Lorenzo Gaetani

Recurrent hyperCKemia with normal muscle biopsy in a pediatric patient with neuromyelitis optica

Neuromyelitis optica (NMO) is a demyelinating disease of the CNS that preferentially affects the optic nerve and spinal cord.1 The presence of circulating autoantibodies (NMO–immunoglobulin G [IgG]) having the water channel aquaporin-4 (AQP-4) as their target antigen is associated with NMO.1 Outside the CNS AQP-4 is present in the distal collecting tubes of the kidney, in parietal cells of the stomach,2 and in fast-twitch fibers of skeletal muscle.3 Several findings support the idea that AQP-4 water channels may be associated to the dystrophin-glycoprotein complex (DGC) in skeletal muscle fibers and AQP-4 expression has been found altered in muscle diseases.4

Synaptic plasticity and experimental autoimmune encephalomyelitis: implications for multiple sclerosis.

Structural and functional neuronal plasticity could play a crucial role during the course of multiple sclerosis (MS). The immune system and the central nervous system (CNS) strictly interact in physiologic conditions and during inflammation to modulate neuroplasticity and in particular the ability of the synapses to undergo long-term changes in the efficacy of synaptic transmission, such as long-term potentiation (LTP). During MS, neuro-inflammation might deeply influence the ability of neuronal networks to express physiologic plasticity, reducing the plastic reserve of the brain, with a negative impact on symptoms progression and cognitive performances. In this manuscript we review the evidence on synaptic plasticity alterations in experimental autoimmune encephalomyelitis (EAE), the most diffuse and widely utilized experimental model of MS, together with their potential underlying mechanisms and clinical relevance. This article is part of a Special Issue entitled SI: Brain and Memory.

Lower urinary tract symptoms and urodynamic dysfunction in clinically isolated syndromes suggestive of multiple sclerosis

Urinary symptoms associated with multiple sclerosis (MS) are common and negatively impact on quality of life, representing a considerable psychosocial and economic burden, often requiring care and hospitalization. Although the importance of identifying and adequately treating urinary symptoms in MS is now well recognized, there is no information, to date, about the real prevalence and impact of bladder symptoms in patients with clinically isolated syndromes (CISs) suggestive of MS.

Hippocampal neuroplasticity and inflammation: relevance for multiple sclerosis

Cognitive impairment is very frequent during multiple sclerosis (MS), involving approximately 40–70% of the patients, with a profound impact on patient’s life. It is now established that among the various central nervous system (CNS) structures involved during the course of MS, the hippocampus is particularly sensitive to the detrimental effects of neuroinflammation. Different studies demonstrated hippocampal involvement during MS, in association with depression and cognitive impairment, such as verbal and visuo-spatial memory deficits, even during the earlier phases of the disease. These cognitive alterations could represent the visible consequences of a hidden synaptic impairment. Indeed, neuronal and immune functions are intertwined and the immune system is able to modulate the efficacy of synaptic transmission and the induction of the main forms of synaptic plasticity, such as long term potentiation (LTP). Hippocampal synaptic plasticity has been studied during the last decades as the physiological basis of human learning and memory and its disruption can be associated with behavioral and cognitive abnormalities. The aim of the present work is to review the available evidence about the presence of hippocampal synaptic plasticity alterations in experimental models of MS, specifically during the course of experimental autoimmune encephalomyelitis (EAE) and to discuss their relevance with regard to human MS. Indeed, the failure of synapses to express plasticity during neuroinflammation could potentially lead to a progressive failure of the brain plastic reserve, possibly contributing to disability progression and cognitive impairment during MS.

Infliximab monotherapy for neuro-Behçet's disease: a case report.

Behçets disease (BD) is a chronic, relapsing, systemic vasculitis of unknown cause involving veins and arteries of all sizes and characterized by protean clinical manifestations. The disease was first described in 1937 as the triad of recurrent oral aphthous ulcers, genital ulceration and uveitis [1]. Neurological involvement is one of the most serious causes of long-term morbidity and mortality in BD [1]. In particular, parenchymal central nervous system (CNS) involvement usually presents with a brainstem syndrome alone or in combination with cognitive-behavioural symptoms [2].

Retinopathy during interferon-β treatment for multiple sclerosis: case report and review of the literature

The onset of new visual symptoms in patients with multiple sclerosis is often associated with a neuro-ophthalmologic manifestation of the disease. However, other possible differential diagnoses need to be ruled out, including drug-induced retinal side effects. Although uncommon, retinal side effects of interferon-beta formulations may occur, and need to be promptly recognized and treated by neurologists. In this manuscript, we report the case of a 37-year-old woman affected by multiple sclerosis diagnosed with interferon beta-associated retinopathy and we review the literature with regard to the epidemiology, clinical presentation, management and follow-up of interferon beta-associated retinopathy. Interferon-beta induced retinopathy seems to be an uncommon and a dose-related side effect in multiple sclerosis patients. Retinopathy tends to completely resolve after treatment discontinuation. Neurologists must be aware that immune-modulatory drugs, in particular interferon beta, have been reported to cause retinal side effects. In multiple sclerosis patients complaining of new visual symptoms during interferon-beta treatment, it is thus advisable to perform an ophthalmological assessment to rule out and properly manage retinopathy.

High risk of early conversion to multiple sclerosis in clinically isolated syndromes with dissemination in space at baseline

INTRODUCTION Multiple sclerosis (MS) usually presents at onset with a clinically isolated syndrome (CIS). According to 2010 McDonald criteria, a diagnosis of MS can be made if CIS patients satisfy clinical/MRI criteria of both dissemination in time (DIT) and space (DIS). OBJECTIVE The aim of this study was to analyze the follow-up data and possible prognostic factors of CIS patients satisfying DIS MRI criteria. PATIENTS AND METHODS We performed a retrospective, multicenter study across 2 Italian centers. Clinical, MRI, and laboratory assessments were performed according to real-life clinical workup. RESULTS Out of the 137 enrolled patients, during a median follow-up time of 3.1years, 116 (84.7%) converted to MS with the large majority (78.4%) of the converters developing MS within 1year. In multivariate analysis, baseline predictors of an earlier conversion were a cerebellar/brainstem CIS (HR 2.00, 95% CI: 1.3-3.0, p=0.001) and the presence of all the Barkhof-Tintore MRI criteria (HR 1.67, 95% CI: 1.1-2.6, p=0.028). CONCLUSIONS Patients with CIS and DIS are at very high risk of an early conversion to MS. The onset with cerebellar/brainstem symptoms and the evidence of a higher MRI lesion load at baseline are the strongest independent predictors of an early conversion to MS.

Multiple sclerosis and chronic progressive external ophthalmoplegia associated with a large scale mitochondrial DNA single deletion

Mitochondrial DNA (mtDNA) mutations are responsible for several diseases involving the central nervous system (CNS) [1]. Mitochondrial disorders, and particularly Leber’s hereditary optic neuropathy (LHON), have been reported in association with both multiple sclerosis (MS) and MS-like magnetic resonance imaging (MRI) patterns, raising important questions about possible common pathophysiological mechanisms [2]. Although LHON shares some common neuropathological features with MS, white matter damage has been reported to be more extensive and unselective in LHON [3]. Interestingly, mitochondria seem to play an important role in the pathogenesis of MS [4]. Indeed, mtDNA deletions and respiratory-deficient neurons have been described in MS [4, 5]. Although chronic progressive external ophthalmoplegia (CPEO) is one of the most frequent clinical presentations of mitochondrial diseases [1], so far the association between MS and CPEO has been reported very rarely [6]. We describe the case of a 41-year-old woman presenting both MS and CPEO due to a novel large deletion in mtDNA. The patient had a history of progressive bilateral ptosis and ophthalmoparesis which started at the age of 7 and slowly evolved into almost complete bilateral external ophthalmoplegia. Her family history was unremarkable. At the age of 41, she experienced for 2 weeks persistent gait instability. She underwent a brain and cervical spine MRI that revealed multiple T2-hyperintense lesions in periventricular, juxtacortical and infratentorial white matter (Fig. 1a, b) and in the cervical spinal cord. Three brain lesions showed gadolinium enhancement (Fig. 1c). Cerebrospinal fluid (CSF) examination showed intrathecal IgG synthesis, and a serological screening for autoimmune and infectious conditions was negative. The patient underwent complete hematological and biochemical examinations including fasting glucose and thyroidal function test, audiometry, visual evoked potentials, electromyography, electrocardiogram and echocardiography: all of these examinations were negative. An ophthalmological assessment was also performed, and no fundoscopic alterations were found. A diagnosis of MS was made according to the 2010 revision of the McDonald criteria. The patient was treated with high-dose steroids and had a complete recovery from the relapse. Given the external ophthalmoplegia, she underwent muscle biopsy that showed ragged red fibers (RRF) and 1 % of cytochrome c oxidase (COX) negative fibers (Fig. 1d). Molecular analysis of muscle mtDNA was then performed. The amplification of mtDNA by longrange PCR with primers 500 Fw and 11 Rv disclosed an additional band, suggesting the presence of a large heteroplasmic deletion of mtDNA (Fig. 1e). A second long-range PCR with primers 5835 Fw and 15978 Rv confirmed the presence of the rearrangement: indeed, it yielded a single smaller species of about 2 kb (Fig. 1f) corresponding to a single deletion of approximately 8 kb. Subsequent PCR amplification and direct sequence analysis L. Gaetani and A. Mignarri equally contributed to the work.

Extracranial Venous Drainage Pattern in Multiple Sclerosis and Healthy Controls: Application of the 2011 Diagnostic Criteria for Chronic Cerebrospinal Venous Insufficiency.

The etiology of multiple sclerosis (MS) is still largely unknown and it has been proposed that an impaired venous drainage from the central nervous system, defined as chronic cerebrospinal venous insufficiency (CCSVI), may play a role in this. We investigated the prevalence of extracranial venous drainage pattern alterations in a cohort of MS patients based on the 2011 revised diagnostic criteria for CCSVI. Thirty-nine MS patients and 18 healthy subjects underwent blinded extra-cranial venous echo-color Doppler sonography to reveal the presence of CCSVI. There was no statistically significant difference between MS patients and healthy controls regarding CCSVI prevalence (p value = 0.53). The results challenge the hypothesis that CCSVI plays a primary role in the pathogenesis of MS.

Microglial activation and the nitric oxide/cGMP/PKG pathway underlie enhanced neuronal vulnerability to mitochondrial dysfunction in experimental multiple sclerosis

During multiple sclerosis (MS), a close link has been demonstrated to occur between inflammation and neuro-axonal degeneration, leading to the hypothesis that immune mechanisms may promote neurodegeneration, leading to irreversible disease progression. Energy deficits and inflammation-driven mitochondrial dysfunction seem to be involved in this process. In this work we investigated, by the use of striatal electrophysiological field-potential recordings, if the inflammatory process associated with experimental autoimmune encephalomyelitis (EAE) is able to influence neuronal vulnerability to the blockade of mitochondrial complex IV, a crucial component for mitochondrial activity responsible of about 90% of total cellular oxygen consumption. We showed that during the acute relapsing phase of EAE, neuronal susceptibility to mitochondrial complex IV inhibition is markedly enhanced. This detrimental effect was counteracted by the pharmacological inhibition of microglia, of nitric oxide (NO) synthesis and its intracellular pathway (involving soluble guanylyl cyclase, sGC, and protein kinase G, PKG). The obtained results suggest that mitochondrial complex IV exerts an important role in maintaining neuronal energetic homeostasis during EAE. The pathological processes associated with experimental MS, and in particular the activation of microglia and of the NO pathway, lead to an increased neuronal vulnerability to mitochondrial complex IV inhibition, representing promising pharmacological targets.