[Subarachnoid hemorrhage in a young girl]. / Een meisje met een subarachnoïdale bloeding.

BACKGROUND: Subarachnoid hemorrhage in children is rare. The most common cause is trauma, followed by an arteriovenous malformation, aneurysm or tumor. CASE DESCRIPTION: We describe the case of an 11-year-old girl who developed sudden headache with nausea and vomiting during athletics training. Her neurological exam was normal. With imaging and a lumbar puncture a subarachnoid hemorrhage was diagnosed, based on a ruptured saccular aneurysm of the right middle cerebral artery. Endovascular treatment was unsuccessful, after which the aneurysm was treated surgically. Postoperative recovery was uneventful. Additional tests for underlying conditions were negative. CONCLUSION: Also in a child with acute headache, nausea, and vomiting, the diagnosis of a subarachnoid hemorrhage should be considered, even if neurological examination is normal. Expeditious diagnosis and treatment are important in order to prevent rebleeding.

[Involving forensic psychiatric patients in scientific research]. / De bereidheid van forensisch psychia­trische patiënten tot deelname aan wetenschappelijk onderzoek.

Background Forensic psychiatric patients are at risk to cause damage to society in the future again, both materially and immaterially. Little is known about the pharmacotherapeutic or psychotherapeutic treatment of the specific psychopathology of forensic psychiatric patients. This is possibly due to scarcity of research in the field, which could be caused by the fact that forensic psychiatric patients are often unwilling to participate in scientific research. Aim To explore the reasons why patients are unwilling to participate in research. Method Sixty-five forensic psychiatric patients were asked about their opinion on participating in pharmacological, psychotherapy, MRI- and DNA research.  Results The main reasons for not participating in pharmacological research were 'patient's belief that they will not benefit from participation in research' and 'physical integrity' (the fear of being physically harmed by participation in research). 'General resistance' (not willing to take part for no particular reason) was the main reason for not participating in psychotherapy-, MRI and DNA research.  Conclusion In order to enhance willingness to take part in research, informing the patients in the right manner with the aim of taking distrust away, would be important. Also, it could be helpful to offer a reward for participation in scientific research, although this could lead to ethical complications.

Incidence and outcome of acquired demyelinating syndromes in Dutch children: update of a nationwide and prospective study.

INTRODUCTION: Acquired demyelinating syndromes (ADS) are immune-mediated demyelinating disorders of the central nervous system in children. A nationwide, multicentre and prospective cohort study was initiated in the Netherlands in 2006, with a reported ADS incidence of 0.66/100,000 per year and MS incidence of 0.15/100,000 per year in the period between 2007 and 2010. In this study, we provide an update on the incidence and the long-term follow-up of ADS in the Netherlands. METHODS: Children < 18 years with a first attack of demyelination were included consecutively from January 2006 to December 2016. Diagnoses were based on the International Paediatric MS study group consensus criteria. Outcome data were collected by neurological and neuropsychological assessments, and telephone call assessments. RESULTS: Between 2011 and 2016, 55/165 of the ADS patients were diagnosed with MS (33%). This resulted in an increased ADS and MS incidence of 0.80/100,000 per year and 0.26/100,000 per year, respectively. Since 2006 a total of 243 ADS patients have been included. During follow-up (median 55 months, IQR 28-84), 137 patients were diagnosed with monophasic disease (56%), 89 with MS (37%) and 17 with multiphasic disease other than MS (7%). At least one form of residual deficit including cognitive impairment was observed in 69% of all ADS patients, even in monophasic ADS. An Expanded Disability Status Scale score of ≥ 5.5 was reached in 3/89 MS patients (3%). CONCLUSION: The reported incidence of ADS in Dutch children has increased since 2010. Residual deficits are common in this group, even in monophasic patients. Therefore, long-term follow-up in ADS patients is warranted.

The long-term association of OCD and depression and its moderators: A four-year follow up study in a large clinical sample.

BACKGROUND: Depression is the most common comorbidity in obsessive-compulsive disorder (OCD). However, the mechanisms of depressive comorbidity in OCD are poorly understood. We assessed the directionality and moderators of the OCD-depression association over time in a large, prospective clinical sample of OCD patients. METHODS: Data were drawn from 382 OCD patients participating at the Netherlands Obsessive-Compulsive Disorder Association (NOCDA) study. Cross-lagged, structural equation modeling analyses were used to assess the temporal association between OCD and depressive symptoms. Assessments were conducted at baseline, two-year and four-year follow up. Cognitive and interpersonal moderators of the prospective association between OCD and depressive symptoms were tested. RESULTS: Cross-lagged analyses demonstrated that OCD predicts depressive symptoms at two-year follow up and not vice a versa. This relationship disappeared at four-year follow up. Secure attachment style moderated the prospective association between OCD and depression. CONCLUSIONS: Depressive comorbidity in OCD might constitute a functional consequence of the incapacitating OCD symptoms. Both OCD and depression symptoms demonstrated strong stability effects between two-year and four-year follow up, which may explain the lack of association between them in that period. Among OCD patients, secure attachment represents a buffer against future depressive symptoms.

Childhood lymphomatoid granulomatosis: a report of 2 cases and review of the literature.

Lymphomatoid granulomatosis (LG) is a B-cell type lymphoproliferative disease. It mainly affects the lungs but may have extrapulmonary manifestations, especially in the central nervous system. The purpose of this study was to review the pediatric cases in the literature and add 2 new cases to the existing literature. A review of the literature was performed on children (0 to 18 years of age at diagnosis) with pathologically proven LG. We found 47 case reports, which, together with 2 new cases, were systematically analyzed. The median age was 12 years. The main symptoms were general, pulmonary, and neurological. Approximately one third of the patients were immunocompromised. High mortality rate was observed. Pediatric LG is a rare disease, which appears to be more frequently seen in immunocompromised patients, especially patients with leukemia. The disease has a high mortality rate; therefore, aggressive therapy according to a high-grade B-cell lymphoma protocol is justified.

Age of onset in obsessive-compulsive disorder: admixture analysis with a large sample.

BACKGROUND: Research into age of onset in obsessive-compulsive disorder (OCD) has indicated significant differences between patients with early and late onset of the disorder. However, multiple criteria have been used arbitrarily for differentiating between early- and late-onset OCD, rendering inconsistent results that are difficult to interpret. METHOD: In the current study, admixture analysis was conducted in a sample of 377 OC patients to determine the number of underlying populations of age of onset and associated demographic and clinical characteristics. Various measures of anxiety, depression, co-morbidity, autism, OCD, tics and attention deficit hyperactivity disorder (ADHD) symptoms were administered. RESULTS: A bimodal age of onset was established and the best-fitting cut-off score between early and late age of onset was 20 years (early age of onset ≤19 years). Patients with early age of onset were more likely to be single. Early age of onset patients demonstrated higher levels of OCD severity and increased symptoms on all OCD dimensions along with increased ADHD symptoms and higher rates of bipolar disorder. CONCLUSIONS: It is suggested that 20 years is the recommended cut-off age for the determination of early versus late age of onset in OCD. Early age of onset is associated with a generally graver OCD clinical picture and increased ADHD symptoms and bipolar disorder rates, which may be related to greater functional implications of the disorder. We propose that age of onset could be an important marker for the subtyping of OCD.

Incidence of acquired demyelinating syndromes of the CNS in Dutch children: a nationwide study.

Acquired demyelinating syndromes (ADS) can be a first presentation of multiple sclerosis (MS) in children. The incidence of these disorders in Europe is currently unknown. Children (<18 years old) living in the Netherlands who presented with ADS were included from January 1, 2007 to December 31, 2010 by the Dutch pediatric MS study group and the Dutch surveillance of rare pediatric disorders. Demographic and clinical data were collected. Eighty-six patients were identified over 4 years, resulting in an incidence of 0.66/1,00,000 per year. Most patients presented with polyfocal ADS without encephalopathy (30%), followed by polyfocal ADS with encephalopathy (24%), optic neuritis (ON, 22%), monofocal ADS (16%), transverse myelitis (3%), and neuromyelitis optica (3%). Patients with polyfocal ADS with encephalopathy were younger (median 3.9 years) than patients with ON (median 14.6 years, p < 0.001) or monofocal ADS (median 16.0 years, p < 0.001). Patients with polyfocal ADS without encephalopathy (median 9.2 years) were also younger than monofocal ADS patients (median 16.0 years, p < 0.001). There was a slight female preponderance in all groups except the ON group, and a relatively large number of ADS patients (29%) reported a non-European ancestry. Familial autoimmune diseases were reported in 23%, more often in patients with relapsing disease than monophasic disease (46 vs. 15%, p = 0.002) and occurring most often in the maternal family (84%, p < 0.001). During the study period, 23% of patients were subsequently diagnosed with MS. The annual incidence of ADS in the Netherlands is 0.66/1,00,000 children/year. A polyfocal disease onset of ADS was most common.

Blood and CSF Biomarker Dynamics in Multiple Sclerosis: Implications for Data Interpretation.

Background. Disability in multiple sclerosis (MS) is related to neuroaxonal degeneration. A reliable blood biomarker for neuroaxonal degeneration is needed. Objectives. To explore the relationship between cerebrospinal fluid (CSF) and serum concentrations of a protein biomarker for neuroaxonal degeneration, the neurofilaments heavy chain (NfH). Methods. An exploratory cross-sectional (n = 51) and longitudinal (n = 34) study on cerebrospinal fluid (CSF) and serum NfH phosphoform levels in patients with MS. The expanded disability status scale (EDSS), CSF, and serum levels of NfH-SMI34 and NfH-SMI35 were quantified at baseline. Disability progression was assessed at 3-year followup. Results. At baseline, patients with primary progressive MS (PPMS, EDSS 6) and secondary progressive MS (SPMS, EDSS 6) were more disabled compared to patients with relapsing remitting MS (RRMS, EDSS 2, P < .0001). Serum and CSF NfH phosphoform levels were not correlated. Baseline serum levels of the NfH-SMI34 were significantly (P < .05) higher in patients with PPMS (2.05 ng/mL) compared to SPMS (0.03 ng/mL) and RRMS (1.56 ng/mL). In SPMS higher serum than CSF NfH-SMI34 levels predicted disability progression from baseline (ΔEDSS 2, P < .05). In RRMS higher CSF than serum NfH-SMI35 levels predicted disability progression (ΔEDSS 2, P < .05). Conclusion. Serum and CSF NfH-SMI34 and NfH-SMI35 levels did not correlate with each other in MS. The quantitative relationship of CSF and serum NfH levels suggests that neuroaxonal degeneration of the central nervous system is the likely cause for disability progression in RRMS. In more severely disabled patients with PP/SPMS, subtle pathology of the peripheral nervous system cannot be excluded as an alternative source for blood NfH levels. Therefore, the interpretation of blood protein biomarker data in diseases of the central nervous system (CNS) should consider the possibility that pathology of the peripheral nervous system (PNS) may influence the results.

Normal CSF ferritin levels in MS suggest against etiologic role of chronic venous insufficiency.

OBJECTIVES: Chronic cerebrospinal venous insufficiency (CCSVI) has been suggested to be a possible cause of multiple sclerosis (MS). If the presumed mechanism of venous stasis-related parenchymal iron deposition and neurodegeneration were true, then upregulation of intrathecal iron transport proteins may be expected. METHODS: This was a cross-sectional (n = 1,408) and longitudinal (n = 29) study on CSF ferritin levels in patients with MS and a range of neurologic disorders. RESULTS: Pathologic (>12 ng/mL) CSF ferritin levels were observed in 4% of the control patients (median 4 ng/mL), 91% of patients with superficial siderosis (75 ng/mL), 73% of patients with a subarachnoid hemorrhage (59 ng/mL), 10% of patients with relapsing-remitting MS (5 ng/mL), 11% of patients with primary progressive MS (6 ng/mL), 23% of patients with secondary progressive MS (5 ng/mL), and 23% of patients with meningoencephalitis (5 ng/mL). In MS, there was no significant change of CSF ferritin levels over the 3-year follow-up period. CONCLUSION: These data do not support an etiologic role for CCSVI-related parenchymal iron deposition in MS.

Cerebrospinal fluid ATP metabolites in multiple sclerosis.

Increased axonal energy demand and mitochondrial failure have been suggested as possible causes for axonal degeneration and disability in multiple sclerosis. Our objective was to test whether ATP depletion precedes clinical, imaging and biomarker evidence for axonal degeneration in multiple sclerosis. The method consisted of a longitudinal study which included 21 patients with multiple sclerosis. High performance liquid chromatography was used to quantify biomarkers of the ATP metabolism (oxypurines and purines) from the cerebrospinal fluid at baseline. The Expanded Disability Status Scale, MRI brain imaging measures for brain atrophy (ventricular and parenchymal fractions), and cerebrospinal fluid biomarkers for axonal damage (phosphorylated and hyperphosphorylated neurofilaments) were quantified at baseline and 3-year follow-up. Central ATP depletion (sum of ATP metabolites >19.7 micromol/litre) was followed by more severe progression of disability if compared to normal ATP metabolites (median 1.5 versus 0, p< 0.05). Baseline ATP metabolite levels correlated with change of Expanded Disability Status Scale in the pooled cohort (r= 0.66, p= 0.001) and subgroups (relapsing-remitting patients: r= 0.79, p< 0.05 and secondary progressive/primary progressive patients: r= 0.69, p< 0.01). There was no relationship between central ATP metabolites and either biomarker or MRI evidence for axonal degeneration. The data suggests that an increased energy demand in multiple sclerosis may cause a quantifiable degree of central ATP depletion. We speculate that the observed clinical disability may be related to depolarisation associated conduction block.

Fatigue and depression in children with multiple sclerosis and monophasic variants.

BACKGROUND: Fatigue is an important symptom in adult multiple sclerosis (MS) and it is likely to occur in children with MS. It is currently unknown whether children who experienced a monophasic inflammatory demyelinating event of the central nervous system in the past also suffer from fatigue. METHODS: We studied the presence and severity of fatigue in 32 children (18 boys, 14 girls) between 11-17 years old (mean: 14 years, 10 months) with a monophasic inflammatory demyelinating disease (n=22) or definite MS (n=10). This was measured with the Checklist Individual Strength. A score of >or=40 on the severity of fatigue subscale indicated the presence of severe fatigue. We also examined the relation between fatigue and depression (assessed by the Child Depression Inventory). Additionally we measured the health-related quality of life (HRQoL), using the TNO-AZL Child Quality of Life child form. We compared the scores of the MS and monophasic patients with the scores of healthy Dutch children. RESULTS: The highest scores on the fatigue scales subjective fatigue and physical activity were found in the children with MS. Only 1 of the monophasic patients suffered from severe fatigue in contrast to 4 of the MS patients. In the MS group fatigue and depression were correlated. MS patients experienced a lower HRQoL on the scales locomotor functioning, cognitive functioning and interaction with peers. CONCLUSION: The occurrence of fatigue is very rare after a monophasic inflammatory demyelinating event in the past. As expected, fatigue occurs more frequent in paediatric MS patients.

Gender differences in multiple sclerosis: cytokines and vitamin D.

The disproportional increase of the female:male ratio in relapse-onset (relapsing remitting (RR) and secondary progressive (SP)) multiple sclerosis (MS) patients in the last 20 years has further raised scientific interest in gender difference in MS. It has been suggested that the immune system, especially cytokines, plays an important role in the gender issue, as can also be seen in other autoimmune diseases. The immune system is influenced by different factors including hormones and seasonal fluctuations (vitamin D). This overview will highlight the gender differences in MS, with emphasis on the cytokines and vitamin D.

N-acetylaspartic acid in cerebrospinal fluid of multiple sclerosis patients determined by gas-chromatography-mass spectrometry.

BACKGROUND: Axonal degeneration is considered to play a major role in the development of clinical disability in multiple sclerosis (MS). N-AcetylAspartic Acid (NAA) is a neuron-specific marker constantly identified in MR-spectroscopy studies of the normal and MS brain. To our knowledge there are no studies available that evaluated NAA in cerebrospinal fluid (CSF) as a possible marker for disease severity. OBJECTIVE: To evaluate CSF concentrations of NAA in MS in relation to disease phenotype, clinical measures of disability and MRI markers of disease burden. METHODS: NAA concentrations were determined in CSF of 46 patients with MS (26 relapsing remitting (RRMS), 12 secondary progressive (SPMS) and 8 primary progressive (PPMS)). Prior to lumbar puncture, MS-patients underwent MRI and clinical examination, including the Expanded Disability Status Scale (EDSS) and the MS Functional Composite (MSFC). Additionally, CSF concentrations of NAA were determined in 12 patients with other neurological diseases (OND). RESULTS: Median CSF NAA concentration was 0.74 (IQR: 0.59-0.94) in RRMS , 0.54 (IQR: 0.35-0.73) in SPMS and 0.83 mumol/l (IQR: 0.56-1.03) in PPMS patients. SPMS patients had a significantly lower NAA concentration than RRMS patients. NAA concentrations correlated with EDSS (r = )0.37, p = 0.016), MSFC (r = 0.41, p = 0.010), normalised brain volume (r = 0.49, p = 0.001), T2 lesion load (r = )0.35, p = 0.021) and black hole lesion load (r = )0.47, p = 0.002). No differences were observed between OND (median: 0.57 IQR: 0.28-0.73) and MS patients. CONCLUSION: CSF NAA concentration in MS patients is related to clinical performance and MRI measures of disease burden and may therefore be an important neuron specific marker of disease severity and possibly progression.

The new global multiple sclerosis severity score (MSSS) correlates with axonal but not glial biomarkers.

This study investigated whether the new Global Multiple Sclerosis Severity Scale (MSSS) correlated with cerebrospinal fluid biomarkers for axonal and glial pathology. The MSSS correlated with the phosphorylated neurofilament heavy chain (NfH-SM135, R=0.44, P=0.016). The degree of neurofilament phosphorylation (ratio NfH-SM134 to NfH-SM135) was 8-fold higher in severely (median MSSS 6.5) versus mildly (MSSS 3.2) disabled patients (7.3 versus 0.9, P = 0.03). The MSSS may provide a statistically powerful tool for comparing overall disease severity and be useful for validating the biomarker concept in MS.

Sex differences in proinflammatory cytokine profiles of progressive patients in multiple sclerosis.

The objective of this article is to evaluate the presence of sex differences in expression of cytokines in both CD4+ and CD8+ T cells derived from peripheral blood of untreated multiple sclerosis (MS) patients. The predominance of females in MS and other autoimmune diseases may be related to their differential responses in many immunological settings. Recent data show beneficial effect of sex hormones on proinflammatory cytokine levels and on magnetic resonance imaging in MS. Better understanding of gender differences is warranted. In this study 124 MS subjects (M:F; 56:68) and 34 healthy controls (M:F; 12:22) were included. Stimulated peripheral blood-derived CD4+ and CD8+ T cells were analysed for interferon-gamma, interleukin (IL)-2, tumour necrosis factor alpha, IL-4, IL- 10 and IL- 13 production. There were no significant differences for these cytokines between male and female MS subjects in the whole group. Compared to males, female patients had higher proinflammatory cytokine levels in the progressive phase of the disease. In conclusion, the data presented indicate that cytokine production and sex differences in cytokine production might differ between disease phases, probably related to underlying disease mechanisms.

Brain atrophy and lesion load as explaining parameters for cognitive impairment in multiple sclerosis.

Multiple sclerosis (MS) is a multifocal demyelinating disease of the central nervous system, with lesions widespread through the brain and spinal cord. An important manifestation is cognitive impairment, which, though difficult to measure, may have a major social impact. To better understand the relationship between structural tissue damage and cognitive impairment, we examined the extent and spatial distribution of brain lesions, as measured by magnetic resonance imaging (MRI), in relation to abnormal cognitive performance as measured by the Brief Repeatable Battery (BRB) in 82 MS patients. Possible confounders, like fatigue, pain and depression were also assessed. Brain MR image analysis included hyperintense T2 and hypointense T1 lesion load in the whole brain and the four lobes separately, as well as whole brain volume measurements. Cognitive impairment (defined as more than two abnormal tests) was found in 67% of the patients. Moderately strong correlations were found between the subtests of the BRB and the lesion loads in the brain regions hypothesized to be associated with that cognitive test, although these correlations were in general not much stronger than those between the subtests and the overall lesion load (due to strong interrelationships). The Spatial Recall Test correlated best with parietal lesion load; the Symbol Digit Modalities Test, the Paced Auditory Serial Addition Task (PASAT) and the Word List Generation best with frontal, parietal and temporal lesion load; while the Verbal List Generation Test Index correlated only with atrophy. Atrophy and lesion load were the main factors determining the test scores, explaining 10-25% of the variance in the test results, and were more important than fatigue, pain and depression; only depression had a minor, but significant, additional effect on the PASAT. In conclusion, cognitive impairment in MS is moderately dependent on amount (and distribution) of structural brain damage, especially in the more physically impaired patients group.

Axonal damage accumulates in the progressive phase of multiple sclerosis: three year follow up study.

BACKGROUND: Neurofilament phosphoforms (Nf) are principal components of the axoskeleton released during axonal injury. Cerebrospinal fluid (CSF) levels of Nf phosphoforms might be useful surrogate markers for disability in multiple sclerosis (MS), aid in distinguishing clinical subtypes, and provide valuable prognostic information. METHOD: Thirty four patients with MS were included in a three year follow up study along with 318 controls with other non-inflammatory neurological diseases. CSF levels of two Nf heavy chain (NfH) phosphoforms (NfH(SMI35), NfH(SMI34)) were quantified at baseline and three year follow up using new ELISA techniques. Levels of NfH phosphoforms, the degree of phosphorylation (NfH(SMI34):NfH(SMI35) ratio), and changes in NfH levels between baseline and follow up (Delta NfH) were related to the clinical phenotype (RR or SP/PP), to three clinical scales (Kurtzke's EDSS, ambulation index (AI), and nine hole peg test (9HPT)), and to progression of disability. RESULTS: A significantly higher proportion (59%) of patients with SP/PPMS experienced an increase in NfH(SMI35) levels between baseline and follow up compared with those with RRMS (14%, p<0.05). CSF NfH(SMI34) levels at baseline were higher in patients with SP/PP (11 pg/ml) compared with RR (7 pg/ml, p<0.05) and NfH(SMI35) levels were higher at follow up in SP/PP (129 pg/ml) compared with levels below assay sensitivity in RR (p<0.05). NfH(SMI35) correlated with the EDSS (r(s) = 0.54, p<0.01), the AI (r(s) = 0.42, p<0.05), and the 9HPT (r(s) = 0.59, p<0.01) at follow up. CONCLUSION: The increase in NfH during the progressive phase of the disease together with the correlation of NfH(SMI35) with all clinical scales at follow up suggests that cumulative axonal loss is responsible for sustained disability and that high NfH(SMI35) levels are a poor prognostic sign.

Expression of adhesion molecules on peripheral lymphocytes predicts future lesion development in MS.

The expression of adhesion molecules (alpha4beta1-integrin, LFA-1, ICAM-1) on T cells, measured by flow cytometry, was compared in different subtypes of multiple sclerosis (MS) and related to future lesion development as seen as delta T1 and T2 lesion load per year on magnetic resonance imaging (MRI). LFA-1 and alpha4beta1-integrin showed higher expression on CD4 and CD8 T lymphocytes in the secondary progressive compared to the relapsing-remitting (CD4: p<0.01, p=ns, p<0.05; CD8: p<0.001, p<0.001, p<0.001, respectively) and primary progressive MS phase (CD4: p<0.001, p<0.01, p<0.05; CD8: p<0.01, p<0.01, p<0.001, respectively). The adhesion molecule expression of alpha4- (r=0.31; p<0.05) and beta1-integrin (r=0.38; p<0.01) on CD4+ cells and of LFA-1beta on both CD4+ and CD8+ (r=0.28, p<0.05) and r=0.29; p<0.05, respectively) cells was significantly related to increase in T2 lesion load. Our study provides further evidence for the involvement of integrins in lesion development, shown as T2 lesions on MRI in MS.

CSF nitric oxide metabolites are associated with activity and progression of multiple sclerosis.

OBJECTIVE: To investigate the relationship of CSF and the serum nitric oxide metabolites nitrite and nitrate (NOx) to disease activity and progression in patients with multiple sclerosis (MS). METHODS: The study was divided into cross-sectional and follow-up. In the cross-sectional study, 20 patients with relapsing-remitting (RR), 21 with secondary progressive (SP), and 10 with primary progressive (PP) MS and 14 control subjects were included. Patients were assessed on clinical (Expanded Disability Status Scale [EDSS], Ambulation Index [AI], 9-Hole Peg Test [9-HPT]) and MRI measurements. In the follow-up study, 34 MS patients from the cross-sectional study agreed to be assessed again after an average of 3.0 +/- 0.5 years. NOx was measured using a vanadium-based assay. RESULTS: In the cross-sectional study, CSF NOx was raised in patients with RR-MS (p = 0.001) and PP-MS (p = 0.02) vs controls. Higher CSF NOx levels were found in patients with mild disability (AI < or = 6.0; EDSS < or = 4.0; Multiple Sclerosis Severity Score [MSSS] < or = 4.8) vs patients with advanced disease (AI > 6.0 [p = 0.002]; EDSS > 4.0 [p = 0.02]; MSSS > 4.8 [p = 0.01]). In the subgroup of patients having Gd-enhancing MRI lesions (n = 11), correlation between the volume of enhancement and CSF NOx was found (r = 0.74, p = 0.01). In the follow-up study, patients with disability progression had higher baseline CSF NOx levels than those who were stable on EDSS (p = 0.02) or AI (p = 0.03). A positive correlation was found between baseline CSF NOx and the change in MR T2-weighted lesion load (r = 0.4, p = 0.03). CONCLUSIONS: CSF nitrite and nitrate levels were increased in mildly disabled patients with MS and found to correlate with the volume of Gd-enhanced lesions on MRI. Raised baseline CSF NOx was associated with clinical and MRI progression in MS patients over 3-year follow-up.