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Adrenoleukodystrophy (ALD) encompasses different neurological phenotypes, ranging from the most severe cerebral forms (C-ALD) to the less severe adrenomyeloneuropathy (AMN). As visual system can be varyingly involved, we aimed at exploring whether optical coherence tomography (OCT) may detect retinal abnormalities and their longitudinal changes in adult ALD patients. In this cross-sectional and longitudinal study, we measured the thicknesses of peripapillary retinal nerve fiber layer (pRNFL), macular ganglion cell complex (mGCC), and segmented inner and outer macula at baseline and their changes over time in 11 symptomatic adult ALD males and 10 age- and sex-matched healthy controls. Statistical analyses were performed for the patients as complete group, and splitting them into two subgroups, one (C-ALD) with and the other (AMN) without cerebral parieto-occipital white matter (WM) lesions. In the complete ALD group and in the C-ALD subgroup, the average pRNFL, mGCC, and inner macula were significantly thinner than in controls (p ≤ 0.01), whereas in the AMN subgroup, they were constantly, though non-significantly, thinner. Significant outer macula thinning was also observed (p

Objective Dominant optic atrophy (DOA) is the most common inherited optic neuropathy, with a prevalence of 1:12,000 to 1:25,000. OPA1 mutations are found in 70% of DOA patients, with a significant number remaining undiagnosed. Methods We screened 286 index cases presenting optic atrophy, negative for OPA1 mutations, by targeted next generation sequencing or whole exome sequencing. Pathogenicity and molecular mechanisms of the identified variants were studied in yeast and patient-derived fibroblasts. Results Twelve cases (4%) were found to carry novel variants in AFG3L2, a gene that has been associated with autosomal dominant spinocerebellar ataxia 28 (SCA28). Half of cases were familial with a dominant inheritance, whereas the others were sporadic, including de novo mutations. Biallelic mutations were found in 3 probands with severe syndromic optic neuropathy, acting as recessive or phenotype-modifier variants. All the DOA-associated AFG3L2 mutations were clustered in the ATPase domain, whereas SCA28-associated mutations mostly affect the proteolytic domain. The pathogenic role of DOA-associated AFG3L2 mutations was confirmed in yeast, unraveling a mechanism distinct from that of SCA28-associated AFG3L2 mutations. Patients' fibroblasts showed abnormal OPA1 processing, with accumulation of the fission-inducing short forms leading to mitochondrial network fragmentation, not observed in SCA28 patients' cells. Interpretation This study demonstrates that mutations in AFG3L2 are a relevant cause of optic neuropathy, broadening the spectrum of clinical manifestations and genetic mechanisms associated with AFG3L2 mutations, and underscores the pivotal role of OPA1 and its processing in the pathogenesis of DOA. ANN NEUROL 2020 ANN NEUROL 2020;88:18-32.

Idiopathic Intracranial Hypertension (IIH) diagnosis requires lumbar puncture to measure cerebrospinal fluid (CSF) pressure. The Pre-Lumbar puncture Intracranial Hypertension Scale (PLIHS) is aimed to detect cases that will show raised or normal CSF opening pressure.Retrospective analysis of records of patients who underwent lumbar puncture for suspect IIH. The target was CSF opening pressure ≥ 250 mmH2O, whereas a set of known neurological, neuro-ophthalmological and neuro-radiological parameters, plus obesity, were used as predictors in a logistic regression model. The PLIHS was based on significant predictors and a cut-off was validated using chi-squared test around CSF opening pressure ≥ 250 and 200 mmH2O.Records of 162 patients were included: CSF opening pressure was200 mmH2O in 40 and ≥ 250 mmH2O in 95 patients; 85 fulfilled IIH diagnosis. PLIHS is based on Frisén grade 2 or higher papilledema, tinnitus, empty sella, perioptic subarachnoid space distension, and obesity. Score range is 0-7: correlation with CSF opening pressure is 0.508 (p .001), and PLIHS score is different between subjects not diagnosed with IIH, and those diagnosed with IIH both with and without papilledema (p .001). PLIHS score ≤ 2 identifies cerebrospinal fluid pressure 200 mmH2O; PLIHS score ≥ 3 identifies CSF opening pressure ≥ 250 mmH2O, IIH diagnosis, visual acuity ≤0.7, and optic nerve atrophy.The PLIHS, can be used to identify patients who will particularly need LP, thus helping with the organization of the diagnostic work-up by optimising healthcare resources and potentially limit the likelihood to incur in LP-related adverse events.

We report the first Italian family affected by hereditary gelsolin amyloidosis (HGA), a rare autosomal dominant disease characterized by adult-onset slowly progressive cranial neuropathy, lattice corneal dystrophy, and cutis laxa. The index case was a 39-year-old male with a 9-year history of progressive bilateral facial nerve palsy. His mother had two episodes of acute facial palsy, and his maternal aunt and grandfather were also affected. Electrophysiological studies confirmed bilateral facial nerve involvement, without signs of peripheral polyneuropathy, and ophthalmological examination showed bilateral lattice corneal dystrophy, in both the index case and his mother. Gelsolin-gene sequencing revealed the heterozygous c.640G>A mutation (p.Asp187Asn) in the proband, his mother and aunt and also in three apparently asymptomatic relatives. The majority of HGA patients come from Finland, although several cases have been reported from other countries. HGA should be considered in the differential diagnosis of progressive or recurrent bilateral facial neuropathy.

Background and objectives This study retrospectively evaluated the AAP guidelines for diagnosis and risk stratification of Brief Resolved Unexplained Events (BRUE) in a well-characterized cohort of infants admitted with an Apparent Life Threatening Event (ALTE). Further, using prospective follow-up, we endeavored to determine the safety of implementing ambulatory care for the lower risk BRUE population (LR-BRUE) and estimate the cost-savings of this practice. Methods Retrospective application of the BRUE criteria on infants younger than 12 months of age who had been admitted with an ALTE from 2006 to 2016 at a single tertiary care center in Lombardy, Italy. ALTE patients were classified into three groups; (1) Not a BRUE; (2) Lower-risk (LR)-BRUE; and (3) Higher-risk (HR)-BRUE. Patients were contacted prospectively to obtain long-term follow-up outcomes and medical records and billing databases were reviewed. Results Among the 84 infants admitted for an ALTE, 35 (42%) were not a BRUE, 16 (19%) were a LR-BRUE, and 33 (39%) were a HR-BRUE. Only one of the LR-BRUE patients had a subsequent LR-BRUE event, and was later diagnosed with a seizure disorder. Two HR-BRUE babies had also previously presented with a LR-BRUE. Application of the LR-BRUE guidelines would have decreased health expenditure by 20%. There were no deaths or significant morbidities in either BRUE group. Conclusions Applying the recent AAP BRUE guidelines and risk stratification to a well-characterized cohort of admitted ALTE patients is a safe and cost-effective approach. Careful out-patient follow-up is recommended as one of our patients with a LR-BRUE had a recurrence, and was subsequently diagnosed with a seizure disorder.

It is widely known that visuospatial neglect and hemianopia maybe superimposed. We considered the differences in implicit information processing which is effective in patients with neglect but not with hemianopia. We then hypothesize that a prime-word in the neglected field should determine a semantic activation effect but not in a blind hemifield. Moreover eye movements could provide further details. In this work we considered a patient with a bilateral with the presence of either a left visual neglect and a right homonymous hemianopia. Our results supported implicit information processing in the space affected by neglect but not by hemianopia.

Infections by herpesviruses may have severe complications in liver transplant patients. Although prophylactic varicella zoster virus vaccination is strongly recommended and widely applied, severe infection may still occur. We report the case of systemic chronic varicella, which developed in a liver allograft recipient, unresponsive to antiviral drug treatment, successfully treated by varicella zooster-specific CTL. Graft failure ensued, likely, because of massive cytolysis of infected hepatocytes. The patient, who was re-transplanted in the absence of signs of varicella zooster reactivation, is now well and disease free 3 yr after second liver transplant.

Late graft dysfunction (GD) associated with the development of autoantibodies is a common event after pediatric liver transplantation (OLTx) and can present in 2 clinicohistological subsets: de novo autoimmune hepatitis (DNAH) and early chronic rejection (ECR). Sixty out of 247 children developed autoantibodies after OLTx. GD was demonstrated in 22 (37%); based on histology, patients were divided in a DNAH and an ECR group. Portal/periportal inflammatory infiltrate with interface/lobular hepatitis was suggestive for DNAH. Pericentral hepatocytes; confluent dropout with a variable degree of central vein endothelitis, but not with ductopenia (loss of >50% of interlobular bile ducts), was diagnosed as ECR. Nine patients had DNAH and 13 ECR. Five out of 9 in the DNAH group were on cyclosporin (CsA) and 4/9 were on tacrolimus (Tac). In the ECR group, 11 children were treated with CsA and 2 with Tac. All DNAH patients had normal liver function tests on steroids and azathioprine (AZA). Five patients with ECR recovered by increasing calcineurin inhibitors (CNIs) dosage, but in 8/13, including 7 switched from CsA to Tac, AZA and steroids were added to obtain remission of disease. Two patients developed late chronic rejection. DNAH and ECR associated with autoantibodies are forms of late GD after OLTx. DNAH improves after standard treatment of autoimmune hepatitis. ECR has a good response to increased doses of CNIs, although ductopenic chronic rejection may occur. In conclusion, the early differential diagnosis of these conditions and an appropriate treatment seem to allow good overall results reflected by a graft survival of more than 90%.

Endomyocardial biopsy (EMB) is currently the standard method to diagnose acute graft rejection. However, considering the potential complications of this procedure, a noninvasive marker of rejection would be an ideal alternative or at least a helpful adjunct to posttransplant management. We measured myoglobin (Myo), creatine kinase MB mass (CK-MBm), troponin T (cTnT), serum amyloid A (SAA), and C-reactive protein (CRP) in 57 patients (mean age 37.5 years) who underwent orthotopic heart transplantation for end-stage cardiac failure between January and December 2001. Endomyocardial biopsies were performed routinely after surgery and histologically diagnosed rejection was graded according to the criteria of the International Society of Heart and Lung Transplantation. Concomittant with the biopsies, blood samples were drawn from the coronary sinus (central blood samples) and from a peripheral vein (peripheral blood samples) to assay biochemical markers. Among 149 EMB evaluated, 87 were negative (grade 0); 28 showed grade 1a rejection; 26 showed grade 1b; and 8 showed grade > 1b (2 were grade 2, 6 were grade 3a). Grades 0 and 1a were considered to be negative, while grades 1b and >1b were considered positive indicating potential acute graft rejection. cTnT, Myo, CK-MBm, SAA, and CRP levels were measured in 149 central blood samples and 149 peripheral blood samples. Myo and CK-MBm did not show significant changes. cTnT seems to be a potentially useful addition to the EMB results, while SAA and CRP showed variations with respect to EMB grade both in central and peripheral samples.

This research aims to study how semantic priming words can influence behavioral measures (RTs, accuracy), to develop an experimental paradigm to differentiate visual neglect and hemianopia. 69 experimental subjects were involved in four experiments. In each experiment target words were preceded by word primes semantically related, neutral or unrelated to the target. The four experiments differed in terms of: number of prime, prime duration and distance between pc monitor and subject. In general, related primes should improve facilitatory effect in target recognition more than unrelated primes, reducing RTs and increasing response accuracy. After repeated ANOVA analysis applied to each experiment and paired comparisons, it is possible to point out that single related primes, shown for 150 ms, greatly improve response behavior in terms of RTs reduction. For future applications to the clinical field, we assume that neglect patients should be facilitated in these specific experimental conditions, due to implicit contralesional prime processing. On the contrary, hemianopics should nowise be facilitated, due to visual field deficit.

Optic neuropathy secondary to idiopathic intracranial hypertension (IIH) may be a severe complication which must be early identified, adequately monitored and treated to avoid blindness. The aim of this study was to quantify optic nerve involvement at time of diagnosis in a prospectively series of IIH investigated at a single Institution and to identify objective parameters for early diagnosis and follow-up. 38 consecutive patients (9 men, 29 females, mean age 39.8 years) with IIH underwent a complete neuro-ophthalmological evaluation including standardized automated perimetry as functional measurement of optic neuropathy and spectral domain optical coherence tomography (SD-OCT) measurements to grade papilledema or optic nerve atrophy. An overall diagnosis of optic nerve involvement was made in 50 out of 76 eyes (66 %); ophthalmoscopic signs of papilledema were identified in 35 eyes (46 %) while optic disc pallor was found in 13 (17 %). In all patients mean visual field deviation (MD, dB) was -7.2 (range 5.3-33.2). SD-OCT measurements of peripapillary retinal nerve fiber layer thickness (PRNFLT) and of macular ganglion cell complex thickness (MGCCT) obtained in 40 eyes (20 subjects) showed normal PRNFLT in 12 eyes (30 %), increased in 16 (40 %) and reduced in 12 eyes (30 %); normal MGCCT in 26 eyes (65 %), reduced in 14 (35 %). In all eyes average RNFLT was increased (mean 130 μm, range 219-59) and average MGCCT was decreased compared to normal values (mean 89.5 μm, range 198-65). Increased PRNFLT was associated with reduced MGCCT in 4 eyes (10 %) indicating early retrograde optic nerve damage. Decreased PRNFLT was associated with decreased MGCCT in 10 eyes (83 %). These results indicate that, in IIH patients, signs of optic neuropathy can be identified in more than half of cases, even without papilledema evidenced on ophthalmoscopic examination. Moreover, an SD-OCT analysis, which can be definitively useful to quantify optic nerve edema or atrophy, can show damage of retinal ganglion cells in an early phase of the disease.

Headache is a key symptom of idiopathic intracranial hypertension (IIH). Operational diagnostic criteria for "Headache attributed to IIH" are included in the international classification of headache disorders, the ICHD-2. The association of IIH with obesity was established by several reports. We investigate the prevalence of headache and its main clinical features in a clinical sample of IIH patients. The possible correlations between the presence of headache and body mass index (BMI) and intracranial pressure (ICP) levels were studied in a consecutive clinical series of patients, in whom diagnosis of IIH was confirmed by exclusion of secondary forms and by the evidence of increased ICP. Differences for age, BMI, and ICP between patients with and without headache and between males and females were assessed with Mann-Whitney U test. Spearman's correlation analysis was used to assess relationships between age, BMI, and ICP. P value < 0.05 was used to set statistical significance. 40 patients entered the study (9 males, 31 females; mean age 39, 8 years, SD 13.2). Headache was reported by 75 % patients. Those characteristics which are included in the present international diagnostic criteria for "Headache attributed to IIH" were reported by a remarkable proportion of the studied patients, but not by all. On the other hand, some headache features usually attributed to migraine forms, and which are not among the required criteria were present in some patients: pulsating quality and unilateral distribution of pain in around 20 %, and migrainous associated symptoms in more than 40 % of the sample. According to statistical analyses, no differences were found for age, BMI, and ICP between patients with and without headache. Our results confirmed the strong association between headache and IIH. Although no significant correlations between some of the key features of IIH were found in this study, we suggest that further studies on larger series--possibly with a longitudinal evaluation--are needed, to help clinicians in categorizing different subgroups among IIH patients as well as in identifying the main factors influencing the prognosis of this disorder.

Patients with Leber's hereditary optic neuropathy (LHON) have loss of central vision with severe damage of small‐caliber fibers of the papillomacular bundle and optic nerve atrophy. The aim of this study was to define the presence and topographical distribution of brain grey matter (GM) and white matter (WM) injury in LHON patients using voxel‐based morphometry (VBM). The correlation of such changes with neuro‐ophthalmologic findings and measurements of peripapillary retinal nerve fiber layer (RNFL) thickness by optical coherence tomography (OCT) was also assessed. Dual‐echo and fast‐field echo scans were acquired from 12 LHON patients and 12 matched controls. VBM analysis was performed using SPM5 and an ANCOVA model. A complete neuro‐ophthalmologic examination, including standardized automated Humphrey perimetry as well as average and temporal peripapillary RNFL thickness measurements were obtained in all the patients. Compared with controls, average peripapillary RNFL thickness was significantly decreased in LHON patients. LHON patients also had significant reduced GM volume in the bilateral primary visual cortex, and reduced WM volume in the optic chiasm, optic tract, and several areas located in the optic radiations (OR), bilaterally. Visual cortex and OR atrophy were significantly correlated with average and temporal peripapillary RNFL thickness (P < 0.001; r values ranging from 0.76 to 0.89). Brain damage in patients with LHON is not limited to the anterior visual pathways, but extends posteriorly to the OR and the primary visual cortex. Such a damage to the posterior parts of the visual pathways may be due either to trans‐synaptic degeneration secondary to neuroaxonal damage in the retina and optic nerve or to local mitochondrial dysfunction. Hum Brain Mapp, 2010. © 2010 Wiley‐Liss, Inc.

Eleven consecutive patients with a first episode of acute optic neuritis were evaluated, using conventional and magnetization transfer (MT) magnetic resonance imaging (MRI), in order to assess the temporal evolution of optic nerve (ON) damage and to investigate the correlation of ON damage with visual outcome and electrophysiological parameters. Patients underwent neuro-ophthalmological, neurological, electrophysiological, and MRI assessments at baseline and after three and 12 months. ON volumes were measured on coronal T1–weighted images using a local thresholding segmentation technique. MT ratio (MTR) from the ON was derived from gradient echo images. No significant volume difference was detected between affected and healthy ON, both at baseline and follow-up. At baseline, mean MTR values were significantly higher in affected ON than in healthy ON (P = 0.001), whereas at months 3 and 12, the mean MTR values were significantly reduced in the affected ON (P = 0.02 and 0.003, respectively). Mean MTR of the affected ON, corrected for healthy ON values, progressively decreased over time (P = 0.04 at month 3 and P = 0.0012 at month 12). On the contrary, MTR values of healthy ON remained stable. No correlations were found between MTR measures and clinical or electrophysiological data. This study shows the presence of subtle pathological changes, possibly due to residual demyelination and subsequent additional demyelination and impaired remyelination, in the ON of patients with a first episode of optic neuritis. In the early phase of optic neuritis, MT MRI is more sensitive than atrophy measurements in detecting disease-related changes. Multiple Sclerosis 2007; 13: 265–268. http://msj.sagepub.com

Cranioectodermal dysplasia (CED, Sensenbrenner syndrome; OMIM #218330) is an autosomal recessive disorder reported only in 15 cases, which is characterized by dolichocephaly, rhizomelic dwarfism, dental and nail dysplasia, and progressive tubulo-interstitial nephritis (TIN) leading to end-stage renal failure. Herein, we describe a new patient with cranio-ectodermal dysplasia. Unlike previously reported cases, this 4-year-old child presented with tubulo-interstitial nephropathy associated with liver cystic disease and elevated liver enzymes. The liver biopsy demonstrated congenital hepatic fibrosis secondary to ductal plate malformation. The coexistence of a chronic tubulo-interstitial renal disease with lesions associated to malformations of the hepatic ductal plate indicates that CED as a new member of the congenital hepatorenal fibrocystic syndromes.

Background. End-stage cholestatic liver disease (ESCLD) is the main indication for liver replacement in children. Pediatric cadaver-organ-donor shortage has prompted the most important evolutions in the technique of liver transplantation, in particular living-donor liver transplantation (LDLT) and split-liver transplantation (SLT). Methods. Between November 1997 and June 2001, 127 children with ESCLD were evaluated for liver transplantation, and 124 underwent 138 liver transplantations after a median time of 40 days. Causes of liver disease were congenital biliary atresia (n=96), Alagille's syndrome (n=12), Byler's disease (n=8), and other cholestatic diseases (n=8). Results. Ninety (73%) patients received a split-liver graft, 28 (23%) a whole liver, and 6 (4%) a reduced-size liver. Overall 2- and 4-year patient survival rates were 93% and 91%, respectively; the 2- and 4-year graft-survival rates were 84% and 80%, respectively. In split-liver recipients, 4-year patient and graft-survival rates were 91% and 83%, respectively; these were 93% and 78%, respectively, in whole-liver recipients and 67% and 63%, respectively, in reduced-size liver recipients. Retransplantation rate was 11%, whereas mortality rate was 8%. Overall incidence of vascular and biliary complication were 16% and 27%, respectively. Conclusions. SLT can provide liver grafts for children with ESCLD with an outcome similar to the one reported following LDLT, eliminating mortality while they are on a transplantation wait list. The need for pediatric LDLT should be reevaluated and programs of SLT strongly encouraged and supported at a national and international level.

We used a sensitive enzyme-linked immunosorbent assay technique to measure tumor necrosis factor alpha (TNF alpha) levels in serum and cerebrospinal fluid (CSF) samples from 30 patients infected with human immunodeficiency virus type 1 and from 10 normal controls. We found detectable levels of TNF alpha in 19 of 30 CSF and in 17 of 30 serum samples. The values of TNF alpha ranged between 20-90 pg/ml. All the patients had overt AIDS. More elevated TNF alpha levels in CSF correlate with focal damage within the central nervous system (p less than 0.01). Our results suggest that an intrathecal production of TNF alpha may occur during active inflammation in course of AIDS.