Cortical plasticity in AQP4-positive NMOSD: a transcranial magnetic stimulation study.

Aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder (AQP4-NMOSD) is an autoimmune disease characterized by suboptimal recovery from attacks and long-term disability. Experimental data suggest that AQP4 antibodies can disrupt neuroplasticity, a fundamental driver of brain recovery. A well-established method to assess brain LTP is through intermittent theta-burst stimulation (iTBS). This study aimed to explore neuroplasticity in AQP4-NMOSD patients by examining long-term potentiation (LTP) through iTBS. We conducted a proof-of-principle study including 8 patients with AQP4-NMOSD, 8 patients with multiple sclerosis (MS), and 8 healthy controls (HC) in which iTBS was administered to induce LTP-like effects. iTBS-induced LTP exhibited significant differences among the 3 groups (p: 0.006). Notably, AQP4-NMOSD patients demonstrated impaired plasticity compared to both HC (p = 0.01) and pwMS (p = 0.02). This pilot study provides the first in vivo evidence supporting impaired neuroplasticity in AQP4-NMOSD patients. Impaired cortical plasticity may hinder recovery following attacks suggesting a need for targeted rehabilitation strategies.

Incidence and determinants of seizures in multiple sclerosis: a meta-analysis of randomised clinical trials.

BACKGROUND: Seizures are reported to be more prevalent in individuals with multiple sclerosis (MS) compared with the general population. Existing data predominantly originate from population-based studies, which introduce variability in methodologies and are vulnerable to selection and reporting biases. METHODS: This meta-analysis aims to assess the incidence of seizures in patients participating in randomised clinical trials and to identify potential contributing factors. Data were extracted from 60 articles published from 1993 to 2022. The pooled effect size, representing the incidence rate of seizure events, was estimated using a random-effect model. Metaregression was employed to explore factors influencing the pooled effect size. RESULTS: The meta-analysis included data from 53 535 patients and 120 seizure events in a median follow-up of 2 years. The pooled incidence rate of seizures was 68.0 per 100 000 patient-years, significantly higher than the general population rate of 34.6. Generalised tonic-clonic seizures were the most common type reported, although there was a high risk of misclassification for focal seizures with secondary generalisation. Disease progression, longer disease duration, higher disability levels and lower brain volume were associated with a higher incidence of seizures. Particularly, sphingosine-1-phosphate receptor (S1PR) modulators exhibited a 2.45-fold increased risk of seizures compared with placebo or comparators, with a risk difference of 20.5 events per 100 000 patient-years. CONCLUSIONS: Patients with MS face a nearly twofold higher seizure risk compared with the general population. This risk appears to be associated not only with disease burden but also with S1PR modulators. Our findings underscore epilepsy as a significant comorbidity in MS and emphasise the necessity for further research into its triggers, preventive measures and treatment strategies.

Brain reserve and timing of clinical onset in multiple sclerosis.

BACKGROUND: A latent period of variable length elapses between multiple sclerosis (MS) biological onset and the occurrence of the first clinical episode reflecting a central nervous system (CNS) demyelinating event. Factors affecting the duration of such interval are unknown. OBJECTIVE: To explore whether brain reserve, which moderates the impact of structural damage along MS course, could also affect the timing of MS clinical onset. METHODS: We conducted a time-to-event analysis in 326 relapsing-onset multiple sclerosis patients to ascertain the effect of brain reserve, that is, larger maximal lifetime brain growth (MLBG) estimated as intracranial volume, on the risk of an earlier disease onset. For this purpose, we carried out a Cox proportional hazards regression model stratified by sex and adjusted by site and pre-morbid MS risk factors. All patients reached the event (i.e. the disease onset) with no censored case; the age (years) at disease onset was set as the main time variable. RESULTS: We identified a protective effect of brain reserve on the time to disease onset (HR = 0.11, 95% CI = 0.02-0.83, p = 0.032), unchanged when accounting for MS risk factors. CONCLUSION: Brain reserve might counteract the pathological mechanisms ongoing after biological initiation, thus delaying the disease overt clinical manifestation.

Restless leg syndrome as a complication of primary hyperparathyroidism: insights from a retrospective study.

INTRODUCTION: Restless leg syndrome (RLS) is an invalidating neurological disorder with a complex, largely unknown pathophysiology. While RLS is observed in Parkinson's disease and in renal failure, idiopathic cases are common. Limited reports associate RLS with parathyroid hormone (PTH). This study analyzes a cohort of patients with primary hyperparathyroidism (PHPT) and chronic post-surgical hypoparathyroidism (hypo PTH), to investigate RLS prevalence, and associated risk factors. METHODS: Ninety-five patients (54 PHPT, 41 hypo PTH) were consecutively enrolled at the bone metabolism outpatient clinic. The revised IRLSSG diagnostic criteria were used to diagnose RLS, with assessments conducted through face-to-face interviews and neurological examination. When RLS was confirmed, the RLS severity scale was applied. Retrospective records included calcium-phosphate metabolism-related parameters, surgery details, renal lithiasis, fragility fractures, and densitometric features (T-score). RESULTS: RLS was diagnosed in 22.2% PHPT patients, compared to 4.9% of patients with hypo PTH (p = 0.02). Of RLS diagnosed patients, 91.7% had a history of parathyroidectomy, compared to 47.6% of patients without RLS (p = 0.01). Most of the operated patients reported that surgery determined an improvement of symptoms; however, mean score severity of RLS at our evaluation was 15/40, defined as moderate. PTH and calcium levels were not statistically associated to the presence of RLS. CONCLUSION: Our study suggests that PHPT may be one of the etiologies of RLS. Parathyroidectomy alleviates symptoms in the vast majority of the cases but does not remove them.

Unusual CLIPPERS presentation with a predominant spinal cord involvement: case report and review of the literature.

Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) is a discrete nosological entity characterized by punctate and curvilinear gadolinium enhancement "peppering" the pons and a strong response to steroids. MRI images typically show pontine and cerebellar punctate-enhancing lesions, which occasionally spread up to the juxtacortical areas and down to the spinal cord. Interestingly, the more distant the lesion is from the pons, the less intense they become. Herein, we describe an extremely rare case of CLIPPERS presenting with predominant spinal cord involvement; then, we searched in the literature the available cases with a similar presentation. Our case focuses attention on a rare MRI CLIPPERS presentation. Since CLIPPERS has a dramatic response to corticosteroid treatment, it is fundamental to promptly recognize its MRI pattern to start treatment as soon as possible.

Pathophysiology of multiple sclerosis damage and repair: Linking cerebral hypoperfusion to the development of irreversible tissue loss in multiple sclerosis using magnetic resonance imaging.

BACKGROUND AND PURPOSE: Reduced cerebral perfusion has been observed in multiple sclerosis (MS) and may contribute to tissue loss both acutely and chronically. Here, we test the hypothesis that hypoperfusion occurs in MS and relates to the presence of irreversible tissue damage. METHODS: In 91 patients with relapsing MS and 26 healthy controls (HC), gray matter (GM) cerebral blood flow (CBF) was assessed using pulsed arterial spin labeling. GM volume, T1 hypointense and T2 hyperintense lesion volumes (T1LV and T2LV, respectively), and the proportion of T2-hyperintense lesion volume that appears hypointense on T1-weighted magnetic resonance imaging (T1LV/T2LV) were quantified. GM CBF and GM volume were evaluated globally, as well as regionally, using an atlas-based approach. RESULTS: Global GM CBF was lower in patients (56.9 ± 12.3 mL/100 g/min) than in HC (67.7 ± 10.0 mL/100 g/min; p < 0.001), a difference that was widespread across brain regions. Although total GM volume was comparable between groups, significant reductions were observed in a subset of subcortical structures. GM CBF negatively correlated with T1LV (r = -0.43, p = 0.0002) and T1LV/T2LV (r = -0.37, p = 0.0004), but not with T2LV. CONCLUSIONS: GM hypoperfusion occurs in MS and is associated with irreversible white matter damage, thus suggesting that cerebral hypoperfusion may actively contribute and possibly precede neurodegeneration by hampering tissue repair abilities in MS.

Deep brain stimulation of the dentato-rubro-thalamic tract in a case of Holmes tremor: a constrained spherical deconvolution (CSD)-guided procedure.

Deep brain stimulation (DBS) is an established treatment for movement disorders, including Holmes tremor (HT). HT is a rest and action tremor that occurs as a late symptom of brainstem lesions such as stroke. Unfortunately, it is frequently refractory to medical treatment, hence DBS surgery may be a good option. Due to variable results, the ideal target for DBS in HT still remains to be established, ranging from the thalamus to the globus pallidus internus, to the subthalamic nucleus. Pre-operative imaging also is very challenging, as the complexity of brain fiber architecture may prevent the correct positioning of the directional lead. Herein, we describe the case of a patient affected by a rubral tremor secondary to a brain hemorrhage, who had advanced pre-operative neuroimaging with constrained spherical deconvolution (CSD)-based tractography obtained from diffusion-weighted imaging (DWI) to identify the dentato-rubro-thalamic tract, involved in the pathophysiology of HT. The patient was then addressed to an awake DBS surgery, and with the help of intraoperative microelectrode recordings, a tailored DRTT-targeted procedure was performed. The stimulation determined an almost complete tremor suppression, with no significant side effects at a follow-up of 6 months, paving the way towards new effective techniques for the planning, i.e., CSD-based tractography and the treatment of refractory tremors.

A true isolated cognitive relapse in multiple sclerosis.

Isolated cognitive relapses (ICRs) have been a matter of debate for the past few years. Currently, there is no clear consensus on such an entity, as cognitive decline usually accompanies typical multiple sclerosis (MS) relapses. Herein, we present the neuropsychological and neurophysiological manifestations of a patient who suddenly complained of confusion and memory loss, showing insight into her deficit, in absence of sensorimotor disturbances. Neuroimaging revealed a large tumefactive gadolinium-enhancing lesion localized in the left medial temporal lobe. The patient's symptoms persisted for months afterwards, despite corticosteroid treatment. We believe our patient experienced a true ICR. ICRs are rare entities in MS, but we should be alert to their existence in order to treat them promptly. Deepening their pathophysiology is equally important and neuropsychology combined with neurophysiology may be useful in this regard.

Similarities and differences between multiple sclerosis and type 1 diabetes.

Multiple sclerosis (MS) and type 1 diabetes (T1D) are chronic conditions that result from dysfunction of the immune system. Their common root in autoimmunity stimulates interest in the exploration of similarities and differences between the two diseases. Genetic susceptibility is relevant, creating a substrate, on which environmental factors act as a trigger of an aberrant immune response. Despite being both T-cell mediated disorders with a strong involvement of the humoral arm, immunomodulation is a mainstay of MS management, whereas hormone replacement therapy remains the principal approach for T1D. T1D is usually diagnosed in children and adolescents, while MS is typical of young adults. This difference has implications for disease progression and treatment. The SARS-CoV-2 pandemic and its effect on immunity may affect the prevalence of these conditions, as well as their clinical manifestation.

Non convulsive refractory status epilepticus induced by thiocolchicoside (TCC) intrathecal injection: A case report.

TCC is a semisynthetic molecule widely used in clinical settings as a pain killer and myorelaxant. Several neurological side effects have been reported in association with TCC treatment including somnolence, confusion and seizure, the latter in a lower percentage of patients. Some previous reports described seizure onset after TCC intake in adulthood. However, major epileptological complication, namely status epilepticus, has never been previously reported in association with TCC treatment. In our report, we describe a case of acute refractory non-convulsive status epilepticus (NCSE) in the context of a TCC-induced acute toxic encephalopathy (ATE) in a woman without any previous neurological or physical comorbidities.

Cerebral venous thrombosis without thrombocytopenia after a single dose of COVID-19 (Ad26.COV2.S) vaccine injection: a case report.

BACKGROUND: The coronavirus pandemic became the hard challenge for the modern global health system. To date, vaccination is the best strategy against Sars-Cov-2-related illness. About 3 billions of people received at least one of the approved vaccines. The related adverse events were reported during the various experimental phases, but newer and less common side effects are emerging post-marketing. Vaccine-induced thrombocytopenia with thrombosis (VITT) is one of these insidious adverse reactions and it is considered responsible of venous thrombosis, in both the splanchnic and the cerebral circulation. Although its mechanism has been presumably established, resembling that observed in heparin-induced thrombocytopenia, some venous thromboses seem not to recognize this etiology and their pathogenesis remains unknown. Here we described a case of cerebral venous thrombosis after administration of the Ad26.COV2.S, presenting without thrombocytopenia, paving the way for possible novel causes of this vaccine-induced pathological condition. CASE PRESENTATION: A 45-year-old woman came to our observation for bilateral periorbital headache associated with retro-orbital pain started 8 days after administration of COVID vaccine Jannsen. Ophthalmologic exam showing a bilateral papilledema raised the suspicion of intracranial hypertension. Cerebral magnetic resonance imaging revealed signal alteration with T1-positive contrast enhancement in the right temporal and insular lobes suggestive of cerebral venous thrombosis. The absence of thrombocytopenia and platelet factor 4 (PF-4) antibodies led the clinicians to rule out VITT. The patient was treated successfully with warfarin. CONCLUSION: Venous thrombosis occurring after COVID-19 vaccination represents an adverse event of special interest. Patients with thrombosis and thrombocytopenia appear to be affected by a general thrombophilic state, sustained by an autoimmune mechanism, and show a higher mortality. Thrombosis without thrombocytopenia's pathogenesis has not yet been clarified, but laboratory data and good response to vitamin K antagonists help clinicians in the differential diagnosis with VITT. Future research will allow us to discover other possible mechanisms and maybe identify a subgroup of patients with a higher risk of developing this medical complication.

Contribution of Metabolomics to Multiple Sclerosis Diagnosis, Prognosis and Treatment.

Metabolomics-based technologies map in vivo biochemical changes that may be used as early indicators of pathological abnormalities prior to the development of clinical symptoms in neurological conditions. Metabolomics may also reveal biochemical pathways implicated in tissue dysfunction and damage and thus assist in the development of novel targeted therapeutics for neuroinflammation and neurodegeneration. Metabolomics holds promise as a non-invasive, high-throughput and cost-effective tool for early diagnosis, follow-up and monitoring of treatment response in multiple sclerosis (MS), in combination with clinical and imaging measures. In this review, we offer evidence in support of the potential of metabolomics as a biomarker and drug discovery tool in MS. We also use pathway analysis of metabolites that are described as potential biomarkers in the literature of MS biofluids to identify the most promising molecules and upstream regulators, and show novel, still unexplored metabolic pathways, whose investigation may open novel avenues of research.

Comorbidities of primary headache disorders: a literature review with meta-analysis.

BACKGROUND: Primary headache disorders are common and burdensome conditions. They are associated to several comorbidities, such as cardiovascular or psychiatric ones, which, in turn, contribute to the global burden of headache. The aim of this study is to provide a comprehensive description of the pooled prevalence of comorbidities of primary headache disorders using a meta-analytical approach based on studies published between 2000 and 2020. METHODS: Scopus was searched for primary research (clinical and population studies) in which medical comorbidities were described in adults with primary headache disorders. Comorbidities were extracted using a taxonomy derived from the Global Burden of Disease (GBD) study. We compared prevalence of comorbidities among headache sufferers against general population using GBD-2019 estimates, and compared comorbidities' proportions in clinical vs. population studies, and by age and gender. RESULTS: A total of 139 studies reporting information on 4.19 million subjects with primary headaches were included: in total 2.75 million comorbidities were reported (median per subject 0.64, interquartile range 0.32-1.07). The most frequently addressed comorbidities were: depressive disorders, addressed in 51 studies (pooled proportion 23 %, 95 % CI 20-26 %); hypertension, addressed in 48 studies (pooled proportion 24 %, 95 % CI 22-26 %); anxiety disorders addressed in 40 studies (pooled proportion 25 %, 95 % CI 22-28 %). For conditions such as anxiety, depression and back pain, prevalence among headache sufferers was higher than in GBD-2109 estimates. Associations with average age and female prevalence within studies showed that hypertension was more frequent in studies with higher age and less females, whereas fibromyalgia, restless leg syndrome, and depressive disorders were more frequent in studies with younger age and more female. CONCLUSIONS: Some of the most relevant comorbidities of primary headache disorders - back pain, anxiety and depression, diabetes, ischemic heart disease and stroke - are among the most burdensome conditions, together with headache themselves, according to the GBD study. A joint treatment of headaches and of these comorbidities may positively impact on headache sufferers' health status and contribute to reduce the impact of a group of highly burdensome diseases.

Advanced MRI Techniques: Diagnosis and Follow-Up of Multiple Sclerosis.

Brain and spinal cord imaging plays a pivotal role in aiding clinicians with the diagnosis and monitoring of multiple sclerosis. Nevertheless, the significance of magnetic resonance imaging in MS extends beyond its clinical utility. Advanced imaging modalities have facilitated the in vivo detection of various components of MS pathogenesis, and, in recent years, MRI biomarkers have been utilized to assess the response of patients with relapsing-remitting MS to the available treatments. Similarly, MRI indicators of neurodegeneration demonstrate potential as primary and secondary endpoints in clinical trials targeting progressive phenotypes. This review aims to provide an overview of the latest advancements in brain and spinal cord neuroimaging in MS.

Neurophysiological methods for assessing and treating cognitive impairment in multiple sclerosis: A scoping review of the literature.

In recent years, there has been a growing interest in exploring the non-classical symptoms of multiple sclerosis (MS), with a particular focus on cognitive impairments associated with the disease's progression. These cognitive symptoms are now recognized as crucial elements in the assessment of disease activity. In this context, neurophysiology has emerged as a valuable and accessible tool for studying and addressing cognitive decline in individuals with MS. This scoping literature review investigates the role of neurophysiology in assessing and treating cognitive impairment in MS patients. The review focuses on Electroencephalography (EEG), Non-Invasive Brain Stimulation (NIBS), and magnetoencephalography (MEG) to assess cognitive decline in MS patients. Moreover, we discuss all the papers that tried to treat this cognitive impairment with NIBS techniques. While several neurophysiological markers show potential, standardization of protocols is essential for enhancing the reliability and consistency of these approaches. Further research is warranted to explore other NIBS techniques and deepen our understanding of the neurophysiological underpinnings of cognitive deficits in MS.

Transverse myelitis in children and adults.

Transverse myelitis is a noncompressive myelopathy of inflammatory origin. The causes are broad, ranging from infective or toxic to immuno-mediated etiology. They can be manifestations of systemic diseases, such as sarcoidosis and systemic lupus erythematous, or phenotypes of neuroinflammation; in a portion of cases, the etiology remains unknown, leading to the designation idiopathic. The clinical presentation of transverse myelitis depends on the level of spinal cord damage and may include sensorimotor deficits and autonomic dysfunction. The age of onset of the disorder can impact the symptoms and outcomes of affected patients, with differences in manifestation and prognosis between children and adults. Spinal cord magnetic resonance imaging and cerebrospinal fluid examination are the main diagnostic tools that can guide clinicians in the diagnostic process, even though the search for antibodies that target the structural components of the neural tissue (anti-aquaporin4 antibodies and anti-myelin-oligodendrocyte antibodies) helps in the distinction among the immune-mediated phenotypes. Management and outcomes depend on the underlying cause, with different probabilities of relapse according to the phenotypes. Hence, immunosuppression is often recommended for the immune-mediated diseases that may have a higher risk of recurrence. Age at onset has implications for the choice of treatment.

Lessons from immunotherapies in multiple sclerosis.

The improved understanding of multiple sclerosis (MS) neurobiology alongside the development of novel markers of disease will allow precision medicine to be applied to MS patients, bringing the promise of improved care. Combinations of clinical and paraclinical data are currently used for diagnosis and prognosis. The addition of advanced magnetic resonance imaging and biofluid markers has been strongly encouraged, since classifying patients according to the underlying biology will improve monitoring and treatment strategies. For example, silent progression seems to contribute significantly more than relapses to overall disability accumulation, but currently approved treatments for MS act mainly on neuroinflammation and offer only a partial protection against neurodegeneration. Further research, involving traditional and adaptive trial designs, should strive to halt, repair or protect against central nervous system damage. To personalize new treatments, their selectivity, tolerability, ease of administration, and safety must be considered, while to personalize treatment approaches, patient preferences, risk-aversion, and lifestyle must be factored in, and patient feedback used to indicate real-world treatment efficacy. The use of biosensors and machine-learning approaches to integrate biological, anatomical, and physiological parameters will take personalized medicine a step closer toward the patient's virtual twin, in which treatments can be tried before they are applied.

Leg restlessness and hyperparathyroidism in Parkinson's disease, a further clue to RLS pathogenesis?

Background: Non-motor manifestations are the main features of Parkinson's disease (PD). These have been associated with vitamin D abnormalities, but the role of parathormone (PTH) is still obscure. Among the non-motor symptoms of PD, the pathogenesis of restless leg syndrome (RLS) is still debated, but it has been associated with the vitamin D/PTH axis in other disease models. Our study deepens the association between vitamin D and PTH with the prevalence of non-motor symptoms of PD and explores such a relationship in patients reporting leg restlessness. Methods: Fifty patients with PD were extensively investigated with motor and non-motor scales. Data on serum levels of vitamin D, PTH, and related metabolites were obtained, and patients were stratified as having vitamin D deficiency or hyperparathyroidism according to standardized criteria. Results: Overall, 80% of patients with PD exhibited low vitamin D levels, and hyperparathyroidism was diagnosed in 45%. The analysis of the non-motor symptoms profile using the non-motor symptom questionnaire (NMSQ) revealed 36% of leg restlessness, a main feature of RLS. This was significantly associated with worse motor symptoms, quality of sleep, and quality of life. Moreover, it was associated with hyperparathyroidism (OR: 3.48) and with PTH levels, independent of vitamin D, calcium/phosphate levels, and motor status. Conclusion: Our results suggest a significant association between the vitamin D/PTH axis and leg restlessness in PD. PTH has a putative role in nociceptive modulation, and previous evidence on hyperparathyroidism has suggested a possible interrelation with RLS. Further investigations are necessary to add PTH to the non-dopaminergic non-motor landscape of PD.