Exchangeable copper: a reflection of the neurological severity in Wilson's disease.

BACKGROUND AND PURPOSE: The severity of Wilson's disease (WD) is linked to free copper accumulating in the liver and brain. Exchangeable copper (CuEXC) is a new technique to determine plasmatic copper and is useful in the diagnosis of WD. It is hypothesized that it may also enable a good evaluation of extra-hepatic involvement and its severity. METHODS: Forty-eight newly diagnosed WD patients were prospectively evaluated using hepatic, neurological, ophthalmological and brain magnetic resonance imaging (MRI) scores. Three phenotypic presentations were distinguished: pre-symptomatic, hepatic and extra-hepatic. CuEXC was determined in addition to standard copper assays before decoppering therapy. Correlations between biological parameters and the different scores were determined and compared in the hepatic and extra-hepatic groups. RESULTS: Extra-hepatic patients had significantly higher CuEXC values than those with the hepatic form (P < 0.0001). The overall ability of CuEXC to separate the two forms was satisfactory, with an area under the curve of 0.883 (95% confidence interval 0.771-0.996) and an optimal threshold for extra-hepatic diagnosis of 2.08 µmol/l (sensitivity 85.7%; specificity 94.1%). In extra-hepatic patients, CuEXC was the only biological marker to be positively correlated with the Unified Wilson Disease Rating Score (r = 0.45, P = 0.016), the Kayser-Fleischer ring score (r = 0.46, P = 0.014) and the brain MRI score (r = 0.38, P = 0.048), but it was not correlated with the hepatic score. CONCLUSIONS: Exchangeable copper determination is useful when diagnosing WD as a value >2.08 µmol/l is indicative of the severity of the extra-hepatic involvement. In the case of purely hepatic presentation, atypical or mild neurological signs, it should encourage physicians to search for lesions in the brain and eyes.

Bone status and fractures in 85 adults with Wilson's disease.

UNLABELLED: Wilson's disease is characterized by copper deposition, especially in the liver and central nervous system. We assessed the prevalent fractures and bone mineral density (BMD) and related risk factors in 85 patients. BMD was normal, but patients with severe neurological involvement, low BMI, and/or amenorrhea are at risk for fractures. INTRODUCTION: Wilson's disease (WD) is characterized by copper deposition, especially in the liver and central nervous system. Two studies showed a high prevalence of osteoporosis in WD patients. We wanted to assess the prevalent fractures and bone mineral density (BMD) and to identify risk factors for bone loss and fractures in a large group of WD patients. METHODS: In this prospective cross-sectional survey at National center of reference for WD, we included 85 patients, 47 women, and 38 men, with a mean age of 35 ± 10 years, and mean time from diagnosis to study of 21 ± 9 years; 57 (67%) patients had neurological signs. Peripheral fractures, prevalent radiological vertebral fractures (VFx), and dual-energy X-ray absorptiometry BMD measurements at the femoral neck (FN) and lumbar spine (LS) were studied. RESULTS: Mean LS and FN Z-score was normal (-0.37 ± 1.20 at LS and -0.06 ± 1.20 at FN). BMI <19 kg/m(2) and amenorrhea were associated with low BMD. Prevalent peripheral fractures were noted in 43 (51%) and VF in 7 (8%) patients. Severity of neurological involvement and male sex was associated with peripheral fractures, whereas older age, severe neurological involvement, and low BMD and Z-score values were associated with VF. CONCLUSION: Our data showing normal BMD overall do not support routine bone status evaluation in adults with WD. However, patients with severe neurological involvement, low BMI, and/or amenorrhea are at risk factors for fractures and may require specific monitoring.

[Have centers of rare neurological diseases modified practices and the care of Wilson's disease?]. / Les centres maladies rares en neurologie ont-ils changé les pratiques et la prise en charge de la maladie de Wilson?

Wilson's disease is a particularly rare disease. It is a multisystemic affection related to a genetic abnormality of copper metabolism. Drug treatment is particularly effective if administered at an early stage of the disease and continued throughout life. The French Wilson's disease center, certified for only the one disorder, is easily identifiable by everyone, professionals and patients, which has allowed a rapid increase in the number of patients followed by the center, and considerably reduced the delay between first symptoms and diagnosis. Of its numerous ongoing research projects, it is important to mention the development of a new diagnostic test that would allow the speedy introduction of treatment of both the symptomatic forms and presymptomatic familial forms. Collaborations among professionals permit multidisciplinary care and improve the follow-up of patients in terms of all their medical and social aspects. In addition, the organization of the French Wilson's disease network serves as an exemplar for the implementation of Wilson's disease networks in other European countries and the development of collaborations between Wilson's disease patients'associations across Europe. At present, the center is also working to improve the care of patients presenting with other inherited or acquired pathologies related to copper and other heavy metals.

Samuel Alexander Kinnier Wilson. Wilson's disease, Queen Square and neurology.

This historical article describes the life and work of the British physician Samuel Alexander Kinnier Wilson (1878-1937), who was one of the world's greatest neurologists of the first half of the 20th century. Early in his career, Wilson spent one year in Paris in 1903 where he learned from Pierre-Marie at Bicêtre Hospital. He subsequently retained uninterrupted links with French neurology. He also visited in Leipzig the German anatomist Paul Flechsig. In 1904, Wilson returned to London, where he worked for the rest of his life at the National Hospital for the Paralysed and Epileptic (later the National Hospital for Nervous Diseases, and today the National Hospital for Neurology and Neurosurgery) in Queen Square, and also at Kings' College Hospital. He wrote on 'the old motor system and the new', on disorders of motility and muscle tone, on the epilepsies, on aphasia, apraxia, tics, and pathologic laughing and crying, and most importantly on Wilson's disease. The other objective of our paper is to commemorate the centenary of Wilson's most important work published in 1912 in Brain, and also in Revue Neurologique, on an illness newly recognized and characterized by him entitled "Progressive lenticular degeneration, a familial nervous disease associated with liver cirrhosis". He analyzed 12 clinical cases, four of whom he followed himself, but also four cases previously published by others and a further two that he considered in retrospect had the same disease as he was describing. The pathological profile combined necrotic damage in the lenticular nuclei of the brain and hepatic cirrhosis. This major original work is summarized and discussed in the present paper. Wilson not only delineated what was later called hepato-lenticular degeneration and Wilson's disease, but also introduced for the first time the terms extrapyramidal syndrome and extrapyramidal system, stressing the role of the basal ganglia in motility. The present historical work emphasizes the special contributions made by Wilson to the study of movement disorders, including akinesia and bradykinesia in Parkinson's disease, and their relation to basal ganglia pathology.

Wilson's disease, 100 years later .

Texts published, in 1912, 100 years ago, by Sir K. Wilson on his eponymous disease in Brain, The Lancet and La Revue Neurologique highlight the relevance of his descriptions in the light of the current knowledge. Wilson's invocation of an "unknown toxin" appears today as a prophetic intuition as the presence of excess copper in the liver was mentioned for the first time a year later whereas the role of copper in this disease was not described until 1929. Progress has been made to better understand the physiology of Wilson's disease (WD). The ATP7B gene implicated in WD is located on chromosome 13 and more than 500 mutations and 100 polymorphisms have been to date identified. The phenotypic expression is highly variable, even within a family. This can partly be explained by environmental factors as nutrition. Modulator genes are also involved in the phenotypic expression of the disease. Most of symptoms observed in WD have already been described in detail by Wilson in 1912, but subsequent progress was made over the following 100 years, helping the physician diagnose WD. Hepatic and neurological symptoms are the most frequent expressions of the disease. Other extrahepatic features include renal manifestations, osteoarticular disorders, myocardial abnormalities, endocrine disturbances, realizing a multisystemic disease. The diagnosis of the disease is based on a combination of clinical symptoms, biological, radiological and genetic data and new tools (Brain MRI, relative exchangeable copper…) allow reducing delay to diagnosis. Therapeutic findings have also changed the disease prognosis. Treatment is based on the use of copper chelators to promote copper excretion from the body (D-penicillamine and Triethylenetetramine) and zinc salts to reduce copper absorption. Tetratiomolybdate appears to be a promising treatment. While significant progress has been made during this century, many physiological aspects of this disease remain unknown and require further research to find answers in the next 100 years.

Cognitive profile in Wilson's disease: a case series of 31 patients.

BACKGROUND: Wilson's disease (WD) is a rare autosomal recessive disorder of copper metabolism. If untreated, WD, which is initially a liver disease, can turn into a multi-systemic disease with neurological involvement. Very few studies have described cognitive impairment in WD. The aim of this study is to report the cognitive profile of 31 treated WD patients. METHODS: Patients were classed into two groups using the Unified Wilson Disease Rating Scale (UWDRS): WD patients without neurological signs (WD-N(-)) (n=13), and WD patients with neurological signs (WD-N(+)) (n=18). The patients participated in a neuropsychological assessment evaluating memory, executive function and visuo-spatial abilities. RESULTS: Both groups performed well for verbal intelligence and episodic memory skills. However, the majority of these patients exhibited altered performance for at least one cognitive test, particularly in the executive domain. The WD-N(+) group performed less well than the WD-N(-) group on cognitive tests involving rapid motor function, abstract thinking, working memory and top-down inhibitory control. CONCLUSIONS: Cognitive impairment in treated WD patients essentially affects executive function involving fronto-striatal circuits. Verbal intelligence and episodic memory abilities seem to be remarkably preserved. Neuropsychological assessment is a valuable tool to evaluate the presence and the consequences of these cognitive impairments in WD patients with or without neurological signs in the course of this chronic disease.

[Could speech rate of Wilson's disease dysarthric patient be improved in dual task condition?]. / Le débit de parole du patient wilsonien dysarthrique peut-il être amélioré en condition de double tâche?

INTRODUCTION: Dysarthria is one of the first sign of neurological Wilson's disease and is often characterized by a decreased speech rate. The aim of this study is to determine the abilities of Wilson's disease dysarthric patients to control their speech rate. We examined the impact of dual-tasking on the speech rate of patients as compared to healthy control speakers and in relation with their ability to accelerate speech rate when instructed to do so. METHODS: Twenty-six patients and twenty-six age- and sex-matched healthy controls repeated a sentence during 20 seconds at a comfortable speech rate used as reference. They were then asked to perform the same repetition task but in dual task conditions, in which sentence repetition was done while performing three types of executive grapho-motor tasks. Finally, the ability to control speech rate was tested by asking the speakers to perform the sentence repetition task alone but at a fast rate of speech. RESULTS: A significantly slower speech rate was observed for all patients as compared to controls. In the dual-task conditions, while the speech rate of healthy speakers accelerated significantly, two behaviors are found for the patients. Forty-two percent of the patients reproduced the control pattern with a significant increased in speech rate, while the other group significantly decreased their speech rate. Comparison of the ability of the two groups to intentionally modulate speech rate, when instructed to accelerate, shows that significantly better acceleration was achieved by speakers in the former group compared with the latter. CONCLUSIONS: This study supports the finding that patients with Wilson's disease exhibit an impaired speech rate and also impaired control of speech rate. Indirect assessment of speech rate modulation with the help of a dual-task paradigm has proven to be useful to distinguish patient behaviors. This paradigm could also be envisioned as a tool for rehabilitation.

Corpus callosum abnormalities in Wilson's disease.

INTRODUCTION: Wilson's disease (WD) with neurological presentation is associated with brain lesions classically localised in globus pallidus, putamen, thalamus, mesencephalon, pons and dentate nucleus. Lesions of corpus callosum (CC) have not been studied in a broad population of patients with WD. OBJECTIVE: Evaluation of the frequency of CC lesions in patients with neurological symptoms related to WD. METHOD: The authors included all patients with neurological expression of WD, followed in the French national centre for WD who had a brain MRI between March 2006 and December 2008. The localisation of brain lesions was analysed and the frequency of lesions in CC evaluated. All patients were assessed using the Unified Wilson's Disease Rating Scale. For patients with abnormalities located in CC, a clinical dysconnexion syndrome was investigated. RESULTS: Among 81 patients (45 men, mean age: 34.8 years, from 12 to 74 years) with neurological expression, 42% had white-matter lesions on fluid-attenuated inversion recovery MRI. 23.4% of patients presented CC lesions, limited to the posterior part (splenium). The severity of disability estimated by Unified Wilson's Disease Rating Scale was correlated with the presence of CC lesions on MRI. CONCLUSION: Abnormalities in CC are not unusual (23.4%). Together with lesions of basal ganglia, CC signal changes should suggest the diagnosis of WD.

[An unrecognized cause of myelopathy associated with copper deficiency: the use of denture cream]. / Une cause méconnue de myélopathie par carence en cuivre: l'utilisation de pâte adhésive dentaire.

We report two patients with myelopathy associated with copper deficiency and pancytopenia. Excessive intake of zinc can lead to a severe deficiency of copper reducing the absorption of ingested copper. The patients had in common consumption of denture adhesive paste containing zinc. In both patients, laboratory tests showed a combination of copper deficiency, hyperzincemia and increased urinary zinc level. The use of a denture cream was stopped. Copper supplementation, initially subcutaneously then oral corrected the copper deficiency and pancytopenia. Clinically, the pain faded but the gait disturbance persisted. Copper deficiency associated with the use of denture cream rich in zinc is an unrecognized cause of myelopathy associated with pancytopenia which should be diagnosed early to establish appropriate therapeutic measures to minimize neurological complications.

Effect of gabapentin on oculomotor control and parkinsonism in patients with progressive supranuclear palsy.

The efficacy of gabapentin on motor, oculomotor and frontal lobe symptoms was evaluated in patients with progressive supranuclear palsy (PSP) in a pilot study. Fourteen patients were included and seven of them received gabapentin. Clinical evaluation and horizontal eye movement recordings were performed at inclusion and 5-weeks later. Motor score and saccade latency in the visually guided saccade (VGS) task were identical in the two groups. However, the error rate in the antisaccade task was significantly decreased in the gabapentin group. This preliminary study shows that gabapentin improves reflexive saccade inhibition in patients with PSP but does not improve the latency of VGSs.

[Resolution of choreic movements associated with HIV encephalitis with anti-retroviral therapy]. / Mouvements choréiques résolutifs sous traitement anti-rétroviral au cours d'une encéphalite à VIH.

INTRODUCTION: Infection of the central nervous system with human immunodeficiency virus (HIV) can be associated with movement disorders. CASE REPORT: A case of chorea during HIV encephalitis which responded well to antiretroviral therapy is reported. Choreic movements disappeared with a decrease of MRI lesions observed in basal ganglia. CONCLUSION: The efficacy of anti-retroviral therapy in choreic movements, a rare syndrome with HIV encephalitis, can be underlined.

[Movement disorders and botulinum toxin in neurology]. / Mouvements anormaux et toxine botulique en neurologie.

Botulinum toxin has been a useful treatment in many movement disorders and more recently in other non-neurological motor dysfunctions for more than 15 years. Here, we review the various indications in neurology, mainly in the field of movement disorders. From 1973 to 2002, we searched the Medline database on this topic. We selected the most useful and relevant papers, with a special interest in dystonia. We summarized the results in the main indications (spasmodic torticollis, bleparospasm, hemifacial spasm) and in other manifestations such as writer's cramp, oromandibular dystonia, tremor, tics and myoclonus. We discuss the data of literature and compare them with the experience of the French movement disorders groups.

[Parkinsonian disorders: from clinical manifestations to diagnostic classification]. / Les syndromes parkinsoniens : de l'analyse sémiologique au diagnostic nosologique.

Parkinsonism may include atypical clinical manifestations, which are warning signs for the clinicians and motivate further investigations to identify an etiology other than idiopathic Parkinson's disease. The dismemberment of pathological entities, the advances of morphological and functional imaging of the brain, and new insights into molecular biology have successively led to more precise clinical phenotype and mechanisms. Except for etiologies with specific treatment, such as Wilson's disease or Parkinsonism secondary to a lesion of basal ganglia, or the discontinuation of a culprit drug, the treatment of Parkinsonian syndrome is mainly based on a multidisciplinary approach, involving occupational therapist, physiotherapist, speech therapist, psychologist and social worker. L-Dopa may be tried but it is less effective in atypical Parkinsonian syndrome than in Parkinson's disease. Formal diagnosis, only achievable post-mortem, is not available during the lifetime of the patient. Although some additional tests provide undeniable assistance, the clinical approach remains an essential and critical step to avoid costly and unnecessary investigations.

[Abnormal copper metabolism in adult]. / Anomalies du métabolisme du cuivre chez l'adulte.

Copper is essential for many enzymatic reactions and in neurotransmitter biosynthesis. Its deficiency or its excess has consequences on many organs, especially the liver and the brain. The biochemical tests performed in case of suspicion of copper metabolism disorder are difficult to analyse. They include the measurement of serum ceruloplasmin, serum copper and 24h urinary copper excretion. The interpretation must take into account the clinical features. We distinguish mainly: (1) copper deficiency, acquired in malabsorption or in copper diet deficiency, or related to a genetic disease (Menkes disease); (2) copper overload, acquired or from a genetic origin (Wilson disease); (3) aceruloplasminemia, reducing ferroxidase activity leading to iron overload. It is important to diagnose these diseases as some of them have an effective treatment if it is started early enough.

Long term exposure to the chemokine CCL2 activates the nigrostriatal dopamine system: a novel mechanism for the control of dopamine release.

Accumulating evidence show that chemokines can modulate the activity of neurons through various mechanisms. Recently, we demonstrated that CCR2, the main receptor for the chemokine CCL2, is constitutively expressed in dopamine neurons in the rat substantia nigra. Here we show that unilateral intranigral injections of CCL2 (50 ng) in freely moving rats increase extracellular concentrations of dopamine and its metabolites and decrease dopamine content in the ipsilateral dorsal striatum. Furthermore, these CCL2 injections are responsible for an increase in locomotor activity resulting in contralateral circling behavior. Using patch-clamp recordings of dopaminergic neurons in slices of the rat substantia nigra, we observed that a prolonged exposure (>8 min) to 10 nM CCL2 significantly increases the membrane resistance of dopaminergic neurons by closure of background channels mainly selective to potassium ions. This leads to an enhancement of dopaminergic neuron discharge in pacemaker or burst mode necessary for dopamine release. We provide here the first evidence that application of CCL2 on dopaminergic neurons increases their excitability, dopamine release and related locomotor activity.