Acute amnestic syndrome in fornix lesions: a systematic review of reported cases with a focus on differential diagnosis.

Introduction: Acute amnestic syndrome is an uncommon clinical presentation of neurological disease. Differential diagnosis encompasses several syndromes including Wernicke-Korsakoff and transient global amnesia (TGA). Structural lesions of the fornix account for a minority of cases of acute amnestic syndromes. Etiology varies from iatrogenic injury to ischemic, inflammatory, or neoplastic lesions. A prompt diagnosis of the underlying pathology is essential but challenging. The aim of this review is to systematically review the existing literature regarding cases of acute amnestic syndrome associated with non-iatrogenic lesions of the fornix. Methods: We performed a systematic literature search on PubMed, Scopus, and Web of Science up to September 2023 to identify case reports and case series of patients with amnestic syndrome due to fornix lesions. The systematic review was conducted according to PRISMA guidelines. The research was limited to articles written in English. Cases of fornix damage directly ascribable to a surgical procedure were excluded. Results: A total of 52 publications reporting 55 cases were included in the review. Focusing on acute/subacute onset, vascular etiology was highly prevalent, being responsible for 78% of cases, 40/55 (74%) of which were due to acute ischemic stroke. The amnestic syndrome was characterized by anterograde amnesia in all patients, associated with retrograde amnesia in 27% of cases. Amnesia was an isolated presentation in most cases. Up to two thirds of patients had persistent memory deficits of any severity at follow-up. Discussion: Acute amnestic syndrome can be rarely caused by fornix lesions. In most cases of acute/subacute presentation, the etiology is ischemic stroke, mainly caused by strokes involving the subcallosal artery territory. The differential diagnosis is challenging and a distinction from common mimics is often difficult on a clinical basis. A high index of suspicion should be maintained to avoid misdiagnosis and provide adequate acute treatment to patients with time-dependent disease, also employing advanced neuroimaging. More research is needed to better understand the outcome and identify prognostic factors in patients with amnestic syndrome due to fornix lesions.

Arterial spin labelling qualitative assessment in paediatric patients with MRI-negative epilepsy.

AIM: To evaluate the usefulness of arterial spin labelling (ASL) qualitative analysis for the localisation of seizure-related perfusion abnormalities in paediatric patients with negative brain magnetic resonance imaging (MRI) epilepsy. MATERIALS AND METHODS: Forty-two patients with a diagnosis of MRI-negative focal or generalised epilepsy, who underwent electroencephalogram (EEG) and MRI with ASL in the interictal phase were included. Perfusion abnormalities were evaluated through a qualitative assessment and then compared to EEG seizure focus. RESULTS: Among the 42 patients, 26 had focal epilepsy and 16 had generalised epilepsy. Thirty-three patients (79%) showed a perfusion abnormality, mainly hypoperfusion (74.5% of all ASL alterations), whereas hyperperfused alterations were more represented in patients who experienced the last seizure either less than 48 hours prior to ASL acquisition or in the time interval from 1 week to 1 month prior to ASL acquisition (p=0.034). Concordance of ASL abnormality and EEG focus was found in 33 patients (78.5%), as complete in 17 (40.5%) and as partial in 16 (38%). A trend of higher concordance was found in focal epilepsies compared to generalised epilepsies (p=0.059). The concordance between ASL and EEG major alterations was higher for hyperperfused anomalies than for hypoperfused ones (p=0.009). Variables such as age, sedation, and time from last seizure were not significant contributors for concordance. CONCLUSIONS: The combined use of qualitative ASL and brain MRI and scalp EEG could be a potential tool in daily clinical practice.

Cortical malformations and COL4A1 mutation: Three new cases.

AIM: The COL4A1 gene (13q34) encodes the α1 chain of type IV collagen, a crucial component of the basal membrane. COL4A1 mutations have been identified as a cause of a multisystem disease. Brain MRI in COL4A1-mutated patients typically shows vascular abnormalities and white matter lesions. Cortical malformations (specifically schizencephaly) have also recently been described in these patients, suggesting that these, too, could be part of the phenotypic spectrum of COL4A1 mutations. The aim of our work was to retrospectively evaluate COL4A1-mutated subjects diagnosed at our centers in order to assess the frequency and define the type of cortical malformations encountered in these individuals. METHOD: We retrospectively reviewed MRI data of 18 carriers of COL4A1 mutations diagnosed in our centers between 2010 and 2016. RESULTS: We identified polymicrogyria in two patients, and schizencephaly in the mother of a further patient. INTERPRETATION: Our findings confirm that cortical malformations should be considered to fall within the phenotypic spectrum of COL4A1 mutations and show that not only schizencephaly but also polymicrogyria can also be found in mutated individuals. Although further studies are needed to clarify the underlying pathogenetic mechanism, independently of this, the timing of the brain damage could be the crucial factor determining the type of lesion.

Stroke-like events after brain radiotherapy: a large series with long-term follow-up.

BACKGROUND AND PURPOSE: Patients with a history of brain radiotherapy can experience acute stroke-like syndromes related to the delayed effects of brain radiation, including stroke-like migraine attacks after radiation therapy syndrome, peri-ictal pseudoprogression and acute late-onset encephalopathy after radiation therapy syndrome. The aim of this study was to collect evidence on the long-term outcome and treatment of these conditions, whose knowledge is undermined by their rarity and fragmented description. METHODS: Cases were collected, both prospectively and retrospectively, amongst six neuro-oncology departments. Inclusion criteria were as follows: (i) history of brain radiotherapy (completed at least 6 months before the acute episode); (ii) new onset of acute/subacute neurological symptoms; (iii) exclusion of all etiologies unrelated to brain irradiation. A review of current literature on stroke-like syndromes was performed to corroborate our findings. RESULTS: Thirty-two patients with acute neurological conditions attributed to the delayed effects of radiation were identified, including 26 patients with stroke-like syndromes. Patients with stroke-like syndromes commonly presented with a mosaic of symptoms, including focal deficits (77%), encephalopathy (50%), seizures (35%) and headache (35%). Seventy-three percent of them had acute consistent magnetic resonance imaging alterations. Treatment included high-dose steroids in 65% of cases. Twenty-two patients recovered completely (85%). Sixteen patients (62%) experienced relapses (median follow-up 3.5 years). A literature review identified 87 additional stroke-like cases with similar characteristics. CONCLUSIONS: Stroke-like events related to brain irradiation may be associated with permanent sequelae. Steroids are often administered on empirical grounds, as they are thought to accelerate recovery. Relapses are common, highlighting the need to elaborate adequate prevention strategies.

Altered TDP-43-dependent splicing in HSPB8-related distal hereditary motor neuropathy and myofibrillar myopathy.

BACKGROUND AND PURPOSE: Mutations in the small heat-shock protein 22 gene (HSPB8) have been associated with Charcot-Marie-Tooth disease type 2L, distal hereditary motor neuropathy (dHMN) type IIa and, more recently, distal myopathy/myofibrillar myopathy (MFM) with protein aggregates and TDP-43 inclusions. The aim was to report a novel family with HSPB8K141E -related dHMN/MFM and to investigate, in a patient muscle biopsy, whether the presence of protein aggregates was paralleled by altered TDP-43 function. METHODS: We reviewed clinical and genetic data. We assessed TDP-43 expression by qPCR and alternative splicing of four previously validated direct TDP-43 target exons in four genes by reverse transcriptase-polymerase chain reaction. RESULTS: The triplets and their mother presented in the second to third decade of life with progressive weakness affecting distal and proximal lower limb and truncal muscles. Nerve conduction study showed a motor axonal neuropathy. The clinical features, moderately raised creatin kinase levels, selective pattern of muscle involvement on magnetic resonance imaging and pathological changes on muscle biopsy, including the presence of protein aggregates, supported the diagnosis of a contemporary primary muscle involvement. In affected muscle tissue we observed a consistent alteration of TDP-43-dependent splicing in three out of four TDP-43-target transcripts (POLDIP3, FNIP1 and BRD8), as well as a significant decrease of TDP-43 mRNA levels. CONCLUSIONS: Our study confirmed the role of mutated HSPB8 as a cause of a combined neuromuscular disorder encompassing dHMN and MFM with protein aggregates. We identified impaired RNA metabolism, secondary to TDP-43 loss of function, as a possible pathological mechanism of HSPB8K141E toxicity, leading to muscle and nerve degeneration.

Late-onset Pompe disease: a genetic-radiological correlation on cerebral vascular anomalies.

Pompe disease is an autosomal recessive disorder in which deficiency of the lysosomal enzyme acid alpha-glucosidase results in the accumulation of glycogen mostly in muscle tissues. Several reports suggest a higher incidence of intracranial vascular abnormalities (IVAs) in this condition, as well as brain microbleeds and cerebral vasculopathy. The aim of our study was to evaluate through neuroimaging studies the incidence of these anomalies in our cohort of late-onset Pompe disease (LOPD) patients asymptomatic for cerebrovascular disease, looking for correlations with clinical and genetic data. We studied 18 LOPD patients with brain magnetic resonance angiography (MRA), or contrast-enhanced computed tomography (CECT). Diameters of individual arteries were measured and compared with average values as proposed in the literature. We found IVAs in 13 of the 18 patients, mostly dilatative arteriopathy affecting the vertebrobasilar system. The anterior circle was involved in seven of the 18 patients. The diameter of the basilar artery at 1 cm was found to correlate both with age (spearman rho, p = 0.037) and disease duration (p = 0.004), but no other statistically significant correlation was documented. The incidence of intracranial dilatative arteriopathy in LOPD was higher than in the general population, confirming the literature data. However, we did not find intracranial aneurysms microbleeds or significant cerebrovascular disease. Abnormalities in the anterior and the posterior circle of Willis correlated with age and disease duration, but not with the severity of muscle/respiratory involvement or with genetic data. Further studies in larger cohorts of patients are needed to confirm these findings.

MR Micro-Neurography and a Segmentation Protocol Applied to Diabetic Neuropathy.

The aim of this study was to assess with MRI morphometric ultrastructural changes in nerves affected by diabetic peripheral neuropathy (DPN). We used an MR micro-neurography imaging protocol and a semiautomated technique of tissue segmentation to visualize and measure the volume of internal nerve components, such as the epineurium and nerve fascicles. The tibial nerves of 16 patients affected by DPN and of 15 healthy volunteers were imaged. Nerves volume (NV), fascicles volume (FV), fascicles to nerve ratio (FNR), and nerves cross-sectional areas (CSA) were obtained. In patients with DPN the NV was increased and the FNR was decreased, as a result of an increase of the epineurium (FNR in diabetic neuropathy 0,665; in controls 0,699, p = 0,040). CSA was increased in subjects with DPN (12,84 mm2 versus 10,22 mm2, p = 0,003). The FV was increased in patients with moderate to severe DPN. We have demonstrated structural changes occurring in nerves affected by DPN, which otherwise are assessable only with an invasive biopsy. MR micro-neurography appears to be suitable for the study of microscopic changes in tibial nerves of diabetic patients.

Combined central and peripheral demyelination: Clinical features, diagnostic findings, and treatment.

Combined central and peripheral demyelination (CCPD) is rare, and current knowledge is based on case reports and small case series. The aim of our study was to describe the clinical features, diagnostic results, treatment and outcomes in a large cohort of patients with CCPD. Thirty-one patients entered this retrospective, observational, two-center study. In 20 patients (65%) CCPD presented, after an infection, as myeloradiculoneuropathy, encephalopathy, cranial neuropathy, length-dependent peripheral neuropathy, or pseudo-Guillain-Barré syndrome. Demyelinating features of peripheral nerve damage fulfilling European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS) electrodiagnostic criteria for CIDP were found in 23 patients (74%), and spatial dissemination of demyelinating lesions on brain MRI fulfilling the 2010 McDonald criteria for multiple sclerosis (MS) in 11 (46%). Two thirds of the patients had a relapsing or progressive disease course, usually related to the appearance of new spinal cord lesions or worsening of the peripheral neuropathy, and showed unsatisfactory responses to high-dose corticosteroids and intravenous immunoglobulins. The clinical presentation of CCPD was severe in 22 patients (71%), who were left significantly disabled. Our data suggest that CCPD has heterogeneous features and shows frequent post-infectious onset, primary peripheral nervous system or central nervous system involvement, a monophasic or chronic disease course, inadequate response to treatments, and a generally poor outcome. We therefore conclude that the current diagnostic criteria for MS and CIDP may not fully encompass the spectrum of possible manifestations of CCPD, whose pathogenesis remains largely unknown.

Advanced magnetic resonance imaging of neuromyelitis optica: a multiparametric approach.

BACKGROUND: Several authors have used advanced magnetic resonance imaging (MRI) techniques to investigate whether patients with neuromyelitis optica (NMO) have occult damage in normal-appearing brain tissue, similarly to multiple sclerosis (MS). To date, the literature contains no data derived from the combined use of several advanced MRI techniques in the same NMO subjects. OBJECTIVE: We set out to determine whether occult damage could be detected in the normal-appearing brain tissue of a small group of patients with NMO using a multiparametric MRI approach. METHODS: Eight female patients affected by NMO (age range 44-58 years) and seven sex- and age-matched healthy controls were included. The techniques used on a 1.5 T MRI imaging scanner were magnetization transfer imaging, diffusion tensor imaging, tract-based spatial statistics, spectroscopy and voxel-based morphometry in order to analyse normal-appearing white matter and normal-appearing grey matter. RESULTS: Structural and metabolic parameters showed no abnormalities in normal-appearing white matter of patients with NMO. Conversely, tract-based spatial statistics demonstrated a selective alteration of the optic pathways and the lateral geniculate nuclei. Diffusion tensor imaging values in the normal-appearing grey matter were found to be significantly different in the patients with NMO versus the healthy controls. Moreover, voxel-based morphometry analysis demonstrated a significant density and volume reduction of the sensorimotor cortex and the visual cortex. CONCLUSIONS: Our data disclosed occult structural damage in the brain of patients with NMO, predominantly involving regions connected with motor and visual systems. This damage seems to be the direct consequence of transsynaptic degeneration triggered by lesions of the optic nerve and spine.

DTI and MR Volumetry of Hippocampus-PC/PCC Circuit: In Search of Early Micro- and Macrostructural Signs of Alzheimers's Disease.

Hippocampal damage, by DTI or MR volumetry, and PET hypoperfusion of precuneus/posterior cingulate cortex (PC/PCC) were proposed as biomarkers of conversion from preclinical (MCI) to clinical stage of Alzheimer's disease (AD). This study evaluated structural damage, by DTI and MR volumetry, of hippocampi and tracts connecting hippocampus to PC/PCC (hipp-PC/PCC) in 10 AD, 10 MCI, and 18 healthy controls (CTRL). Normalized volumes, mean diffusivity (MD), and fractional anisotropy (FA) were obtained for grey matter (GM), white matter (WM), hippocampi, PC/PCC, and hipp-PC/PCC tracts. In hippocampi and hipp-PC/PCC tracts, decreased volumes and increased MD were found in AD versus CTRL (P < .001). The same results with lower significance (P < .05) were found in MCI versus CTRL. Verbal memory correlated (P < .05) in AD with left hippocampal and hipp-PC/PCC tract MD, and in MCI with FA of total WM. Both DTI and MR volumetry of hippocampi and hipp-PC/PCC tracts detect early signs of AD in MCI patients.

Alien hand syndrome in left posterior stroke.

Alien hand syndrome is a rare neurological disorder characterized by involuntary and uncontrollable motor behaviour, usually of an arm or hand. The patient perceives the affected limb as alien, and may personify it. The case of a 61-year-old right-handed woman who developed right posterior AHS after ischaemic stroke in the left posterior cerebral artery territory is reported. Neuroimaging studies disclosed no frontal or parietal involvement, while a posterior thalamic lesion was detected. A possible role of the thalamus in the genesis of AHS is discussed.

Acute transient inflammatory leukoencephalopathy in HIV.

HIV-related acute inflammatory leukoencephalopathy of undetermined origin (AIL) is characterized by abrupt onset of symptoms generally associated with focal brain lesions and inflammatory CSF findings. A previously asymptomatic 31-year-old HIV+ woman presented with acute cognitive difficulties, right hemiparesis and dysphasia. Brain MRI showed a large contrast-enhancing lesion in the left frontal lobe; brain biopsy revealed an inflammatory process. No etiological agent was found in blood, CSF or brain tissue. The patient was given systemic steroids and gammaglobulins and put on HAART. Clinical conditions progressively and completely recovered. Further brain MRI showed the shrinkage of the lesion with no contrast enhancement. Our case could be classified as AIL in HIV resembling ADEM pattern and highlights the importance of taking into consideration. ADEM in the diagnostic process of HIV-related leukoencephalopathy even if the typical features are lacking, as immunodeficiency could modify both presentation and disease course.

New molecular findings in congenital myopathies due to selenoprotein N gene mutations.

Selenoprotein N-related myopathy (SEPN1-RM) is an early-onset muscle disorder that can manifest clinically as congenital muscular dystrophy with spinal rigidity and can result in specific pathological entities such as multiminicore disease, desmin-related myopathy with Mallory body-like inclusions, and congenital fiber-type disproportion. Here we describe the clinical, histopathological, muscle magnetic resonance imaging (MRI) and genetic findings of three Italian SEPN1-RM families. Proband 1 is a 31-year-old female who was floppy at birth and developed axial and mild lower limb-girdle weakness. The second proband is a 13-year-old boy with RSMD1. Probands 3 and 4 were brothers showing clinical phenotype of congenital myopathy. Muscle MRI demonstrated selective involvement of sartorius, gluteal muscles and distal gastrocnemius and sparing of rectus femoris and gracilis. Muscle histopathology showed in proband 1 myopathic changes with mild connective tissue increase and some fibres lacking the Z-line, while probands 2 and 3 had multiminicores. SEPN1 gene analysis revealed five mutations, three of which are novel. Proband 1 was a compound heterozygote for a 92-bp (exon 1) and a 1-bp deletion (exon 9); proband 2 had a 99-bp deletion and a 10-bp duplication in exon 1, and proband 3 presented a novel homozygous mutation in intron 10 acceptor splice site.

HIV-related acute inflammatory leukoencephalopathy of undetermined origin: review of the literature.

HIV-related acute inflammatory leukoencephalopathy of undetermined origin (AIL) has been anecdotally described in literature as being responsible for cognitive and motor deficits. We carried out a review of all the cases of AIL published in literature. Articles were selected according to 2 criteria: acute onset of symptoms; undetermined aetiology and non-fulfilment of multiple sclerosis diagnostic criteria. They were then analyzed in terms of clinical, biological and instrumental features, therapy, diagnostic classification and prognosis. Although rare (21 patients out of about 4,000 publications), AIL is of particular interest, as the comprehension of its mechanisms could give some insight into the direct and immune-mediated actions of HIV within the brain. All the reported patients share several clinical, histopathological, radiological and CSF features, leading to hypothesize a similar aetiopathogenetic mechanism. Conversely, we observed a high heterogeneity of treatment and diagnostic classification, which could have conditioned the broad prognostic variability. The absence of a defined aetiology leads to consider these forms as a particular subgroup of not determined leucoencephalopathies (NDLE), with both MRI and histological pattern dominated by inflammation as distinctive feature.

Congenital muscular dystrophies with cognitive impairment. A population study.

BACKGROUND: Cognitive impairment has been reported in a significant proportion of patients with congenital muscular dystrophies (CMD), generally associated with brain changes. OBJECTIVES: The aim of this study was to establish 1) the overall prevalence of CMD and cognitive impairment in the Italian population; 2) the frequency of individual genetically defined forms; and 3) the presence of distinct phenotypes not associated with mutations in the known genes. METHODS: We included all patients with CMD and cognitive impairment followed in all the Italian tertiary neuromuscular centers. Clinical, brain MRI, and morphologic data were collected. Genetic screening of the known genes was performed according to clinical and muscle biopsy findings. RESULTS: Ninety-two of the 160 (58%) patients with CMD followed in our centers had cognitive impairment. alpha-Dystroglycan (alpha-DG) reduction on muscle biopsy was found in 73/92 (79%), with 42/73 carrying mutations in the known genes. Another 6/92 (7%) showed a laminin alpha2 deficiency on muscle biopsy and 5 of the 6 carried mutations in LAMA2. The remaining 13/92 (14%) patients had normal alpha-DG and laminin alpha2 expression on muscle. CONCLUSIONS: This is the first population study establishing the prevalence of CMD and cognitive impairment and providing a classification on the basis of clinical, MRI, and genetic findings. We also showed that cognitive impairment was not always associated with alpha-DG or laminin alpha2 reduction or with structural brain changes.

Changes in nutritional status and body composition during enzyme replacement therapy in adult-onset type II glycogenosis.

BACKGROUND: In adult glycogen storage disease type II (GSDII), a single-gene mutation causes reduction of the lysosomal enzyme acid alpha-glucosidse. This produces a chronic proximal myopathy with respiratory involvement. Enzyme replacement treatment (ERT) has recently become available and is expected to improve muscle strength. This should result in increased lean body mass. In this study we evaluate body composition and nutritional status in GSDII, and assess whether these parameters changed during treatment. METHODS: Seventeen patients with late-onset GSDII, aged 52.6 +/- 16.8 years, received ERT for >18 months. Dietary habits and metabolic profiles of glucids, lipids, and proteins were assessed. Body composition was calculated using anthropometry and bioelectrical impedence analysis. RESULTS: On inclusion, we found increased fat mass (FM) in five patients in severe disease stage; all had normal body mass index (BMI). FM correlated inversely, and lean mass (LM) directly, with creatine kinase, prealbumin and albumin levels. After treatment, BMI and FM significantly increased, while LM only showed a trend toward increase. Prealbumin and albumin levels increased as early as after the first months of ERT. DISCUSSION: Body mass index value may underestimate FM in patients in severe stage of disease, due to altered body composition. In severely affected patients, laboratory parameters revealed a relative protein malnutrition, that was reversed by ERT, this reflecting restoration of normal muscle metabolic pathways. Increased BMI may indicate a reduction in energy consumption during exercise or respiration, along with clinical improvement.

User interface of a teleradiology system for the MR assessment of multiple sclerosis.

The aim of this study was to assess the image display of a web-based teleradiology system that uses a common web browser and has no need of proprietary applets, plug-ins, or dedicated software for DICOM display. The teleradiology system (TS) is connected to the Internet by ADSL and to radiological modalities using the DICOM standard with TCP/IP. Images were displayed on a PC through Internet connection with the remote TS using a common web browser. MS lesion number and volume in T1- and T2-weighted images (T1w and T2w, respectively) of 30 brain MR studies were quantified using both the TS and a conventional software. Wilcoxon signed ranks test and intraclass correlation coefficient (ICC) were used to assess the variability and concordance between intra- and inter-observer and TS and conventional DICOM viewer, setting significance at p < 0.05. No significant differences in T1w and T2w volumes between the TS and the conventional software were found by either operator. The ICC results showed a high level of inter-operator agreement in volume estimation in T1w and T2w images using the two systems. Quantitative assessment of MS lesion volumes in T1w and T2w images with a user interface of a teleradiology system that allows the consultation by means of a common web browser, without the need for proprietary plug-ins, applets, or dedicated software for DICOM display showed no significant differences from, and almost complete agreement with, conventional DICOM viewers.