Serum and cerebrospinal fluid neurofilament light chains measured by SIMOA™, Ella™, and Lumipulse™ in multiple sclerosis naïve patients.

BACKGROUND: Neurofilament light chains (NfL) are cytoskeletal biomarkers of axonal damage, about 40-fold higher in cerebrospinal fluid (CSF) compared to serum, and requiring ultrasensitive techniques to be measured in this latter fluid. OBJECTIVES: To compare CSF and serum NfL levels in multiple sclerosis (MS) patients using different platforms. METHODS: 60 newly diagnosed relapsing-remitting MS patients (38 females; median age: 36.5 years, range: 15-60) were enrolled before steroid or disease-modifying treatments. CSF and serum NfL were measured with: the commercial Ella™ microfluidic platform (Bio-Techne), the Lumipulse™ Chemiluminescent Enzyme ImmunoAssay (Fujirebio), and the SIMOA™ on the SR-X instrument using NF-light assays (Quanterix). RESULTS: CSF and serum NfL absolute levels strongly correlated between assays, although being more elevated with Ella™. Passing-Bablok regression showed high agreement in measuring CSF NfL between assays (with greater proportional difference using Ella™), and very high agreement for serum comparing SIMOA™ and Lumipulse™. Similarly, the Bland-Altman comparison evidenced lower biases for Lumipulse™ for both fluids. CONCLUSIONS: CSF and serum NfL in naïve MS patients are reliably measured with all assays. Although not interchangeable, SIMOA™ and Lumipulse™ showed high agreement for serum and CSF values.

Intrathecal kappa free light chains as markers for multiple sclerosis.

Cerebrospinal fluid (CSF) kappa free light chain (KFLC) index has been described as a reliable marker of intrathecal IgG synthesis to diagnose multiple sclerosis (MS). Our aims were: (1) to compare the efficiency of KFLC through different interpretation approaches in diagnosing MS. (2) to evaluate the prognostic value of KFLC in radiologically and clinically isolated syndromes (RIS-CIS). We enrolled 133 MS patients and 240 with other neurological diseases (93 inflammatory including 18 RIS-CIS, 147 non-inflammatory). Albumin, lambda free light chain (LFLC) and KFLC were measured in the CSF and serum by nephelometry. We included two groups of markers: (a) corrected for blood-CSF barrier permeability: immunoglobulin G (IgG), KFLC and LFLC indexes. (b) CSF ratios (not including albumin and serum-correction): CSF KFLC/LFLC, CSF KFLC/IgG, CSF LFLC/IgG. KFLC were significantly higher in MS patients compared to those with other diseases (both inflammatory or not). KFLC index and CSF KFLC/IgG ratio showed high sensitivity (93% and 86.5%) and moderate specificity (85% and 88%) in diagnosing MS. RIS-CIS patients who converted to MS showed greater KFLC index and CSF KFLC/IgG. Despite OB are confirmed to be the gold-standard to detect intrathecal IgG synthesis, the KFLC confirmed their accuracy in MS diagnosis. A "kappa-oriented" response characterizes MS and has a prognostic impact in the RIS-CIS population.

Kappa free light chains could predict early disease course in multiple sclerosis.

BACKGROUND: Cerebrospinal fluid (CSF) kappa free light chains (KFLC) have been suggested as quantitative alternative to oligoclonal bands (OB) in multiple sclerosis (MS) diagnosis. Despite OB have been associated to poor disease prognosis, little is known on KFLC in predicting MS early progression. Our aim is to evaluate the prognostic value of KFLC in a cohort of Italian MS patients. METHODS: 100 patients (64 females) underwent CSF analysis during their diagnostic MS work-up. We collected clinical/paraclinical features (gender, age at onset, clinical course, early MS treatments (within 1 year), gadolinium-enhancing (Gd+) lesions), calculated K index (ratio CSF-serum KFLC and albumin), and MS severity score (MSSS) at last follow up (minimum 1 year). Statistical analysis included Mann-Whitney descriptive analysis, Spearman correlation for independent samples, and linear regression for significant predictors. RESULTS: K index resulted a significant predictor for disability over time being higher in patients who developed greater MSSS. Accordingly, K index was also significantly increased in patients undergoing early versus delayed treatment (N = 50/100, p = 0.046). A similar role in predicting MS disability was confirmed for age at onset. No other factors were retained in our regression model. Of note, K index was not associated to known MS prognostic markers such as gender, age at onset, and Gd+ lesions (N = 31/96). CONCLUSION: Our study suggests KFLC as a CSF quantitative marker to predict early disability in MS (despite not being a substitute for OB).

MOG-antibody demyelinating diseases: a case of post-partum severe rhombencephalitis and transverse myelitis.

INTRODUCTION: Myelin oligodendrocyte glycoprotein antibodies (MOG-IgG) associated disorders present with a spectrum of clinical pictures including brainstem involvement. CASE REPORT: A patient with the sudden onset of a post-partum severe rhombencephalitis causing respiratory failure (12 years after a mild transverse myelitis). Despite the aggressive clinical course, she had an impressive recovery after plasmapheresis, and no further relapses on immunosuppression. CONCLUSION: MOG-IgG disorders could relapse several years after onset and involve brainstem. Good prognosis is possible after treatment.

The measuring of substantia nigra hyperechogenicity in an Italian cohort of Parkinson disease patients: a case/control study (NOBIS Study).

Transcranial sonography (TCS) shows an increased echogenic area of the substantia nigra (SN) in patients with Parkinson disease (PD). It has been increasingly used in the diagnosis of PD and its differentiation from atypical parkinsonian syndromes. Here, we studied the diagnostic accuracy of SN TCS in Italian patients. In this blinded cross-sectional study (NOBIS study), two expert neuro-sonologists performed TCS in 25 PD patients and 29 age- and sex-matched controls. The study participants were completely hidden to the TCS investigators using large drapery. One month later, the SN TCS recordings were re-read by the initial investigator, and cross-read by the second reader. Diagnostic accuracy was estimated on the first reading, intra-reader reliability on re-reading, and inter-reader reliability on cross-readings. The mean SN echogenic area was larger in the patients (0.24 cm2) than in the controls (0.15 cm2; Mann-Whitney test, p < 0.001). SN measures did not differ between right and left, or between ipsilateral and contralateral to the clinically more affected side. There was no correlation between SN echogenicity and PD severity or duration. High intra-reader (concordance correlation coefficient 0.93) and inter-reader (0.98) agreement of SN measurements was found. The diagnostic accuracy for the detection of PD was high (area under receiver-operating characteristic curve 0.91; 95% CI 0.83-1.00) with an optimum cut-off value for SN echogenic area of 0.18 cm2 with the device used here (specificity 0.83-0.90; sensitivity 0.72-0.92). This study supports the use of SN TCS in the diagnostic workup of PD if performed by trained readers.

Polymorphisms of dopamine receptor genes and risk of visual hallucinations in Parkinson's patients.

BACKGROUND: Visual hallucinations (VHs) are frequent non-motor complication of Parkinson's disease (PD), associated to a negative prognosis. Previous studies showed an association between dopamine receptor (DR) gene (DR) variants and psychosis in Alzheimer's disease, addictions, schizophrenia, and bipolar disorder. However, there are only a few studies on DR variants and VHs in PD, which did not provide conclusive results. OBJECTIVES: The present study aimed to determine whether genetic differences of DR are associated with visual hallucinations (VHs) in a cohort of Parkinson's disease (PD) patients. METHODS: A case-control study of 84 PD subjects, 42 with and 42 without VHs,that were matched for age, gender, disease duration, and dopaminergic medication was conducted. Polymerase chain reaction for SNPs in both D1-like (DRD1A-48G [rs4532] and C62T [rs686], DRD5T798C [rs6283]) and D2-like DR (DRD2G2137A [rs1800497] and C957T [rs6277], DRD3G25A [rs6280] and G712C [rs1800828], DRD4C616G [rs747302] and nR VNTR 48bp) analyzed genomic DNA. RESULTS: Patients carrying allele T at DRD1C62T had an increased risk of VHs, expressed as OR (95 % CI, p value), of 10.7 (2.9-40, p = 0.0001). Moreover, patients with DRD1-48 GG and 62TT genotype displayed shorter time to VHs, whereas a longer time to VHs was found in subjects carrying the DRD4 CG alleles. CONCLUSIONS: PD patients with VHs display higher frequency of DR SNPs associated with increased D1-like activity and decreased D2-like activity. Our data are in line with associations reported in other neurodegenerative and psychiatric conditions. Results likely provide valuable information for personalizing pharmacological therapy in PD patients.

Variations of the perforin gene in patients with chronic inflammatory demyelinating polyradiculoneuropathy.

Perforin (PRF) has a key role in the function of cytotoxic T and natural killer cells. Rare variations of PRF1 predispose to autoimmunity. Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an autoimmune disease of the peripheral nervous system, involving defective lymphocyte apoptosis. The aim of this study was to investigate the role of PRF1 in CIDP. The entire coding region of PRF1 was sequenced in 94 patients and 158 controls. We found three missense variations leading to amino acid substitutions and one nonsense variation resulting in a premature stop codon. All variations would decrease PRF activity. Their overall frequency was significantly higher in patients than in controls (odds ratio (OR)=4.47). The most frequent variation was p.Ala91Val (OR=3.92) previously associated with other autoimmune diseases. Clinical analysis showed that PRF1 variations were more frequent in relapsing patients and in patients displaying axonal damage. These data suggest that PRF1 variations may influence CIDP development and course.

Peripheral nervous system involvement in Parkinson's disease: evidence and controversies.

BACKGROUND: In recent years, non-motor features of Parkinson's disease (PD) have received increasing attention and PD is currently considered a systemic rather than a pure basal ganglia disorder. Among the systemic features, peripheral neuropathy (PN) is a recent acquisition since the first case-control study reporting increased frequency of PN in PD dates back to 2008. METHODS: We reviewed available literature on peripheral nervous system (PNS) involvement in PD. RESULTS: Evidence of α-synuclein deposition in the PNS and small nerve fiber deterioration in both drug-naïve and treated PD patients is becoming stronger. In addition, several recent reports documented a significant role of levodopa exposure together with group B vitamin deficiency in facilitating the development of PN and case reports suggested that treatment with continuous levodopa intestinal infusion may increase the risk of acute PN compared to both oral levodopa and other dopaminergic treatments. CONCLUSION: It is currently debated whether PN is an intrinsic disease-related feature, a consequence of levodopa treatment or both. In this review, we will discuss the different hypotheses, as well as our perspective on open issues and controversies.

Timo ectópico cervical y hemiagenesia tiroidea / Ectopic cervical thymic tissue and thyroid hemiagenesis

La presencia de timo ectópico cervical es el resultado de la alteración en su migración durante la embriogénesis. Su degeneración maligna es muy infrecuente, pero es necesario establecer el diagnóstico mediante un estudio histológico. La hemiagenesia tiroidea es una alteración en el desarrollo de la glándula tiroides, un hallazgo accidental en la mayoría de los casos. Afecta más frecuentemente a las mujeres y su localización más habitual es el lóbulo tiroideo izquierdo. La mayoría de los pacientes presenta una función tiroidea normal. La asociación de hemiagenesia tiroidea y timo ectópico cervical no se ha descrito hasta el momento en la población pediátrica. Existe un solo caso descrito en adultos. Se presenta un caso clínico de hemiagenesia del lóbulo tiroideo derecho asociado a timo ectópico cervical localizado en la región tiroidea (AU)

Ectopical cervical thymus is the result of a disturbance in migration during embryogenesis. Although malignant transformations are scarce, the differential diagnosis needs to be established by pathology study. Thyroid hemiagenesis is a rare developmental anomaly which is usually detected incidentally. It affects more commonly females and the left lobe. Clinically, these patients are euthyroid in most of the cases. Ectopic cervical thymic tissue associated with thyroid hemiagenesis has never been described before in children and only one case has been described in adults. We report one case of hemiagenesis of the right thyroid lobe and ectopic cervical thymic tissue located in thyroid area (AU)

Transorbital sonography in acute optic neuritis: a case-control study.

BACKGROUND AND PURPOSE: Acute unilateral optic neuritis is associated with a thickening of the retrobulbar portion of the optic nerve as revealed by transorbital sonography, but no comparison has been made between nerve sheath diameter and optic nerve diameter in patients with acute optic neuritis versus healthy controls. We evaluated optic nerve sheath diameter and optic nerve diameter in patients with acute optic neuritis and healthy controls and compared optic nerve sheath diameter and optic nerve diameter with visual-evoked potentials in patients. MATERIALS AND METHODS: A case-control study was performed in 2 centers. Twenty-one consecutive patients with onset of visual loss during the prior 10 days and established acute noncompressive unilateral optic neuritis were compared with 21 healthy controls, matched for sex and age (±5 years). Two experienced vascular sonographers performed the study by using B-mode transorbital sonography. Visual-evoked potentials were performed on the same day as the transorbital sonography and were evaluated by an expert neurophysiologist. Sonographers and the neurophysiologist were blinded to the status of the patient or control and to clinical information, including the side of the affected eye. RESULTS: The median optic nerve sheath diameter was thicker on the affected side (6.3 mm; interquartile range, 5.9-7.2 mm) compared with the nonaffected side (5.5 mm; interquartile range, 5.1-6.2 mm; P < .0001) and controls (5.2 mm; interquartile range, 4.8-5.5 mm; P < .0001). The median optic nerve diameter was 3.0 mm (range, 2.8-3.1 mm) on the affected side and 2.9 mm (range, 2.8-3.1 mm) on the nonaffected side (P = not significant.). Both sides were thicker than those in controls (2.7 mm; interquartile range, 2.5-2.8 mm; P = .001 and .009). No correlation was found between optic nerve sheath diameter and optic nerve diameter and amplitude and latency of visual-evoked potentials in patients with optic neuritis. CONCLUSIONS: Transorbital sonography is a promising tool to support the clinical diagnosis of acute optic neuritis. Further studies are needed to define its specific role in the diagnosis and follow-up of optic neuritis.

Revisiting the molecular mechanism of neurological manifestations in antiphospholipid syndrome: beyond vascular damage.

Antiphospholipid syndrome (APS) is a multiorgan disease often affecting the central nervous system (CNS). Typically, neurological manifestations of APS include thrombosis of cerebral vessels leading to stroke and requiring prompt initiation of treatment with antiplatelet drugs or anticoagulant therapy. In these cases, alterations of the coagulation system at various levels caused by multiple effects of antiphospholipid antibodies (aPL) have been postulated to explain the vascular damage to the CNS in APS. However, several nonvascular neurological manifestations of APS have progressively emerged over the past years. Nonthrombotic, immune-mediated mechanisms altering physiological basal ganglia function have been recently suggested to play a central role in the pathogenesis of these manifestations that include, among others, movement disorders such as chorea and behavioral and cognitive alterations. Similar clinical manifestations have been described in other autoimmune CNS diseases such as anti-NMDAR and anti-VGCK encephalitis, suggesting that the spectrum of immune-mediated basal ganglia disorders is expanding, possibly sharing some pathophysiological mechanisms. In this review, we will focus on thrombotic and nonthrombotic neurological manifestations of APS with particular attention to immune-mediated actions of aPL on the vascular system and the basal ganglia.

Prevalence and features of peripheral neuropathy in Parkinson's disease patients under different therapeutic regimens.

BACKGROUND: Recent reports suggest increased frequency of peripheral neuropathy (PN) in Parkinson's disease (PD) patients on levodopa compared with age-matched controls particularly during continuous levodopa delivery by intestinal infusion (CLDII). The aim of this study is to compare frequency, clinical features, and outcome of PN in PD patients undergoing different therapeutic regimens. METHODS: Three groups of consecutive PD patients, 50 on intestinal levodopa (CLDII), 50 on oral levodopa (O-LD) and 50 on other dopaminergic treatment (ODT), were enrolled in this study to assess frequency of PN using clinical and neurophysiological parameters. A biochemical study of all PN patients was performed. RESULTS: Frequency of PN of no evident cause was 28% in CLDII, 20% in O-LD, and 6% in ODT patients. Clinically, 71% of CLDII patients and all O-LD and ODT PN patients displayed a subacute sensory PN. In contrast, 29% of CLDII patients presented acute motor PN. Levodopa daily dose, vitamin B12 (VB12) and homocysteine (hcy) levels differed significantly in patients with PN compared to patients without PN. CONCLUSIONS: Our findings support the relationship between levodopa and PN and confirm that an imbalance in VB12/hcy may be a key pathogenic factor. We suggest two different, possibly overlapping mechanisms of PN in patients on CDLII: axonal degeneration due to vitamin deficiency and inflammatory damage. Whether inflammatory damage is triggered by vitamin deficiency and/or by modifications in the intestinal micro-environment should be further explored. Proper vitamin supplementation may prevent peripheral damage in most cases.

The role of T cell apoptosis in nervous system autoimmunity.

Fas is a transmembrane receptor involved in the death program of several cell lines, including T lymphocytes. Deleterious mutations hitting genes involved in the Fas pathway cause the autoimmune lymphoprolipherative syndrome (ALPS). Moreover, defective Fas function is involved in the development of common autoimmune diseases, including autoimmune syndromes hitting the nervous system, such as multiple sclerosis (MS) and chronic inflammatory demyelinating polyneuropathy (CIDP). In this review, we first explore some peculiar aspects of Fas mediated apoptosis in the central versus peripheral nervous system (CNS, PNS); thereafter, we analyze what is currently known on the role of T cell apoptosis in both MS and CIDP, which, in this regard, may be seen as two faces of the same coin. In fact, we show that, in both diseases, defective Fas mediated apoptosis plays a crucial role favoring disease development and its chronic evolution.

Rituximab in patients with chronic inflammatory demyelinating polyradiculoneuropathy: a report of 13 cases and review of the literature.

BACKGROUND: A few case reports have shown controversial results of rituximab efficacy in patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). OBJECTIVE: To analyse the efficacy of rituximab in a large CIDP cohort. METHODS: A retrospective, observational and multicentre study on the use of rituximab in CIDP. 13 Italian CIDP patients were treated with rituximab after the partial or complete lack of efficacy of conventional therapies. Eight patients had co-occurring haematological diseases. Patients who improved by at least two points in standard clinical scales, or who reduced or discontinued the pre-rituximab therapies, were considered as responders. RESULTS: Nine patients (seven with haematological diseases) responded to rituximab: six of them, who were non-responders to conventional therapies, improved clinically, and the other three maintained the improvement that they usually achieved with intravenous immunoglobulin or plasma exchange. Significantly associated with shorter disease duration, rituximab responses started after a median period of 2.0 months (range, 1-6) and lasted for a median period of 1 year (range, 1-5). CONCLUSIONS: Rituximab seems to be a promising therapeutic choice when it targets both CIDP and co-occurring haematological diseases. Timely post-onset administration of rituximab seems to be associated with better responses.

Progressive multifocal leucoencephalopathy after autologous bone marrow transplantation: a treatment option.

A patient with multiple myeloma was treated with high-dose chemotherapy followed by two autologous bone marrow transplantations (ABMTs). Nine months after the second ABMT the patient complained of severe left hemiparesis, paraesthesias, left homonymous visual field defects and gait ataxia. She was diagnosed with progressive multifocal leucoencephalopathy (PML) confirmed by detection of JC virus (JCV) DNA and prescribed cidofovir every other week and mirtazapine daily. Her symptoms and signs remained stable and after 6 months the JCV DNA was undetectable in the cerebrospinal fluid. Repeated MRI scans demonstrated the stabilisation of demyelinating lesion volume; after more than 2 years of follow-up the patient's neurological examination does not show significant variations. Combination of cidofovir and mirtazapine may be helpful in the treatment of PML in HIV-negative patients.

Progranulin gene variability increases the risk for primary progressive multiple sclerosis in males.

Progranulin (GRN) gene variability has been analyzed in a sample of 354 patients with multiple sclerosis (MS) compared with 343 controls. No significant differences were observed, but by stratifying according to MS subtypes, a significant increased frequency of the rs2879096 TT genotype was found in primary progressive MS (PPMS) patients versus controls (16.0 vs 3.5%, P=0.023, odds ratio (OR) 5.2, 95% confidence interval (CI) 1.2-21.4). In addition, in PPMS, an association with the C allele of rs4792938 was observed (55.3 vs 33.5%, P=0.011, OR 2.4, 95% CI 1.2-4.7). An independent population was studied as replication, failing to confirm results previously obtained. Stratifying according to gender, an association with rs4792938 C allele was found in male PPMS patients compared with controls (40.7 vs 26.9%, P=0.002, OR 1.87, 95% CI 1.2-2.8). An association with the rs2879096T allele was observed (29.2 in patients compared with 18.9% in controls, P=0.012, OR 1.77, 95% CI 1.1-2.8). Haplotype analysis showed that TC haplotype frequency is increased in PPMS male patients compared with male controls (25.7 vs 16.6%; P=0.02, OR 1.69, 95% CI 1.1-2.7), whereas the respective GC haplotype seems to exert a protective effect, as its frequency is decreased in patients compared with controls (55.8% vs 70.9%; P=0.001, OR 0.52, 95% CI 0.4-0.8). Therefore, GRN haplotypes likely influence the risk of developing PPMS in males.

A nationwide retrospective analysis on the effect of immune therapies in patients with chronic inflammatory demyelinating polyradiculoneuropathy.

BACKGROUND AND PURPOSE: The guidelines for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) therapy suggest to use immunoglobulins (IVIg) and steroid as first-line therapies. Patients who do not respond to one of the two drugs should be switched to the other drug. We collected therapeutic outcome data in patients followed at 11 centres in order to document the clinical practice in Italy. METHODS: Clinical and electrophysiological data of patients with CIDP were entered into a central database. The clinical outcome (Rankin Scale) and drug side effects (SE) for first- and second-line therapies were recorded. RESULTS: A total of 267 patients were included. The percentage of responders (R) to first-line therapy [steroid or IVIg or plasma exchange (PE)] was 69%; this number increased to 81% when patients who switched to different therapies were included. Overall, the percentage of R to IVIg was similar to R to steroids (P = 0.07) and higher than R to PE (P < 0.001). Of the main therapies, PE frequently caused SE (19%), followed by steroids (12.5%) and IVIg (4%). CONCLUSIONS: Switching between traditional therapies increases the number of responder patients. IVIg was confirmed to be a therapy with low SE.

Variations of the perforin gene in patients with multiple sclerosis.

Perforin is involved in cell-mediated cytotoxicity and mutations of its gene (PRF1) cause familial hemophagocytic lymphohistiocytosis (FLH2). PRF1 sequencing in 190 patients with multiple sclerosis and 268 controls detected two FLH2-associated variations (A91V, N252S) in both groups and six novel mutations (C999T, G1065A, G1428A, A1620G, G719A, C1069T) in patients. All together, carriers of these variations were more frequent in patients than in controls (phenotype frequency: 17 vs 9%, P=0.0166; odds ratio (OR)=2.06, 95% confidence interval (CI): 1.13-3.77). Although A91V was the most frequent variation and displayed a trend of association with multiple sclerosis (MS) in the first population of patients and controls (frequency of the 91V allele: 0.076 vs 0.043, P=0.044), we used it as a marker to confirm PRF1 involvement in MS and assessed its frequency in a second population of 966 patients and 1520 controls. Frequency of the 91V allele was significantly higher in patients than in controls also in the second population (0.075 vs 0.058%, P=0.019). In the combined cohorts of 1156 patients and 1788 controls, presence of the 91V allele in single or double dose conferred an OR=1.38 (95% CI=1.10-1.74). These data suggest that A91V and possibly other perforin variations indicate susceptibility to MS.

MDC/CCL22 intrathecal levels in patients with multiple sclerosis.

MDC/CCL22 has been detected in the brain of mice with experimental autoimmune encephalomyelitis. MDC/CCL22 cerebrospinal fluid levels were evaluated in 56 patients with multiple sclerosis (MS) and in 17 controls. No significant differences were found, even when stratifying patients according to the disease subtype. Stratifying by gender, significantly increased MDC/CCL22 levels were observed in female patients when compared with female controls and male patients (109.03 versus 98.54 and 99.37 pg/mL, P = 0.034 and 0.018, respectively). Therefore, MDC/CCL22 is likely to play a role in the development of MS in females only, possibly influencing the intracerebral recruitment of Th2 cells, which produce anti-inflammatory cytokines.

CXCL10 haplotypes and multiple sclerosis: association and correlation with clinical course.

CXCL10 (interferon-gamma-inducible protein-10) levels are increased in cerebrospinal fluid of multiple sclerosis (MS) patients with symptomatic attacks of inflammatory demyelination, supporting a role for this molecule in MS pathogenesis. Two hundred and twenty-six patients with MS and 235 controls were genotyped for G --> C and T --> C single nucleotide polymorphisms (SNPs) in exon 4 of CXCL10 gene. Haplotypes were tested for association and correlated with clinical variables. The two SNPs studied were in complete linkage disequilibrium. None of the determined haplotypes was associated with MS. However, carriers of the GGTT haplotype (defined as wild type, according to the sequence in National Centre for Biotechnology Information (NCBI) database) had a significantly lower progression index than non-carriers (P = 0.016). Furthermore, amongst patients who had an initial relapsing remitting (RR) course of the disease, the time between onset and second episode was significantly longer in GGTT carriers (P = 0.021). Considering secondary progressive (SP)-MS patients, the time between the initial RR form and the subsequent worsening to SP was longer in this group (P = 0.08). Therefore, the GGTT haplotype of the CXCL10 gene is not a susceptibility factor for the development of MS, but is probably to influence the course of MS, possibly contributing to slow down the progression of the disease.