Classification and differential diagnosis of Wilson's disease.

Wilson's disease is characterized by hepatic and extrapyramidal movement disorders (EPS) with variable manifestation primarily between age 5 and 45. This variability often makes an early diagnosis difficult. A classification defines different clinical variants of Wilson's disease, which enables classifying the current clinical findings and making an early tentative diagnosis. Until the unequivocal proof or an autosomal recessive disorder of the hepatic copper transporter ATP7B has been ruled out, differential diagnoses have to be examined. Laboratory-chemical parameters of copper metabolism can both be deviations from the norm not related to the disease as well as other copper metabolism disorders besides Wilson's disease. In addition to known diseases such as Menkes disease, occipital horn syndrome (OHS), Indian childhood cirrhosis (ICC) and ceruloplasmin deficiency, recently discovered disorders are taken into account. These include MEDNIK syndrome, Huppke-Brendel syndrome and CCS chaperone deficiency. Another main focus is on differential diagnoses of childhood icterus correlated with age and anaemia as well as disorders of the extrapyramidal motor system. The Kayser-Fleischer ring (KFR) is qualified as classical ophthalmologic manifestation. The recently described manganese storage disease presents another rare metabolic disorder with symptoms similar to Wilson's disease. As this overview shows, Wilson's disease fits into a broad spectrum of internal and neurological disease patterns with icterus, anaemia and EPS.

Morphological and functional imaging in neurological and non-neurological Wilson's patients.

Wilson's disease causes disturbances of the central nervous system, affecting it both directly through copper toxicity and indirectly subject to a copper-induced hepatopathy, resulting in morphological and physiological changes in brain structures that can be captured by means of magnetic resonance imaging (MRI), (123)I-ß-CIT (2ß-carbomethoxy-3ß (4-iodophenyl)tropane)-SPECT (single photon emission computed tomography), (123)I-IBZM (benzamide)-SPECT and [(18)F]FDG -PET (fluorodeoxyglucose-positron emission tomography). MRI can reveal even slight morphological changes in non-neurological Wilson's patients. More marked findings in neurological Wilson's patients become evident in T1- and T2-weighted MRI. T1-weighted MRI predominantly detects atrophic changes, whereas T2-weighted MRI regularly records signal changes in the putamen. With the aid of these three nuclear-medicine examinations, nigrostriatal and metabolic disturbances are identified in neurological Wilson's patients only. Sufficient decoppering therapy prevents progression and even tends to improve symptoms. A correlation between any of the imaging findings in patients with the genetic phenotype and the incidence of the most common mutation H1069Q (homozygote or compound heterozygote) or other mutations could not be substantiated.

Fine motor skills disorders in the course of Wilson's disease.

OBJECTIVES: Fine motor skills disorders belong to the neurological manifestation of Wilson's disease. The aim of this study is to investigate if fine motor performance changes during the course of the disease and with therapy. METHODS: In 15 neurological patients with Wilson's disease, severity of neurological symptoms was assessed with a neurology score. A test battery consisting of the hand writing of a test sentence, lines of "double-I" and retracing a circle was carried out for analysis. By means of a computer-aided analysis of the patient's handwriting, 10 kinematic parameters of the writing trace were calculated. These parameters were determined once at the very beginning of the study and then again after 7 years. RESULTS: Improvement of clinical symptoms was observed after onset of therapy only within the first 2 years. In contrast to the standard population, a reduced degree of automation could be detected both at the beginning and at the end of the 7-year interval. There was no significant change in 8 out of the 10 kinematic parameters during the observation period, 2 deteriorated. DISCUSSION: The absence of a significant increase in fine motor disturbances proves, on the one hand, the efficacy of the therapy regime applied. On the other hand, the end point of a possible reversibility had been reached. A computer-aided analysis of the patient's handwriting allows for a sensitive detection of the "functional scar" in the extrapyramidal control and can subsequently prompt a timely correction of therapy in case of progression.

[Postictal paranoid-hallucinatory psychosis in cryptogenic epilepsy]. / Postiktale paranoid-halluzinatorische psychosebei kryptogener epilepsie.

BACKGROUND: Postictal psychosis is an important complication inpatients with epilepsy. METHOD: We report a male patient with pre-existing epilepsy who developed acute psychosis with delusions and acoustic hallucinations, two days after a prolonged complex-partial seizure. Upon treatment with diazepam and haloperidol, the psychosis subsided within three days. RESULT: The optimation of antiepileptic drugs is the main point to prevent seizures and postictal psychotic episodes in epilepsy. CONCLUSION: This case shows that close collaboration between neurologists and psychiatrists on epilepsy associated psychoses is decisive for an optimal success of therapy.

Intrathecal synthesis of autoantibodies against tissue transglutaminase.

Anti-tissue transglutaminase (tTG) antibodies (AtTGA) are typically found in serum of patients with untreated coeliac disease (CD). tTG catalyses crosslinking of peptides an activity supposed to be important in neurological disorders. tTG occurs in cerebrospinal fluid (CSF) and its assay in CSF was suggested to be diagnostically useful. However, nothing is known about AtTGA in CSF. Therefore, in 129 unselected CSF-serum pairs IgA- and IgG-AtTGA were assayed by ELISA using human recombinant tTG. For comparison, IgA- and IgG-anti-gliadin antibodies (AGA), typically coexisting with AtTGA were measured. Albumin, total IgA and IgG and further parameters were determined according to routine programme recommended by the European CSF consensus group. AtTGA were detected in 27 (IgA) and in 63 (IgG) CSF samples. Antibody indices (AI) could be calculated for AtTGA from 21 (IgA) and from 61 (IgG) sample pairs. AI for AtTGA was >2 in 11 (IgA) and in 22 (IgG) sample pairs, hinting to intrathecal antibody synthesis. AI for AGA was >2 only for 1 (IgA) and 2 (IgG) sample pairs. Patients with normal routine findings had significantly higher AI for IgA-AtTGA than patients with abnormal findings. This is the first demonstration of AtTGA in CSF and their intrathecal synthesis. The pathogenetic relevance of this new autoantibody species remains to be clarified.

Diabetic neuropathy in patients with "latent autoimmune diabetes of the adults" (LADA) compared with patients with type 1 and type 2 diabetes.

OBJECTIVE: In previous studies, a lower incidence of diabetes-related complications such as diabetic neuropathy has been reported in patients with early stages of type 1 diabetes compared with type 2 diabetes. The aim of this study was to compare the prevalence of diabetic neuropathy in patients with manifestation of a slow onset type 1 diabetes in adulthood - latent autoimmune diabetes in adults (LADA) - with classical type 1 and type 2 diabetes patients. RESEARCH DESIGN AND METHODS: Altogether, 37 patients (14 LADA, 9 type 1 and 14 type 2 diabetes) with short term diabetes (duration < 5 years) were investigated for diabetic neuropathy on the basis of clinical and neuroelectrophysiological evaluations. The neurological functions were evaluated by a standardized questionnaire and clinical examination. In electrophysiological evaluations the different nerve fibres were investigated using motor and sensory nerve conduction studies, quantitative thermotesting, vibratometry and autonomic function tests (heart rate variability). RESULTS: LADA patients had a significantly lower clinical examination score (p = 0.008), cardiorespiratory reflex index (p = 0.009) and cold perception threshold index (p = 0.004). The neurological symptom score, the indices of motor and sensory nerve conduction, the index of thermotesting (warm perception threshold) and the vibratometry showed a trend to higher values in LADA patients than in type 2 diabetes patients. There were no significant differences between LADA and type 1 diabetes patients. CONCLUSIONS: LADA patients had fewer features of diabetic neuropathy than type 2 diabetes patients in the early stages of disease, thus being more similar to classical type 1 diabetes patients who normally develop diabetic neuropathy rather late.

Concordant pre- and postsynaptic deficits of dopaminergic neurotransmission in neurologic Wilson disease.

BACKGROUND AND PURPOSE: Although previous brain imaging studies of Wilson disease (WD) focused on the dopaminergic system, correlational data on the integrity of the pre- and postsynaptic compartments are lacking. The present study was initiated to intra-individually determine the integrity of these compartments in patients with WD. METHODS: A total of 46 patients with WD and 10 matched control subjects underwent [(123)I]2beta-carbomethoxy-3beta-(4[(123)I]iodophenyl)tropane ([(123)I]beta-CIT) and [(123)I]iodobenzamide ([(123)I]IBZM) single photon emission CT (SPECT). For both radiotracers, specific striatal binding ratios (with the cerebellum as the reference region) were calculated after a standardized region-of-interest technique was applied. In addition, the severity of putative neurologic symptoms was evaluated by using a linear scoring system. RESULTS: In patients without neurologic symptoms, striatal binding ratios of both radiotracers did not differ from those of the control group (13.8 +/- 3.1 vs 12.0 +/- 3.4 and 2.00 +/- 0.19 vs 1.90 +/- 0.27; n.s.). In symptomatic patients, however, striatal binding ratios for both [(123)I]beta-CIT and [(123)I]IBZM were significantly reduced (9.1 +/- 2.3 and 1.64 +/- 0.18; P <.001). In all patients with WD, the [(123)I]beta-CIT and [(123)I]IBZM binding ratios were significantly correlated (r = 0.65, P <.001), as were SPECT parameters and the severity of the neurologic symptoms (r = -0.60 and -0.62; P <.001). CONCLUSION: These findings of a concordant bicompartmental dopaminergic deficit in neurologic WD provide in vivo evidence for assigning WD to the group of secondary Parkinsonian syndromes. These results could be relevant in therapeutic decision making in patients with this copper deposition disorder.

Correlation between automated writing movements and striatal dopaminergic innervation in patients with Wilson's disease.

Handwriting defects are an early sign of motor impairment in patients with Wilson's disease. The basal ganglia being the primary site of copper accumulation in the brain suggests a correlation with lesions in the nigrostiatal dopaminergic system. We have analysed and correlated striatal dopaminergic innervation using [(123)I]beta-CIT-SPECT and automated handwriting movements in 37 patients with Wilson's disease. There was a significant correlation of putaminal dopaminergic innervation with fine motor ability (p < 0,05 for NIV [number of inversion in velocity], NIA [number of inversion in acceleration], frequency). These data suggest that loss of dorsolateral striatal dopaminergic innervation has a pathophysiological function for decreased automated motor control in Wilson's disease. Furthermore analysis of automated handwriting movements could be useful for therapy monitoring and evaluation of striatal dopaminergic innervation.

Genotype correlation with fine motor symptoms in patients with Wilson's disease.

Wilson's disease, an autosomal recessive disorder of copper metabolism, is caused by about 200 different mutations of the ATP7B gene. Using a genotype-phenotype correlation, 36 patients were examined to see whether the disorder of the automatic handwriting movement depends on the genotype. The findings of this study indicated that no such link exists. Neither the profile of the impairment of the fine motor parameters nor the severity and frequency of pathological findings were different among the three genotype groups (homozygous for H1069Q, compound homozygous for H1069Q and other mutations). By contrast, fine motor disorders were found to correlate with the clinical symptoms recorded when therapy began. The pathophysiology of the basal ganglia and the cerebellar loop therefore cannot be directly attributed to the genotype of the mutation in the ATP7B gene.