Fleischer Ring Research Articles

Characteristics of neurological Wilson's disease without Kayser–Fleischer ring

BackgroundAlthough Kayser–Fleischer ring has been regarded as a key diagnostic feature of neurologic Wilson's disease, there have been previous reports of neurologic Wilson's disease patients without Kayser–Fleischer ring. We assessed the characteristics of neurologic Wilson's disease patients without Kayser–Fleischer ring. MethodsWe enrolled neurologic Wilson's disease patients from 4 university hospitals by review of medical records in this study. Patients with neurologic Wilson's disease were diagnosed based on the neurologic symptoms and international scoring system for the diagnosis of Wilson's disease. All subjects were divided into two groups according to the presence of a Kayser–Fleischer ring. We compared demographic data, laboratory findings and imaging findings of the liver and brain between the two groups. ResultsThere were 12 (26.7%) patients without Kayser–Fleischer ring out of a total of 45 neurologic Wilson's disease patients. The Wilson's disease patients without Kayser–Fleischer ring demonstrated a higher ceruloplasmin concentration and serum copper level than those with Kayser–Fleischer ring. In addition, liver cirrhosis and typical signal changes in brain magnetic resonance imaging were less common in neurologic Wilson's disease patients without Kayser–Fleischer ring. ConclusionBased on our results, the absence of Kayser–Fleischer ring can be regarded as a form of neurologic Wilson's disease with less copper involvement. In addition, it is important to understand these features and to perform further investigations if patients without Kayser–Fleischer ring are suspected of having neurologic Wilson's disease.

Identification of a novel Wilson disease gene mutation frequent in Upper Austria: a genetic and clinical study

Wilson disease (WD), a disorder of copper metabolism is caused by mutations in the ATP7B gene, a copper transporting ATPase. In the present study we describe a novel mutation in exon 9 of the ATP7B gene. The ATP7B gene was analyzed for mutations by denaturing HPLC and direct sequencing. DNA from 100 healthy blood donors from the same geographic area was examined as control. Sixteen (7.4%) out of the 216 patients diagnosed with WD in Austria carried the newly identified R816S(c.2448G>T) point mutation in exon 9 (4 male, age: 19 (6-30) years, median (range)). One patient was homozygous for R816S(c.2448G>T). Thirteen patients were compound heterozygotes (p.H1069Q(c.3207C>A)/R816S(c.2448G>T) (N=6), P539L/R816S(c.2448G>T) (N=3), each one G710S/R816S(c.2448G>T), P767P(2299insC)/R816S(c.2448G>T), W779G/R816S(c.2448G>T), T1220M/R816S(c.2448G>T)). In two patients no second mutation was identified. Interestingly, all but three of the patients originated within a distinct geographical area in Austria. Eleven patients presented with hepatic disease, 3 patients with neurological disease and 2 were asymptomatic sisters of an index case. A liver biopsy was available in 14 patients. Three patients showed advanced liver disease with liver transplantation for acute hepatic failure in two. The remaining patients had only mild histological changes, most commonly steatosis. Chronic hepatitis was described in five patients. Kayser-Fleischer ring was present in five patients. None of the 100 healthy controls carried the mutation. We describe a novel mutation in the ATP7B gene, occurring in patients originated from a distinct geographical area in Austria associated with a variable course of the disease.

Kayser–Fleischer ring in Wilson's disease: A cohort study

AimsTo evaluate Wilson's disease (WD) features in Sardinian patients with Kayser–Fleischer (KF) ring and to evaluate correlations between modifications in KF and anti-copper therapy and systemic WD evolution. Patients and methodsSixty-seven WD patients (35m/32 f; mean age 41years) were retrospectively studied. At diagnosis and during follow up comprehensive ophthalmologic and neurologic examinations, brain RMN and ECD SPECT, detailed objective laboratory studies and hepatic histological examination were performed on all patients for analysis. All patients were given anti-copper therapy with d-Penicillamine in mono-therapy or in combination with Zinc Salts. ResultsAt diagnosis, KF was observed in 27% of patients with equal distribution in all age groups. Significant correlations between KF at diagnosis, neuro-psychiatric manifestations and pathologic features in brain RMN and in brain ECD SPECT were found at diagnosis. During follow up, a decrease in, or regression of KF was seen in 14% of patients. Anti-copper therapy leads to KF regression and prevents the appearance of KF. No significant correlations were observed between KF regression and clinical neurological or neuro-imaging improvement nor between KF modifications and clinical hepatic improvement. ConclusionsOur study highlights the peculiar features of Sardinian WD patients: low representation of KF, its equal distribution in all age groups, significant correlation between KF at diagnosis and clinical neurological manifestations, pathologic brain RMN and brain ECD-SPECT are highlighted by our study. Anti-copper therapy induces KF regression and prevents its onset. Therefore, KF ring does appear to be a predictive factor in the neurological and hepatic evolution of WD.

Three cases of Wilson’s disease masquerading as childhood muscular dystrophy

Various authors have reported that Wilson’s disease in India may masquerade as childhood muscular dystrophy. It is a potentially treatable condition and therefore, early recognition is important and every suspected patient with childhood muscular dystrophy should be examined for the presence of Kayser–Fleischer ring in the cornea and also be screened for copper profile. We report three such cases who were initially diagnosed as childhood muscular dystrophy but on subsequent screening turned out to be cases of Wilson’s disease.

Toric soft contact lens fit in a postoperative LASIK keratoectasia patient with high and irregular astigmatism

Background Keratoectasia is a rare but well-known complication after laser-assisted in situ keratomileusis (LASIK). Patients with this condition can have high and irregular astigmatism. When the treatment of the high astigmatic correction cannot be accomplished surgically or when the keratoectasia patient rejects surgical enhancement, optical correction with devices such as soft or rigid gas-permeable contact lenses may be pursued. In fact, toric soft contact lenses are a good first option for fitting postoperative keratoectasia patients. Case report A 58-year-old white male presented for an examination with a complaint of decreased distance vision in the right eye (OD) after having traditional LASIK for myopia with astigmatism in both eyes (OU) in 1999 and limbal relaxing incision enhancement OD in 2003. Refraction showed high mixed astigmatism OD (+1.75 -5.75×075). Slit lamp examination found irregularity of the cornea, evidenced by an inferior cone with pigmented Fleischer ring OD. Video keratometry had keratometry readings of 43.50 at 160, 39.87 at 070, elevated shape measure (0.40), elevated corneal irregularity measure (3.96), an inferior cone on the elevation map, and asymmetric bowtie with elongation inferonasally on the axial map, which confirmed the diagnosis of postoperative keratoectasia. Because new surgical treatments at that time for corneal ectasia were in their infancy and not approved by the U.S. Food and Drug Administration, the patient opted for a trial toric soft contact lens fitting, which improved his corrected distance visual acuity to 20/25. Conclusion This case report confirms that toric soft contact lenses are a good first choice in fitting patients with high and irregular astigmatism from postoperative LASIK corneal ectasia. It also confirms that excellent vision and comfort with toric soft contact lenses is possible in these patients.

A clinical study of Wilson’s disease: The experience of a single Egyptian Paediatric Hepatology Unit

Background and study aims Most paediatric patients with Wilson’s disease (WD) present with hepatic manifestations, but some may have neurologic or psychiatric features. Our aim was to define the clinical, biochemical features and the outcome of therapy of a group of Egyptian children diagnosed with WD. Patients and methods The study was carried out at the Paediatric Hepatology Unit at Cairo University Children’s Hospital, Egypt; 54 patients were diagnosed with WD from 1996 to 2009. The diagnosis was based on low serum ceruloplasmin levels, increased urinary copper concentrations before or after D-penicillamine challenge and/or the presence of Kayser–Fleischer (K–F) rings. Results The clinical presentation was as follows: hepatic presentation in 33 patients (61%), hepato-neurologic 3 (5.5%), neurologic 5 (9.3%) and presymptomatic 13 (24%). Twelve couples had more than one affected sib. Increased urinary copper concentrations before or after D-penicillamine challenge was found in all patients, low serum ceruloplasmin in 97% and K–F rings in 31.5%. All patients were treated with penicillamine and zinc sulphate except one presymptomatic case who was treated with zinc sulphate only. Three patients underwent liver transplantation and eight patients died after a median duration of treatment of 6 months (1–36). The hepatic symptoms improved with treatment but the neurological symptoms remained stationary. Conclusions Clinical and biochemical assays remain the standard for diagnosis of WD. Penicillamine and zinc therapy can effectively treat WD with hepatic symptoms. Liver transplantation remains life saving for those with fulminant and end stage WD. Screening for presymptomatic sibs is of utmost importance.

Central corneal iron line arising from hyperopic orthokeratology

Mt Pleasant, Queensland, AustraliaE-mail: bradkirkwood@bigpond.comSubmitted: 3 August 2010Revised: 10 October 2010Accepted for publication: 10 November2010A corneal iron line, viewed as a faint yellowto dark brown deposit in the epitheliallayer, may occur in an otherwise normalcornea or in association with corneal con-ditions and post-corneal surgical proce-dures. Commonly, a horizontal iron line(Hudson–Stahli line) can be located inthe lower third of the cornea. Characteris-tic iron lines may also occur at the base ofthe cone in keratoconus (Fleischer ring),just inferior to a trabeculectomy bleb(Ferry’s line) and at the advancing edge ofa pterygium (Stocker’s line). Indeed, withany pigmented corneal changes, cliniciansshould be mindful of vortex kerato-pathy associated with systemic conditions(Fabry’s disease) and oral medication (forexample, amiodarone).Iron deposits have been reported widelywith refractive corneal procedures such aslaser

Late occurrence of granular dystrophy in bilateral keratoconus: Penetrating keratoplasty and long-term follow-up

We report a rare case of keratoconus with granular dystrophy with a follow-up of two decades, documenting the sequential presentation of two diseases confirmed by histology and genetic studies. A 13-year-old boy was diagnosed in 1988 with keratoconus in both eyes (BE) based on slit-lamp biomicroscopy findings of corneal ectasia in BE accompanied by Fleischer's ring, Vogt's striae, a small, old, healed hydrops. The left eye (LE) had central corneal thinning and scar in the central area involving the mid and posterior stroma secondary to healed hydrops. Penetrating keratoplasty (PKP) was advised. The boy was lost to follow-up till 1991 and presented with white, dot-like opacities in the central cornea in the RE only, suggestive of granular corneal dystrophy. Similar findings of white, dot-like opacities were noted in the LE in 1995 and the patient subsequently underwent PKP in BE. Histopathology of corneal buttons confirmed the presence of patchy, crystal-like orange deposits, which stained bright red with Masson's trichrome. Mutational analysis of the TGFBI gene in patient's DNA revealed a heterozygous mutation corresponding to a change in Arg555Trp in the keratoepithelin protein. Granular dystrophy recurred after 8 years in the RE.

Hemolytic Anemia as a Presenting Feature of Wilson’s Disease: A Case Report

Wilson's disease is a rare inherited disorder of copper metabolism causing severe damage to vital organs. Liver and brain disorders are the main manifestations. Severe hemolytic anemia is an unusual complication of Wilson's disease. We present a case who developed spherocytic acute hemolytic anemia (Coomb's negative) as the initial manifestation of Wilson's disease. On examination Kayser- Fleischer ring was found. Laboratory data supported a diagnosis of Wilson's disease.

Molecular pathology of Wilson’s disease: A brief

Department of Cell Biology and Immunology, Centro de Biologia Molecular Severo Ochoa and Centro de Enfermedades Hepaticas y Digestivas (CIBEREHD), Universidad Autonoma de Madrid, 28049 Madrid, Spain; INSERM Unite 757, Orsay F-91400, France; Universite Paris-Sud, UMR-S 757, Orsay F-91405, France; AP-HP Hopital Paul Brousse, Centre Hepato-Biliaire, Villejuif F-94800, France; Universite Paris-Sud, UMR-S 785, Villejuif F-94800, France; Inserm, Unite 785, Villejuif F-94800, France; Centre de Reference de la maladie de Wilson Centre Hepato-Biliaire Hopital Paul Brousse, Villejuif, France

Keratoconus: A review

Keratoconus is the most common primary ectasia. It usually occurs in the second decade of life and affects both genders and all ethnicities. The estimated prevalence in the general population is 54 per 100,000. Ocular signs and symptoms vary depending on disease severity. Early forms normally go unnoticed unless corneal topography is performed. Disease progression is manifested with a loss of visual acuity which cannot be compensated for with spectacles. Corneal thinning frequently precedes ectasia. In moderate and advance cases, a hemosiderin arc or circle line, known as Fleischer's ring, is frequently seen around the cone base. Vogt's striaes, which are fine vertical lines produced by Descemet's membrane compression, is another characteristic sign. Most patients eventually develop corneal scarring. Munson's sign, a V-shape deformation of the lower eyelid in downward position; Rizzuti's sign, a bright reflection from the nasal area of the limbus when light is directed to the limbus temporal area; and breakages in Descemet's membrane causing acute stromal oedema, known as hydrops, are observed in advanced stages. Classifications based on morphology, disease evolution, ocular signs and index-based systems of keratoconus have been proposed. Theories into the genetic, biomechanical and biochemical causes of keratoconus have been suggested. Management varies depending on disease severity. Incipient cases are managed with spectacles, mild to moderate cases with contact lenses and severe cases can be treated with keratoplasty. This article provides a review on the definition, epidemiology, clinical features, classification, histopathology, aetiology and pathogenesis, and management and treatment strategies for keratoconus.

The eye in Wilson disease

Although the distinctive and diagnostically valuable signs present in the eyes of patients with symptomatic Wilson disease have been described in specialist journals and in monographs1,2 on this disease, they have received little attention in the general literature. Furthermore, they have not been definitively illustrated. These are the Kayser–Fleischer (KF) rings (Figure 1) and the sunflower cataracts. As a result, many physicians, although they know of such signs, have never seen them or as a result may have missed them when present, as did Wilson3 himself in his original description of the disease which now bears his name. Indeed, for many years he denied that they were related to this condition. The rings were first described by Kayser in 1902 and then by Fleischer in 1909.4,5 The fact that the rings are composed of copper was finally established by Gerlach and Rohsrschneider as late as 1949,6 shortly after Cumings7 had demonstrated that excess copper was deposited in the brains and livers of patients dying of this disease. That the corneal rings were indeed due to copper deposition was confirmed by Sternlieb.8 Originally, it was believed that the presence of such copper containing rings were diagnostic of Wilson disease but in 1975 Fleming and his associates9 were able to show that …

Recurrent Limb Weakness in a 17-Year-Old Boy

Wilson disease is a relatively rare inherited disorder of copper accumulation and toxicity, caused by a defect in an enzyme that is part of the pathway of biliary excretion of excess copper. A 17-year-old boy presented with numerous episodes of hypokalemic weakness of the lower limbs of undetermined etiology since 12 years of age. Clinically, lower-motor neuron type of weakness of the limbs with preserved reflexes and paucity of sensory abnormalities were prominent. The investigations revealed distal renal tubular acidosis, hepatitis, and bilateral Kayser-Fleischer ring. The diagnosis of Wilson disease was confirmed by the demonstration of low serum ceruloplasmin, high serum copper, and high urinary copper excretion per se and after penicillamine challenge. He responded satisfactorily to penicillamine and zinc. Careful search of an underlying etiology in children presenting with hypokalemic weakness of the limbs in the face of metabolic acidosis and unexplained hepatitis may reveal Wilson disease.

Rings around cones

A 65-year-old Caucasian male was referred for suspected keratoconus with Fleischer ring in both eyes. He had worn hard contact lenses since 1975 and recently changed to rigid gas permeable...

Longitudinal analysis of corneal topography in suspected keratoconus

Aims:To examine the incidence of progression of suspected keratoconus to true keratoconus and compare quantitative descriptors of corneal topography between eyes with and without progression.Methods:34 eyes with suspected keratoconus were...

Mania as the first manifestation of Wilson’s disease

Although mental changes are frequent in Wilson's disease, severe psychiatric disorders occur uncommonly and usually accompany the neurological picture. There are few reports in the literature of Wilson's disease patients with typical bipolar affective disorder (BPAD). The authors report the case of a patient with Wilson's disease whose initial manifestation was a manic episode followed by depression. Tremor in the upper limbs appeared one year after the onset of symptoms. The diagnosis of Wilson's disease was established three years after the first symptoms appeared, based on the neuropsychiatric picture, the detection of Kayser-Fleischer rings and the results of diagnostic tests indicating chronic liver disease and copper excess. ATP7B genotyping and magnetic resonance imaging of the brain with proton spectroscopy study were also performed. The patient became asymptomatic two years after starting treatment with penicillamine and remained non-symptomatic controlled during the eight-year follow-up period, without any specific treatment for the BPAD. To our knowledge, this is a singular report of a case of Wilson's disease in which a manic episode preceded the onset of neurological symptoms. The association between Wilson's disease and bipolar disorder is discussed.

Non-ceruloplasmin-bound copper in routine clinical practice in different laboratories

Background Copper is an essential nutrient but is toxic when the free form is in excess. Wilson's disease (WD) is an autosomal recessive disorder of copper excess. Its diagnosis is a challenge, especially in the absence of obvious neurological changes, or Kayser–Fleischer rings. Non-ceruloplasmin-bound copper is a calculated parameter devised for the investigation of patients who potentially have WD. Methods We compared non-ceruloplasmin-bound copper from three different laboratories. We retrospectively reviewed paired ceruloplasmin and copper data and calculated non-ceruloplasmin-bound copper. Comparative statistics, linear regression, chi-square test and graphical techniques were employed to compare the data. Results All three assays had negative results for over 20% of the non-ceruloplasmin-bound copper concentrations; this was not significantly different. However, there were statistically significant differences for the 97.5th percentile. When plotted against the ceruloplasmin and copper concentrations, significant differences existed for both the visual and linear regression data between the three different laboratories. Conclusions Non-ceruloplasmin-bound copper cut-offs may not be transferable between laboratories. Each laboratory should derive its own cut-offs for the 97.5th percentile, as there are differences due to assays, populations or both.

A study of clinical, MRI and multimodality evoked potentials in neurologic Wilson disease

The aims of this study were evaluate motor, somatosensory, visual and auditory brainstem evoked potential (MEP, SEP, VEP, ABER) changes in Wilson disease (WD) and correlate these with magnetic resonance imaging (MRI) and clinical findings. Neurologic WD diagnosed on the basis of clinical, ceruloplasmin and Kayser-Fleischer ring were evaluated including pedigree charting, hepatic, renal, hematologic and osteoarticular manifestations. Blood counts, serum chemistry, MRI, MEP to tibialis anterior, tibial SEP, VEP and ABER were performed. Evoked potential (EP) changes were correlated with clinical and MRI findings. Eighteen WD patients were recruited from 17 families whose mean age was 16 years. Movement disorders were present in 14, cognitive decline in 12 and pyramidal signs in 12 patients. MRI revealed involvement of basal ganglia in 80%, thalamus in 40%, brain stem in 46.7% and subcortical white matter in 53.3%. MEP was abnormal in 35.7%, SEP in 30.8%, VEP in 57% and ABER in 61.5% patients; the latter three EP changes were subclinical. Frequency and number of EP abnormalities were higher with increasing severity of illness. SEP, VEP and ABER reveals subclinical abnormality and MEP helps in documenting both clinical and subclinical abnormalities. Number of EP abnormalities increases with increasing clinical severity of WD.

Wilson disease—A practical approach to diagnosis, treatment and follow-up

Wilson disease is an inherited, autosomal recessive, copper accumulation and toxicity disorder that affects about 30 individuals per million. This rare disease is caused by mutations in the gene encoding a copper-transporting P-type ATPase, which is important for copper excretion into bile, leading to copper accumulation in the liver. Toxic copper concentrations can also be found in the brain and kidney, and clinical phenotypes include hepatic, haemolytic, neurologic and psychiatric diseases. Diagnosis is based on the combination of clinical features and findings such as increased urinary copper excretion, reduced levels of serum ceruloplasmin, high concentrations of copper in liver tissues and Kayser–Fleischer rings. Genetic studies are also becoming available for clinical use, but the utility of direct mutation analysis is limited. Wilson disease can be treated, and early diagnosis is essential: the goal of therapy is to reduce copper accumulation either by enhancing its urinary excretion or by decreasing its intestinal absorption. Medical therapies include penicillamine, trientine, zinc and tetrathiomolibdate. Liver transplantation is a relatively successful treatment option when medical therapy fails or in case of acute liver failure, even though it is also characterized by short- and long-term complications.

Late-Onset Wilson’s Disease

The clinical symptoms and age at onset of Wilson's disease (WD) are highly variable. This study investigated patients who became symptomatic at >40 years of age. Clinical features, laboratory data, and mutation analysis were evaluated in 46 (3.8%) of 1223 patients who were investigated in a multinational study on genotype-phenotype correlations (1053 index patients, 170 siblings) who were >40 years of age at onset of symptoms and, in 2 asymptomatic siblings, diagnosed at >40 years of age. Thirty-one patients presented with neurologic symptoms (mean age, 44.5 years; range, 40-52; male/female, 14/17), 15 presented with liver disease (mean age, 47.1 years; range, 40-58; male/female, 6/9), and 2 were asymptomatic siblings. Hepatic copper content was measured in 17 patients and was above 250 microg/g dry weight in 13. One patient with hepatic presentation had "fulminant" WD, the remaining 14 abnormal liver function tests and/or hepatomegaly. Liver biopsy specimens were available in 13 patients presenting with liver disease (cirrhosis, 10; chronic hepatitis, 2; steatosis, 1; no abnormalities, 1) and in 14 neurologic patients (cirrhosis, 9; advanced fibrosis, 1; chronic hepatitis, 2; no abnormalities, 2). Twenty-seven of the 46 index cases had mutations on both chromosomes (including 13 H1069Q/H1069Q), 13 on just 1 chromosome. Late-onset WD is a frequently overlooked condition. The diagnostic features and the frequency of late-onset WD gene mutations were not different than in patients with an earlier onset of disease. Factors other than ATP7B mutations may modify the phenotypic presentation of WD.