[Presacral lesion at the rima ani]. / Präsakrale Raumforderung an der Rima ani.

A 26-year-old woman presented with a painful bulge at the rima ani. The tumor was located in the presacral region. Histological examination revealed a well-circumscribed biphenotypical tumor with papillary configured myxoid areas and strongly sclerosing regions. This case of a myxopapillary ependymoma is a rare example of a myxoid neoplastic lesion in the sacral region.

[The histological confirmation of diffuse axonal injury in severe brain injury survivors]. / Der histologische Nachweis des diffusen axonalen Hirnschadens bei Überlebenden schwerer Schädel-Hirntraumen.

Diffuse axonal injury (DAI) plays a major role after traumatic brain injury (TBI). Its imaging is based on computed tomography (CT) or magnetic resonance imaging (MRI). However, DAI is a histological diagnosis. Histopathological findings on survival after TBI are very rare. Hence, it is unclear whether the neuroradiological findings are of clinical relevance. Cerebral specimens were taken in 24 patients with TBI requiring surgery. The presence of histopathological evidence for DAI was evaluated. Specimens were taken from an extracranial brain prolapse (n = 2) and from peripheral parts of a brain contusion (n = 22). Histological findings were correlated to the clinical course and the neurological status. A clinical follow-up was carried out 6 months after the surgery using the Glasgow Outcome Score (GOS). The study was approved by the local ethics committee. Specimens taken were temporal (n = 11), frontal (n = 8), parietal (n = 4) and cerebellar (n = 1). The incidence of DAI within these specimens was 30% (7 with DAI, 17 without DAI). DAI was verifiable up to 3 days after trauma. There was no correlation between DAI and Marshall classification in CT. The period of coma was longer in subjects with DAI. There was no difference in GOS in the case of a verified DAI. These results enforce the prognostic and neuroradiologic relevance of DAI. However, it is debatable whether the pathomorphologic findings in CT or MRI represent the histological findings of DAI. We suggest a multicentre study for further clarification.

[Measurement of the central corneal thickness using optical reflectometry and ultrasound]. / Messung der zentralen Hornhautdicke mittels optischer Reflektometrie im Vergleich zur Ultraschall-Pachymetrie.

AIM: The aim of this study was to evaluate measurements of the central corneal thickness using OLCR and ultrasound pachymetry (IOPac). MATERIALS AND METHODS: In a retrospective observational study, fifty patients were assessed. Central corneal thickness was measured using OLCR and ultrasound. RESULTS: The IOPac system shows results for the central corneal thickness between 419 µm and 613 µm. The OLCR values ranged between 421 and 598 µm. The coefficient of variation was 1.12 % in the case of the IOPac and 0.97 % in the case of the OLCR. The paired Student's t-test showed no significant differences between the two methods. The agreement between the two methods was high with r = 0.929. CONCLUSIONS: The agreement between the results for the central corneal thickness using OLCR and ultrasound is high. The OLCR is a non-touch technology that does not require local anaesthesia, thus further reducing the risk of infection or mechanical trauma. Especially in surgical applications or glaucoma assessments, movement artefacts need to be ruled out, which potentially could cause wrong values and thus lead to wrong decisions.

[Headaches from an ophthalmological perspective]. / Kopfschmerzen aus ophthalmologischer Sicht.

Headaches are a common and widespread complaint. Differential diagnostics are crucial for successful therapy and often require an interdisciplinary approach. General practitioners tend to refer patients with extraordinary types of headaches to physicians specialized in neurology, ophthalmology and otolaryngology. This article offers an overview about the range of headache disorders particularly associated with the ophthalmologic anatomy and function.

Genomic duplication resulting in increased copy number of genes encoding the sister chromatid cohesion complex conveys clinical consequences distinct from Cornelia de Lange.

BACKGROUND: Cornelia de Lange syndrome (CdLS) is a multisystem congenital anomaly disorder. Heterozygous point mutations in three genes (NIPBL, SMC3 and SMC1A), encoding components of the sister chromatid cohesion apparatus, are responsible for approximately 50-60% of CdLS cases. Recent studies have revealed a high degree of genomic rearrangements (for example, deletions and duplications) in the human genome, which result in gene copy number variations (CNVs). CNVs have been associated with a wide range of both Mendelian and complex traits including disease phenotypes such as Charcot-Marie-Tooth type 1A, Pelizaeus-Merzbacher, Parkinson, Alzheimer, autism and schizophrenia. Increased versus decreased copy number of the same gene can potentially cause either similar or different clinical features. METHODS AND RESULTS: This study identified duplications on chromosomes 5 or X using genome wide array comparative genomic hybridisation (aCGH). The duplicated regions contain either the NIPBL or the SMC1A genes. Junction sequences analyses revealed the involvement of three genomic rearrangement mechanisms. The patients share some common features including mental retardation, developmental delay, sleep abnormalities, and craniofacial and limb defects. The systems affected are the same as in CdLS, but clinical manifestations are distinct from CdLS; particularly the absence of the CdLS facial gestalt. CONCLUSIONS: The results confirm the notion that duplication CNV of genes can be a common mechanism for human genetic diseases. Defining the clinical consequences for a specific gene dosage alteration represents a new "reverse genomics" trend in medical genetics that is reciprocal to the traditional approach of delineation of the common clinical phenotype preceding the discovery of the genetic aetiology.

Mutations in FAM20C also identified in non-lethal osteosclerotic bone dysplasia.

Raine syndrome is an osteosclerotic bone dysplasia, which has proved to be lethal within the first few weeks of life in all the reported cases to date. We recently identified a chromosomal rearrangement and telomeric microdeletion in a patient with Raine syndrome and subsequently identified mutations in the FAM20C gene, located within the deleted region, in six additional Raine syndrome cases. The phenotype of Raine syndrome in the cases examined was remarkably consistent with generalized osteosclerosis of all bones, periosteal bone formation, characteristic facial phenotype and lethal within the first few weeks of life. In the current study, we have identified two unrelated individuals who presented at birth with a sclerosing bone dysplasia with features very similar to those in Raine syndrome but who survived infancy and are now aged 8 and 11 years, respectively. Mutations in FAM20C, consistent with autosomal recessive inheritance, were identified in both cases. In the first case, a homozygous non-synonymous mutation in exon 7 (1309G>A D437N) was identified, and in the second case, compound heterozygosity for non-synonymous mutations in exon 2 (731T>A I244N) and in exon 3 (796G>A G266R) was revealed. Raine syndrome has been previously considered to be a neonatal lethal condition. However, the identification of mutations in these two patients confirms a broader phenotypic spectrum and that mutation of FAM20C does not always lead to the infantile lethality previously seen as a prerequisite for Raine syndrome diagnosis.

[Results of the ocular hypertension treatment study and the confocal scanning laser ophthalmoscopy ancillary study and evaluation of the heidelberg retina tomograph]. / Konsequenzen der "Ocular Hypertension Treatment Study" und der "Confocal Scanning Laser Ophthalmoscopy Ancillary Study" auf die Befundauswertung des Heidelberg Retina Tomographen.

The Ocular Hypertension Treatment Study (OHTS) has shown that analyzing changes of the optic disc configuration is superior to evaluating visual field findings for the early detection of primary open angle glaucoma. The Confocal Scanning Laser Ophthalmoscopy Ancillary Study (CSLO) is the first study to reveal that certain topographic baseline measurements of the optic disc are significantly associated with the development of primary open angle glaucoma in patients with ocular hypertension. An abnormally increased "mean height contour" value proved to be the individual parameter connected with the highest risk. The reliability of the Moorfields Regression Analysis of certain individual sectors during early detection of a primary angle glaucoma is higher than that of the global measurement. The temporal superior and inferior as well as the nasal inferior sectors have the highest positive predictive values and the largest risks in both univariate and multivariate analysis.

[Intravitreal anti-VEGF therapy with bevacizumab for neovascular AMD]. / Intravitreale Anti-VEGF-Therapie mit Bevacizumab bei neovaskulärer AMD.

PURPOSE: To report on the efficacy of intravitreal bevacizumab as off-label therapy in different angiographic subtypes in neovascular age-related macular degeneration (AMD). METHODS: Seventy-five patients with neovascular AMD and recent disease progression were classified into different angiographic subtypes and were treated with intravitreal bevacizumab (1.25 mg/0.05 ml) at 6-week intervals. Patients with subfoveal classic choroidal neovascularization (CNV) also received photodynamic therapy. ETDRS visual acuity, ophthalmic exams, and optic coherence tomography (OCT) were performed before treatment, 1 week after treatment, and then on a 6-week basis. Fluorescein angiographies and medical check-ups were also done. RESULTS: Bevacizumab led to stabilization of visual acuity (loss of less than 15 letters) in all angiographic subtypes during a follow-up of 37+/-13 weeks. Patients with occult extrafoveal CNV (n=6) profited the most and gained 2+/-2 lines. Treatment with intravitreal bevacizumab was very well tolerated in all patients, with neither systemic nor intraocular side effects, with the exception of one retinal pigment epithelium tear. CONCLUSION: Intravitreal bevacizumab treatment is efficacious in all angiographic CNV subtypes and leads to reduction of macular edema and stabilization or improvement in visual acuity.

[OCT-guided reinjection of 2.5 mg bevacizumab for treating macular edema due to retinal vein occlusion]. / OCT-Befund als Reinjektionskriterium für die 2,5-mg-Bevacizumab-Therapie bei venösen retinalen Verschlüssen.

BACKGROUND: Macular edema (ME) due to retinal vein occlusion can be successfully treated with intravitreal bevacizumab therapy. There is no common recommendation concerning time intervals and criteria for reinjection. METHOD: Sixty-three patients (follow-up 30+/-18 weeks) received intravitreal injections of 2.5 mg bevacizumab. Reinjection was performed only if optical coherence tomography (OCT) showed persistent or recurrent ME. Check-ups were performed every 6-8 weeks. RESULTS: There was complete resolution of macular edema in 31 patients after the first injection (improvement in visual acuity 3.7+/-3.7 lines); 65.2% of these patients developed recurrence of ME within 13.3+/-4.4 weeks, which completely resolved again after a second injection. Visual acuity gained the same level as after the first injection. Another relapse of ME in this group occurred in 69% of patients after another 13.4+/-5.4 weeks. Patients with persistent ME after the first injection (n=32) received a second injection, initially leading to resolution of ME in 33.3%, but all of these patients had a relapse within 13.9+/-4.1 weeks. CONCLUSION: OCT-guided reinjection leads to anatomic and functional stabilization or improvement even if transient recurrence of ME occurs.

[Bevacizumab for the treatment of macular edema secondary to retinal vein occlusion]. / Bevacizumab zur Therapie des Makulaödems infolge venöser retinaler Gefässverschlüsse.

BACKGROUND: Retinal vein occlusion often leads to macular edema as a result of an elevated level of intravitreal VEGF. We report on the anatomic and functional results after intravitreal bevacizumab injections in patients with retinal vein occlusion. METHODS: In a prospective study, 18 patients with central, and 22 patients with branch retinal vein occlusion, all of whom had persistent macular edema (>300 microm) received 2.5 mg intravitreal bevacizumab. ETDRS visual acuity, ophthalmic examination and stratus OCT were performed at baseline, 1 week after injection and then monthly. Further injections were given every 6 weeks in patients with persistent or recurring macular edema. RESULTS: The findings did not deteriorate in any of the 40 patients. The injections (mean of 2.6+/-1.4 injections/patient) were very well tolerated in all cases during a mean follow-up of 23+/-13 weeks. On the last visit, 73.3% of patients with central retinal vein occlusion and 76.5% of those with branch retinal vein occlusion were found to have significantly improved visual acuity (by at least 3 lines). Mean central retinal thickness had decreased from 921+/-264 to 239+/-66.2 microm in patients with central retinal vein occlusion, and from 678+/-221 to 236+/-78 microm in patients with branch retinal vein occlusion. CONCLUSIONS: Neither intraocular nor systemic side-effects were observed in this study after repeated intravitreal injections of 2.5 mg bevacizumab. Current results suggest that intravitreal anti-VEGF therapy is a promising option in macular edema secondary to retinal vein occlusion.

[Diagnosis of dementia in the doctor's office]. / Einfache Tests erhärten die Diagnose.

Alzheimer's dementia can readily be diagnosed by the general practitioner on the basis of the anamnestic data provided by the patient's relatives and quantified by MMST and DemTect. The diagnosis should be confirmed by a neurologist. EEG and mapping methods reveal slowing of alpha activity, increased theta activity and reduced reactivity reflecting the postulated cholinergic deficit. Toxic effects caused by medication, and the course of the disease can be monitored by means of the EEG. Magnetic resonance tomography and cranial computed tomography are necessary.

Male cases of incontinentia pigmenti: case report and review.

Male patients with Bloch-Sulzberger incontinentia pigmenti (IP type II) are rare and more severely affected than their female counterparts, with a significant occurrence of sex chromosome aneuploidy. This document introduces a new male IP type II patient and reviews 48 males reported with IP. Twenty-eight of the 49 patients meet current criteria for diagnosis of IP type II. The phenotype is variable and the incidence of documented developmental delay is 25%. Five patients had Klinefelter syndrome (47,XXY). Most patients were reported prior to 1961 when chromosome analysis was not available. Biopsy and laboratory reports considered to be "consistent with" the diagnosis of IP were seen in patients meeting criteria as well as those who would not currently be given the diagnosis. The histologic findings considered diagnostic are varied. This variability may be accounted for by differences in stage of disease, biopsy site, histologic technique, and reporting style. Conversely, this may indicate that the diagnostic weight given to the biopsy should be reconsidered. Eosinophilia was not a consistent finding. Overall, differences in reporting, ascertainment, and length of follow-up lead to difficulty in interpreting or predicting the natural history of males with IP type II. Based on the existing literature, they appear to have a higher rate of mental retardation than the general population, but there does not appear to be a correlation between severity of physical and mental involvement. The presence of sex chromosome aneuploidy documented in the more recent cases emphasizes the need for chromosome analysis in any male patient suspected of IP type II.

Replication banding and molecular studies of a mosaic, unbalanced dic(X;15)(Xpter-->Xq26.1::15p11-->15qter).

We present a patient with a chromosomal mosaicism involving the X chromosome. One cell line is 45,X and the other has a de novo paternally derived dicentric X;15 translocation. Her karyotype is therefore 45,X/45,X,dic(X;15)(Xpter-->Xq26.1::15p11-->15 qter) based on G-banding. The presence of 2 centromeres on the derivative X was confirmed by fluorescence in situ hybridization (FISH) and a deletion of Xq26.1-->qter was confirmed by polymerase chain reaction (PCR) using DXS52 and DXYS154. Replication banding studies indicate that the derivative X is late replicating. Based on these studies, it is unclear whether inactivation has spread to proximal 15q. The patient has a unique phenotype distinct from Ullrich-Turner or Prader-Willi syndromes, but includes ataxia and language delay which are commonly seen in Angelman syndrome. These findings are contrary to those anticipated since deficiency of paternal genes at 15q12 typically leads to Prader-Willi syndrome. Molecular analysis of PCR-based polymorphisms of chromosome 15 and X indicates that uniparental disomy is not present for the X chromosome or chromosome 15 in either cell line. It is hypothesized that her phenotype results from the interaction of the 2 abnormal genotypes. Each abnormality may be diluted by the mosaicism and, in the derivative X line, by the possible variation among cells of inactivation spreading to chromosome 15.

Mitochondrial complex I and III mutations and neutral-lipid storage in activated mononuclear macrophages and neutrophils: a case presenting with necrotizing myopathy, poikiloderma atrophicans vasculare, and xanthogranulomatous bursitis.

We report the case of a 57-year-old woman suffering from xanthogranulomatous bursitis, necrotizing myopathy, and poikiloderma atrophicans vasculare, which are associated with marked accumulation of neutral-lipid storage phagocytes. The observed lipid storage was restricted to activated phagocytes independent of the presence of tissue necrosis and was not seen either in circulating blood leukocytes or in muscle fibers. The patient's daughter disclosed xanthomatous inflammatory reaction with profound delay of wound healing secondary to pelviscopy. Examination of the mitochondrial DNAs of the patient, her daughter, and her two grandchildren revealed two homoplasmic mutations at positions 13708 and 15257 of the mitochondrial genome. We discuss the involvement of these mutations in the pathogenesis of xanthomatous and xanthogranulomatous inflammation. Further investigations are required to test whether impairment of aerobic energy production independent from mitochondrial DNA mutations (eg, by hypoxia or microbial toxins) similarly can cause the accumulation of lipid-laden macrophages and explain the persistency of xanthogranulomatous inflammation.

Limits of the genetic revolution.

The genetic revolution will touch all disciplines of medicine, much like the antibiotic discoveries in the last century did. However, genetic medicine is not an immediate "magic bullet" for all noninfectious conditions. Despite the sometimes melodramatic announcements by the lay media, there are hurdles to overcome before genetic treatments become as ubiquitous as antibiotics. These barriers fall into 3 categories: molecular, economic, and behavioral. First, the molecular difficulties include the biochemical complexity of genes and genetic disease, variation in pathogenesis among races, and gene-environment interaction. Second, economic disincentive to develop orphan drugs, and the expense of such medications, may hinder production of treatments for truly rare genetic diseases. Third, patients are unlikely to be any more compliant with new medications or recommendations than they are with the current ones. The "magic bullet" of folic acid is not used by the majority of women who are aware of its usefulness in preventing birth defects. While the genetic revolution has much potential, the complexity of genetics itself is difficult and the current barriers to useful treatment will not change. As with oncological and transplantation technology, great strides are likely to be made, but only at a measured pace.

Disseminated neocortical and subcortical encephalopathy (DNSE) with widespread activation of brain macrophages: a new dementia disorder? Autopsy reports of two postmenopausal women from families with mitochondrial DNA mutations.

In this study we present 2 postmenopausal women who showed clinical symptoms that resembled those of a rather well-defined group of vascular dementia disorders, termed subcortical dementia (Binswanger disease, CADASIL). Patient 1 exhibited mitochondrial DNA (mtDNA) variants in the ND5 gene at position 13,708 and the Cytb gene at position 15,257. These DNA variants have been described in a number of neurologic disorders, but their pathogenetic potential is unclear. Patient 2 showed the same DNA alterations and an additional mtDNA variant at position 15,812 in the Cytb gene. The principal neurohistologic features of the 2 atrophic brains presented here include: subtotal selective neuronal cell loss in the cortex and, to a lesser degree, in the basal ganglia (claustrum, putamen, globus pallidus), sparing palaeocortex and periarchaeocortex, and a very characteristic and diagnostic feature was detachment of astrocytic processes from capillary walls resulting in pericapillary space formation. These pericapillary spaces were partially filled with macrophages. The spaces were not associated with total breakdown of the blood vessel walls as demonstrated by the absence of erythrocytes, lymphocytes, or polymorphonuclear leukocytes outside the vascular bed of the brain; progressive subcortical encephalopathy, as it is seen in subcortical dementia (Binswanger), but lacking arterial lipohyalinosis. The cerebral grey and white matter revealed cuffing of arteries and arterioles by adventitial macrophages. The neocortical and subcortical changes were accompanied by myriads of activated macrophages filled with lipids. The pathology of our 2 cases differs from that of other neurodegenerative disorders and we suggest the term of "disseminated neocortical and subcortical encephalopathy (DNSE) with widespread activation of brain macrophages".

Association of the LHON 13,708 and 15,257 mitochondrial DNA mutations with neurodegenerative diseases distinct from LHON.

300 patients suffering from neurodegenerative diseases distinct from Leber hereditary optic neuropathy (LHON) were screened for the presence of mitochondrial DNA mutations. We report on nine patients, eight female and one male, who all harboured mutations at positions 13,708 and 15,257 of the mitochondrial DNA. Both mutations have previously been claimed to be associated with LHON. Based on our results, these mutations occur in a number of different neurodegenerative diseases and therefore cannot be regarded as "LHON" mutations.

[Diagnosis and follow-up in glaucoma patients using the Heidelberg retina tomograph]. / Diagnostik und Verlaufskontrolle beim Glaukom mit dem Heidelberg Retina Tomograph.

The development of laser scanning tomography in the late 1980s enabled the possibility of an exact three-dimensional biomorphorphometry of the optic nerve head. This technique is designed for 3D measurement of the topography of the optic disc with high accuracy and reproducibility. With the development of the Heidelberg retina tomograph with highly advanced and user-friendly software, a quick examination is possible. Currently the instrument is already used on a routine basis in the ophthalmological practice. It has been shown that glaucomatous changes of the optic disc can be detected using laser scanning tomography before perimetric deterioration occurs. Therefore this technique is crucial in the follow-up of glaucoma patients.