肝豆状核变性的早期临床表现及误诊分析

目的:探讨肝豆状核变性(wilson’s disease WD)的早期临床表现及早期诊断,旨在提高临床医生对本病的 认识,减少误诊。方法:回顾性分析50例WD病的早期临床表现、实验室及特殊检查、首次误诊情况。结果:50例患者 中,神经、精神异常者35例,肝炎、肝硬化13例,伴消化道出血2例。关节痛2例。K-F环阳性49例。血清铜蓝蛋白、血 清铜均降低。误诊最常见的依次为各种类型肝炎、肝硬化、精神疾患、关节炎、脱髓鞘脑病、胶质瘤、肌营养不良、肾炎、癫 痫、贫血、消化道大出血和Leigh、脊髓病等,误诊率达34％。结论:WD多见于青少年,神经系统及肝损害为主要临床表 现,常伴有肾脏损害,K-F角膜环是重要阳性体征,头颅CT或MRI可作为辅助诊断手段。本病易被长期误诊或诊断不 明,早期治疗对预后至关重要。建议对具有上述易被误诊疾病症状的患者常规行角膜K-F环及铜代谢检查,以免误诊误 治。     

Oral zinc sulphate as long-term treatment in Wilson's disease (hepatolenticular degeneration).

Clinical amelioration, clearance of Kayser-Fleischer rings and rising of ceruloplasmin concentration are described in a patient with the classical findings of Wilson's disease. These changes occurred during a 14-year period in which he used oral zinc sulphate (three times daily 200 mg) as the only medication to influence copper metabolism. Before starting this long-term zinc sulphate therapy he had used D-penicillamine (three times daily 300 mg) for only 6 weeks. The antagonistic action of zinc sulphate on copper resorption with amelioration of the clinical condition has been described before in this patient in 1961 by Schouwink. The patient had used at that time oral zinc sulphate for approximately 1.5 years. No changes in Kayser-Fleischer rings and ceruloplasmin levels were mentioned. Our findings suggest that oral zinc sulphate may not only prevent storage of copper in the tissues but may also contribute to the mobilization and excretion of deposits of copper.     

Wilson病46例临床分析

目的探讨W ilson病的临床表现特点和诊治。方法分析我院46例W ilson病患者的临床表现、辅助检查及治疗方案。结果本文46例患者,41.3%以消化道症状首发;34.8%早期误诊,均为神经系统以外症状起病者。所有患者化验血清铜兰蛋白均降低,89.13%K-F环阳性,颅内以双基底节对称性病变多见。5例行肝移植治疗,余41例予常规治疗。结论 W ilson病临床表现复杂,涉及多系统,易误诊。D-青霉胺、锌剂、肝移植是目前治疗W ilson病的有效方法。     

Effect of liver transplantation on neurological manifestations in Wilson disease

BACKGROUND: Liver transplantation (LT) is the sole resolutive therapy for Wilson disease (WD) and is the treatment of choice for patients with WD who have fulminant hepatic failure or end-stage cirrhosis. Although its role in managing the neurological manifestations of WD is not yet conclusive, LT has recently been advocated as a therapy for neurologically affected patients with WD with stable liver function. OBJECTIVE: To evaluate the effect of LT on the neurological manifestations of WD. OBSERVATION: A 44-year-old man with WD with cirrhosis and neurological symptoms (motor dysfunction and cognitive impairment) experienced a dramatic improvement in motor function early after LT, as well as normalization of copper balance and the disappearance of Kayser-Fleischer rings. Abnormalities seen on magnetic resonance imaging scans were reversed 18 months after LT. Cognitive testing 2 years after LT showed a moderate global improvement. CONCLUSIONS: In this case, LT healed the neurological manifestations of WD. To date, this favorable result has been seen in almost 80% of cases. However, the decision to perform LT in patients with WD solely on the basis of neurological impairment must be considered experimental.     

Evoked potentials in children with Wilson's disease

We assessed multimodal evoked potentials (EPs) in 13 children with newly diagnosed neurologically symptomatic Wilson's disease (WD) and in their first degree symptom-free relatives, consisting of seven presymptomatic and 15 asymptomatic siblings and 22 asymptomatic parents. EP abnormalities of at least one modality and one side stimulation were observed in 38.5% of patients, 42.9% of presymptomatic siblings, 21.4% of asymptomatic siblings and 18.2% of parents. Patients tended to have more prolonged central latencies of EPs. However, the left I-V interpeak brainstem auditory EP latency difference was the only one to reach at the statistical significance (P = 0.001). Abnormal VEP P100 latency was detected more frequently in presymptomatic siblings than those in asymptomatic ones (42.9% vs 7.1%, P = 0.049). In all relatives, other diagnostic tests including electroencephalography, electromyography and head magnetic resonance imaging (MRI) for subclinical nervous system involvement and Kayser-Fleischer rings examination yielded normal results. In pre/asymptomatic siblings, genetic and biochemical studies may aid to initiate treatment prior to the development of permanent tissue damage. Our results indicate that abnormal EPs may signal unique pathological finding in some subjects. Importantly, these abnormalities occur earlier than Kayser-Fleischer rings and MRI lesions. In early stages of WD, EP recordings may, therefore, be used to help decide on treatment initiation and treatment efficacy evaluation. Moreover, EP recordings can readily be added to family screening studies.     

脑型肝豆状核变性临床特征与MRI分析(附12例报告)

目的:探讨肝豆状核变性的临床特点与头颅MRI特征,为早期诊断及治疗提供参考。方法:回顾性归纳分析12例肝豆状核变性患者的临床表现及神经影像学特点。结果:平均发病年龄23.5岁;以锥体外系症状为首发10例;性格改变1例;学习成绩下降1例,K-F环均为阳性;头颅MRI特征为对称性基底节区、丘脑、中脑及桥脑异常信号。结论:肝豆状核变性临床表现多样,血清铜蓝蛋白检测、角膜K-F环及头颅MRI检查对诊断本病有重要意义。     

Zinc in the treatment of hepatolenticular degeneration: report of 3 cases]

Three patients with symptoms and signs of hepatolenticular degeneration (HLD) who developed serious renal side effects of D-penicillamine (DP) had their therapeutic schedule changed to zinc. Patient 1, a 55 year-old man had been well until 12 years old, when skeletal changes (osteomalacia) due to tubular renal disturbance began. His diagnosis of HLD had first been established at age of 32 when he presented with "wing-beat" tremor. He was then begun on DP and his neurological symptoms resolved within one year of initiating therapy but skeletal abnormalities remained unchanged as a sequel. During the next 22 years the patient was continued on DP therapy but with poor compliance. Then the reappearance of his neurological manifestations occurred several times. By the age of 53, after one year without therapy, his neurological status has worse. DP was reinstituted but some weeks later his renal laboratory parameters became severely affected. DP was discontinued and zinc sulfate (220 mg three times daily) was introduced. On this therapeutic regimen his renal laboratory parameters returned to previous level after one month. Within one year on this therapeutic regimen neurological manifestations were resolved. After 31 months on zinc treatment he remains neurologically asymptomatic and his renal function is satisfactory. Patient 2, a 41 year old woman had been her diagnosis of HLD at age of 20, when following the diagnosis of the disease in her old brother, she was found to have the laboratory features of HLD and bilateral Kayser-Fleischer rings. DP treatment was recommended at that time but she quit the follow-up. When she was 23, an esophageal variceal bleeding occurred.(ABSTRACT TRUNCATED AT 250 WORDS)     

Hypoceruloplasminemia-related movement disorder without Kayser-Fleischer rings is different from Wilson disease and not involved in ATP7B mutation

Objective:  To explore the relationship between hypoceruloplasminemia-related movement disorder (HCMD) without Kayser-Fleischer rings in Wilson disease (WD) and ATP7B gene mutation.
Methods:  Clinical feature, serum ceruloplasmin (CP), total serum copper, non-CP-bound serum copper (nCC), urine copper, and ATP7B gene sequence were investigated in 24 patients with HCMD.
Results:  The patients with HCMD exhibited a long-term stable course of diseases. Serum CP in HCMD group (0.178 ± 0.025 g/l) was lower than healthy control group (0.291 ± 0.049 g/l, P  < 0.05). Total serum copper in HCMD group was 0.578 ± 0.284 μg/l and was lower than normal lower limit obviously (≤0.80 μg/l). nCC was 0.143 ± 0.073 μg/l and reached 29.18 ± 19.61% of total serum copper. Urine copper in HCMD group was 303.82 ± 225.68 μg/24 h and was higher than normal upper limit obviously (≤70 μg/24 h). A heterozygous nonsense mutation of single nucleotide acid was found in one patient with spasmodic torticollis. Four single nucleotide polymorphisms (SNP) were found and their frequencies were not different between health control group and HCMD group. Four patients exhibited consistent sequence of ATP7B gene listed by GeneBank without any mutation and SNP.
Conclusion:  Hypoceruloplasminemia-related movement disorder without Kayser-Fleischer rings, which exhibits mild low serum CP and a long-term stability of disease course, is different from WD and not associated with ATP7B gene mutation. Further investigation of molecular biology should be encouraged.     

The pilot Stroke Data Bank: definition, design, and data

Four university centers collaborated to contribute 1158 patients with acute episodes of cerebrovascular disease to the pilot Stroke Data Bank, initiated by NINCDS in 1978. During the pilot project a standard set of data collection forms were developed and used at each of the collaborating centers. Data on clinical course, laboratory findings, therapy and outcome were gathered prospectively throughout the patient's hospitalization and at specified follow-up intervals. Using operational definitions of stroke sub-types, consecutive cases were systematically allocated to specific categories of brain and vascular pathology. The definitions were based on clinical criteria as well as on laboratory data, including computerized tomography (CT), and angiography findings. This paper describes the pilot Stroke Data Bank and presents the distribution of cases by diagnostic and demographic categories. It represents one of the largest series of prospectively collected stroke cases studied by CT (90% of the cases) and angiography (42%). Based upon the methods and processes of this pilot study, a main phase of the Stroke Data Bank has been established to address a number of questions pertaining to stroke classification, evolution, diagnosis, and prognosis.     

Limb-girdle syndrome: a genetic study of 22 large Brazilian families. Comparison with X-linked Duchenne and Becker dystrophies

The differential clinical diagnosis between the X-linked muscular dystrophies (DMD and BMD) and autosomal recessive limb-girdle muscular dystrophy (LGMD), which is extremely important for genetic counseling, may be very difficult. The aim of the present report is to describe clinical and laboratory findings in patients from large families, with AR inheritance, in an attempt to characterize better cases which have been diagnosed as LGMD compared with the X-linked forms. The main features analysed are: age of onset and of confinement to a wheelchair, reproductive performance, serum enzymes (CK and PK) and dystrophin assessment (through immunohistochemistry and Western blot). Twenty-two families, with 62 affected patients diagnosed as limb-girdle muscular dystrophy, were included in this report. In 19 families, the patients had a milder clinical course, while in the remaining 3, the progression of the disease was continuous and clinically similar to X-linked DMD ("DMD-like"). A high consanguinity rate was observed among the parents of the affected patients (77%). No major clinical difference was observed between the X-linked and the AR forms. However, muscle dystrophin was found qualitatively and quantitatively normal in the autosomal forms but absent or abnormal in the X-linked ones. The reproductive performance was significantly higher for male than female patients. In addition, a surprising finding was the significantly greater fitness estimated for male LGMD cases as compared with Becker patients of comparable age studied in our center. The implications of such findings are discussed.     

36例神经梅毒的临床特点及诊断分析

目的 总结神经梅毒的临床特点及诊断. 方法 回顾性分析中山大学附属第=三医院神经科自2002年1月至2008年11月收治的36例神经梅毒患者的临床分型、临床特点、误诊情况、脑脊液(CSF)检查和MR改变. 结果本组患者发病年龄30～78岁.平均48.1岁:男性明显多于女性;常见类型为间质型(18例)、实质型(麻痹性痴呆,10例)、无症状型(4例)神经梅毒;最常见的症状是精神异常及痴呆,其次是局灶神经功能损害如瘫痪、构音障碍等;误诊率高达55.6%.最易被误诊为病毒性脑炎和脑血管意外;CSF的生化异常表现为白细胞数增加、蛋白升高:CSF-梅毒螺旋体明胶凝集试验(TPPA)阳性率(91.7%)明显高于CSF-性病研究实验室试验CSF-(WORE)阳性率(55.6%)和CSF-梅毒螺旋体IgM抗体试验(CSF-ELlSA-TP-IgM)阳性率(38.9%),差异均有统计学意义(P<0.05);影像学表现多样化. 结论 神经梅毒的诊断目前尚无金标准.其临床表现和影像学改变多样化,CSF梅毒螺旋体抗体检查是诊断神经梅毒的重要依据,诊断应主要依靠CSF检查并进综合分析.     

Osteoarthropathy of hepatolenticular degeneration

Ninety-six joints of 25 patients with hepatolenticular degeneration have been studied by means of scintigraphs with technetium (^99mTc), a method which can disclose early synovial inflammation and postinflammatory articular degeneration. Signs of synovitis were found in 22 joints of 10 patients (40%) and degenerative changes were present in 15 joints of eight patients (32%). Eleven patients complained of joint pains; in four of them they were the presenting symptom. the radiological study showed osteoporosis in 22 patients (88%); flexion deformity was found in two cases, anomalous osteophytes in two, and signs of growth arrest, features of rheumatoid arthritis and aseptic necrosis in one case each. the pathogenesis of osteoarticular changes in Wilson's disease is discussed.     

Multiple sclerosis in children under 6 years of age.

OBJECTIVES: To characterize MS patients with the earliest onset of disease. BACKGROUND: MS-primarily a disease of young adulthood-begins in childhood in 3 to 5% of cases. However, onset before 10 years of age is considered exceptional. Accordingly, inclusion age at onset is generally between 10 and 59 years. METHODS: Information was obtained on patients with MS treated at our institution (n = 6) or from reports in Medline or bibliographies. Onset of disease was before 6 years of age, for a total of 49 patients (29 girls, 20 boys). RESULTS: All patients had clinically defined MS according to Poser's criteria; 22 were also laboratory supported. The female/male ratio (1.4) was lower than that usually recorded for adult onset MS (2.0) and that of MS with onset between 6 and 15 years (2.2 to 3.0). The group of patients (n = 5) with onset before 24 months of age showed the lowest ratio (0.6) and carried the most unfavorable prognosis. Among initial symptoms, ataxia was preponderant (61%). Optic nerve involvement became more frequent with age. Generalized or partial seizures occurred in 22% of cases. First inter-attack interval was less than 1 year in 63% of the cases. The yearly relapse rate ranged from 1.1 at disease onset to 0.2 after 9 years from disease onset. At follow-up (mean length 6.8 years), the disease was relapsing-remitting in 84% patients and the grade of recovery was complete in 64%. CONCLUSIONS: Definite MS can be consistently diagnosed by current criteria for adult onset MS in patients with the earliest onset of disease who show peculiar clinical features and natural history. These findings may suggest a reconsideration of current lower limits for MS diagnostic criteria.     

不伴感觉神经受累的肯尼迪病5例临床特征分析

目的分析不伴有感觉异常肯尼迪病的临床特征、血清学检查、电生理检查等,以指导临床诊断降低误诊率。方法收集经基因明确诊断的肯尼迪病5例,详细询问其病史,进行全面的体格检查包括详尽的神经系统查体,收集并分析其实验室检查指标、电生理检查特点,及基因测定AR基因1号外显子CAG重复序列。结果5例患者均无明显阳性家族史,均为男性,平均起病年龄(39.8±7.2)岁,从发病到确诊平均病程(9.0±5.2)年,3例患者起病部位为双下肢近端无力,1例患者为口周及颊部"肉跳"感,1例患者为男性乳腺发育;最显著的临床表现为舌肌萎缩、舌肌纤颤、四肢近端肌肉无力;5例患者均无临床及电生理测定的感觉异常。结论肯尼迪病是一种累及下运动神经元的神经变性疾病,感觉不受累的患者也应考虑肯尼迪病,确诊依赖基因测定。     

Multiple sclerosis: report on 200 cases from Curitiba, Southern Brazil and comparison with other Brazilian series

We reviewed the clinical and laboratory findings of 200 patients in Curitiba, Southern Brazil (25 degrees 25'40" S; 49 degrees 16'23" W-GR), with multiple sclerosis (MS)according to Poser's criteria. The patients were classified as: clinically definite (A1 and A2) - 142 patients (71%); laboratory-supported definite - 42 patients (21%); and clinically probable - 16 patients (8%). Relapsing-remitting (RR) form was the most common clinical presentation, with 182 (91%), followed by primary progressive (PP)(16 cases, 8%), and only 2 cases with secondarily progressive form (SP). Nine women and 7 men totalized the 16 PP cases. The mean age of onset was 32.0+/-9.9 (median 32 years). The gender ratio was female 1.8:1 male. All patients, except 3 African-Brazilian, were white. Seven (3.5%) patients developed a clinical history of Devic's syndrome. The initial clinical picture included brainstem/cerebellar syndrome in 126 (63%) cases, sensorial findings in 106 (53%)patients, motor (pyramidal) syndrome in 102 (49.5%), and optic neuritis in 79 (39.5%) cases. 122 (61%) patients had a final EDSS score < 3.5; 45 (22.5%) a score between 3.5 and 5.5, and 33 (16.5%) a score > or = 6.0. There was no significant correlation between the number of relapses or duration of disease with EDSS scores (Spearman's test). Only 14 (7%) of the total number presented the benign form (EDSS< 3.5 after 10 years of disease). We observed a later age of onset and initial clinical findings with higher frequency of brainstem/cerebellar syndrome and optic neuritis, when compared to other Brazilian and Western series     

Wilson's disease: clinical diagnosis and "faces of panda" signs in magnetic resonance imaging. Case report

A 25 year-old man was admitted with polymorph symptomatology resembling basal ganglia disease associated with psychiatric manifestations. The patient had been treated with pericyazine. The drug was stopped but the symptomatology did not improve. The diagnosis of Wilson's disease was established through ophthalmologic examination with slit-lamp that revealed the Kayser-Fleischer ring and laboratory abnormalities showing a low serum ceruloplasmin level and increased urinary copper excretion. T2-weighted axial magnetic resonance imaging demonstrated the " face of panda signs" in the midbrain and pons.     

Prevalence of radiological and clinical cerebrovascular disease in idiopathic Parkinson's disease

Comorbid cerebrovascular disease (CVD) can occur in idiopathic Parkinson's disease (IPD) but its reported prevalence varies considerably. CVD may alter the clinical presentation, course and prognosis in IPD. We aimed to determine the prevalence of radiological and clinical CVD in a neurology clinic IPD population. We undertook a retrospective case-control study of neurology clinic patients with IPD for whom cerebral imaging was available, and excluding probable vascular parkinsonism. IPD diagnosis was validated against UK PDS brain bank criteria. Age and sex-matched controls were identified from patients attending neurology clinics with headache. The presence of radiological cerebrovascular disease, symptomatic CVD (stroke and TIA), and CVD risk factors was recorded for cases and controls. Radiological findings were validated by an experienced consultant neuroradiologist using a structured proforma. Eighty-five cases and 85 controls were studied, based on the number of cases for whom brain imaging existed (CT in 50, MRI in 35) and the number of cases for whom suitable controls could be identified. Indications for brain imaging amongst cases were varied. Cases and controls comprised 55(65%) males, mean (±SD) age (years) 67.4 ± 10.1 (cases), 66.6 ± 9.9 (controls). Radiological CVD was significantly commoner amongst cases (39%) than controls (22%) (p = 0.02, chi-square; odds ratio 2.2, 95% CI: 1.1-4.6). Cases also had significantly more symptomatic CVD, but not CVD risk factors, than controls. Our findings suggest a higher prevalence of radiological and clinical CVD in patients with IPD compared to controls.     

Diagnostic value of periodic complexes in Creutzfeldt-Jakob disease

In 1996, our group published objective electroencephalogram (EEG) criteria to define periodic sharp-wave complexes (PSWCs) suggestive for Creutzfeldt-Jakob disease (CJD). These criteria have since then been strictly applied in all cases reported to us as possible CJD in the course of the German CJD surveillance study. Furthermore, EEG analysis of the records was performed without any additional information on complementary clinical and laboratory data. In this study, we investigated sensitivity, specificity, and the predictive values of these EEG criteria exclusively in cases in which autopsy confirmed (n=150) or excluded (n=56) CJD. EEG criteria were positive in 64% (n=96) of the CJD cases and falsely positive in 9% (n=5) of other dementias. The resulting figures for sensitivity, specificity, and positive and negative predictive values were 64%, 91%, 95%, and 49%, respectively. In the falsely positive cases, Alzheimer's disease (n=4) and vascular dementia (n=1) were the underlying diseases. However, only in one of these five cases both clinical and EEG data would have led to the false-positive result to diagnose probable CJD. These data prove the high diagnostic value of our objective EEG criteria in CJD.     

COVID-19-Associated Encephalopathy: Systematic Review of Case Reports

Background and PurposeSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) primarily attacks the respiratory system, but there are also several reports of the involvement of the central nervous system, with one of the manifestations being encephalopathy. The relatively new emergence of COVID-19 means that few studies have investigated the clinical profile of encephalopathy associated with this disease. This study aimed to determine the clinical profile, laboratory, and imaging results of encephalopathy associated with COVID-19.MethodsThree databases, namely PubMed/MEDLINE, Embase, and Scopus, were systematically searched for case reports and case series related to COVID-19-associated encephalopathy published from January 1, 2019 to July 20, 2020.ResultsThis review included 24 studies involving 33 cases. The most-reported neurological symptoms were disorientation/confusion (72.72%), decreased consciousness (54.54%), and seizures (27.27%). Laboratory examinations revealed increases in the C-reactive protein level (48.48%), the lactate dehydrogenase level (30.30%), and lymphopenia (27.27%). Brain imaging did not produce any pathological findings in 51.51% of the cases. Electroencephalography showed generalized slowing in 45.45% of the cases. Elevated protein (42.42%) and lymphocytosis (24.24%) were found in the cerebrospinal fluid. Fifteen patients were reportedly discharged from the hospital in a stable condition, while four cases of mortality were recorded.ConclusionsThe clinical, laboratory, and imaging findings in this review support the hypothesis that cerebral damage in COVID-19-associated encephalopathy is caused by cytokine-immune-mediated inflammation rather than by direct invasion.     

An unusual neurological disorder of copper metabolism clinically resembling Wilson's disease but biochemically a distinct entity

A patient with progressive neurological disease resembling Wilson's disease but in whom Kayser-Fleischer rings were absent, was given ⁶⁷Cu and ⁶⁴Cu, orally and intravenously, to measure the rate of absorption of copper using a convolution integral. The data show an abnormal distribution of body copper resulting in low copper concentrations in plasma, urine and liver but with an accumulation in the lower bowel probably due to a defect in mucosal transport. The importance of differentiating this condition from Wilson's disease is stressed.