Homozygous LAMC3 mutation links to structural and functional changes in visual attention networks.

The occipital lobe contains a substantial part of the neural machinery involved in visual perception. Mutations in the LAMC3 gene have recently been shown to cause complex bilateral occipital cortical gyration abnormalities. However, to what extent these structural changes impact visual behavior is not known. We recorded responses for two screening test batteries targeting visual function (Leuven - Perceptual Organization Screening Test, Cortical Vision Screening Test) and measured eye fixation performance in a visual attention experiment from a patient with homozygous LAMC3 gene mutation. Using voxel-based morphometry (VBM) we quantitatively assessed the extent of structural changes brought on by the genetic mutation by comparing mean cortical curvature, cortical thickness, and gray matter volume in 34 cortical areas between patient and an age-, sex-, and education-matched control group. Anatomical connectivity between these cortical areas was investigated by a structural covariance analysis. Visual screening-, and behavioral results revealed that the patient's impairments were predominantly in visuo-spatial attention. Consistent with this, VBM and structural connectivity results revealed significant structural changes in cortical regions subserving attentional functions. We conclude that the LAMC3 gene mutation affects cortical areas beyond the occipital lobe and primarily those visual functions that involve heavily distributed networks - such as visuo-spatial attention.

Mitochondrial serine protease HTRA2 p.G399S in a kindred with essential tremor and Parkinson disease.

Essential tremor is one of the most frequent movement disorders of humans and can be associated with substantial disability. Some but not all persons with essential tremor develop signs of Parkinson disease, and the relationship between the conditions has not been clear. In a six-generation consanguineous Turkish kindred with both essential tremor and Parkinson disease, we carried out whole exome sequencing and pedigree analysis, identifying HTRA2 p.G399S as the allele likely responsible for both conditions. Essential tremor was present in persons either heterozygous or homozygous for this allele. Homozygosity was associated with earlier age at onset of tremor (P < 0.0001), more severe postural tremor (P < 0.0001), and more severe kinetic tremor (P = 0.0019). Homozygotes, but not heterozygotes, developed Parkinson signs in the middle age. Among population controls from the same Anatolian region as the family, frequency of HTRA2 p.G399S was 0.0027, slightly lower than other populations. HTRA2 encodes a mitochondrial serine protease. Loss of function of HtrA2 was previously shown to lead to parkinsonian features in motor neuron degeneration (mnd2) mice. HTRA2 p.G399S was previously shown to lead to mitochondrial dysfunction, altered mitochondrial morphology, and decreased protease activity, but epidemiologic studies of an association between HTRA2 and Parkinson disease yielded conflicting results. Our results suggest that in some families, HTRA2 p.G399S is responsible for hereditary essential tremor and that homozygotes for this allele develop Parkinson disease. This hypothesis has implications for understanding the pathogenesis of essential tremor and its relationship to Parkinson disease.

White matter involvement beyond the optic nerves in CRION as assessed by diffusion tensor imaging.

BACKGROUND: Chronic relapsing inflammatory optic neuropathy (CRION) is an inflammatory optic neuropathy, characterized by relapses and remissions in patients with normal brain and spinal magnetic resonance imaging (MRI). Discrepancy from other demyelinating diseases is important, and it is still uncertain whether CRION is restricted to the optic pathways or it affects other brain white matter (WM) structures. OBJECTIVE: To assess WM structure in patients with CRION by using diffusion tensor imaging (DTI). METHODS: DTI was performed in six CRION patients and six age- and sex-matched healthy controls on a 3 T scanner. Tract-based spatial statistics (TBSS) was used for voxelwise statistical analysis of DTI data. Fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), radial diffusivity (RD) measures were obtained. RESULTS: TBSS analysis revealed two different patterns of WM alterations in patients with CRION. The optic chiasm and connected structures had significantly higher FA and lower RD, AD and MD in the patients than in the healthy controls. On the other hand, anterior frontal bundles of inferior fronto-occipital tracts, left uncinate fascicule and internal capsule showed decreased FA and increased RD. No correlation was found between the clinical variables and diffusion measures. CONCLUSION: WM appearing normal on brain MRI shows widespread abnormalities in a cohort of CRION patients as assessed by DTI.

Homozygosity mapping and targeted genomic sequencing reveal the gene responsible for cerebellar hypoplasia and quadrupedal locomotion in a consanguineous kindred.

The biological basis for the development of the cerebro-cerebellar structures required for posture and gait in humans is poorly understood. We investigated a large consanguineous family from Turkey exhibiting an extremely rare phenotype associated with quadrupedal locomotion, mental retardation, and cerebro-cerebellar hypoplasia, linked to a 7.1-Mb region of homozygosity on chromosome 17p13.1-13.3. Diffusion weighted imaging and fiber tractography of the patients' brains revealed morphological abnormalities in the cerebellum and corpus callosum, in particular atrophy of superior, middle, and inferior peduncles of the cerebellum. Structural magnetic resonance imaging showed additional morphometric abnormalities in several cortical areas, including the corpus callosum, precentral gyrus, and Brodmann areas BA6, BA44, and BA45. Targeted sequencing of the entire homozygous region in three affected individuals and two obligate carriers uncovered a private missense mutation, WDR81 p.P856L, which cosegregated with the condition in the extended family. The mutation lies in a highly conserved region of WDR81, flanked by an N-terminal BEACH domain and C-terminal WD40 beta-propeller domains. WDR81 is predicted to be a transmembrane protein. It is highly expressed in the cerebellum and corpus callosum, in particular in the Purkinje cell layer of the cerebellum. WDR81 represents the third gene, after VLDLR and CA8, implicated in quadrupedal locomotion in humans.

A diagnostic challenge: dilated pupil.

PURPOSE OF REVIEW: Dilated pupil is a diagnostic challenge encountered by neurologists and ophthalmologists. The aim of this review is to provide an overview of the current data and guidelines concerning dilated pupils. RECENT FINDINGS: The majority of recent reports on dilated pupils are indicative of several medical conditions that require evaluation. The topical synthetic parasympatholytic agents; local contamination of antihistamines with their antimuscarinic effects; atropine, scopolamine, and tropane alkaloids in all species of Datura plants may produce mydriasis. SUMMARY: The causes of pupillary dilatation can be unilateral, bilateral, and transient. The clinical approach to dilated pupils requires stepwise evaluation, and based on the findings, unnecessary and costly procedures can be avoided.

Pupillary Involvement in Miller Fisher Syndrome.

Miller Fisher Syndrome is characterised by the classical triad of ophthalmoplegia, ataxia, and areflexia. Ophthalmoparesis without ataxia, without areflexia, or with neither have been attributed as atypical forms of MFS. We report two patients with MFS who had tonic pupils and raised anti-GQ1b antibody titres. Bilateral dilated pupils (either tonic or fixed) can be a manifestation of MFS and anti-GQ1b immunoglobulin G (IgG) antibodies are useful to confirm the diagnosis in unexplained cases. The site of involvement is thought to be the ciliary ganglion or short ciliary nerves.

Neuro-ophthalmology of subacute sclerosing panencephalitis: two cases and a review of the literature.

PURPOSE OF REVIEW: To review the literature on early visual manifestations of subacute sclerosing panencephalitis (SSPE) with regard to two patients who had visual problems preceding the onset of neurological symptoms. One patient had cortical visual disturbances and the other had visual loss due to retinal pigment epithelial changes. RECENT FINDINGS: SSPE is a chronic encephalitis characterized by a history of measles infection and a progressive disease of the central nervous system that still occurs frequently in countries with insufficient measles immunization. Visual manifestations can occur as a result of involvement of the pathways that lead from the retina to the occipital cortex during the course of the disease, but are rare as a presenting sign. Fundus changes, especially macular retinitis and macular pigment disturbances, appear to be the most common ocular manifestations of SSPE. SUMMARY: Ophthalmologists must be aware that SSPE can knock their door with ocular findings of SSPE, months or years before the onset of neurological symptoms.

Idiopathic Hypertrophic Cranial Pachymeningitis Associated With Intermediate Uveitis.

The authors report a case with idiopathic hypertrophic cranial pachymeningitis associated with intermediate uveitis. The patient complained of decreased vision in both eyes, especially the right. Ophthalmic examination revealed right optic disc pallor, bilateral vitritis, and cystoid macular edema. Magnetic resonance imaging revealed marked enhancement of a dural lesion. The macular edema responded well to medical treatment. Intermediate uveitis has not yet been reported in the context of idiopathic hypertrophic cranial pachymeningitis.

Cortical connectivity in the face of congenital structural changes-A case of homozygous LAMC3 mutation.

The homozygous LAMC3 gene mutation is associated with severe bilateral smoothening and thickening of the lateral occipital cortex . Despite this and further significant changes in gray matter structure, a patient harboring this mutation exhibited a range of remarkably intact perceptual abilities . One possible explanation of this perceptual sparing could be that the white matter structural integrity and functional connectivity in relevant pathways remained intact. To test this idea, we used diffusion tensor and functional magnetic resonance imaging to investigate functional connectivity in resting-state networks in major structural pathways involved in object perception and visual attention and corresponding microstructural integrity in a patient with homozygous LAMC3 mutation and sex, age, education, and socioeconomically matched healthy control group. White matter microstructural integrity results indicated widespread disruptions in both intra- and interhemispheric structural connections except inferior longitudinal fasciculus. With a few exceptions, the functional connectivity between the patient's adjacent gray matter regions of major white matter tracts of interest was conserved. In addition, functional localizers for face, object, and place areas showed similar results with a representative control, providing an explanation for the patient's intact face, place, and object recognition abilities. To generalize this finding, we also compared functional connectivity between early visual areas and face, place, and object category-selective areas, and we found that the functional connectivity of the patient was not different from the control group. Overall, our results provided complementary information about the effects of LAMC3 gene mutation on the human brain including intact temporo-occipital structural and functional connectivity that are compatible with preserved perceptual abilities.

Encephalopathy due to carnitine deficiency in an adult patient with gluten enteropathy.

A 48-year-old male patient had two episodes of fever, headache, confusion and seizures following an upper respiratory tract infection. Electroencephalography (EEG) revealed diffuse slowing of background activity. Plasma free carnitine and serum lipid levels were low; fecal fat content and serum antigliadin antibodies were elevated. Duodenal biopsy was compatible with gluten enteropathy. Symptoms improved after the patient was started on a gluten-free diet and carnitine replacement therapy. No recurrence was observed within a four-year follow-up. Carnitine deficiency in adulthood is unusual, and encephalopathy due to carnitine deficiency as a result of celiac disease has not been described previously.

Acute Acquired Comitant Esotropia in Adults: Is It Neurologic or Not?

Objectives. Acute acquired comitant esotropia (AACE) can be a diagnostic challenge for ophthalmologists and neurologists because of its association with neurological pathologies. Our study describes a series of adult patients with AACE of undetermined etiology. Methods. Data on the clinical findings of patients presented with AACE of undetermined etiology with a minimum follow-up of 1 year were retrieved from the medical records and the results analyzed. Results. A series of 9 esotropia cases (age range: 20-43 years) was reviewed. All patients had full duction and versions, without an A-pattern or V-pattern. All patients had esotropia for distance and near. Neurological evaluation in all cases was normal. Among patients, 3 were treated with prisms, 4 were treated with strabismus surgery, and 1 was treated with botulinum toxin injections; 1 patient declined treatment. In treated patients posttreatment sensory testing indicated restoration of binocularity that remained stable throughout follow-up of 1-9 years. The patient that declined treatment had binocular function with base-out prisms. Conclusion. Acute onset esotropia may be seen without a neurological pathology in adults. Good motor and sensory outcomes can be achieved in these patients with AACE of undetermined etiology via surgical and nonsurgical methods.

Wall-eyed bilateral internuclear ophtalmoplegia presenting as monocular alternating nystagmus: a non-epileptic phenomenon in a case of diffuse axonal injury.

A 15-year-old male in a persistent vegetative state due to diffuse axonal injury presented with seizures and spontaneous alternating monocular nystagmus. The cranial MRI revealed diffuse axonal injury involving supratentorial and infratentorial structures, and the splenium of the corpus callosum. The monocular alternating nystagmus was thought to be independent of seizures and occurred as a result of diffuse axonal injury affecting the medial longitudinal fasciculus bilaterally.

[Creutzfeldt-Jakob disease: a case that initiated with psychiatric symptoms]. / Creutzfeldt-Jakob Hastaligi: Psikiyatrik Belirtilerle Baslayan Bir Olgu.

Creutzfeldt-Jakob disease (CJD) is a rapidly progressive prion disease that causes deficits involving movement, cognition, and mental status. The clinical heterogeneity of the disease can make diagnosis difficult. Thorough neurologic, cognitive, and psychiatric examinations are necessary for observing its clinical features. In this case report we describe a 62-year-old male patient who was initially followed with a diagnosis of depression and later was diagnosed with CJD. The patient had a one-year history of anhedonia, loss of interest, social withdrawal, anxiety and decrease in speech and was given paroxetin 20 mg/day with a diagnosis of depression. During follow up, neurological symptoms including ataxia and rigidity became evident and dementia and akinetic mutism developed in a rapidly progressive course. Although electroencephalography (EEG) and magnetic resonance imaging (MRI) revealed nonspecific findings initially, typical findings for CJD were seen during the follow up. The positive 14-3-3 protein in CSF supported the diagnosis. The aim of this report is to emphasize the fact that CJD may present with different psychiatric symptoms and can be initially misdiagnosed. CJD should be considered in the differential diagnosis of patients who have focal neurological signs in addition to psychiatric symptoms. Repeated neurological examinations, EEG and cranial MRI may help in the diagnosis of these patients.

Neuromyelitis Optica and Neuromyelitis Optica Spectrum Disorder Patients in Turkish Cohort: Demographic, Clinical, and Laboratory Features.

BACKGROUND: Neuromyelitis optica (NMO) is an immune-mediated, chronic relapsing, inflammatory disease characterized by severe attacks of optic neuritis and myelitis. OBJECTIVE: To determine the demographic, clinical, and laboratory features; antibody status; and treatment modalities of patients with NMO and neuromyelitis optica spectrum disorders in a Turkish cohort from 11 centers. METHODS: A total of 182 patients were included in this study. Data on age at disease onset, sex, type of attacks, clinical presentation, analysis of cerebrospinal fluid, serum antiaquaporin-4 antibody status, annual progression index, and medical and family histories were collected. RESULTS: Mean age was 38.43±12.40 years (range, 13 to 75 y), and mean age at disease onset was 31.29±12.40 years (median, 29 y; range, 10 to 74 y). In NMO group, the rate of NMO immunoglobulin (Ig)G positivity was 62.5%. The annual progression index was significantly higher in the longitudinally extending spinal cord lesion. The mean Expanded Disability Status Scale score was higher in the late than early-onset NMO group. CONCLUSION: Our results revealed a lower rate of NMO IgG positivity, more severe disability in patients with NMO/neuromyelitis optica spectrum disorders presenting with either transverse myelitis or late-onset NMO, and no correlation between disability and NMO IgG status.

Postoperative progressive visual loss.

A 61-year-old man was admitted with postoperative progressive bilateral visual loss following a parasagittal meningioma resection. No risk factor predisposing to an ischemic optic neuropathy was present and routine radiologic examinations did not reveal any pathology of the central or peripheral visual pathways. Mucin-positive adenocarcinoma cells were detected in the cytological examination and orbital MRI revealed metastatic infiltration of the optic chiasm and optic nerves. The primary site of the malignancy could not be established.

Intracavernous granular cell tumor.

BACKGROUND: Granular cell tumors in the central nervous system are quite rare. To date, only 6 cases of granular cell tumor arising from cranial nerves have been reported in the literature. To the best of our knowledge, we present the first case of a predominant intracavernous granular-cell tumor arising from oculomotor nerve. CASE PRESENTATION: A 42-year-old man presented with third-nerve paresis and decreased visual acuity on the left side. Magnetic resonance imaging showed a mainly intracavernous mass partially extending to the superior orbital fissure and entrance of the optic canal. Using a pterional craniotomy, the tumor was removed from within the cavernous sinus via combined superior and lateral intradural approach, and optic nerve was also decompressed. Histologically, the tumor was diagnosed as a granular cell tumor. CONCLUSIONS: Although it is quite rare, granular cell tumor should be included into the differential diagnosis of intracavernous masses because surgical treatment is curative.

Panuveitis associated with multiple sclerosis complicated by cerebral venous thrombosis.

PURPOSE: To report cerebral venous thrombosis as a complication of intravenous corticosteroid treatment in a patient with multiple sclerosis. METHOD: A case report. A 44-year-old woman with a previous diagnosis of multiple sclerosis presented with panuveitis and retinal perivasculitis. Intravenous pulse corticosteroid therapy was given for three days. RESULTS: The panuveitis and retinal periphlebitis began to resolve within one week; however, ten days after the last corticosteroid dose, the patient was hospitalized with the diagnosis of cerebral venous thrombosis. CONCLUSION: Although intravenous corticosteroid treatment for uveitis associated with multiple sclerosis can be very helpful, the patient should be monitored closely for systemic side effects.

Acute visual loss: just the beginning?

A 47-year-old man presented with sudden visual loss, optic disk edema, retinal ischemia, and limited upgaze in the left eye. Initial MRI revealed thickened, enhancing left optic nerve. Extensive work-up for an inflammatory and infiltrative etiology was positive only for Borrelia burgdorferi IgM by Western blot. Six weeks later the patient had numbness and weakness on his left side. MRI showed enhancing lesions extending from the left optic nerve to the optic chiasm, along the visual pathways bilaterally, mainly on the right side from optic tract to lateral geniculate body and pulvinar. Stereotactic biopsy of the right pulvinar lesion revealed glioblastoma. The tumor progressed rapidly, and the patient died 11 weeks after the onset of first symptoms.