Wilson disease: neurologic features.

Wilson disease (WD) is a neurodegenerative disorder, which presents as a spectrum of neurologic manifestations that includes tremor, bradykinesia, rigidity, dystonia, chorea, dysarthria, and dysphagia, together with a combination of neurologic symptoms that can easily lead to misdiagnosis. An early diagnosis of WD, and appropriate anticopper treatment, usually leads to a marked improvement in patient health. Conversely, delayed diagnosis can result in persistent pathology, which, left untreated, can ultimately prove lethal. The aim of this chapter is to present a detailed description of the neurologic features of WD, including their evaluation, together with relevant ophthalmologic examinations, brain neuroimaging, and other laboratory measurements that show the extent of the involvement of the nervous system.

[The Correlation between Blood Uric Acid and Goldstein Grading in Hepatolenticular Degeneration Patients with Different Chinese Medical Syndrome Types].

OBJECTIVE: To observe blood uric acid levels and Goldstein grading, as well as their correlation in Wilson's disease (WD) patients with different Chinese medical syndrome types. METHODS: Totally 906 WD patients in line with inclusive criteria were assigned to 6 groups, i.e., the heart spirit confused by phlegm group (HSCP, 26 cases), the phlegm-fire disturbing heart group (PFDH, 90 cases), the retention of damp-heat group (RDH, 113 cases), deficiency of qi and blood group (DQB, 168 cases), the deficiency of Gan-yin and Shen-yin group (DGYSY, 327 cases), the deficiency of Gan and Shen group (DGS, 182 cases) due to different Chinese medical syndrome types. Recruited were another 160 healthy subjects having similar ages and diet structures, who came for medical examinations, as the healthy control group. Venous blood was collected from the medial cubital vein of each-patient on an empty stomach in early mornings to detect blood uric acid levels. Results Blood uric acid levels were lower in each syndrome type group than in the healthy control group (146.08 +/- 67.24 micromol/L in the HSCP group; 157.08 +/- 69.77 micromol/L in the PFDH group; 162.58 +/- 97.72 micromol/L in the RDH group; 156.20 +/- 62.63 micromol/L in the DQB group; 161.83 +/- 111.23 micromol/L in the DGYSY group; 194.41 +/- 90.01 micromol/L in the DGS group; 242.39 +/- 87.55 micromol/L in the healthy control group, P < 0.01). Blood uric acid levels were higher in the DGYSY group than in the other 5 syndrome groups (P < 0.01). Correlation analyses between Goldstein grading and blood uric acid showed that, along with increased Goldstein grade (that was aggravating disease conditions), WD patients' blood uric acid levels decreased (P < 0.01). CONCLUSIONS: WD patient's blood uric acid levels decreased more. Blood uric acid levels and Goldstein grading were different in various Chinese medical syndrome types. Blood uric acid levels had certain value in assessing the severity of WD.

D-penicillamine versus zinc sulfate as first-line therapy for Wilson's disease.

BACKGROUND AND PURPOSE: To compare the course of treatment in patients with symptomatic Wilson's disease (WD) receiving either D-penicillamine (DPA) or zinc sulfate (ZS) as first-line therapy. METHODS: In all, 143 consecutive patients diagnosed with symptomatic WD from January 2005 to December 2009, followed until December 2010, were included. The decision about first-line therapy was made individually after discussion with the patient. Physicians had no clear preference of one drug over the other. Data were analyzed in subgroups with predominantly neurological (DPA, 35; ZS, 21) and hepatic (DPA, 36; ZS, 51) presentation of WD. RESULTS: According to Kaplan-Meier analysis, neurological WD patients scheduled for DPA had a similar probability of not remaining on first-line therapy as patients receiving ZS (20% vs. 24% at the end of follow-up), with adjusted odds ratio (OR) of 0.9 (95% CI 0.2-3.5). In patients with hepatic WD, this probability was significantly higher for DPA (31% vs. 12%; adjusted OR 3.0, 95% CI 0.9-9.9), especially in the first 6 months. Early worsening occurred only in neurological WD patients, with no differences between both treatment groups (35% vs. 19%; OR 2.8, 95% CI 0.7-10.8). Neurological improvement and decrease of liver enzymes were achieved with similar frequency. Compliance with DPA was better in hepatic (97% vs. 80%) but not in neurological patients (91% vs. 81%). Drug adverse effects were more common on DPA (15% vs. 3%). CONCLUSIONS: DPA and ZS are effective in the majority of WD patients. Neither therapy appears to be clearly superior. Therefore ZS may be considered a reasonable alternative to DPA as a first-line therapy.

[Chronic liver diseases--new therapy. Are biopsies necessary?]. / Chronische Lebererkrankungen--neue Therapie. Benötigen wir die Biopsie?

Chronic liver disease can often reliably be assessed only by examination of biopsy material. In this article the possible indications for liver biopsy in viral hepatitis B and C, autoimmune liver disease, steatohepatitis and hereditary metabolic diseases are described. A biopsy may be useful in cases with unclear clinical or serological situations or with questionable chronicity and comorbidities. The assessment of biopsy material should be based on guideline-based classification systems. The value of biopsy diagnosis benefits from a close interdisciplinary clinical pathological cooperation.

Correlación clínica- para-clínica en un escolar con hipertensión porta de etiología a esclarecer / Clinical-paraclinical in a school with portal hypertension to determine

La hipertensión porta (HTP) es el resultado del incremento de la presión dentro del sistema venoso porta. Se presenta con poca frecuencia en el paciente pediátrico pero es una de las mayores causas de morbilidad y mortalidad en el niño con enfermedad hepática. La mayoría de los pacientes con http presentan un estado hiperdinámico, lo cual aumenta el flujo venoso porta y mantiene la hipertensión. Puede ser secundaria a obstrucción a nivel prehepático, intrahepático o extrahehepático.

Portal hypertension (PH) is the result of increased pressure within the portal venous system. It occurs infrequently in the pediatric patient but it is a major cause of morbidity and mortality in children with liver disease. Most patients with PH have a hyperdynamic state, which increases venous flow and portal hypertension remains. May be secondary to obstruction at prehepatic, intrahepatic or extrahehepatic.

Liver transplantation in Wilson's disease: are its indications established?

UNLABELLED: The indications of progressive neurological deterioration despite no hepatic insufficiency, for liver transplant (OLT) in patients with Wilson's disease (WD) who do not improve with medical treatment is widely debated. The aim of this paper was to present our OLT experience in WD. PATIENTS AND METHODS: Fourteen patients were given a transplant after the diagnosis of WD for the following indications: in four patients, a steady neurological deterioration that failed to respond to chelation treatment (all with Child grade A liver function); in nine patients, Child grade C hepatic insufficiency, in whom medical treatment had failed (one of these patients also presented with severe neurological alterations); and in one patient, acute hepatic failure secondary to E. Coli infection of the ascitic fluid. RESULTS: Two patients died, one due to severe pancreatitis in the immediate postoperative period and the other, who was transplanted for neurological involvement, experienced an acute rejection episode treated with methylprednisolone in the first postoperative month and, in the 4th month, another episode of acute rejection, failed to respond to corticoids and required OKT-3 administration. She subsequently developed bilateral bronchopneumonia due to cytomegalovirus that led to her death. During the immediate postoperative period all of the cupremia, cupriuria, and ceruloplasmin levels returned to normal. The liver function in the 12 patients currently alive was totally normal after a follow-up of 8 years (range, 1-15 years) with actuarial 5-year survival of 85.7%. CONCLUSIONS: These cases demonstrated that OLT may mobilize copper sufficiently from the central nervous system to correct severe neurological deficits, a result that medical therapy alone cannot achieve. We suggest that OLT be considered for patients with WD who have crippling neurological and psychological diseases, even if liver function is stable.

[Classification of Wilson's disease based on neurophysiological parameters]. / Klassifikation des Morbus Wilson auf der Basis neurophysiologischer Parameter.

In addition to hepatolenticular degeneration in Wilson's disease, sensory and extrapyramidal motoric systems are also disturbed. In this study a classification on the basis of neurophysiological parameters (EAEP, VEP, MSEP, TSEP and MEP) was established according to subclinical disturbances of these pathways in patients with Wilson's disease on long-term treatment. A cluster analysis of latencies of these evoked potentials was performed. The results of cluster analysis revealed three types of electrophysiological profiles: type I with normal latencies and types II and III showing different patterns of prolonged latencies. However, there was no correlation between clinical classification and the results of cluster analysis based on the electrophysiological data. The neurophysiological based classification provides additional information about central manifestations and aids in characterizing the progress of the disease.

Classification of fine-motoric disturbances in Wilson's disease using artificial neural networks.

Patients suffering from Wilson's disease are divided into several types according clinical symptoms only at time of manifestation. Thereby two main subgroups exist: neurologic and non-neurologic types. After long-term therapy the neurological symptoms occurring in hepatolenticular degeneration may be improved but frequently with remaining fine-motoric disturbances which should be used for evaluation of the actual patient state. These disturbances are difficult to assess in an exact and objective manner by clinical examination. Therefore we measured fine-motoric passive and active abilities based on a standardized test set using the VSCOPE-system. The parallel evaluation of all fine-motoric data using an artificial neural network leads to a reclassification of these patients based on actual fine-motoric abilities but not reflecting the clinical classification at time of manifestation.

Successful pregnancies and abortions in symptomatic and asymptomatic Wilson's disease.

BACKGROUND: There are only a few reports regarding the fertility and outcome of pregnancy in Wilson's disease (WD) and none from India. The authors in this study discuss various aspects of fertility in 16 women with WD. METHODS: Retrospective analysis of data from a large cohort of WD, being followed at a tertiary care center. RESULTS: Sixteen patients had conceived on 59 occasions with 30 successful pregnancies, 24 spontaneous abortions, 2 medical terminations of pregnancy and 3 still births. Diagnosis of WD was established after conception in 10 presymptomatic patients while six patients were already on treatment. Among these 16 patients, 9 had history of spontaneous abortions and 12 had successful pregnancies. None of the clinical features of WD changed during pregnancy, with or without treatment. All the 30 babies were full-term and delivered healthy. CONCLUSION: Recurrent abortions are common especially in women with untreated Wilson's disease. However, successful pregnancies and uneventful full-term delivery may occur in mothers of WD on treatment and in undiagnosed, undetected presymptomatic patients. Pregnancy does not seem to have adverse effect on the clinical course of Wilson's disease. Teratogenecity was not seen in the present series with low-dose penicillamine and zinc sulphate.

Diagnosis and phenotypic classification of Wilson disease.

Wilson disease is an inherited autosomal recessive disorder of hepatic copper metabolism leading to copper accumulation in hepatocytes and in extrahepatic organs such as the brain and the cornea. Originally Wilson disease was described as a neurodegerative disorder associated with cirrhosis of the liver. Later, Wilson disease was observed in children and adolescents presenting with acute or chronic liver disease without any neurologic symptoms. While diagnosis of neurologic Wilson disease is straightforward, it may be quite difficult in non-neurologic cases. Up to now, no single diagnostic test can exclude or confirm Wilson disease with 100% certainty. In 1993, the gene responsible for Wilson disease was cloned and localized on chromosome 13q14.3 (MIM277900) (1, 2). The Wilson disease gene ATP7B encodes a P-type ATPase. More than 200 disease causing mutations of this gene have been described so far (3). Most of these mutations occur in single families, only a few are more frequent (like H1069Q, 3400delC and 2299insC in Caucasian (4-6) or R778L in Japanese (7), Chinese and Korean patients). Studies of phenotype-genotype relations are hampered by the lack of standard diagnostic criteria and phenotypic classifications. To overcome this problem, a working party discussed these problems in depth at the 8th International Meeting on Wilson disease and Menkes disease in Leipzig/Germany (April 16-18, 2001). After the meeting, a preliminary draft of a consensus report was mailed to all active participants and their comments were incorporated in the final text.

Investigation of fine-motor disturbances in Wilson's disease.

Patients suffering from Wilson's disease (WD) can be divided into two main subgroups: neurologic and nonneurologic WD. We measured passive and active fine-motor abilities of 37 WD patients and 24 randomly selected volunteers. The measurement was based on a standardized test set in a defined environment for detection of disturbed finemotor control. The set contains 5 tests comprising rest tremor, postural tremor, target tapping, forefinger tapping and spiral painting, reflecting different aspects of movement disorders. The tests showed significant differences between neurologic WD and volunteers, especially for tasks defining active control. In neurologic WD we found no differences between subgroups whereas for non-neurologic WD we often detected slight movement disorders. The detected movement disorders cam be interpreted as persistent disorders after long-term therapy.

Self-rated emotional functioning of patients with neurological or asymptomatic form of Wilson's disease.

Psychopathology was assessed in 50 patients with the neurological form of Wilson's disease (WD-N) and in 17 asymptomatic patients (WD-A) compared to matched healthy controls and to rheumatoid arthritis (RA) control patients using The Hopkins Symptom Checklist. As hypothesized, WD-N patients had significantly lower interpersonal sensitivity and aggression/hostility scores than had healthy controls, but did not differ from them either in depression or anxiety levels. Retarded depression and anxiety were higher among RA patients than in WD-N patients. This nondistressed response to the chronic disabling disease was even more salient in 19 WD patients with lesions in basal ganglia only. WD-A patients did not differ from their healthy peers, which suggests a tendency towards hypercompensation and denial in the former. WD-N patients' limited awareness of their deficits (including impaired control of affective behavior) seems to result from their brain damage implicating the basal ganglia.

[Wilson disease in 2003]. / Wilson-kór 2003.

The actuality of this review is based on the results of a recent international consensus conference on the diagnosis and phenotypic classification of Wilson disease published in 2003. The mechanism of the genetically determined copper elimination failure and the copper toxicity, the clinical presentation forms, the diagnosis and treatment of the disease is reviewed. Wilson disease should be taken into consideration in case of any liver disease of unknown origin or neuropsychiatric symptoms. The internationally accepted scoring system is presented.

Comparison of clinical types of Wilson's disease and glucose metabolism in extrapyramidal motor brain regions.

In Wilson's disease a disturbed glucose metabolism especially in striatal and cerebellar areas has been reported. This is correlated with the severity of extrapyramidal motor symptoms (EPS). These findings are only based on a small number of patients. Up to now it is unknown whether EPS are caused by various patterns of disturbed basal ganglia glucose metabolism. We investigated 37 patients and 9 normal volunteers to characterize the disturbed glucose metabolism in Wilson's disease more precisely. The glucose metabolism was determined in 5 cerebellar and cerebral areas (putamen, caput nuclei caudati, cerebellum, midbrain and thalamic area) by using (18)F-Fluorodesoxyglucose-Positron-Emission-Tomography ( [(18)F]FDG-PET). The database was evaluated by a cluster analysis. Additionally, the severity extrapyramidal motor symptoms were judged by a clinical score system. Three characteristic patterns of glucose metabolism in basal ganglia were obtained. Two of them may be assigned to patients with neurological symptoms whereas the third cluster corresponds to most patients without EPS or normal volunteers. The clusters can be identified by characteristic consumption rates in this 5 brain areas. The severity of EPS can not clearly be assigned to one of the clusters with disturbed glucose metabolism. However, the most severe cases are characterized by the lowest consumption in the striatal area. When there is marked improvement of EPS impaired glucose consumption reveals a persistent brain lesion. Finally, the neurological symptoms in Wilson's disease are caused by (at least) two different patterns of disturbed glucose metabolism in basal ganglia and cerebellum. The severity of EPS seems to be determined by a disturbed consumption in the striatal area.

Quantitative study of pathological forms of astroglia in Wilson's disease.

The number and distribution of Alzheimer type I and II cells (Alz I and II) as well as Opalski cells (Opl) were estimated in chosen brain regions of seven autopsied cases with Wilson's disease (WD). The authors of this study focused especially on the question whether the kind and intensity of astrocytes is linked to the clinical form of the disease and to the intensity of brain damage. Alz I and II cells were counted by the use of the HE method, whereas the number of Opl cells was calculated using the PAS method. The study revealed that among the three types of cells the number of Alz II cells was the highest and that of Alz I cells was the lowest. The distributional patterns of these three types of cells were different. Alz I cells were found mainly in the putamen. Alz II cells were observed diffusely, although they occurred in different numbers in the whole brain. The highest number of Opl cells was found in the putamen. Alz I cells were found only in the neurological type of the disease. The highest number of Alz II cells was seen in the hepatic type of the disease, whereas the highest number of Opl cells was observed in the neurological "mixed" forms. Moreover, intensity of tissue damage with presence of necroses was greatest in neurological WD. In the hepatic type dispersed areas of status spongiosus were observed, without presence of necroses. Our study revealed that the type and amount of the pathological astroglia may correlate both with the clinical form of WD and intensity of tissue damage. Alz II cells seem to be a characteristic feature of the early stage of astroglial response to the pathogenic factor whereas Alz I and Opl cells occur in WD only in the advanced stage of tissue damage.

Enfermedad de Wilson: una revisión a propósito de experiencia clínica en 16 pacientes / Wilson's disease: a review apropos of clinical experience in 16 patients

Wilson's disease is an inherited disorder of copper metabolism. We report 16 patients (6 males) with the disease; 6 had hepatic involvement and 3 were asymptomatic. The age onset was 9 years for hepatic and 17 years for neurologic involvement. The mean delay in diagnosis was 14 months. Chronic hepatitis, cirrhosis and fulminant hepatic failure were the clinical forms of liver disease. Patients with neurologic disorders had behavioral disturbances and extrapyramidal manifestations such as dystonia and parkinsonism. Patients had a good response to penicillamine, except 3 that died of liver complications, in whom the treatment was delayed or discontinued. We conclude that this metabolic disease must be suspected in pubertal children and in adults of less than 30 years old with liver disease of unknown origin or behavioral alterations associated to an extrapyramidal syndrome

Wilson's disease: evidence of subgroups derived from clinical findings and brain lesions.

Using exploratory factor analysis, we prospectively investigated neuropsychiatric symptoms and structural brain lesions of 47 patients with proven Wilson's disease and identified three subgroups. The first subgroup clinically exhibited bradykinesia, rigidity, cognitive impairment, and an organic mood syndrome and by MRI showed a dilatation of the third ventricle. The second subgroup was characterized by ataxia, tremor, reduced functional capacity, and focal thalamic lesions. The third subgroup showed dyskinesia, dysarthria, an organic personality syndrome, and focal lesions in the putamen and in the pallidum.