cause, 4 years after surgery. CONCLUSION: This study shows that bilateral DBS of the GPi effectively reduces the severity of drug-resistant hyperkinetic movement disorders such as present in ChAc.

Cefalea numular: aclarando conceptos / Nummular headache: shedding light on some concepts

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Expansion of regulatory CD8+ T-lymphocytes and fall of activated CD8+ T-lymphocytes after i.v. methyl-prednisolone for multiple sclerosis relapse.

INTRODUCTION: Multiple sclerosis (MS) is a multifocal chronic inflammatory demyelinating disease of the central nervous system. Axonal damage correlates with the presence of macrophages and CD8+ T-lymphocytes at brain lesions. The gold standard of therapy at MS relapse are iv glucocorticoids (GC). The aim of the study was to assess the changes on the different subsets of circulating CD8+ T-lymphocytes at relapse and after iv GC therapy. PATIENTS AND METHODS: We consecutively studied 20 patients at MS relapse before and at day 5 after initiation of i.v. methyl-prednisolone (MP) therapy (1 g/day for 3-5 days). CD4+ and CD8+ T-lymphocytes subsets were studied by multiparametric flow-cytometry. As control group, 18 healthy subjects were studied. RESULTS: Treatment with i.v. MP suppressed activated (CD8+CD38+HLA-DR+, p=0.05) and effector memory (CD8+CD27-CD45RO+) T-lymphocytes (p=0.07). By contrast, an increase of naïve (CD8+CD27+CD45RO-) (p=0.07) and regulatory CD8+CD25+ T-lymphocytes was observed (p<0.002). At MS relapse, there was an inverse correlation between regulatory CD8+CD25+CD28- T-lymphocytes and activated CD4+ (r = -0.6; p=0.012) and CD8+ (r = -0.66; p=0.004) T-lymphocytes. After i.v. MP treatment, positive correlation between regulatory CD4+CD25+high T-lymphocytes and CD8+CD25+ T-lymphocytes was observed (r=0.74; p<0.0001). CONCLUSIONS: Our data suggest that i.v. MP may contribute to changes observed on the differentiation of CD8+ T-lymphocytes, namely blocking their complete maturation, and expansion of regulatory CD8+ T-lymphocytes. We hypothesize an additional effect of i.v. MP in inhibiting axonal damage which may add a neuroprotective effect on MS relapse.

Efficacy of long-term continuous subcutaneous apomorphine infusion in advanced Parkinson's disease with motor fluctuations: a multicenter study.

Continuous subcutaneous apomorphine infusion (CSAI) is, at present, an alternative option for advanced Parkinson's disease (PD) with motor fluctuations. We studied the evolution of patients with PD and severe motor fluctuations long-term treated with CSAI. We reviewed data from 82 patients with PD (mean age, 67 +/- 11.07; disease duration, 14.39 +/- 5.7 years) and severe motor fluctuations referred to 35 tertiary hospitals in Spain. These patients were long-term treated (for at least 3 months) with CSAI and tolerated the procedure without serious side effects. We compared the baseline data of these 82 patients (before CSAI) with those obtained from the last follow-up visit of each patient. The mean follow-up of CSAI was 19.93 +/- 16.3 months. Mean daily dose of CSAI was 72.00 +/- 21.38 mg run over 14.05 +/- 1.81 hours. We found a statistically significant reduction in off-hours, according to self-scoring diaries (6.64 +/- 3.09 vs. 1.36 +/- 1.42 hours/day, P < 0.0001), total and motor UPDRS scores (P < 0.0001), dyskinesia severity (P < 0.0006), and equivalent dose of antiparkinsonian therapy (1,405 +/- 536.7 vs. 800.1 +/- 472.9 mg of levodopa equivalent units P < 0.0001). CSAI is an effective option for patients with PD and severe fluctuations, poorly controlled by conventional oral drug treatment.

Hysterical chorea: Report of an outbreak and movie documentation by Arthur Van Gehuchten (1861-1914).

Psychogenic movement disorders remain a frequent and important clinical problem. First described in the Middle Ages, the dancing mania is considered to be one form of mass hysteria characterized by outbreaks of collective movement disorders. Patients may exhibit a wide variety of movement and gait disturbances, including tremulousness, jerks, or convulsions, usually with a sudden onset. Arthur Van Gehuchten (1861-1914), a distinguished Belgian neuroanatomist and neurologist, reported an outbreak of sudden involuntary movements in 13 adolescent girls residing in an orphanage. The description is to be found in his book Les Maladies nerveuses, completed before 1914 and published posthumously in 1920. The chapter is illustrated with sequential photographs of a girl exhibiting a peculiar gait, which is descriptively referred to as "chorée salutatoire" (saluting chorea). The original film with these pictures has been retrieved and is presented here together with a very similar film excerpt also found in Van Gehuchten's film collection. Van Gehuchten's movie documentation of a psychogenic movement disorder--labeled chorea but which should probably be considered as dystonia according to contemporary classification--appears to be unique. This report illustrates the tremendous value of moving pictures in recording and analyzing movement disorders.

Interferon beta-1a therapy enhances CD4+ regulatory T-cell function: an ex vivo and in vitro longitudinal study in relapsing-remitting multiple sclerosis.

Interferon beta-1a (IFNâ-1a) has demonstrated efficacy in multiple sclerosis (MS), although its mechanism of action remains only partly understood. We evaluated the ex vivo and in vitro effects of IFNâ-1a (Rebif) on regulatory T-cell (T(Reg)) function in 22 relapsing-remitting MS patients and 16 healthy controls. T(Reg) function was significantly enhanced after 3 and 6 months of IFNbeta-1a therapy. Furthermore, there was a trend towards increasing proportions of total CD4(+)CD25(+) and CD4(+)CD25(+)GITR(+) T(Reg) after 6 months of IFNbeta-1a therapy when compared with baseline. In conclusion, IFNbeta-1a therapy enhances T(Reg) function, and this may be relevant in the inflammatory environment of MS lesions.

Pergolide versus levodopa monotherapy in early Parkinson's disease patients: The PELMOPET study.

Dopamine agonists are used as initial treatment in patients with Parkinson's disease (PD) to reduce incidence and severity of motor complications. This paradigm is based on long-term studies, allowing "rescue" therapy with levodopa. The present strict monotherapy study (PELMOPET, the acronym for the pergolide-versus-L-dopa-monotherapy-and-positron-emission-tomography trial) evaluated the efficacy and safety of pergolide versus levodopa without levodopa "rescue" medication. This multicenter, double-blind, randomized, 3-year trial compared pergolide monotherapy (n=148) with levodopa monotherapy (n=146) in dopamine-naive patients with early PD (Hoehn and Yahr stage 1-2.5). Primary efficacy measures were clinical efficacy, severity and time to onset of motor complications, and disease progression. During the 3 years, severity of motor complications was significantly lower and time to onset of dyskinesia was significantly delayed in the group receiving pergolide (3.23 mg/day) compared with those receiving levodopa (504 mg/day). However, time to onset of motor complications was not longer in patients receiving pergolide after 3 years. Symptomatic relief (assessed by Unified Parkinson's Disease Rating Scale [UPDRS], UPDRS II, and III, Clinical Global Impressions [CGI] severity, and CGI and Patient Global Impressions [PGI] improvement) was significantly greater in patients receiving levodopa. Adverse events led to discontinuation of therapy in 17.6% of pergolide patients and 9.6% of levodopa patients. This is the first study comparing strict monotherapy with a dopamine agonist versus levodopa in previously untreated early PD. In principle, both levodopa and a dopamine agonist such as pergolide seem to be suitable options as initial PD therapy. The choice remains with the treating physician based on the different efficacy and adverse event profiles.

Systemic diseases that cause movement disorders.

The present review is aimed at providing practical assistance to the clinical neurologist in reaching a diagnosis, understanding the pathogenic mechanisms of movement disorders associated with systemic diseases, and determining appropriate therapy. Infectious disease by direct effect or as an acquired autoimmune neurological disease, stroke, hypoxia-ischemia, paraneoplastic syndromes, collagen disorders, endocrine, liver and kidney diseases that may cause hypokinetic or hyperkinetic abnormal movement are considered separately. The type and evolution of abnormal movement caused by systemic disease vary with age and underlying pathology. Therapy for abnormal movements should include a primary treatment for the systemic disease.

Usos y abusos en el diagnóstico de los trastornos psicogénicos del movimiento / Use and abuse in the diagnosis of psychogenic movement disorders

En los últimos años pareciera haber sido redescubierta la posibilidad de que los movimientos involuntarios anormales constituyan un síntoma de la histeria de conversión. Se constata un movimiento pendular nuevamente; los trastornos psicogénicos del movimiento parecen estar siendo sobrediagnosticados, a pesar de su relativa rareza. Esta tendencia puede ser explicada de diversas maneras. En primer lugar, por la misma naturaleza de los trastornos del movimiento en general, los cuales a menudo presentan apariencias extrañas o patrones poco habituales que pueden sorprender incluso al especialista experimentado. En segundo término, debido a que el diagnóstico de los trastornos del movimiento es principalmente fenomenológico, se tiende a considerar los casos raros o bizarros como psicogénicos, reviviendo ciertamente antiguas tendencias de la neurología clínica. Más aún, actualmente los neurólogos jóvenes están mal entrenados para reconocer la histeria, pudiendo fácilmente aplicar este diagnóstico a síntomas esotéricos o entendidos pobremente, especialmente si coexisten con perturbaciones psiquiátricas. Los criterios diagnósticos actuales que incluyen conceptos tales como trastornos del movimiento establecidos clínicamente, documentados, probables y posibles, reflejan bien estas dificultades diagnósticas pero son difíciles de recordar, poco prácticas e incluso engañosas. Claves que permiten sospechar un trastorno psicogénico subyacente son el comienzo abrupto, los eventos vitales concomitantes, la litigación, la inconsistencia de síntomas y la asociación con incapacidades pseudoneurológicas, tales como la debilidad y pérdida sensorial. Sin embargo, sólo se puede efectuar un diagnóstico definitivo cuando: 1) El movimiento anormal en cuestión aparece fenomenológicamente incompatible con el trastorno del movimiento que puede simular. El examen electrofisiológico puede ayudar en el temblor, en los síndromes de sobresalto y en la mioclonía pero no sirve en la distonía y el parkinsonismo. 2) Es posible revertir consistentemente el movimiento a través de la administración de placebo bien planeada. Se debe admitir que persistirá un cierto grado de incertidumbre en algunos casos (probables o posibles), en los cuales estos prerrequisitos puaden no ser factibles. Sin embargo, la sospecha -aunque imposible de probar- de una causa o refuerzo psicogénico de síntomas, aún en cuadros orgánicos, no es patrimonio exclusivo de los trastornos del movimiento