Epidemiology of seropositive myasthenia gravis in Sardinia: A population-based study in the district of Sassari.

INTRODUCTION/AIMS: The global incidence and prevalence of myasthenia gravis (MG) range between 6-31/million and 10-37/100,000, respectively. Sardinia is a high-risk region for different immune-mediated disorders, but the epidemiology of MG remains unclear. We determined the epidemiology of MG with acetylcholine receptor (AChR)-immunoglobulin G (IgG) and muscle-specific tyrosine kinase (MuSK)-IgG in the district of Sassari (North-Western Sardinia; population, 325,288). METHODS: From the laboratory of the University Hospital of Sassari (reference for AChR/MuSK-IgG testing in Sardinia since 1998) and the main neurology units in Sardinia, we retrospectively identified MG patients with (1) AChR-IgG and/or MuSK-IgG positivity by radioimmunoprecipitation assay; and (2) residency in the district of Sassari. Incidence (January 2010-December 2019) and prevalence (December 31, 2019) were calculated. RESULTS: A total of 202 patients were included (incident, 107; prevalent, 180). Antibody specificities were AChR (n = 187 [93%]) and MuSK (n = 15 [7%]). The crude MG incidence (95% confidence interval) was 32.6 (26.8-39.2)/million, while prevalence was 55.3 (47.7-63.9)/100,000. After age-standardization to the world population, incidence decreased to 18.4 (14.3-22.5)/million, while prevalence decreased to 31.6 (26.1-37.0)/100,000. Among incident cases, age strata (years) at MG onset were: <18 (2%), 18-49 (14%), 50-64 (21%), and ≥65 (63%). DISCUSSION: Sardinia is a high-risk region for MG, with a prevalence that exceeds the European threshold for rare disease. Identification of the environmental and genetic determinants of this risk may improve our understanding of disease pathophysiology.

In vitro treatments with ceftriaxone promote elimination of mutant glial fibrillary acidic protein and transcription down-regulation.

Alexander disease is a rare, untreatable and usually fatal neurodegenerative disorder caused by heterozygous mutations of the glial fibrillary acidic protein (GFAP) gene which ultimately lead to formation of aggregates, containing also alphaB-Crystallin, HSP27, ubiquitin and proteasome components. Recent findings indicate that up-regulation of alphaB-Crystallin in mice carrying GFAP mutations may temper the pathogenesis of the disease. Neuroprotective effects of ceftriaxone have been reported in various animal models and, noteworthy, we have recently shown that the chronic use of ceftriaxone in a patient affected by an adult form of Alexander disease could halt its progression and ameliorate some of the symptoms. Here we show that ceftriaxone is able to reduce the intracytoplasmic aggregates of mutant GFAP in a cellular model of Alexander disease. Underlying mechanisms include mutant GFAP elimination, concurrent with up-regulation of HSP27 and alphaB-Crystallin, polyubiquitination and autophagy. Ceftriaxone has also been shown to modulate the proteasome system, thus decreasing NF-kappaB activation and GFAP promoter transcriptional regulation, which further accounts for the down-modulation of GFAP protein levels. These mechanisms provide previously unknown neuroprotective targets of ceftriaxone and confirm its potential therapeutic role in patients with Alexander disease and other neurodegenerative disorders with astrocyte involvement.

HERV-K Modulates the Immune Response in ALS Patients.

Human endogenous retrovirus (HERV)-K env-su glycoprotein has been documented in amyotrophic lateral sclerosis (ALS), where HERV-K env-su 19-37 antibody levels significantly correlated with clinical measures of disease severity. Herein, we investigated further the humoral and cell-mediated immune response against specific antigenic peptides derived from HERV-K in ALS. HERV-K env glycoprotein expression on peripheral blood mononuclear cells (PBMCs) membrane and cytokines and chemokines after stimulation with HERV-K env 19-37 and HERV-K env 109-126 were quantified in patients and healthy controls (HCs). HERV-K env glycoprotein was more expressed in B cells and NK cells of ALS patients compared to HCs, whereas HERV-K env transcripts were similar in ALS and HCs. In ALS patients, specific stimulation with HERV-K env 109-126 peptide showed a higher expression of IL-6 by CD19/B cells. Both peptides, however, were able to induce a great production of IFN-γ by stimulation CD19/B cells, and yielded a higher expression of MIP-1α and a lower expression of MCP-1. HERV-K env 19-37 peptide induced a great production of TNF-α in CD8/T cells. In conclusion, we observed the ability of HERV-K to modulate the immune system, generating mediators mainly involved in proinflammatory response.

Antibody response against HERV-W in patients with MOG-IgG associated disorders, multiple sclerosis and NMOSD.

Increased expression of the retroviruses of HERV-W family has been linked to multiple sclerosis (MS) pathophysiology; nothing is known at the moment about MOG-IgG associated disorders. We compared antibody response against HERV-W peptides among patients with MOG-IgG associated disorders, multiple sclerosis (MS) and aquaporin-4 (AQP4)-IgG positive neuromyelitis optica spectrum disorder (NMOSD). A total of 102 serum samples were retrospectively analyzed. Antibody reactivity against HERV-W env peptides was similar in MOG-IgG associated disorders and MS, but different from AQP4-IgG positive NMOSD. Our findings expand the diagnostic role of HERV-W antibodies to the spectrum of demyelinating disorders associated with MOG-IgG.

Levetiracetam in stiff-person syndrome.

We studied the effects of oral levetiracetam (LEV) (500 mg twice daily) in three women with stiff-person syndrome in a single-blind, placebo-controlled study. The severity of muscle rigidity and of paroxysmal symptoms was assessed by EMG and clinically by a rating scale of 0-4 and by the Patients Global Impressions Scale. LEV was well tolerated. On active treatment all patients improved as assessed by any of the objective or subjective outcome measures. No response was noticed on placebo. Our data indicate that in patients with SPS, LEV is well tolerated and has a therapeutic role in the management of both muscle stiffness and life-threatening paroxysmal respiratory spasms.

Antibody response against HERV-W env surface peptides differentiates multiple sclerosis and neuromyelitis optica spectrum disorder.

Background: A specific humoral immune response against HERV-W envelope surface (env-su) glycoprotein antigens has been reported in serum of patients with multiple sclerosis (MS). However, it has not been evaluated to date in patients with neuromyelitis optica spectrum disorder (NMOSD). Objective: The objective of this paper is to investigate whether antibody (Ab) response against HERV-W env-su antigenic peptides differs between NMOSD and MS. Methods: Serum samples were collected from 36 patients with NMOSD, 36 patients with MS and 36 healthy control individuals (HCs). An indirect ELISA was set up to detect specific Abs against HERV-W env-su peptides. Results: Our data showed that two antigenic peptides, particularly HERV-Wenv93-108 and HERV-Wenv248-262, were statistically significantly present only in serum of MS compared to NMOSD and HCs. Thus, the specific humoral immune response against HERV-W env-su glycoprotein antigens found in MS is widely missing in NMOSD. Conclusion: Increased circulating serum levels of these HERV-W Abs may be suitable as additional biomarkers to better differentiate MS from NMOSD.

Carbamazepine, clonazepam and focal reflex proprioceptive seizures.

We studied a 34-year-old man with focal tonic-clonic seizures sometimes elicited by some active postures of the right hand and evolving at times to secondary generalization. Treatment with carbamazepine (CBZ) in combination with parenteral diazepam induced both a dramatic increase of focal reflex proprioceptive seizures and choreoathetoid dyskinesias in the affected hand. CBZ was withdrawn and clonazepam (CZP) given 2 mg daily, with complete relief of seizures and choreoathetoid dyskinesias. CZP had a suppressive effect on seizures for over 15 years, without development of tolerance.

Focal and secondarily generalised convulsive status epilepticus induced by thiocolchicoside in the rat.

The objective of this study was to document the convulsant properties of thiocolchicoside in rats, and to characterise the electroclinical pattern of epileptic seizures. Experiments were carried out in three groups of male Wistar rats: in group A, thiocolchicoside was applied topically to the pia, or given by microinjection to the cerebral cortex (2 microg/microl); in group B, the drug was administered parenterally (6 mg/kg) to rats with minimal lesions of the dura and arachnoid membranes; in group C, thiocolchicoside was administered parenterally (up to 12 mg/kg) to intact rats. In all animals, electroclinical activity was continuously monitored for at least 3 hours after thiocolchicoside injection or application. In group A, electrographic and behavioural activity of focal motor seizures occurred in 100% of animals, developing into a focal status epilepticus; in group B, a multifocal epileptic pattern with secondary generalisation, clinically characterised by clonic or tonic-clonic seizures occurred in 100% of animals, until a secondarily generalised convulsive status epilepticus; in group C, none of animals showed either electrographic or behavioural seizure activity. Our study documents that thiocolchicoside has a powerful convulsant activity in the rat, perhaps due to an antagonistic interaction of the compound with a cortical subtype of the GABA(A) receptor.

Ceftriaxone for Alexander's Disease: A Four-Year Follow-Up.

In 2010, we reported the successful clinical outcome related to a 20-month course of intravenous, cyclical ceftriaxone, in a patient with adult-onset Alexander's disease. We now provide evidence that the progression of the patient's signs/symptoms was halted and reversed with a 4-year-long extension of the trial.The patient's clinical signs/symptoms were evaluated before the start and every 6 months for 6 years. For the early 2 years, without therapy, and for the following 4 years, after intravenous ceftriaxone 2 g daily, for 3 weeks monthly during the initial 4 months, then for 15 days monthly.Gait ataxia and dysarthria were assessed clinically on a 0 to 4 scale. Palatal myoclonus and nystagmus/oscillopsia were monitored by videotape and a self-evaluation scale. The degree of disability, measured by a modified Rankin scale, and the brain MRI were periodically evaluated.Before ceftriaxone therapy, in a 2-year period, gait ataxia and dysarthria worsened from mild to marked, palatal myoclonus spread from the soft palate to lower facial muscles, and the patient complained of oscillopsia. After 4 years of ceftriaxone therapy, gait ataxia and dysarthria improved, from marked to mild at clinical rating scales. The palatal myoclonus was undetectable; the patient did not complained of oscillopsia and declared a progressively better quality of life. Ceftriaxone was safe.This case report provides Class IV evidence that intravenous cycles of ceftriaxone may halt and/or reverse the progression of neurodegeneration in patients with adult-onset Alexander's disease and may significantly improve their quality of life.

"Erratic" complex partial status epilepticus as a presenting feature of MELAS.

Patients with the syndrome of mitochondrial encephalopathy, lactic acidosis, and strokelike episodes (MELAS) may rarely present with complex partial status epilepticus (CPSE) at clinical onset. We report on a 38-year-old woman with MELAS presenting with multifocal CPSE and periodic lateralized epileptiform discharges (PLEDs) on EEG during her first strokelike episode. CT scan documented a right temporo-parieto-occipital strokelike lesion. EEG showed prolonged seizure discharges with alternating focus over the temporo-occipital and frontotemporal regions of the right hemisphere; moreover, right frontotemporal PLEDs were evident when the seizure activity was localized in the temporo-occipital region. The electroclinical status and CT findings normalized gradually on carbamazepine therapy. The four other patients with MELAS described in the literature as presenting with CPSE showed unifocal epileptic discharges on EEG. We report for the first time a case in which multifocal CPSE is the presenting feature of MELAS. Our findings document the multifocality of neuronal hyperexcitability in the context of the cerebral strokelike lesion in this syndrome.