Loss of DIAPH1 causes SCBMS, combined immunodeficiency, and mitochondrial dysfunction.

BACKGROUND: Homozygous loss of DIAPH1 results in seizures, cortical blindness, and microcephaly syndrome (SCBMS). We studied 5 Finnish and 2 Omani patients with loss of DIAPH1 presenting with SCBMS, mitochondrial dysfunction, and immunodeficiency. OBJECTIVE: We sought to further characterize phenotypes and disease mechanisms associated with loss of DIAPH1. METHODS: Exome sequencing, genotyping and haplotype analysis, B- and T-cell phenotyping, in vitro lymphocyte stimulation assays, analyses of mitochondrial function, immunofluorescence staining for cytoskeletal proteins and mitochondria, and CRISPR-Cas9 DIAPH1 knockout in heathy donor PBMCs were used. RESULTS: Genetic analyses found all Finnish patients homozygous for a rare DIAPH1 splice-variant (NM_005219:c.684+1G>A) enriched in the Finnish population, and Omani patients homozygous for a previously described pathogenic DIAPH1 frameshift-variant (NM_005219:c.2769delT;p.F923fs). In addition to microcephaly, epilepsy, and cortical blindness characteristic to SCBMS, the patients presented with infection susceptibility due to defective lymphocyte maturation and 3 patients developed B-cell lymphoma. Patients' immunophenotype was characterized by poor lymphocyte activation and proliferation, defective B-cell maturation, and lack of naive T cells. CRISPR-Cas9 knockout of DIAPH1 in PBMCs from healthy donors replicated the T-cell activation defect. Patient-derived peripheral blood T cells exhibited impaired adhesion and inefficient microtubule-organizing center repositioning to the immunologic synapse. The clinical symptoms and laboratory tests also suggested mitochondrial dysfunction. Experiments with immortalized, patient-derived fibroblasts indicated that DIAPH1 affects the amount of complex IV of the mitochondrial respiratory chain. CONCLUSIONS: Our data demonstrate that individuals with SCBMS can have combined immune deficiency and implicate defective cytoskeletal organization and mitochondrial dysfunction in SCBMS pathogenesis.

Characteristic facial features and cortical blindness distinguish the DOCK7-related epileptic encephalopathy.

BACKGROUND: The epileptic encephalopathies display extensive locus and allelic heterogeneity. Biallelic truncating DOCK7 variants were recently reported in five children with early-onset epilepsy, intellectual disability, and cortical blindness, indicating that DOCK7 deficiency causes a specific type of epileptic encephalopathy. METHODS: We identified 23- and 27-year-old siblings with the clinical pattern reported for DOCK7 deficiency, and conducted genome-wide linkage analysis and WES. The consequences of a DOCK7 variant were analyzed on the transcript and protein level in patients' fibroblasts. RESULTS: We identified a novel homozygous DOCK7 frameshift variant, an intragenic tandem duplication of 124-kb, previously missed by CGH array, in adult patients. Patients display atrophy in the occipital lobe and pontine hypoplasia with marked pontobulbar sulcus, and focal atrophy of occasional cerebellar folia is a novel finding. Recognizable dysmorphic features include normo-brachycephaly, narrow forehead, low anterior and posterior hairlines, prominent ears, full cheeks, and long eyelashes. Our patients function on the level of 4-year-old children, never showed signs of regression, and seizures are largely controlled with multi-pharmacotherapy. Studies of patients' fibroblasts showed nonsense-mediated RNA decay and lack of DOCK7 protein. CONCLUSION: DOCK7 deficiency causes a definable clinical entity, a recognizable type of epileptic encephalopathy.

The Age-Dependent Neural Substrates of Blindsight.

Some patients who are considered cortically blind due to the loss of their primary visual cortex (V1) show a remarkable ability to act upon or discriminate between visual stimuli presented to their blind field, without any awareness of those stimuli. This phenomenon is often referred to as blindsight. Despite the range of spared visual abilities, the identification of the pathways mediating blindsight remains an active and contentious topic in the field. In this review, we discuss recent findings of the candidate pathways and their relative contributions to different forms of blindsight across the lifespan to illustrate the varied nature of unconscious visual processing.

Anton's Syndrome associated with autotopagnosia.

We describe an unusual case of a 68-year-old male affected by cerebral amyloid angiopathy and cortical blindness associated with Anton's syndrome. In addition, our patient presented with autotopagnosia, a form of agnosia characterized by loss of body spatial representation. Neuropsychological assessment evidenced cognitive impairment. Magnetic Resonance Imaging showed hemorrhagic foci in the left occipital and right occipito-parietal lobe, paratrigonal white matter, and post-ischemic parenchymal gliosis. The pattern-reversal of visual evoked potentials were indicative bilateral visual pathway of integrity of the. After a neurological damage, patients could show a denial of their own deficit; however, the association between anosognosia and autotopagnosia represents a rare neurological condition. The simultaneous onset of unusual neuropsychological syndromes could be related to involvement of a complex brain network.

Clinicopathological findings of an MM2-cortical-type sporadic Creutzfeldt-Jakob disease patient with cortical blindness during a course of glaucoma and age-related macular degeneration.

Here, we report an autopsy-verified patient with MM2-coritical-type sporadic Creutzfeldt-Jakob disease (MM2C-type sCJD) presenting cortical blindness during a course of glaucoma and age-related macular degeneration, and focus on the difficulties involved in early clinical diagnosis. An 83-year-old man was admitted to our hospital 15 months after the onset of cortical blindness, and 9 months after the onset of progressive dementia. Neurological examination revealed dementia, frontal signs, visual disturbance, dysphagia, myoclonus and exaggerated tendon reflexes in the four extremities. Diffusion-weighted MRI (DW-MRI) showed cortical hyperintensities predominantly in the bilateral occipital lobes. PRNP gene analysis showed no mutations with methionine homozygosity at codon 129. Cerebrospinal fluid (CSF) examination revealed elevation of 14-3-3 and total tau protein. The symptoms progressed gradually, and the patient died of aspiration pneumonia, 30 months after the onset. Neuropathological examination revealed extensive large confluent vacuole-type spongiform changes in the cerebral cortices. Prion protein (PrP) immunostaining showed perivascular and plaque-type PrP deposits. We diagnosed our patient as MM2C-type sCJD. There are two difficulties in the early clinical diagnosis of MM2C-type sCJD with ocular disease in the elderly; delayed utilization of DW-MRI, and accompaniment of ocular disease. For early diagnosis of MM2C-type sCJD, we conclude that clinician should perform DW-MRI for patients with isolated dementia or cortical visual disturbance.

Ceguera cortical como manifestación inicial de endocarditis trombótica no bacteriana / Cortical blindness as initial manifestation of nonbacterial thrombotic endocarditis

La endocarditis trombótica no bacteriana, antiguamente conocida como endocarditis marántica, es una entidad infrecuente en la que se desarrollan vegetaciones estériles, compuestas por fibrina en las válvulas del corazón. Suele diagnosticarse en el momento de la autopsia o en enfermedades oncológicas avanzadas. Las neoplasias malignas más frecuentemente asociadas con esta entidad son las de pulmón, páncreas, estómago y adenocarcinomas de origen primario desconocido. Es necesario descartar la endocarditis infecciosa y establecer la presencia de vegetaciones valvulares mediante ecocardiografía. Presentamos el caso de una paciente con diagnóstico reciente de adenocarcinoma de estómago en estadio avanzado que presentó ceguera cortical e imágenes compatibles con isquemia cerebral. El ecocardiograma transesofágico mostró dos vegetaciones en válvula mitral. Los hemocultivos fueron negativos. Se enfatiza la importancia de sospechar endocarditis trombótica no bacteriana en enfermos con cáncer y embolismo sistémico.

Nonbacterial thrombotic endocarditis, formerly known as marantic endocarditis, it is an infrequent entity in which sterile, fibrin vegetations develop on heart valve leaflets. It is often diagnosed at the time of autopsy or in late-stage malignancies. The most common malignancies associated with nonbacterial thrombotic endocarditis are lung, pancreatic, gastric cancer and adenocarcinomas of an unknown primary site. Diagnosis requires ruling out infective endocarditis and establishing the presence of valvular vegetations using echocardiography. We report the case of a patient with a recent diagnosis of advanced gastric adenocarcinoma who presented with cortical blindness. The computed tomography was compatible with cerebral ischemia. The transoesophageal echocardiogram showed two vegetations in mitral valve. Blood cultures were negative. We emphasize the importance of suspecting nonbacterial thrombotic endocarditis in patients with cancer and systemic embolism.

[Cortical blindness as initial manifestation of nonbacterial thrombotic endocarditis]. / Ceguera cortical como manifestación inicial de endocarditis trombótica no bacteriana.

Nonbacterial thrombotic endocarditis, formerly known as marantic endocarditis, it is an infrequent entity in which sterile, fibrin vegetations develop on heart valve leaflets. It is often diagnosed at the time of autopsy or in latestage malignancies. The most common malignancies associated with nonbacterial thrombotic endocarditis are lung, pancreatic, gastric cancer and adenocarcinomas of an unknown primary site. Diagnosis requires ruling out infective endocarditis and establishing the presence of valvular vegetations using echocardiography. We report the case of a patient with a recent diagnosis of advanced gastric adenocarcinoma who presented with cortical blindness. The computed tomography was compatible with cerebral ischemia. The transoesophageal echocardiogram showed two vegetations in mitral valve. Blood cultures were negative. We emphasize the importance of suspecting nonbacterial thrombotic endocarditis in patients with cancer and systemic embolism.

Functional neuroanatomy of blindsight revealed by activation likelihood estimation meta-analysis.

Blindsight, the residual abilities of patients with cortical blindness to respond proficiently to stimuli they do not consciously acknowledge, offers a unique opportunity to study the functional and anatomical mechanisms sustaining visual awareness. Over decades, the phenomenon has been documented in a wide number of different patients, across independent laboratories, and for a variety of tasks and stimulus properties. Nevertheless, the functional neuroanatomy of blindsight remains elusive and alternative proposals have been put forth. To tackle this issue from a novel perspective, we performed a quantitative Activation Likelihood Estimation (ALE) meta-analysis on the neuroimaging literature available on blindsight. Significant activity was reported in subcortical structures, such as the superior colliculus, pulvinar and amygdala, as well as in cortical extrastriate areas along the dorsal and ventral visual stream. This data-driven functional network collectively defines the extant neural fingerprint of blindsight. To further characterize the unique combination of segregation and integration in brain networks engaged in blindsight, we measured the relationship between active areas and experimental features in the original studies, their clustering and hierarchical organization. Results support a network-based organization in the functional neuroanatomy of blindsight, which likely reflects the intersection of different stimulus properties and behavioural tasks examined. We suggest that the conceptualization of blindsight as a constellation of multiple nonconscious visual abilities is better apt as a summary of present-day wisdom, thereby mirroring the variety of existing V1-independent pathway and their different functional roles.

Occipital ulegyria causing epilepsy and visual impairment: an easily overlooked epilepsy syndrome.

Ulegyria refers to scarring of the cerebral cortex usually arising from perinatal ischaemia. The scarring has a specific configuration in which small atrophic circumvolutions at the bottom of a sulcus underlie an intact spared gyral apex. This disconnection of overlying cortex may allow an "epileptogenic" island of cortex to generate seizures. Ulegyria is often associated with epilepsy and developmental delay, however, the syndromic association of visual impairment with epilepsy due to occipital ulegyria may not be recognised as a specific entity. Here, we report a series of five patients with occipital ulegyria who presented with widely variable seizure semiology and an array of visual deficits. In some patients, the link between the epilepsy and the visual impairment was not appreciated until they attended an epilepsy clinic.

Visual discrimination training improves Humphrey perimetry in chronic cortically induced blindness.

OBJECTIVE: To assess if visual discrimination training improves performance on visual perimetry tests in chronic stroke patients with visual cortex involvement. METHODS: 24-2 and 10-2 Humphrey visual fields were analyzed for 17 chronic cortically blind stroke patients prior to and following visual discrimination training, as well as in 5 untrained, cortically blind controls. Trained patients practiced direction discrimination, orientation discrimination, or both, at nonoverlapping, blind field locations. All pretraining and posttraining discrimination performance and Humphrey fields were collected with online eye tracking, ensuring gaze-contingent stimulus presentation. RESULTS: Trained patients recovered ∼108 degrees2 of vision on average, while untrained patients spontaneously improved over an area of ∼16 degrees2. Improvement was not affected by patient age, time since lesion, size of initial deficit, or training type, but was proportional to the amount of training performed. Untrained patients counterbalanced their improvements with worsening of sensitivity over ∼9 degrees2 of their visual field. Worsening was minimal in trained patients. Finally, although discrimination performance improved at all trained locations, changes in Humphrey sensitivity occurred both within trained regions and beyond, extending over a larger area along the blind field border. CONCLUSIONS: In adults with chronic cortical visual impairment, the blind field border appears to have enhanced plastic potential, which can be recruited by gaze-controlled visual discrimination training to expand the visible field. Our findings underscore a critical need for future studies to measure the effects of vision restoration approaches on perimetry in larger cohorts of patients.

Exploring cortical atrophy and its clinical and biochemical correlates in Wilson's disease using voxel based morphometry.

OBJECTIVES: To determine cortical grey matter (GM) changes and their clinical and biochemical correlates in patients with Wilson's disease using voxel based morphometry (VBM). METHODS: Clinical and imaging data of 10 patients (all male, mean age 16.0 ± 6.3years) with Wilson's Disease were analyzed. T1W volumetric MRI data of patients without obvious cortical atrophy or signal changes on conventional MRI was compared with MRI of 11 matched control subjects using VBM analysis with Statistical Parametric Mapping 8. Results were expressed at statistical threshold of p < 0.05 (FWE corrected) and p < 0.001 (uncorrected). Multiple regression analysis was done to analyze possible relation between GM atrophy, duration of disease and biochemical abnormalities. RESULTS: Compared to controls, patients showed scattered areas of reduced GM volume in bilateral caudate head, medial part of right globus pallidus and body of right caudate (FWE corrected p < 0.05). At p < 0.001(uncorrected) widespread areas of cortical atrophy were also noted involving the frontal and temporal lobes, lentiform nuclei, cerebellum and thalamus. Significant positive correlation (uncorrected p < 0.001) were noted between (i) duration of disease and cortical GM volume of frontal, parietal and temporal lobes and cerebellum (ii) serum copper levels and GM volume of right medial frontal gyrus and paracentral lobule. CONCLUSIONS: To the best of our knowledge, this is the first VBM study in patients with Wilson's disease. In spite of apparently normal cortex on visual inspection of MRI, decreased cortical GM volume was detected using VBM. In addition, serum copper may act as surrogate marker of cortical abnormalities in Wilson's disease.

Síndrome de encefalopatía posterior reversible y síndrome de vasoconstricción cerebral reversible: diagnóstico diferencial de cefalea en el puerperio / Posterior reversible encephalopathy syndrome and cerebrovascular constriction syndrome in the differential diagnosis of post-partum headaches

La cefalea en el periodo puerperal puede ser debida a múltiples causas. En el contexto de una paciente que ha recibido previamente analgesia epidural, la cefalea puede ser etiquetada de cefalea pospunción dural, a pesar de que sus características no sean típicas de este cuadro clínico. Presentamos el caso de una puérpera con punción dural accidental durante la realización de anestesia epidural, que desarrolló cefalea en el tercer día posparto. Se sospechó inicialmente cefalea pospunción dural, pero la aparición posterior de convulsiones y pérdida de visión hizo que se reconsiderase el diagnóstico. A propósito de este caso revisamos las características clínicas y fisiopatológicas del síndrome de encefalopatía posterior reversible y el síndrome de vasoconstricción cerebral reversible, así como el diagnóstico diferencial de la cefalea en el periodo puerperal (AU)

Postpartum headache can be due to many causes. In a patient with previous epidural analgesia, the headache can be attributed to post-dural puncture headache, even if the symptoms are not typical of this clinical entity. We report a case of a post-partum with accidental dural tap during the insertion of an epidural catheter for labour analgesia, and who referred to headaches in the third post-partum day. Initially, a post-dural puncture headache was suspected, but the subsequent onset of seizures and visual impairment meant that the diagnosis had to be reconsidered. In this case report, the clinical and pathophysiological features of posterior reversible encephalopathy syndrome and reversible cerebral vasoconstriction syndrome, as well as the differential diagnosis of post-partum headaches are described (AU)

Late onset reversible cortical blindness following electrocution.

An elderly gentleman presented with acute onset of bilateral visual blurring and generalized headache after 1 week post electrocution injury. Clinically, the symptoms were attributed to cortical lesion. Magnetic resonance imaging (MRI) of brain revealed bilaterally symmetrical diffusion restriction in parietal and occipital areas. Treatment with intravenous steroids resulted in remarkable improvement in symptoms. Neurological injury secondary to electrocution is a well described entity having a variety of clinical presentation. We put forward our experience with this unique case presenting as post electrocution delayed onset of visual symptoms. Discussion and review of literature related to this clinical entity will also be presented.

Progressive cortical visual failure associated with occipital calcification and coeliac disease with relative preservation of the dorsal 'action' pathway.

We describe the first reported case of a patient with coeliac disease and cerebral occipital calcification who shows a progressive and seemingly selective failure to recognise visual stimuli. This decline was tracked over a study period of 22 years and occurred in the absence of primary sensory or widespread intellectual impairment. Subsequent tests revealed that although the patient was unable to use shape and contour information to visually identify objects, she was nevertheless able to use this information to reach, grasp and manipulate objects under central, immediate vision. This preservation of visuo-motor control was echoed in her day-to-day ability to navigate and live at home independently. We conclude that occipital calcification following coeliac disease can lead to prominent higher visual failure that, under prescribed viewing conditions, is consistent with separable mechanisms for visual perception and action control.

The blind brain: how (lack of) vision shapes the morphological and functional architecture of the human brain.

Since the early days, how we represent the world around us has been a matter of philosophical speculation. Over the last few decades, modern neuroscience, and specifically the development of methodologies for the structural and the functional exploration of the brain have made it possible to investigate old questions with an innovative approach. In this brief review, we discuss the main findings from a series of brain anatomical and functional studies conducted in sighted and congenitally blind individuals by our's and others' laboratories. Historically, research on the 'blind brain' has focused mainly on the cross-modal plastic changes that follow sensory deprivation. More recently, a novel line of research has been developed to determine to what extent visual experience is truly required to achieve a representation of the surrounding environment. Overall, the results of these studies indicate that most of the brain fine morphological and functional architecture is programmed to develop and function independently from any visual experience. Distinct cortical areas are able to process information in a supramodal fashion, that is, independently from the sensory modality that carries that information to the brain. These observations strongly support the hypothesis of a modality-independent, i.e. more abstract, cortical organization, and may contribute to explain how congenitally blind individuals may interact efficiently with an external world that they have never seen.

Color picture drawings without form and eye movements: a case report of visual form agnosia in a girl.

The case of an 8-year-old girl who manifested cortical blindness and whose color drawings of faces and objects were without outlines is reported. Her birth was uneventful. When she was 10 months old, she fell down to the floor from a chair, resulting in a subarachnoidal hemorrhage. A repeat brain MRI revealed localized lesions in the visual cortices in the right and left hemispheres. As she grew older she was found to have visual imperceptions. She was found to have difficulties in learning visually the names of objects with form and letters, and in recognizing faces of her family. However, she was able to discriminate well the colors of faces and objects and learn easily the names of the objects with form by touching. She seemed to utilize subcortical vision for seeing colors of faces and objects.

Post-anesthetic cortical blindness in cats: twenty cases.

The medical records of 20 cats with post-anesthetic cortical blindness were reviewed. Information collected included signalment and health status, reason for anesthesia, anesthetic protocols and adverse events, post-anesthetic visual and neurological abnormalities, clinical outcome, and risk factors. The vascular anatomy of the cat brain was reviewed by cadaver dissections. Thirteen cats were anaesthetised for dentistry, four for endoscopy, two for neutering procedures and one for urethral obstruction. A mouth gag was used in 16/20 cats. Three cats had had cardiac arrest, whereas in the remaining 17 cases, no specific cause of blindness was identified. Seventeen cats (85%) had neurological deficits in addition to blindness. Fourteen of 20 cats (70%) had documented recovery of vision, whereas four (20%) remained blind. Two cats (10%) were lost to follow up while still blind. Ten of 17 cats (59%) with neurological deficits had full recovery from neurological disease, two (12%) had mild persistent deficits and one (6%) was euthanased as it failed to recover. Four cats (23%) without documented resolution of neurological signs were lost to follow up. Mouth gags were identified as a potential risk factor for cerebral ischemia and blindness in cats.

Cortical vision loss as a prominent feature of H1N1 encephalopathy.

A 20-year-old woman infected with the 2009 H1N1 strain of influenza A developed bilateral visual loss. Brain MRI showed restricted diffusion of the parietal and occipital lobes, and her spinal fluid did not contain inflammatory cells. This report describes an unusual case of H1N1 influenza A virus infection primarily affecting the posterior visual pathways.

Cortical blindness associated with autonomic dysreflexia in a man with tetraplegia: a rare but serious complication.

CONTEXT: To describe a case of a 44-year-old man with complete C4 tetraplegia who developed transient cortical blindness in the subacute setting following episodes of autonomic dysreflexia. FINDINGS: Transient cortical blindness the day after surgery for appendicitis that had resulted in severe autonomic dysreflexia (AD) requiring aggressive blood pressure management. Imaging showed no evidence of acute stroke, but did show vasospasm in the occipital lobes. Vision improved over the next couple of months. CONCLUSION/CLINICAL RELEVANCE: This case illustrates a possible profound vasomotor phenomenon (cortical blindness) associated with AD and its symptomatic treatment. Early recognition of AD and treatment of its underlying cause cannot be overemphasized.