Tatiana Koudriavtseva

Demyelinating and Thrombotic Diseases of the Central Nervous System: Common Pathogenic and Triggering Factors

Demyelinating diseases of the central nervous system (CNS) affect prevalently young adults and represent the main cause of neurological disability after trauma in this population (1). Multiple sclerosis (MS), acute disseminated encephalomyelitis (ADEM), and neuromyelitis optica (NMO) are the most common inflammatory-demyelinating disorders of the CNS (1, 2). Multiple sclerosis shares several features with antiphospholipid syndrome (APS) including the clinical presentation, the relapsing–remitting course, the higher incidence in females of childbearing age, and the presence of similar white matter (WM) lesions at MRI (3). Likewise, both neurological symptoms and MRI lesions may overlap in ADEM and in the initial presentation of APS (4). Therefore, MS, ADEM, and APS are part of the reciprocal differential diagnosis (2). APS represents also one of the main risk factors for cerebral venous thrombosis (CVT) (5), which is not usually included in the differential diagnosis of demyelinating diseases. However, several reports in literature have described an association between CVT and MS (6–9). Although an accurate differential diagnosis is desirable for ensuring a more targeted therapy, the examination of the shared features between thrombotic and demyelinating diseases of the CNS would help to understand their common pathogenic mechanisms.

Neuroinflammation, neurodegeneration and regeneration in multiple sclerosis: intercorrelated manifestations of the immune response

Multiple sclerosis (MS) is a chronic immune-mediated inflammatory-demyelinating disorder of the central nervous system, with a strong neurodegenerative component. The question whether neurodegeneration in MS is independent or related to neuroinflammation has been long debated, but not yet fully clarified. Furthermore, little is still known on how neuroinflammation and neurodegeneration in MS are related to potential regenerative processes. In this perspective, we briefly discuss main clinical, pathological and experimental evidence on the relationship between neuroinflammation and neurodegeneration in MS, and on their connection with regeneration. We discuss that these processes in MS might represent intercorrelated manifestations of the immune response, especially of the innate immunity.

Brain Atrophy as a Measure of Neuroprotective Drug Effects in Multiple Sclerosis: Influence of Inflammation

Multiple Sclerosis (MS) is a chronic inflammatory and neurodegenerative disease of the central nervous system, and the second cause of neurological disability after trauma in young adults in the Western world. The efficacy of disease-modifying treatments (DMTs) in relapsing-remitting (RR) and secondary-progressive (SP) MS is usually surrogated by assessing new/enlarged T2 and gadolinium (Gd)-enhancing lesions on magnetic resonance imaging (MRI) scans. More recently, brain atrophy has been incorporated as an outcome measure in MS clinical trials due to its reproducibility, correlation with disability, and detectability from early disease stages. Brain atrophy measures, however, could lead to equivocal conclusions if a series of factors are not taken into account, particularly the influence of inflammation.

Anti-annexin antibodies, cholesterol levels and disability in multiple sclerosis.

So far, no studies have been conducted to evaluate possible correlations between lipid/lipoprotein levels and the anti-phospholipid antibody (aPL) positivity in multiple sclerosis (MS). In this cross-sectional study, we aimed to investigate the relationships between serum lipid profile and aPL positivity rates in MS patients, and their possible differences among secondary-progressive MS (SPMS) patients, relapsing-remitting MS patients in remission (REM) and in relapse (REL). We included 16 SPMS, 58 REM and 26 REL. Their sera were tested for aPL (anti-cardiolipin, anti-β2glycoproteinI, anti-prothrombin, anti-annexinV), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglycerides (TG) and lipoprotein(a) levels. High TC levels were more frequent in SPMS patients than other groups (p=0.05). The REL had significantly higher rates of positivity for anti-β2glycoproteinI IgM (p<0.0001), anti-prothrombin IgG and IgM (both p=0.05) than the other groups. A significant positive correlation was found between age and both TC and LDL-C, disability and both TC and LDL-C, disease duration and LDL-C. TC levels were significantly higher (p=0.007) in anti-annexinV-IgG positive patients. The anti-annexinV-IgG positivity significantly associated with high levels of TC (p=0.002) and LDL-C (p=0.03). Our results support the hypothesis that both thrombogenic and neurodegenerative mechanisms associated with an abnormal cholesterol homeostasis might contribute to MS progression. Our study may have interesting practical implications, which could potentially open new therapeutic approaches in the context of appropriately designed clinical trials.

Thrombotic Processes in Multiple Sclerosis as Manifestation of Innate Immune Activation

Multiple sclerosis (MS) is a chronic demyelinating inflammatory disease of the central nervous system (CNS) affecting prevalently young adults (1, 2). The pathogenesis of MS has long been attributed to self-reactive T cells but recently the relevant role of B cells has also been recognized (2, 3). Furthermore, it has been demonstrated that innate immunity has a pivotal role in the beginning and in advanced stages of MS (4–6). Innate immunity represents the immediate non-specific defense against infections and dangerous agents acting through its essential arms such as inflammation and blood coagulation (7–10). The coagulant processes are normally balanced by the natural anti-coagulant system needed to limit the host damage, and their imbalance leads to venous thrombosis (7, 8). Many evidences reported below support a significant presence of local and systemic thrombotic events in MS confirming the global over-stimulation of innate immunity for both its inflammatory and coagulant components.

Concurrence of multiple sclerosis and brain tumors

Multiple sclerosis (MS) is a chronic demyelinating inflammatory disease of the central nervous system (CNS) with multi-factorial pathogenesis that includes genetic and environmental factors. A primary brain tumor is a neoplasm developing from the cells of the brain. There is high heterogeneity of primary brain tumors (about 100 different types); however, most of them develop from the glial cells. Although several types of brain tumors have been widely described in association with MS (1–20), including astrocytoma (5, 9), oligodendroglioma (12, 17), and glioblastoma (3, 11, 14, 18), it is not clear whether their occurrence is accidental or consequent to causal events. Moreover, it is not completely defined if MS and brain tumors, when associated, have a different course. The true incidence of brain tumors in MS patients is difficult to define because the diagnosis of a brain tumor in MS patients may seem more frequent than in the general population due to frequent neuroimaging scans performed in these patients (21). At the same time, pseudo-tumoral MS lesions may resemble gliomas, and conversely, early stage gliomas may resemble MS. Brain tumors in MS patients may be diagnosed later or even post-mortem (22), especially in patients with progressive MS, since the new symptoms may be attributed to the gradual clinical progression of MS rather than to the slow growing of tumor itself (23). A recent study reported that MS patients have a decreased overall cancer risk, but an increased risk for brain tumor (24). If immunosuppressive treatment for MS might promote cancerogenesis is still matter of debate, it is difficult to explain on this basis why MS patients have a decreased overall cancer risk and an increased risk only for brain and genitourinary tract tumors (24). A successive systematic analysis showed no increased or decreased risks for glioma in MS patients, while an increased risk was found for meningioma, as a result of incidental findings (25). Moreover, several autoimmune diseases influence negatively the survival in glioma and meningioma, likely due to pre-existent disability or treatment limitations (25).

Antiphospholipid antibodies: a possible biomarker of disease activity in multiple sclerosis and neuromyelitis optica spectrum disorders

Multiple sclerosis (MS) and neuromyelitis optica spectrum disorders (NMOSD) are chronic inflammatory demyelinating disease of the central nervous system. MS usually begins with a relapsing-remitting course manifesting with relapses followed by recovery. Most patients will enter a secondary progressive phase characterized by steady accumulation of disability. NMOSD is a more severe disorder characterized by optic neuritis, longitudinally extensive myelitis and autoantibody positivity against the water channel aquaporin-4. It has been demonstrated that reactivity for different autoantibodies, including antinuclear and antiphospholipid antibodies (aPL), is more frequent in NMOSD compared to MS [1, 2]. Iong and colleagues [1] have confirmed a significantly higher positive rate for anticardiolipin antibodies (aCL) in NMOSD (45.7 %) compared to MS (5.6 %). We found a similar aCL positivity (5 %) in MS patients, although the overall aPL positive rate increased up to 60 % when the reactivity for more aPL was evaluated [3]. Based on the literature data, it appears that the rate of aPL positivity in MS is related to both the number of antibodies used and the severity of the disease stage [3–6]. Indeed, aPL positivity was reported to be higher in secondary progressive than in relapsing-remitting phase [4, 5], and to be correlated with the T2-lesion volume at MRI [5]. Moreover, aPL positive relapsing-remitting MS patients developed more severe clinical and MRI disease progression compared to aPL negative ones over a 3-year follow-up [7]. Nevertheless, the highest rate of aPL positivity (about 80 %) was found only during MS relapse [3, 4, 6] correlating with the number of MRI enhancing lesions [6]. Interestingly, aPL positivity significantly decreased in the same patients in remission [3, 4]. Iong’s paper [1] has reported a similar trend also in NMOSD: patients positive for both IgG and IgM aCL were older and with a higher level of disability compared to patients positive only for IgG aCL who were, in turn, older than aCL negative patients. Moreover, aCL positivity in NMOSD patients has been associated with greater antithrombin-III activity and D-dimer levels, a product of fibrin degradation, thus confirming the association of aCL with thrombotic processes. To our knowledge, only few studies have evaluated coagulation factors in MS [8–13], generally confirming the activation of the coagulation cascade. However, the presence of thrombotic processes in MS has been well-recognized [14]. Since aPL are found not only in antiphospholipid syndrome (APS), NMOSD and MS, but also in many inflammatory diseases and infections, it is reasonable to suppose that they may be a nonspecific biomarker of underlying universal inflammatory-thrombotic events. Thus, aPL may reflect the intensity of these pathological processes i.e. the disease severity/activity rather than its specificity. In fact, another study, based on patients’ positivity for anti-b2glycoprotein-I, has classified the different types of MRI cerebral lesions in: typical inflammatory, typical vascular and the most common atypical lesions, proposed by the authors as a frontier syndrome between APS and MS [15]. This could also mean that aPL are prevalently involved in the clearance of damaged molecular and cellular components containing phospholipids rather than triggering the disease. Therefore, the higher aPL reactivity rate in T. Koudriavtseva (&) D. Plantone R. Renna Multiple Sclerosis Center, Unit of Neurology, Regina Elena National Cancer Institute, IFO, Via Elio Chianesi 53, 00144 Rome, Italy e-mail: tatiana.koud@gmail.com; koudriavtseva@ifo.it

Brain perfusion by arterial spin labeling MRI in multiple sclerosis.

The role of MRI in multiple sclerosis (MS) has been well established for decades. Moreover, new MRI techniques have been developed to better understand the complex pathogenesis of this disease, since the use of conventional MRI techniques is partially limited by its weak associations with clinical features and low sensitivity for gray matter (GM) involvement and diffuse damage of white matter (WM) [1]. These limitations become even more significant in the disease shift from the predominantly inflammatory to degenerative phase [1]. MS has been traditionally considered a demyelinating inflammatory disorder of the central nervous system; however, vascular involvement and perfusion abnormalities are recently receiving an increasing interest [2]. Earlier PET and SPECT studies showed metabolic alterations and perfusion deficits in cognitively impaired MS patients, particularly at the cortical level in the left frontal and temporal lobes [3]. Recently, a dynamic susceptibility contrast-enhanced (DSC) MRI showed in MS a globally reduced but regionally mixed cerebral blood flow (CBF). Decreased CBF has been demonstrated in both normalappearing WM (NAWM) [4–7] and deep GM [6, 7] in relapsing–remitting MS (RRMS) patients, which had also a significantly reduced CBF in the putamen compared to patients with clinically isolated syndrome (CIS) [7]. Interestingly, the greater reduction of NAWM CBF was found in primary-progressive MS compared to RRMS [5, 6], though NAWM CBF was decreased even in CIS patients [7]. A regional increase of CBF has been detected in early lesion stages, up to 3 weeks prior to brain–blood barrier (BBB) breakdown with subsequent contrast enhancement [8]. Furthermore, NAWM CBF was shown to significantly correlate with clinical disability [5], whereas GM CBF correlated with neuropsychological dysfunctions [6]. Due to recent increasing availability of higher field strength scanners, a new MRI technique called arterial spin labeling (ASL) has been proposed as a useful research tool in several neurological diseases. Interestingly, a reduction of GM CBF measured by ASL was confirmed in all MS patients compared to healthy controls while NAWM CBF has been alternatively found decreased in some studies [9– 11], or increased in others [12, 13]. The reason for the increased NAWM CBF in few studies could be the incomplete separation between NAWM and both WM and enhanced lesions due to the relatively coarse resolution of ASL and non-use of exogenous contrast. Most T1-hypointense lesions were concentrated in WM regions with lower CBF, whilst the T2-hyperintense lesions were distributed in WM regions with both higher and lower CBF [11]. The negative correlations between the T2-hyperintense lesion volume and regional CBF have been showed in several brain areas [14]. Moreover, cerebral vasoreactivity (CVR) from normocapnic to hypercapnic CBF was found diminished in MS patients compared to healthy controls indicating an impaired CBF regulation [15]. Since decreased GM CVR correlated positively with GM atrophy and negatively with the lesion volume, it was hypothesized that the impaired CBF regulation may cause neurodegeneration due to an insufficient blood supply [15]. Similar to & Tatiana Koudriavtseva tatiana.koud@gmail.com

HIV and decreased risk of multiple sclerosis: role of low CD4+ lymphocyte count and male prevalence

In this retrospective case-control study, we compared the number of circulating lymphocyte subsets among 31 healthy controls, 18 naïve and 40 antiretroviral-treated HIV patients, 28 untreated and 18 treated relapsing-remitting multiple sclerosis (MS) patients. Lymphocyte subsets were no different between untreated MS patients and controls. Untreated and treated MS had a lower CD8+ count and a higher CD4+ number compared to untreated and treated HIV patients except similar CD4+ number between treated MS and HIV patients. CD4/CD8 ratio was lower in female HIV non-responders and in relapsing MS women compared, respectively, to female HIV responders and remitting MS women, and there were no differences in men.

Neurological diseases associated with autoantibodies targeting the voltage-gated potassium channel complex: immunobiology and clinical characteristics

Domenico Plantone, Rosaria Renna, Tatiana Koudriavtseva Multiple Sclerosis Center, Unit of Neurology, Regina Elena National Cancer Institute, 00144 Rome, Italy. Voltage‐gated potassium channels (VGKCs) represent a group of tetrameric signaling proteins with several functions, including modulation of neuronal excitability and neurotransmitter release. Moreover, VGKCs give a key contribution to the generation of the action potential. VGKCs are complexed with other neuronal proteins, and it is now widely known that serum autoantibodies directed against VGKCs are actually directed against the potassium channel subunits only in a minority of patients. By contrast, these autoantibodies more commonly target three proteins that are complexed with alpha‐dendrotoxin‐labeled potassium channels in brain extracts. These three proteins are contactin‐associated protein‐2 (Caspr‐2), leucine‐rich, glioma inactivated 1 (LGI‐1) protein and the protein Tag‐1/contactin‐2. Neoplasms are detected only in a minority of seropositive patients for VGKC complex‐IgG and do not significantly associate with Caspr‐2 or LGI‐1. Among all the cancers described in association with VGKC complex‐IgG, lung carcinoma, thymoma, and hematologic malignancies are the most commonly detected. We will review all the major neurological conditions associated with VGKC complex‐IgG. These include Isaacs’ syndrome, Morvan syndrome, limbic encephalitis, facio‐brachial dystonic seizures, chorea and other movement disorders, epilepsy, psychosis, gastrointestinal neuromuscular diseases, a subacute encephalopathy that mimics Creutzfeldt‐Jakob prion disease both clinically and radiologically and autoimmune chronic pain. The vast majority of these conditions are reversible by immunotherapy, and it is becoming increasingly recognized that early diagnosis and detection of VGKC complex‐IgG is critical in order to rapidly start the treatment. As a result, VGKC complex‐IgG are now part of the investigation of patients with unexplained subacute onset of epilepsy, memory or cognitive problems, or peripheral nerve hyperexcitability syndromes.