Maria Di Gregorio

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

Heterozygous X-linked adrenoleukodystrophy-associated myelopathy mimicking primary progressive multiple sclerosis

We describe the case of a 73-year-old woman who was referred to our clinic because of a 10-year history of slowly progressive spastic paraparesis. The patient underwent a brain and spinal cord MRI that showed the presence of bihemispheral white matter hyperintensities and of a spinal cord lesion (Fig. 1). She was referred to our clinic because of suspected late-onset primary progressive multiple sclerosis. On admission, a neurologic examination showed the presence of paraparesis, increased leg tone and a spastic gait. All reflexes were brisk and a bilateral Babinski sign was elicited. Diminished sensation of vibration in both legs and bilateral hypoesthesia below the T5 level were present. Results of routine hematologic tests were normal, as were the screenings for autoimmune and infectious conditions (including testing for ANA, LAC, ACA, ANCA and antiborrelia, VDRL, and TPHA serologies). Cerebrospinal fluid isoelectric focusing showed no oligoclonal IgG bands. There was no family history of multiple sclerosis. However, the patient reported that several women (her mother, two sisters and two first-degree nieces) in her family were affected by a slowly progressive form of spastic paraparesis and that two of her brothers died when they were children after having developed motor and cognitive symptoms (Fig. 2). The differential diagnosis of primary progressive multiple sclerosis presenting as progressive spastic paraparesis includes different genetic conditions such as leucodystrophies and hereditary spastic paraplegia [1]. In particular, X-linked adrenoleukodystrophy (X-ALD) is a genetic disorder secondary to alterations in the ABCD1 (ATP-binding cassette, sub-family D, member 1) gene that shows a wide range of phenotypic expression, from a severe cerebral progressive form in childhood to a mild adult myelopathy [2]. For this reason, the molecular analysis of the ABCD1 gene was performed on DNA extracted from peripheral blood of the patient and her relatives, and revealed a heterozygous two base pair deletion at position 1415–1416 in exon 5 (c.1415_1416delAG; p.Gln472ArgfsX83), the most common mutation in X-ALD families [3]. In females heterozygous for X-ALD, neurologic symptoms are frequent [4]. In particular, it is estimated that up to 50% of women who are heterozygous for X-ALD may develop a slowly progressive myelopathy [2]. In contrast to multiple sclerosis, spinal cord involvement in X-ALD is not characterized by an overt inflammatory component [5] and conventional spinal cord MRI usually does not show significant abnormalities other than cord atrophy late in the disease [6]. Similarly, brain MRI abnormalities attributable to ALD are seen on conventional T2-weighted images only in a small number of XALD heterozygotes [6, 7]. In our patient, a hyperintense lesion with more pronounced involvement of the dorsal M. Di Filippo (&) E. Luchetti M. Di Gregorio N. Tambasco P. Sarchielli P. Calabresi Section of Neurology, S. Maria della Misericordia Hospital, University of Perugia, Perugia, Italy e-mail: difilippo@unipg.it

Expression of cathepsins S and D signals a distinctive biochemical trait in CD34+ hematopoietic stem cells of relapsing–remitting multiple sclerosis patients

Background: The elucidation of mechanistic aspects of relapsing–remitting multiple sclerosis (RRMS) pathogenesis may offer valuable insights into diagnostic decisions and medical treatment. Results: Two lysosomal proteases, cathepsins S and D (CatS and CatD), display an exclusive pattern of expression in CD34+ hematopoietic stem cells (HSCs) from peripheral blood of acute MS (A-MS) patients (n = 20). While both enzymes normally exist as precursor forms in the HSCs of healthy individuals (n = 30), the same cells from A-MS patients consistently exhibit mature enzymes. Further, mature cathepsins are expressed at lower rates in stable MS subjects (S-MS, n = 15) and revert to precursor proteins after interferon-β1a treatment (n = 5). Mature CatD and CatS were induced in HSCs of healthy donors that were either co-cultured with PBMCs of A-MS patients or exposed to their plasma, suggesting a functional involvement of soluble agents. Following HSC exposure to several cytokines known to be implicated in MS, and based on relative cytokine levels displayed in A-MS, S-MS and control individuals, we identified IL-16 as a specific cell signaling factor associated with cathepsin processing. Conclusions: These data point to an evident correlation between CatS and CatD expression and MS clinical stage, and define a biochemical trait in HSCs with functional, medical, and diagnostic relevance.

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.

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.

Visual pathway involvement in multiple sclerosis: Look straight in the eyes

Visual symptoms are a common clinical manifestation of multiple sclerosis (MS) and are frequently due to acute optic neuritis (ON). However, the entire visual pathway can be involved throughout the disease course. We describe the case of a young MS patient who experienced visual symptoms that were eventually found to be caused by retinal periphlebitis, an inflammatory process of the anterior visual pathway, which is common during MS, but rarely symptomatic. This case reinforces the concept that in all MS patients complaining visual symptoms, a complete work-up should be performed in order to rule out possible ON mimicries.