Cognitive Impairment in Neurological Diseases.

The complex link between cognitive impairment and neurological disorders underscores the intricacies of neurological sciences [...].

Norovirus-associated neurological manifestations: summarizing the evidence.

Norovirus, a positive-stranded RNA virus, is one of the leading causes of acute gastroenteritis among all age groups worldwide. The neurological manifestations of norovirus are underrecognized, but several wide-spectrum neurological manifestations have been reported among infected individuals in the last few years. Our objective was to summarize the features of norovirus-associated neurological disorders based on the available literature. We used the existing PRISMA consensus statement. Data were collected from PubMed, EMBASE, Web of Science, and Scopus databases up to Jan 30, 2023, using pre-specified searching strategies. Twenty-one articles were selected for the qualitative synthesis. Among these, seven hundred and seventy-four patients with norovirus-associated neurological manifestations were reported. Most cases were seizure episodes, infection-induced encephalopathy, and immune-driven disorders. However, only a few studies have addressed the pathogenesis of norovirus-related neurological complications. The pathogenesis of these manifestations may be mediated by either neurotropism or aberrant immune-mediated injury, or both, depending on the affected system. Our review could help clinicians to recognize these neurological manifestations better and earlier while deepening the understanding of the pathogenesis of this viral infection.

P300 Wave Alterations and Cognitive Impairment in Cerebellum Lesions.

Patients with cognitive deficits have a prolonged latency and reduced amplitude of the P300 wave. However, no study has correlated P300 wave alterations with the cognitive performance of patients with cerebellar lesions. We aimed to determine if the cognitive status of these patients was associated with P300 wave alterations. We recruited 30 patients with cerebellar lesions from the wards of the N.R.S. Medical College, Kolkata, in West Bengal (India). The Kolkata Cognitive Screening Battery tasks and the Frontal Assessment Battery (FAB) were used to assess the cognitive status and the International Cooperative Ataxia Rating Scale (ICARS) for cerebellar signs. We compared the results with the normative data of the Indian population. Patients had P300 wave alterations with a significant increase in latency and a non-significant trend in amplitude. In a multivariate model, P300 wave latency was positively associated with the ICARS kinetic subscale (p = 0.005) and age (p = 0.009), regardless of sex and years of education. In the model that included cognitive variables, P300 wave latency was negatively associated with performance in phonemic fluency (p = 0.035) and construction (p = 0.009). Furthermore, P300 wave amplitude was positively associated with the FAB total score (p < 0.001). In closing, patients with cerebellar lesions had an increase in latency and a decrease in the amplitude of the P300 wave. These P300 wave alterations were also associated with worse cognitive performance and some of the subscales of the ICARS, reinforcing that the cerebellum has motor, cognitive, and affective functions.

Abnormal functional connectivity in radiologically isolated syndrome: A resting-state fMRI study.

BACKGROUND: Radiologically isolated syndrome (RIS) patients might have psychiatric and cognitive deficits, which suggests an involvement of major resting-state functional networks. Notwithstanding, very little is known about the neural networks involved in RIS. OBJECTIVE: To examine functional connectivity differences between RIS and healthy controls using resting-state functional magnetic resonance imaging (fMRI). METHODS: Resting-state fMRI data in 25 RIS patients and 28 healthy controls were analyzed using an independent component analysis; in addition, seed-based correlation analysis was used to obtain more information about specific differences in the functional connectivity of resting-state networks. Participants also underwent neuropsychological testing. RESULTS: RIS patients did not differ from the healthy controls regarding age, sex, and years of education. However, in memory (verbal and visuospatial) and executive functions, RIS patients' cognitive performance was significantly worse than the healthy controls. In addition, fluid intelligence was also affected. Twelve out of 25 (48%) RIS patients failed at least one cognitive test, and six (24.0%) had cognitive impairment. Compared to healthy controls, RIS patients showed higher functional connectivity between the default mode network and the right middle and superior frontal gyri and between the central executive network and the right thalamus (pFDR < 0.05; corrected). In addition, the seed-based correlation analysis revealed that RIS patients presented higher functional connectivity between the posterior cingulate cortex, an important hub in neural networks, and the right precuneus. CONCLUSION: RIS patients had abnormal brain connectivity in major resting-state neural networks and worse performance in neurocognitive tests. This entity should be considered not an "incidental finding" but an exclusively non-motor (neurocognitive) variant of multiple sclerosis.

Downbeat Nystagmus as a Presenting Manifestation of Neurolisteriosis in a Pregnant Woman.

Listeria monocytogenes has tropism towards two immunologically "privileged" sites, the fetoplacental unit in pregnant women and the central nervous system (neurolisteriosis) in immunocompromised individuals. We report a case of neurolisteriosis in a previously asymptomatic pregnant woman from rural West Bengal, India, who presented with a subacute onset febrile illness with features of rhombencephalitis and a predominantly midline-cerebellopathy (slow and dysmetric saccades, florid downbeat nystagmus, horizontal nystagmus, and ataxia). With timely detection and the institution of prolonged intravenous antibiotic therapy, both the mother and the fetus were saved uneventfully.

Acute onset movement disorders in diabetes mellitus: A clinical series of 59 patients.

BACKGROUND AND PURPOSE: No previous study has assessed the frequency and clinical-radiological characteristics of patients with diabetes mellitus (DM) and acute onset nonchoreic and nonballistic movements. We conducted a prospective study to investigate the spectrum of acute onset movement disorders in DM. METHODS: We recruited all the patients with acute onset movement disorders and hyperglycemia who attended the wards of three hospitals in West Bengal, India from August 2014 to July 2021. RESULTS: Among the 59 patients (mean age = 55.4 ± 14.3 years, 52.5% men) who were included, 41 (69.5%) had choreic or ballistic movements, and 18 (30.5%) had nonchoreic and nonballistic movements. Ballism was the most common movement disorder (n = 18, 30.5%), followed by pure chorea (n = 15, 25.4%), choreoathetosis (n = 8, 13.6%), tremor (n = 5, 8.5%), hemifacial spasm (n = 3, 5.1%), parkinsonism (n = 3, 5.1%), myoclonus (n = 3, 5.1%), dystonia (n = 2, 3.4%), and restless leg syndrome (n = 2, 3.4%). The mean duration of DM was 9.8 ± 11.4 years (89.8% of the patients had type 2 DM). Nonketotic hyperglycemia was frequently (76.3%) detected. The majority (55.9%) had no magnetic resonance imaging (MRI) changes; the remaining showed striatal hyperintensity. Eight patients with MRI changes exhibited discordance with sidedness of movements. Most of the patients (76.3%) recovered completely. CONCLUSIONS: This is the largest clinical series depicting the clinical-radiological spectrum of acute onset movement disorders in DM. Of note was that almost one third of patients had nonchoreic and nonballistic movements. Our findings highlight the importance of a capillary blood glucose measurement in patients with acute or subacute onset movement disorders, irrespective of their past glycemic status.

Neuroimaging of Diabetic Striatopathy: More Questions than Answers.

BACKGROUND: Diabetic striatopathy (DS), coined as a generic term, has been defined as a hyperglycemic condition associated with either one of the two following conditions: chorea/ballism or striatal hyperdensity on computed tomography or striatal hyperintensity on T1-weighted magnetic resonance imaging. This review highlights those "gray areas," which need further exploration to understand better hyperglycemia-induced striatal changes and diverse movement disorder phenotypes associated with these changes. RESULTS AND DISCUSSION: We searched in PubMed and Google Scholar the terms "diabetes mellitus," "movement disorders," "diabetic striatopathy," "chorea," "hemichorea," "ballism," "hemichorea-hemiballism," and "neuroradiology" in various combinations (time range from 1980 to March 2022). We selected the publications about our topic of discussion. SUMMARY: Hemichorea-hemiballismus is the most commonly associated movement disorder in DS, and the putamen is the most frequently affected anatomical region. The exact pathophysiological mechanisms remain elusive. Clinical-radiological discordance is not rare. Complete reversal of symptoms with the resolution of the imaging findings is the most prevalent outcome in patients with DS. Dramatic improvement of chorea can be achieved by either insulin monotherapy or combination therapy of insulin and D2-blocker or, in some cases, even spontaneously. CONCLUSION: The term "diabetic striatopathy" is ambiguous and controversial. Pathological mechanisms behind clinical-radiological discordance in hyperglycemia-induced striatopathy need further exploration through well-designed studies. We propose a classification of DS that includes symptomatic DS (striatal neuroimaging lesions in association with a clinically evident movement disorder and hyperglycemia), clinically isolated DS (clinically evident movement disorders without striatal changes in neuroimaging), and radiologically isolated DS.

Moyamoya angiopathy in a case of Klinefelter syndrome.

Moyamoya angiopathy, a rare cerebrovascular condition, can be primary (moyamoya disease) or secondary (moyamoya syndrome). Genetic factors, such as the ring finger protein 213 (RNF213), have been associated with moyamoya disease. However, X-linked moyamoya angiopathy/moyamoya syndrome and hypergonadotropic hypogonadism associated with moyamoya syndrome are rare. We report a case of a 14-year-old boy who presented with transient bilateral hemiparesis, recurrent seizures and cognitive decline. He previously had surgery for left-sided cryptorchidism and had been diagnosed with "epileptic attacks" or "functional movement disorders" in previous hospital admissions. Magnetic resonance angiography of the brain showed narrowing of supraclinoid portion of internal carotid arteries, as well as of middle and anterior cerebral arteries, and the presence of multiple collaterals. These findings were suggestive of moyamoya angiopathy. Laboratory investigations and karyotyping revealed a diagnosis of Klinefelter syndrome. This case presents a unique association of moyamoya angiopathy and Klinefelter syndrome in a boy from a poor socio-economic background, where the diagnosis and adequate treatment were delayed due to a lack of awareness and expertise.

The health status: the ignored risk factor in dementia incidence. NEDICES cohort.

BACKGROUND: The causes of the dementia decrease in affluent countries are not well known but health amelioration could probably play a major role. Nevertheless, although many vascular and systemic disorders in adult life are well-known risk factors (RF) for dementia and Alzheimer disease (AD), health status is rarely considered as a single RF. AIM: To analyse whether the health status and the self-perceived health (SPH) could be RF for dementia and AD and to discuss its biological basis. METHODS: We analysed different objective health measures and SPH as RF for dementia and AD incidence in 4569 participants of the NEDICES cohort by means of Cox-regression models. The mean follow-up period was 3.2 (range: 0.03-6.6) years. RESULTS: Ageing, low education, history of stroke, and "poor" SPH were the main RF for dementia and AD incidence, whereas physical activity was protective. "Poor" SPH had a hazard ratio = 1.66 (95% CI 1.17-2.46; p = 0.012) after controlling for different confounders. DISCUSSION: According to data from NEDICES cohort, SPH is a better predictor of dementia and AD than other more objective health status proxies. SPH should be considered a holistic and biologically rooted indicator of health status, which can predict future development of dementia and AD in older adults. CONCLUSIONS: Our data indicate that it is worthwhile to include the SPH status as a RF in the studies of dementia and AD incidence and to explore the effect of its improvement in the evolution of this incidence.

Eye Movement Alterations in Post-COVID-19 Condition: A Proof-of-Concept Study.

There is much evidence pointing out eye movement alterations in several neurological diseases. To the best of our knowledge, this is the first video-oculography study describing potential alterations of eye movements in the post-COVID-19 condition. Visually guided saccades, memory-guided saccades, and antisaccades in horizontal axis were measured. In all visual tests, the stimulus was deployed with a gap condition. The duration of the test was between 5 and 7 min per participant. A group of n=9 patients with the post-COVID-19 condition was included in this study. Values were compared with a group (n=9) of healthy volunteers whom the SARS-CoV-2 virus had not infected. Features such as centripetal and centrifugal latencies, success rates in memory saccades, antisaccades, and blinks were computed. We found that patients with the post-COVID-19 condition had eye movement alterations mainly in centripetal latency in visually guided saccades, the success rate in memory-guided saccade test, latency in antisaccades, and its standard deviation, which suggests the involvement of frontoparietal networks. Further work is required to understand these eye movements' alterations and their functional consequences.

Toward an Automatic Assessment of Cognitive Dysfunction in Relapsing-Remitting Multiple Sclerosis Patients Using Eye Movement Analysis.

Despite the importance of cognitive function in multiple sclerosis, it is poorly represented in the Expanded Disability Status Scale (EDSS), the commonly used clinical measure to assess disability, suggesting that an analysis of eye movement, which is generated by an extensive and well-coordinated functional network that is engaged in cognitive function, could have the potential to extend and complement this more conventional measure. We aimed to measure the eye movement of a case series of MS patients with relapsing−remitting MS to assess their cognitive status using a conventional gaze tracker. A total of 41 relapsing−remitting MS patients and 43 age-matched healthy controls were recruited for this study. Overall, we could not find a clear common pattern in the eye motor abnormalities. Vertical eye movement was more impaired in MS patients than horizontal movement. Increased latencies were found in the prosaccades and reflexive saccades of antisaccade tests. The smooth pursuit was impaired with more corrections (backup and catchup movements, p<0.01). No correlation was found between eye movement variables and EDSS or disease duration. Despite significant alterations in the behavior of the eye movements in MS patients, which are compatible with altered cognitive status, there is no common pattern of these alterations. We interpret this as a consequence of the patchy, heterogeneous distribution of white matter involvement in MS that provokes multiple combinations of impairment at different points in the different networks involved in eye motor control. Further studies are therefore required.

Visceral Adipose Tissue Molecular Networks and Regulatory microRNA in Pediatric Obesity: An In Silico Approach.

Childhood obesity carries an increased risk of metabolic complications, sleep disturbances, and cancer. Visceral adiposity is independently associated with inflammation and insulin resistance in obese children. However, the underlying pathogenic mechanisms are still unclear. We aimed to detect the gene expression pattern and its regulatory network in the visceral adipose tissue of obese pediatric individuals. Using differentially-expressed genes (DEGs) identified from two publicly available datasets, GSE9624 and GSE88837, we performed functional enrichment, protein-protein interaction, and network analyses to identify pathways, targeting transcription factors (TFs), microRNA (miRNA), and regulatory networks. There were 184 overlapping DEGs with six significant clusters and 19 candidate hub genes. Furthermore, 24 TFs targeted these hub genes. The genes were regulated by miR-16-5p, miR-124-3p, miR-103a-3p, and miR-107, the top miRNA, according to a maximum number of miRNA-mRNA interaction pairs. The miRNA were significantly enriched in several pathways, including lipid metabolism, immune response, vascular inflammation, and brain development, and were associated with prediabetes, diabetic nephropathy, depression, solid tumors, and multiple sclerosis. The genes and miRNA detected in this study involve pathways and diseases related to obesity and obesity-associated complications. The results emphasize the importance of the TGF-ß signaling pathway and its regulatory molecules, the immune system, and the adipocytic apoptotic pathway in pediatric obesity. The networks associated with this condition and the molecular mechanisms through which the potential regulators contribute to pathogenesis are open to investigation.

CfDNA Measurement as a Diagnostic Tool for the Detection of Brain Somatic Mutations in Refractory Epilepsy.

Epilepsy is a neurological disorder that affects more than 50 million people. Its etiology is unknown in approximately 60% of cases, although the existence of a genetic factor is estimated in about 75% of these individuals. Hundreds of genes involved in epilepsy are known, and their number is increasing progressively, especially with next-generation sequencing techniques. However, there are still many cases in which the results of these molecular studies do not fully explain the phenotype of the patients. Somatic mutations specific to brain tissue could contribute to the phenotypic spectrum of epilepsy. Undetectable in the genomic DNA of blood cells, these alterations can be identified in cell-free DNA (cfDNA). We aim to review the current literature regarding the detection of somatic variants in cfDNA to diagnose refractory epilepsy, highlighting novel research directions and suggesting further studies.

Association between LAG3/CD4 Genes Variants and Risk for Multiple Sclerosis.

Several recent works have raised the possibility of the contribution of the lymphocyte activation gene 3 (LAG3) protein in the inflammatory processes of multiple sclerosis (MS). Results of studies on the possible association between LAG3 gene variants and the risk of MS have been inconclusive. In this study, we tried to show the possible association between the most common single nucleotide variants (SNVs) in the CD4 and LAG3 genes (these two genes are closely related) and the risk of MS in the Caucasian Spanish population. We studied the genotypes and allelic variants CD4 rs1922452, CD4 rs951818, and LAG3 rs870849 in 300 patients diagnosed with MS and 400 healthy patients using specific TaqMan-based qPCR assays. We analyzed the possible influence of the genotype frequency on age at the onset of MS, the severity of MS, clinical evolutive subtypes of MS, and the HLADRB1*1501 genotype. The frequencies of the CD4 rs1922452, CD4 rs951818, and LAG3 rs870849 genotypes and allelic variants were not associated with the risk of MS and were unrelated to gender, age at onset and severity of MS, the clinical subtype of MS, and HLADRB1*1501 genotype. The results of the current study showed a lack of association between the CD4 rs1922452, CD4 rs951818, and LAG3 rs870849 SNVs and the risk of developing MS in the Caucasian Spanish population.

Scrub Typhus Presenting as Unilateral Abducens Nerve Palsy.

Scrub typhus, an acute febrile infectious disease prevalent in the "Tsutsugamushi Triangle", is a mite-born rickettsial zoonosis, caused by Orientia tsutsugamushi. Although the clinical presentation is protean, it rarely causes abducens nerve palsy. We report a 14-year-old previously healthy Indian girl who presented with a recent onset right abducens nerve palsy and headache, but without fever and without the classic dermatological manifestation ("eschar") of the disease. After exclusion of common infectious, autoimmune, and neoplastic causes, she was finally diagnosed with scrub typhus associated with an abducens nerve palsy, which responded to doxycycline therapy.

Magnetic resonance imaging-negative myeloneuropathy and bilateral facial paresis unfurling systemic lupus erythematosus.

Systemic lupus erythematosus is a chronic autoimmune connective tissue disorder that can affect all the neuroaxes in the central and peripheral nervous systems. Myelopathy in systemic lupus erythematosus is one of the least common neuropsychiatric syndromes accounting for 1%-2% of cases. Myelopathy has long been diagnosed based on clinical findings, laboratory tests, and gold-standard gadolinium-enhanced magnetic resonance imaging (MRI). MRI-negative myelopathy is a recently described subset of myelopathies. Here, we report the case of a young woman from rural West Bengal, India, who presented with overlapping features of white-matter and gray-matter myelopathy associated with peripheral neuropathy and bilateral asymmetric lower motor neuron-type facial paresis. The historical analysis yielded clues toward an etiological diagnosis of systemic lupus erythematosus, further substantiated by seropositivity of lupus-specific autoantibodies. Her neurological disabilities responded poorly to oral administration of hydroxychloroquine, bolus intravenous administration of methylprednisolone, and high-dose cyclophosphamide therapy but eventually responded remarkably well to cyclical rituximab therapy. This case adds to the tally of cases of MRI-negative lupus myelopathy. MRI-negative myelopathy in systemic lupus erythematosus can be easily missed if not meticulous attention is paid during clinical history taking and examinations.

Seropositive Neuromyelitis Optica in a Case of Undiagnosed Ankylosing Spondylitis: A Neuro-Rheumatological Conundrum.

Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune astrocytopathy against foot processes of aquaporin-4 (AQP4) water channels. Patients with NMOSD tend to have other coexisting autoimmune/connective tissue diseases. However, AQP-4-antibody-positive NMOSD coexisting with ankylosing spondylitis (AS) is rare. AS is an immune-mediated disorder, a subset of axial spondyloarthropathies, which commonly manifests as chronic inflammatory back pain in young people, and it has a strong association with HLA-B27. In this study, a 35-year-old Indian man with an undiagnosed progressive axial spondyloarthropathy (i.e., AS) is reported presenting with acute-onset longitudinally extensive transverse myelitis, a clinical subset of NMOSD. Neuromyelitis optica spectrum disorder (NMOSD), a primary demyelinating disorder of the central nervous system (CNS), is an autoimmune astrocytopathy against foot processes of aquaporin-4 (AQP4) water channels, which manifests with optic neuritis, longitudinally extensive transverse myelitis (LETM), area-postrema syndrome, brainstem syndrome diencephalic syndrome, and cerebral syndrome.1-4 Ankylosing spondylitis (AS) is an immune-mediated disorder, a subset of axial spondyloarthropathies, which commonly manifests as chronic inflammatory back pain in young people, and it has a strong association with HLA-B27.5,6 AS characteristically targets the axial skeleton, peripheral joints, entheses (connective tissues between tendons/ligaments and bones), and gut.5,6 Patients with NMOSD tend to have other coexisting autoimmune/connective tissue diseases.7 For example, cases with NMOSD and multiple sclerosis, which are other autoimmune primary demyelinating disorders of the CNS, have been reported.8,9 However, concurrent existence of AS and NMOSD in the same patient even over years of disease course is rare.10,11 In addition, studies describing neurological manifestations of AS are limited,12 and they focus on joint inflammation and long-standing bony pathology (ankylosis) related to compressive myelopathy, myelo-radiculopathy, and cauda equina syndromes.12,13 The authors present a case of a young Indian man with an undiagnosed progressive AS (misdiagnosed and mismanaged by an indigenous medical practitioner) presenting with acute-onset LETM variant of AQP4-positive NMOSD. A 35-year-old healthy, non-comorbid man from rural India came to the outpatient department with complaints of persistent tingling, numbness, and weakness of both lower limbs (right more than left) for 10 days. The clinical picture showed acute-onset urinary retention, which was relieved by urinary catheterization. An indigenous medical practitioner had prescribed drugs to treat a urinary tract infection. His weakness gradually progressed over the following week, causing him to become bedridden. During the removal of the catheter, he felt urgency, increased frequency of micturition, and overt urinary incontinence. He gave no history suggestive of any girdle-like sensations, root/radicular/tract pain, vertebral pain, trauma, recent vaccination, and diarrheal or febrile illness. For the last 8 months, he had a complaint of an insidious-onset, persistent, bilateral, dull aching pain in the gluteal region accompanied by low-back pain and morning stiffness up to 1 h, which markedly improved with activity and reoccurred following long periods of inactivity. He sometimes had to rise in the middle of the night because of excruciating pain, which could be relieved after moving around the room and corridors for half an hour. He was taking over-the-counter diclofenac tablets for pain relief prescribed by some indigenous medical practitioners who told him that it was due to overwork in agricultural fields, that is, mechanical back pain. He also had a normal X-ray of the lumbosacral spine. He had no addiction liabilities, and none of the family members had ever suffered from a similar kind of illness. He had never consulted any trained medical practitioner, as his previous back-pain-related symptoms responded well to the tablets prescribed by the indigenous medical practitioner(s). During examination, he was found to have recent-onset, asymmetric spastic paraparesis (right more than left) with upper motor neuron-type urinary bladder symptoms. Cognitive assessment (assessed by the Montreal cognitive assessment test) was normal, and posterior column sensations were preserved. Sensory system examination revealed no definite sensory level. Except for the paretic lower limbs, cerebellar functions were normal in other regions. Neuro-ophthalmological examinations were also normal, and no signs of meningeal irritation were observed. The history and course of the disease and clinical examinations were analyzed. Selective tractopathy (early and predominant motor and autonomic tract affection) was suggested for an intramedullary demyelinating pathology affecting the anterior central cord. This case was initially classified as acute-onset non-compressive myelopathy at the lower cervical/upper dorsal region level in a patient with a pre-existing axial spondyloarthropathy. Complete blood cell count; liver, kidney, and thyroid function tests; and plasma glucose and electrolytes were normal, except for an increased erythrocyte sedimentation rate (66 mm in the first hour). Magnetic resonance imaging (MRI) of the spinal cord revealed a demyelinating LETM from C5 to D4 level (Figure 1). Meanwhile, an MRI of the sacroiliac joints revealed bilateral sacroiliitis. Brain and orbital MRIs were devoid of any lesions. Anti-aquaporin 4 (AQP-4) antibodies were tested by cell-based assay in serum and cerebrospinal fluid (CSF), and both were positive. CSF further revealed lymphocytic pleocytosis and increased intrathecal protein production. Visually evoked potential recordings were also normal. In addition, anti-myelin oligodendrocyte glycoprotein antibodies were negative. Anti-nuclear antibody (ANA), ANA-profile, autoimmune vasculitis profile (c-ANCA, p-ANCA), neurovirus panel (i.e., polymerase chain reaction for adenovirus, Epstein-Barr virus, herpes simplex viruses 1 and 2, human herpesviruses 6 and 7, cytomegalovirus, enteroviruses, varicella-zoster virus, Japanese encephalitis, and dengue virus), CSF-polymerase chain reaction for Mycobacterium tuberculosis, angiotensin-converting enzyme, anti-phospholipid, and anti-thyroid antibodies were negative. Anti-CCP-antibody and rheumatoid factor were also negative, including creatine phosphokinase level and serum vitamin B12. Moreover, serologies for hepatitis B, C, human immunodeficiency virus, and scrub typhus were negative. However, HLA-B27 assay was positive. The final diagnosis was AQP4-positive NMOSD associated with AS. He was placed on pulse intravenous methylprednisolone (1 g/day for 5 days). Consequently, his lower limb power improved remarkably. Cyclical rituximab therapy was initiated to prevent relapses. At 3-month follow-up, he had no residual neurological deficit except for persistence of paresthesias. Neuroimaging and visually evoked potential studies revealed no active or new lesions. After 6 months of therapy, a subjective and objective improvement was observed in disease severity based on the Ankylosing Spondylitis Disease Activity Score. Our patient satisfied the new Assessment of SpondyloArthritis International Society diagnostic/classification criteria for AS and the Wingerchuk criteria for NMOSD,4,14 an association that has been rarely reported.10,11 Amid the extra-articular complications of long-standing AS, neurological manifestations are considered infrequent.15 However, subclinical neurological complications may be frequent in AS.12 Common neurological manifestations result from bony (vertebral) ankylosis, subluxation of joints, ossification of anterior and posterior longitudinal ligaments, secondary spinal canal stenosis, bony (vertebral) fractures, and subsequent compressions over nerve radicles/roots/cauda equina, and inflammation-related (entrapment) peripheral neuropathies.12,16,17 Acute transverse myelitis can occur as a subset of several primary demyelinating disorders of the CNS (i.e., multiple sclerosis, NMOSD, myelin oligodendrocyte glycoprotein antibody disease, and acute disseminated encephalomyelitis) and various systemic autoimmune connective tissue disorders (i.e., systemic lupus erythematosus, mixed connective tissue disease, Sjögren syndrome, inflammatory bowel disease, and neurosarcoidosis).18 Acute transverse myelitis (short or long segment) is an infrequent extra-articular complication of AS.18 It has been reported to evolve either as a distinct neurological complication of AS, or it may develop secondary to TNF-alpha-inhibitor therapy for the treatment of AS.18,19 AS is a heritable inflammatory spondyloarthropathy that primarily affects the axial skeleton, which is mediated by T-cells; B-cells only play a minor role.5 On the contrary, the key for the pathogenesis of NMOSD is the production of autoantibodies against AQP-4 channels expressed on astrocytes, leading to complement-mediated damage, with ensuing demyelination. Myelitis usually shows high signal intensity on the tbl2-weighted image and contrast enhancement in the spinal cord.1-4 Despite the difference in molecular mechanisms, the diagnosis of these diseases in the same individual may not be coincidental. Recent evidence has shown T-cell-mediated inflammatory responses in cases of NMOSD.20 In particular, Th17 and Th2-related cytokines are elevated in the CSF of NMO patients.20 Environmental factors such as Escherichia coli have also been proven to aggravate autoimmunity in AS and NMOSD (however, body fluid cultures for Escherichia coli, performed in our patient, showed similar association, and they were found negative two times).21,22 Although large-scale epidemiological studies investigating the underlying pathogenesis related to these diseases are lacking, studies have demonstrated anincreased incidence of optic neuritis among patients with AS.23 Systemic sclerosis and mixed and undifferentiated connective tissue diseases were excluded after expert opinions (from two board-certified rheumatologists and two dermatologists) because of the lack of suggestive clinical findings (e.g., absence of skin thickening, salt-and-pepper appearance, nail changes, Mauskopf facies, sclerodactyly, calcinosis cutis, Raynaud's phenomenon, other cutaneous manifestations, pulmonary arterial hypertension/interstitial lung disease, dysphagia, muscular pain/weakness renal impairments, absence of ANA, anti-centromere antibodies, anti-Scl-70, PM-Scl antibodies, anti-ds DNA, PCNA, CENP-B, anti-nucleosomes, anti-Smith, anti-U1-RNP, anti-Jo1, anti-Mi2, anti-Ro52, anti-La antibodies, and normal C3 and C4 complement levels) (The European League Against Rheumatism and the American College of Rheumatology classification criteria 2019).24 Finally, our patient was treated with intravenous steroids followed by rituximab infusions, a monoclonal anti-CD20 antibody directed against B-cells. In particular, this patient clinically and radiologically responded to immunomodulatory drugs, which might support a possible common pathogenic basis of the two processes. TNF-alpha inhibitors are commonly used as novel therapeutics in AS; however, they can potentially result in serious complications, that is, secondary demyelinating disorders.25 However, such inhibitors in this patient were not used. When used in cases of AS, they show satisfactory results.25,26 Therefore, it was decided to treat him with rituximab only without adding any second immunomodulatory. Other possible therapeutic options include cyclophosphamide and mycophenolate mofetil, but they were not used because of their low efficacy-safety balance. Moreover, plasmapheresis was not available in our specific setting, despite solid evidence that early treatment with therapeutic strategy (5-7 courses) provides good long-term outcomes in patients with NMOSD.27 Therefore, when dealing with a case of acute non-compressive myelopathy, history and clinical examination are important to determine the potential underlying etiology and identify an undermined systemic disorder with apparently unrelated non-specific features. Connective tissue disorders should always be considered as a differential diagnosis and be ruled out in all cases of either seropositive or seronegative NMOSD. A diagnosis of AS should be considered in relevant circumstances when dealing with a case of isolated seronegative LETM. Moreover, early diagnosis and treatment of AS are quintessential to prevent lifelong distressing disabilities. However, whether patients with AS have any extra predilection to develop NMOSD throughout their life requires further studies.

A novel heterozygous mutation in the hydroxymethylbilane synthase gene in a case with acute intermittent porphyria.

Porphyrias are rare metabolic disorders caused by inherited or acquired enzymatic defects in the heme biosynthetic pathway. They are grouped into acute hepatic porphyrias and photocutaneous porphyrias. Acute intermittent porphyria, the most prevalent subtype of acute hepatic porphyrias, is caused by a mutation in the hydroxymethylbilane synthase gene. In this work, a case of a 13 year-old Indian female presenting with multi-organ involvement (Neurological: episodic seizures, behavioral abnormalities, acute onset progressive flaccid-motor quadriparesis, multiple cranial nerve palsies, respiratory paralysis, dysautonomia, and posterior reversible encephalopathy syndrome; Gastrointestinal: recurrent attacks of abdominal pain, nausea/vomiting, isolated transaminitis, and acute pancreatitis; and Renal: metabolic alkalosis and refractory dyselectrolytemia) which resulted in significant diagnostic dilemmas. She was eventually diagnosed as a case of acute intermittent porphyria harboring a novel hydroxymethylbilane synthase gene mutation (p.Arg173Trp).

Antisaccades and memory-guided saccades in genetic generalized epilepsy and temporal lobe epilepsy.

OBJECTIVE: Oculomotor tasks can be used to measure volitional control of behavior sensitive to frontal dysfunction. This study aimed to examine the saccadic eye movement in Genetic Generalized Epilepsy (GGE) which could correlate with the abnormality of the frontal lobe or the thalamo-frontal network. METHODS: Twenty-one patients with GGE were compared with 22 patients with Temporal Lobe Epilepsy (TLE) and 39 healthy controls. Visual-guided saccades, Antisaccades, and Memory-guided saccades as oculomotor tasks were performed using a novel gaze-tracker designed for clinical practice use. RESULTS: Patients with epilepsy (either GEE or TLE) had similar latency, accuracy, and velocity in visual-guided saccades and memory-guided saccades. Patients with epilepsy had similar latencies and correct antisaccade number. However, healthy volunteers, matched by age, had faster responses and more accurate results than patients with epilepsy. CONCLUSIONS: Our investigations did not reveal differences between TLE and GGE patients' groups in visually guided saccades, antisaccades, and memory-guided saccades, thus suggesting that the frontal cortical mechanisms responsible for them are not explicitly impaired in patients with GGE.

Predementia constructs: Mild cognitive impairment or mild neurocognitive disorder? A narrative review.

BACKGROUND: Predementia is a heuristic umbrella concept to classify older adults with cognitive impairment who do not suffer dementia. Many diagnostic entities have been proposed to address this concept, but most of them have not had widespread acceptance. AIMS: To review clinical definitions, epidemiologic data (prevalence, incidence) and rate of conversion to dementia of the main predementia constructs, with special interest in the two most frequently used: mild cognitive impairment (MCI) and minor neurocognitive disorder (miNCD). METHODS: We have selected in three databases (MEDLINE, Web of Science and Google scholar) the references from inception to 31 December 2019 of relevant reviews, population and community-based surveys, and clinical series with >500 participants and >3 years follow-up as the best source of evidence. MAIN RESULTS: The history of predementia constructs shows that MCI is the most referred entity. It is widely recognized as a clinical syndrome harbinger of dementia of several etiologies, mainly MCI due to Alzheimer's disease. The operational definition of MCI has shortcomings: vagueness of its requirement of "preserved independence in functional abilities" and others. The recent miNCD construct presents analogous difficulties. Current data indicate that it is a stricter predementia condition, with lower prevalence than MCI, less sensitivity to cognitive decline and, possibly, higher conversion rate to dementia. CONCLUSIONS: MCI is a widely employed research and clinical entity. Preliminary data indicate that the clinical use of miNCD instead of MCI requires more scientific evidence. Both approaches have common limitations that need to be addressed.