Reversal of threatening blindness after initiation of eculizumab in Purtscher-like retinopathy secondary to atypical hemolytic uremic syndrome.

Purtscher-like retinopathy, a rare manifestation of systemic thrombotic microangiopathy, is a potentially visually debilitating condition with no effective proven treatment. Distinct pathogenic pathways have been proposed as etiological factors. We revisit the etiology of Purtscher-like retinopathy based on the rapid response and profound visual improvement after initiation of systemic intravenous eculizumab, an inhibitor of the complement cascade, in a patient with Purtscher-like retinopathy secondary to familial atypical hemolytic uremic syndrome (aHUS) due to a mutation in complement factor H. We hypothesize that the efficacy of eculizumab in this patient provides evidence for pathogenic events in the retina similar to those encountered in the renal microvasculature of aHUS patients, namely complement-mediated thromboembolization as a result of activation of the complement cascade in endothelial cells with release of tissue factor and development and amplification of a procoagulant state. To the best of our knowledge, this is the first report in the literature of eculizumab as an effective therapeutic strategy in Purtscher-like retinopathy.

Contralateral MRI abnormalities affect seizure and cognitive outcome after hemispherectomy.

OBJECTIVE: To explore whether EEG and MRI abnormalities in the "healthy" hemisphere influence seizure and cognitive outcome after functional hemispherectomy. METHODS: This is a retrospective consecutive cohort study of 43 children who underwent functional hemispherectomy between 1994 and 2008. Results of preoperative EEG recordings were reviewed for the existence of (inter)ictal epileptic or background abnormalities in the contralateral hemisphere. Preoperative MRIs were reexamined for the existence of unequivocal contralateral abnormalities. Postoperative seizure status was assessed, and of 34 children, IQ or mental developmental index (MDI) scores were obtained preoperatively and postoperatively. Seizure freedom was defined as Engel 1A. Contralateral EEG and MRI abnormalities were studied in relation to seizure and cognitive outcome. RESULTS: Thirty-three children achieved seizure freedom (77%). Of the 11 patients with contralateral MRI abnormalities, only 45% were seizure free, compared with 88% of the 32 patients without contralateral MRI lesions (p = 0.030). Children with contralateral MRI abnormalities more often were severely retarded after surgery (MDI/IQ <55; 90% vs 42%, p = 0.030). Postoperative MDI/IQ scores improved in none of the children with, but in 38% of those without contralateral MRI abnormalities (p = 0.034). Contralateral epileptic or background EEG abnormalities did not affect seizure outcome or postoperative cognitive performance. Four of 6 children with bilateral epileptic encephalopathy reached seizure freedom. CONCLUSION: Unambiguous contralateral MRI abnormalities are significantly associated with seizure recurrence, severe mental delay, and lack of cognitive improvement and may be considered a relative contraindication for hemispherectomy. Contralateral EEG abnormalities do not negatively influence postsurgical outcome.

Incidence of retinopathy of prematurity over the last decade in the Central Netherlands.

BACKGROUND AND OBJECTIVES: To retrospectively analyze changes in incidence and risk factors of retinopathy of prematurity (ROP) over two periods, 10 years apart, in the central Netherlands. METHODS: Data of 570 infants admitted between 2001 and 2005, screened for ROP according to the Dutch National guideline, were compared to those of 538 infants admitted between 1991 and 1995. RESULTS: Incidence of ROP decreased significantly over the last decade (40.9% in 1991-1995 vs. 23.3% in 2001-2005, p < 0.001), together with incidence of severe ROP (stage >or=3) (3.3 vs. 1.2%, p < 0.05). In infants with a birth weight (BW) <1,000 g incidence of ROP dropped significantly (67.0 vs. 41.8%, p < 0.001), as well as incidence of severe ROP (8.1 vs. 3.0%, p < 0.05). For infants with a BW >or=1,000 g incidence of ROP also declined significantly (27.1 vs. 13.0%, p < 0.001), that of severe ROP remained unchanged (0.8 vs. 0.3%). In both periods gestational age, duration of artificial ventilation, small for gestational age (SGA) and postnatal steroids were independent risk factors for ROP. CONCLUSIONS: In the central Netherlands, incidence of ROP and severe ROP has significantly decreased, also in infants with BW <1,000 g. Risk factors remained unchanged.

Identification of mutations in the AIPL1, CRB1, GUCY2D, RPE65, and RPGRIP1 genes in patients with juvenile retinitis pigmentosa.

OBJECTIVE: To identify mutations in the AIPL1, CRB1, GUCY2D, RPE65, and RPGRIP1 genes in patients with juvenile retinitis pigmentosa. METHODS: Mutation analysis was carried out in a group of 35 unrelated patients with juvenile autosomal recessive retinitis pigmentosa (ARRP), Leber's congenital amaurosis (LCA), or juvenile isolated retinitis pigmentosa (IRP), by denaturing high performance liquid chromatography followed by direct sequencing. RESULTS: All three groups of patients showed typical combinations of eye signs associated with retinitis pigmentosa: pale optic discs, narrow arterioles, pigmentary changes, and nystagmus. Mutations were found in 34% of PATIENTS: in CRB1 (11%), GUCY2D (11%), RPE65 (6%), and RPGRIP1 (6%). Nine mutations are reported, including a new combination of two mutations in CRB1, and new mutations in GUCY2D and RPGRIP1. The new GUCY2D mutation (c.3283delC, p.Pro1069ArgfsX37) is the first pathological sequence change reported in the intracellular C-terminal domain of GUCY2D, and did not lead to the commonly associated LCA, but to a juvenile retinitis pigmentosa phenotype. The polymorphic nature of three previously described (pathological) sequence changes in AIPL1, CRB1, and RPGRIP1 was established. Seven new polymorphic changes, useful for further association studies, were found. CONCLUSIONS: New and previously described sequence changes were detected in retinitis pigmentosa in CRB1, GUCY2D, and RPGRIP1; and in LCA patients in CRB1, GUCY2D, and RPE65. These data, combined with previous reports, suggest that LCA and juvenile ARRP are closely related and belong to a continuous spectrum of juvenile retinitis pigmentosa.

Paraneoplastic vitelliform retinopathy associated with cutaneous or uveal melanoma and metastases.

PURPOSE: To report unusual vitelliform fundus findings in three cases of paraneoplastic retinopathy associated with metastasised cutaneous or uveal melanoma and in one case, a unique immunoreactivity response. PATIENTS AND METHODS: Observational case series. The histories of three patients with MAR-like paraneoplastic retinopathy were reviewed. Electroretinography, Goldmann perimetry, fluorescein angiography, and in one case optical coherence tomography, immunohistochemistry and Western blotting were performed. RESULTS: All patients revealed similar paraneoplastic vitelliform retinal abnormalities. Symptoms in two cases differed from the classical MAR syndrome. In one case, western blotting and immunohistochemistry demonstrated antibodies against 120-kDa, a soluble photoreceptor protein. No immunoreactivity to retinal bipolar cells was detected. CONCLUSION: The clinical, electrophysiological, and immunological findings in our patients suggest a melanoma associated paraneoplastic origin, like in MAR syndrome. However contrary to MAR syndrome, this paraneoplastic vitelliform retinopathy exhibits a peculiar fundus picture, consisting of serous macular detachment and nummular vitelliform lesions in the posterior pole. This could be an unusual presentation of MAR or a separate paraneoplastic entity.

Leber congenital amaurosis and retinitis pigmentosa with Coats-like exudative vasculopathy are associated with mutations in the crumbs homologue 1 (CRB1) gene.

Mutations in the crumbs homologue 1 (CRB1) gene cause a specific form of retinitis pigmentosa (RP) that is designated "RP12" and is characterized by a preserved para-arteriolar retinal pigment epithelium (PPRPE) and by severe loss of vision at age <20 years. Because of the early onset of disease in patients who have RP with PPRPE, we considered CRB1 to be a good candidate gene for Leber congenital amaurosis (LCA). Mutations were detected in 7 (13%) of 52 patients with LCA from the Netherlands, Germany, and the United States. In addition, CRB1 mutations were detected in five of nine patients who had RP with Coats-like exudative vasculopathy, a relatively rare complication of RP that may progress to partial or total retinal detachment. Given that four of five patients had developed the complication in one eye and that not all siblings with RP have the complication, CRB1 mutations should be considered an important risk factor for the Coats-like reaction, although its development may require additional genetic or environmental factors. Although no clear-cut genotype-phenotype correlation could be established, patients with LCA, which is the most severe retinal dystrophy, carry null alleles more frequently than do patients with RP. Our findings suggest that CRB1 mutations are a frequent cause of LCA and are strongly associated with the development of Coats-like exudative vasculopathy in patients with RP.

Grid laser photocoagulation for macular oedema in uveitis or the Irvine-Gass syndrome.

AIMS: To determine the effect of modified macular grid photocoagulation in patients with refractory macular oedema due to uveitis or cataract extraction. METHODS: In this study 20 patients with macular oedema underwent modified macular grid laser photocoagulation and were followed by means of standardised examinations (day 0, months 2, 6, and 12) consisting of best corrected visual acuity and fluorescein angiography. RESULTS: The mean visual acuity increased from 0.16 before to 0.3 after laser treatment (p = 0.013), and fluorescein leakage was significantly reduced (p = 0.005). Visual prognosis was influenced by duration of the uveitis, not by sex or age. CONCLUSION: Modified macular grid laser photocoagulation had a beneficial effect on macular oedema caused by uveitis or the Irvine-Gass syndrome. A prospective, randomised study is needed to determine the exact place of modified macular grid photocoagulation in the treatment of patients with inflammatory or postsurgical macular oedema.

The effect of intracranial pressure on myelination and the relationship with neurodevelopment in infantile hydrocephalus.

The effect of raised intracranial pressure (ICP), due to infantile hydrocephalus, on the process of myelination has been suggested in the literature. In this study 19 hydrocephalic infants were followed-up with anterior fontanelle pressure (AFP) measurement (assessment of ICP), MRI (assessment of the myelination process and the CSF volume), and neurodevelopmental testing (NDT). There was a high correlation (r = 0.80) between the myelination and NDT scores. The size of the CSF volume showed a poor correlation with the mean AFP, the degree of myelination and the NDT scores. There was, however, a significant correlation between the mean AFP and the degree of myelination (r = 0.67) and also between the mean AFP and the NDT scores (r = 0.70). Longer-term follow-up (mean = 27 months) showed a significant correlation between the early progress of myelination and later developmental level (r = 0.78). Most of the children with a severely delayed myelination, preoperatively, showed a recovery of myelination following CSF drainage. It was concluded that: (1) raised ICP is related to developmental outcome, through the process of myelination; (2) the delay in myelination can be (partially) reversible; and (3) CSF volume is of minor importance regarding neurodevelopment.

Autosomal dominant cerebellar ataxia with retinal degeneration (ADCA II): clinical and neuropathological findings in two pedigrees and genetic linkage to 3p12-p21.1.

OBJECTIVES: To investigate relations between clinical and neuropathological features and age of onset, presence of anticipation, and genetic linkage in autosomal dominant cerebellar ataxia type II (ADCA II). METHODS: The natural history of ADCA II was studied on the basis of clinical and neuropathological findings in two pedigrees and genetic linkage studies were carried out with polymorphic DNA markers in the largest, four generation, pedigree. RESULTS: Ataxia was constant in all age groups. Retinal degeneration with early extinction of the electroretinogram constituted an important component in juvenile and early adult (< 25 years) onset but was variable in late adult presentation. Neuromuscular involvement due to spinal anterior horn disease was an important contributing factor to illness in juvenile cases. Postmortem findings in four patients confirm the general neurodegenerative nature of the disease, which includes prominent spinal anterior horn involvement and widespread involvement of grey and white matter. Genetic linkage was found with markers to chromosome 3p12-p21.1 (maximum pairwise lod score 4.42 at D3S1285). CONCLUSIONS: The sequence of clinical involvement seems related to age at onset. Retinal degeneration is variable in late onset patients and neuromuscular features are important in patients with early onset. Strong anticipation was found in subsequent generations. Linkage of ADCA II to chromosome 3p12-p21.1 is confirmed.

Cataracts, radiculomegaly, septal heart defects and hearing loss in two unrelated adult females with normal intelligence and similar facial appearance: confirmation of a syndrome?

Two unrelated, adult females with normal intelligence are described. They show a similar clinical picture with a long and narrow face, congenital cataract, microphthalmia, microcornea, a high nasal bridge, a short nose, a broad nasal tip, a long philtrum, bilateral hearing loss, persistent primary teeth, oligodontia, variable root length including dental radiculomegaly, heart defects and cutaneous syndactyly of the 2nd-3rd toes. Abnormalities present in only one of the two patients were a cleft palate and a transverse vaginal septum, respectively. There are numerous similarities between our two patients and the family described by Wilkie et al. ((1993): Clin Dysmorphol 2: 114-119) and all may be examples of the same entity.

Further delineation of the acro-renal-ocular syndrome.

A triad of acral, renal, and ocular abnormalities was reported previously in four families. We report on a fifth family, in which a mother, one of her four sons and one of her two daughters are affected. Major findings in the acro-renal-ocular syndrome are upper limb abnormalities, mainly thumb hypoplasia, eye abnormalities such as coloboma and Duane anomaly and renal migration defects. A close embryological-temporal relationship between the traits of this entity suggest a common monogenic cause. The pattern of inheritance is probably autosomal dominant. Because of a wide variability of clinical manifestations, recognition of the syndrome in individual cases may be difficult.

Efficient DNA carrier detection in X linked juvenile retinoschisis.

Juvenile retinoschisis is a rare, X linked hereditary vitroretinal degeneration. Female carriers of the disease do not develop any ocular abnormalities. Therefore, carrier detection by DNA analysis is extremely useful for these females. In order to evaluate the usefulness of a new class of DNA markers for carrier detection in X linked juvenile retinoschisis, DNA carrier detection or carrier exclusion was carried out in four possible carriers for X linked juvenile retinoschisis. The use of these highly polymorphic CA repeats, closely linked to the RS gene, greatly enhances both the reliability and feasibility of carrier detection in X linked juvenile retinoschisis.

Long term ocular and neurological involvement in severe congenital toxoplasmosis.

AIMS: This study was set up to determine the long term ocular and systemic sequelae in patients with severe congenital toxoplasmosis. METHODS: Cross sectional and retrospective study of 17 patients with severe congenital toxoplasmosis. RESULTS: In addition to chorioretinitis (100%), the most common abnormal ocular features were optic nerve atrophy (83%), visual acuity of less than 0.1 (85%), strabismus, and microphthalmos. In 50% of cases we observed iridic abnormalities and about 40% developed a cataract. Overt endocrinological disease, diagnosed in five of 15 patients, included panhypopituitarism (n = 2), gonadal failure with dwarfism (n = 1), precocious puberty with dwarfism and thyroid deficiency (n = 1), and diabetes mellitus and thyroid deficiency (n = 1). The observed endocrinological involvement was associated in all cases with obstructive hydrocephalus with a dilated third ventricle and optic nerve atrophy. CONCLUSION: The recognition of long term ocular, neurological, and endocrinological sequelae of congenital toxoplasmosis is important for medical management of these severely handicapped patients.

Refinement of the chromosomal position of the X linked juvenile retinoschisis gene.

Linkage analysis was carried out in seven X linked juvenile retinoschisis (XLRS) families using four DNA probes and four CA repeat polymorphisms from the Xp22 region. Close linkage was observed between the XLRS locus and DXS207 (theta max = 0.04, Zmax = 3.71), DXS999 (theta max = 0.00, Zmax = 4.59), DXS365 (theta max = 0.07, Zmax = 2.22), and DXS451 (theta max = 0.05, Zmax = 3.26). The analysis of recombination breakpoints and multipoint linkage analysis suggests the order Xpter-DXS16-(DXS43, DXS207)-RS-DXS365-(DXS451, DXS41)-Xcen, thereby refining the position of the XLRS locus to an interval of approximately 3-4 cM. These results improve the feasibility of diagnosis in XLRS considerably, since carriers of this disease cannot be identified clinically.

Autosomal recessive retinitis pigmentosa with preserved para-arteriolar retinal pigment epithelium.

Retinitis pigmentosa with preserved para-arteriolar retinal pigment epithelium is a rare form of retinitis pigmentosa that starts early in life with preservation of retinal pigment epithelium adjacent to and under the retinal arterioles and that has hitherto been described as an isolated form. We examined 22 patients from one large family, together with two isolated patients, and confirmed the presumed autosomal recessive mode of inheritance in this type of retinitis pigmentosa. New findings associated with retinitis pigmentosa with preserved para-arteriolar retinal pigment epithelium were asteroid hyalosis in four (17%) of 24 patients, tortuosity of retinal arterioles in 11 (46%) of 24 patients, peripheral regions of opacified vessels in eight (33%) of 24 patients, and preservation not only of the para-arteriolar pigment epithelium, but also of the peripheral retinal pigment epithelium in 13 (54%) of 24 patients. Previously reported signs present in these patients were nystagmus in six (25%) of 24 patients, hypermetropia in 23 (96%) of 24 patients, optic nerve head drusen in nine (38%) of 24 patients, vascular sheathing in 11 (46%) of 24 patients, maculopathy in all 24 patients (100%), yellow round deposits in the posterior pole in nine (38%) of 24 patients, exudates resembling those in Coats' disease in two (8%) of 24 patients, visual field defects in all 24 patients (100%), and nondeductible electroretinograms in 21 (91%) of 23 patients. Linkage analysis carried out in the large family resulted in the assignment of a gene for retinitis pigmentosa with preserved para-arteriolar retinal pigment epithelium to chromosome 1q31-q32.1.

Thr4Lys rhodopsin mutation is associated with autosomal dominant retinitis pigmentosa of the cone-rod type in a small Dutch family.

A mother and daughter with autosomal dominant retinitis pigmentosa (adRP) were found to carry a cytosine-to-adenine transversion mutation at codon 4 of the rhodopsin gene. This mutation predicts a substitution of lysine for threonine at one of the glycosylation sites in the rhodopsin molecule (Thr4Lys). Both patients presented with a similar phenotype including a tigroid pattern of the posterior pole and a regional predilection for degenerative pigmentary changes in the inferior retina with corresponding visual field defects. The electroretinographic pattern was suggestive of RP of the cone-rod type. This report documents the clinical findings associated with this defined mutation of the rhodopsin gene.