Oligoclonal IgG Bands Research Articles

Treatment of Neuromyelitis Optica

Neuromyelitis optica (NMO) or Devic's disease is an inflammatory neurologic disease characterized by severe optic neuritis and transverse myelitis. Other features of NMO include female preponderance, higher onset age, severe functional disability, longitudinally extensive spinal cord lesions (longer than 3 vertebral segments), and oligoclonal IgG bands negativity. Brain lesions are not uncommon in NMO. The relation between NMO and multiple sclerosis (MS) has long been a matter of controversy, but since the discovery of anti-aquaporin 4 (AQP4) antibody (NMO-IgG), an NMO-specific autoantibody, the clinical, MRI, and laboratory features that distinguish NMO from MS have been clarified. Anti-AQP4 antibody binds to the extracellular domain of AQP4, which is highly expressed in endfeet of astrocytes. Recent neuropathological studies, analysis of CSF-GFAP levels during relapse and experimental studies strongly suggest that NMO is an anti-AQP4 antibody-mediated astrocytopathic disease and that T cell-mediated CNS inflammation is necessary to develop NMO. Also, IL-6 is remarkably elevated in the CSF and appears to regulate plasmablasts to produce anti-AQP4 antibody. Therefore, from the therapeutic point of view, depletion of anti-AQP4 antibody, suppression of T cell response to trigger relapse and anti-IL-6 therapy seem to be pivotal. High-dose intravenous methylprednisolone is the first-line therapy for acute exacerbations of NMO. But plasma exchange should be started soon if corticosteroid is not efficacious. If untreated, AQP4 antibody-positive patients are highly likely to experience relapses within a year. Thus, immunosuppressive therapy (corticosteroids, immunosuppressants, rituximab) should be initiated without delay. Preliminary results suggest that eculizumab, an anti-C5 monoclonal antibody, can also prevent relapse in NMO, Meanwhile, interferon-beta, a first-line disease modifying drug of MS, is not effective in NMO. Symptomatic therapy for pain, paresthesia, spasticity, dysuria and constipation which commonly occur in the chronic stage of NMO is also important to improve patients' quality of life.

Acute Disseminated Encephalomyelitis Following 2009 H1N1 Influenza Vaccination

Since the worldwide spread of the novel influenza type A virus in 2009, trivalent vaccines against H1N1 (pandemic) 09 and seasonal influenza have been used. We describe a 33-year-old woman who presented with hypoesthesia below the Th7 level fifteen days after vaccination without any preceding infection. Cerebrospinal fluid showed an increased level of myelin basic protein and positive oligoclonal IgG bands. Magnetic resonance imaging revealed disseminated lesions in the brain and thoracic cord. Steroid therapy improved her symptoms. She was diagnosed as having acute disseminated encephalomyelitis (ADEM) possibly related to the vaccination. As a potential adverse effect of the influenza vaccine, in addition to Guillain-Barré syndrome, ADEM should also be recognized.

Comorbid Multiple Sclerosis and TDP-43 Proteinopathy in a Gulf War Sea Captain

Comorbid Multiple Sclerosis and TDP-43 Proteinopathy in a Gulf War Sea Captain

Spinal cord tumor versus transverse myelitis

Longitudinally extensive transverse myelitis (LETM) is one of the defining features of neuromyelitis optica (NMO). Despite the well-established criteria, clinical and paraclinical features, the disease is often misdiagnosed and erroneously treated. We report on a case of LETM in a patient with spatially limited NMO spectrum disorder that was misdiagnosed as spinal cord tumor and underwent spinal cord biopsy. A 43-year-old female patient is described. The patient developed spastic tetraparesis over 1 week. Spinal cord magnetic resonance imaging (MRI) revealed LETM, and she was treated with steroids and recovered. Nine months later, her condition worsened and repeat spinal cord MRI was interpreted as a large intramedullary tumor in the cervical region with irregular postcontrast enhancement. Biopsy revealed demyelination. Cerebrospinal fluid (CSF) analysis revealed positive oligoclonal IgG bands, and serum was positive for NMO-IgG antibody. The patient was diagnosed with spatially limited NMO spectrum disorder, treated with plasma exchange, high-dose corticosteroids, and cyclophosphamide, and with good recovery. The factors favoring inflammatory LETM are acute or subacute onset of clinical symptoms, positive oligoclonal bands in the CSF, positive NMO-IgG or other antibodies, and brain MRI showing demyelinating lesions. Postcontrast axial MRI sequences of the spinal cord can also be helpful. In doubtful situations, a trial of therapy and follow-up MRI a month later might be a more prudent approach if the patient is not rapidly deteriorating.

Linear scleroderma en coup the sabre, progressive facial hemiatrophy and Rasmussen encephalitis : a single disease spectrum?

Results 9 patients presented with LSCS, followed in 5 of them by progressive hemifacial atrophy (PFH) within 2 years. 3 patients presented with PFH, all 3 had additional scleroderma lesions. Their median(range) age at presentation was 8(4-17)yrs. Extracutaneous manifestations were equally found in LSCS and PFH+LSCS patients. They comprised asymmetry of tooth arches/missing teeth(1), ophthalmologic problems (eyelid ptosis, enophtalmia, bilateral anterior uveitis and renal papillary asymmetry)(4), epileptic seizures with hyperintense signals on MRI and hypoperfusion on SPECT in 1 LSCS (fig) and 1 PFH patient, severe migraine attacks(2), polyarthritis(2), vitiligo(1), celiac disease(1). ANA were found in 3 LSCS, 2 PFH+LSCS patients. Distinct oligoclonal IgG bands were found in CSF (not in blood) in patients with PFH and seizures. A skin biopsy in a PFH lesion showed fibrosis associated with a lymphocytic infiltrate, IgM and IgG deposits. A brain biopsy in one PFH patient with epilepsy was consistent with Rasmussen encephalitis.

Clinicopathological considerations in acute disseminated encephalomyelitis (ADEM): a fulminant case with favorable outcome

We report the clinical course and pathological features of a 52-year-old woman with fulminant acute disseminated encephalomyelitis (ADEM). She presented with subacute tetraparesis, which developed over 2 days, and progressive loss of consciousness. CCT showed pronounced bihemispherical and periventricular edema. Multifocal glioma was suspected, and the patient was referred for brain biopsy to the neurosurgery department at our hospital. On admission, the patient presented with progressive tetraparesis and aphasia. Subsequently, she developed epileptic seizures. Cranial magnetic resonance imaging (MRI) revealed confluent bihemispherical and periventricular white matter edema (Fig. 1a) with abnormal patchy gadolinium enhancement, compatible with progressive multifocal leukoencephalopathy (PML), multifocal brain tumor or ADEM. Cerebrospinal fluid (CSF) analysis revealed mild pleocytosis (11 cells/ll) with increased protein levels, and normal glucose and lactate levels. No intrathecal IgG and IgM synthesis or oligoclonal bands (OCB) were observed in CSF. Antiviral and antibiotic treatment was initiated. Stereotactic brain biopsy from right frontal periventricular white matter (Fig. 1b) was performed 5 days after disease onset. Histopathology ruled out malignant brain tumor but showed acute perivascular inflammation.

Cerebrospinal fluid findings in adults with acute Lyme neuroborreliosis

Presence of BB-specific antibodies in the cerebrospinal fluid (CSF) with evidence of their intrathecal production in conjunction with the white cell count in the CSF and typical clinical symptoms is the traditional diagnostic gold standard of Lyme neuroborreliosis (LNB). Few data are available on the CSF lactate concentration in European adults with the diagnosis of acute LNB. The objective of the study was to investigate the CSF changes during acute LNB. Routine CSF parameters [leukocyte count, protein, lactate and albumin concentrations, CSF/serum quotients of albumin (QAlb), IgG, IgA and IgM, and oligoclonal IgG bands] and the Borrelia burgdorferi (BB)-specific antibody index were retrospectively studied in relation to the clinical presentation in patients diagnosed with acute LNB. A total of 118 patients with LNB were categorized into the following groups according to their symptoms at presentation; group 1: polyradiculoneuritis (Bannwarth’s syndrome), group 2: isolated facial palsy and group 3: predominantly meningitic course of the disease. In addition to the CSF of patients with acute LNB, CSF of 19 patients with viral meningitis (VM) and 3 with neurolues (NL) were analyzed. There were 97 patients classified with definite LNB, and 21 as probable LNB. Neck stiffness and fever were reported by 15.3% of patients. Most of these patients were younger than 50 years. Polyradiculoneuritis was frequently found in patients older than 50 years. Lymphopleocytosis was found in all patients. Only 5 patients had a CSF lactate ≥3.5 mmol/l, and the mean CSF lactate level was not elevated (2.1 ± 0.6 mmol/l). The patients with definite LNB had significantly higher lactate levels than patients with probable LNB. Elevated lactate levels were accompanied by fever and headache. In the Reiber nomograms, intrathecal immunoglobulin synthesis was found for IgM in 70.2% followed by IgG in 19.5%. Isoelectric focussing detected an intrathecal IgG synthesis in 83 patients (70.3%). Elevated BB AIs in the CSF were found in 97 patients (82.2%). Patients with VM showed lower CSF protein concentration and CSF/serum quotients of albumin than LNB patients. In acute LNB, all patients had elevated cerebrospinal fluid (CSF) leukocyte counts. In contrast to infections by other bacteria, CSF lactate was lower than 3.5 mmol/l in all but 5 patients. The CSF findings did not differ between polyradiculoneuritis, facial palsy, and meningitis. The CSF in LNB patients strongly differed from CSF in VM patients with respect to protein concentration and the CSF/serum albumin quotient.

Lipid arrays identify myelin-derived lipids and lipid complexes as prominent targets for oligoclonal band antibodies in multiple sclerosis

The presence of oligoclonal bands of IgG (OCB) in cerebrospinal fluid (CSF) is used to establish a diagnosis of multiple sclerosis (MS), but their specificity has remained an enigma since its first description over forty years ago. We now report that the use of lipid arrays identifies heteromeric complexes of myelin derived lipids as a prominent target for this intrathecal B cell response.

Utility of oligoclonal IgG band detection for MS diagnosis in daily clinical practice

An early and accurate diagnosis of multiple sclerosis (MS) is very important, since it allows early treatment initiation, which reduces the activity of the disease. Oligoclonal IgG band (OCGB) detection is a good ancillary tool for MS diagnosis. However, it was argued that its usefulness was limited by the high interlaboratory variability. In the last years, different techniques for OCGB detection have appeared. We performed a blinded aleatorized multicenter study in 19 Spanish hospitals to assess the accuracy and reproducibility of OCGB detection in this new scenario. We studied cerebrospinal fluid (CSF) and serum samples from 114 neurological patients. Every hospital contributed to the study with triplicated pairs of CSF and serum samples of six patients and analyzed 18 different samples. Global analysis rendered a sensitivity of 92.1%, a specificity of 95.1% and a Kappa value of 0.81. This shows that current techniques for OCGB detection have good accuracy and a high interlaboratory reproducibility and thus, represent a good tool for MS diagnosis. When we analyzed separately the different techniques used for OCGB detection, the highest concordance was observed in western blot with alkaline phosphatase detection (kappa=0.91). This indicates that high sensitivity techniques improve the reproducibility of this assay.

Adult onset Pompe disease associated with multiple sclerosis

Dear Sirs,A 27-year-old woman was referred to our center regardingprogressive lower extremity weakness. Her symptomsbegan 3 years ago with fatigue related to the exertion andmild proximal lower extremity weakness. She had nomotor development issues and she denied family history ofneurological disease. There were non ocular or sensorycomplaints. At the age of 20, a routine analysis demon-strated an increase of liver enzymes with a normalabdominal echography. She refused hepatic biopsy andhepatology follow-up visits.The force was reduced to grade 4/5 symmetrically in thehip flexion. The right knee reflex was absent and presentedleft ankle clonus. Plantar responses were extensor. Theexam of the sensory was normal except for a diminishedvibratory sensory in right leg. She was unable to walk ontip-toes and heels. Laboratory investigations showed ALT119 UI/I (7-31), AST 98 UI/I (10-38), and CK 728 UI/I(20-170). Thyroid function, vitamin B12, folate, and acomplete autoimmune profile were normal. Blood exami-nation showed no evidence of herpes virus, CMV, EBV,syphilis, borrelia, HIV-1/2, HTLV-1, or hepatotropic viru-ses. Brain MRI T2-weighted images and FLAIR revealed 8hyperintense lesions involving periventricular white matter,juxtacortical areas, and one left mesencephalic lesion,suggestive of demyelination. None of them demonstratedgadolinium enhancement. MRI of the whole spinal cord wasnormal (Fig. 1). Intrathecal IgG-oligoclonal bands werepresent in the cerebrospinal fluid examination and no ple-ocytosis. Visual-evoked potentials showed delayedresponses on both eyes. Nerve conduction studies werenormal but the results of the electromyography were con-sistent with a myopathic pattern; thus, a deltoid musclebiopsy was performed. Histopathology demonstrated thepresence of vacuoles with abnormal accumulation on peri-odic acid-Schiff (PAS) stain (Fig. 2). The enzyme activityin lymphocytes was 19.00 nmol 9 min 9 g (patient) ver-sus 614.00 nmol 9 min 9 g (controls), and was similarlylow in skin biopsy as well as in the muscle biopsy reliable toglycogen storage disease type 2. The analysis of the GAAgene found heterozygosity for IVS1-13T[G (also called c.-32-13T[G), a frequent pathogenic mutation among adultpatients with Pompe disease, as well as heterozygosity forthe unknown change M1L(1A[T), an unclassified variant.A liver biopsy confirmed the diagnosis of mild chronichepatitis. In the subsequent 2 years, the patient has suffereda progression in her symptoms. Although enzyme replace-ment therapy was started, her limb weakness has worsenedand she is able to walk with the assistance of a cane. NewsMRIs showed the presence of new T2-hyperintense whitematter lesions. According to McDonald’s criteria, a diag-nosis of primary progressive multiple sclerosis (PPMS) wasmade [1].MS and combined muscle disease has only beendescribed in a few case reports: a boy affected with cen-tronuclear myopathy who developed RRMS [2], a case ofcombined facio-scapulo-humeral muscular dystrophy [3],a case with combined myotonic dystrophy [4], and twocases of MS and mitochondrial myopathy [5]. This is thefirst report of a patient with both Pompe myopathy andmultiple sclerosis. Given the high prevalence of multiplesclerosis in our population, we consider that the associationbetween these two entities in our patient is casual. Pompe

Cerebrospinal fluid findings in aquaporin-4 antibody positive neuromyelitis optica: Results from 211 lumbar punctures

Background Neuromyelitis optica (NMO, Devic disease) is a severely disabling autoimmune disorder of the CNS, which was considered a subtype of multiple sclerosis (MS) for many decades. Recently, however, highly specific serum autoantibodies (termed NMO-IgG or AQP4-Ab) have been discovered in a subset (60–80%) of patients with NMO. These antibodies were subsequently shown to be directly involved in the pathogenesis of the condition. AQP4-Ab positive NMO is now considered an immunopathogenetically distinct disease in its own right. However, to date little is known about the cerebrospinal fluid (CSF) in AQP4-Ab positive NMO. Objective To describe systematically the CSF profile of AQP4-Ab positive patients with NMO or its formes frustes, longitudinally extensive myelitis and optic neuritis. Material and methods Cytological and protein biochemical results from 211 lumbar punctures in 89 AQP4-Ab positive patients of mostly Caucasian origin with neuromyelitis optica spectrum disorders (NMOSD) were analysed retrospectively. Results CSF-restricted oligoclonal IgG bands, a hallmark of MS, were absent in most patients. If present, intrathecal IgG (and, more rarely, IgM) synthesis was low, transient, and, importantly, restricted to acute relapses. CSF pleocytosis was present in around 50% of samples, was mainly mild (median, 19 cells/μl; range 6–380), and frequently included neutrophils, eosinophils, activated lymphocytes, and/or plasma cells. Albumin CSF/serum ratios, total protein and CSF L-lactate levels correlated significantly with disease activity as well as with the length of the spinal cord lesions in patients with acute myelitis. CSF findings differed significantly between patients with acute myelitis and patients with acute optic neuritis at the time of LP. Pleocytosis and blood CSF barrier dysfunction were also present during remission in some patients, possibly indicating sustained subclinical disease activity. Conclusion AQP4-Ab positive NMOSD is characterized by CSF features that are distinct from those in MS. Our findings are important for the differential diagnosis of MS and NMOSD and add to our understanding of the immunopathogenesis of this devastating condition.

A case of glycine-receptor antibody-associated encephalomyelitis with rigidity and myoclonus (PERM): clinical course, treatment and CSF findings

Over several months a 58-year-old man developed muscle stiffness, myoclonus and experienced several sudden falls caused by sensory and acoustic stimuli. On neurological examination, a severe startle reaction could be triggered by unexpected noises and there was stiffness, especially of the back and lower limb muscles, with myoclonus, lower limb paraparesis, muscle rigidity and increased tendon reflexes without further pyramidal signs. He was not able to walk without help. He also exhibited a mild pontine syndrome with disturbed smooth pursuit eye movements and diplopia. Electrophysiological studies revealed ubiquitous early recruitment and continuous motor unit activity as described for stiff person syndrome by Meinck and Thompson [1]. Cerebral MRI scans were normal. Antibodies against glutamic acid decarboxylase (GAD), amphiphysin, CYFRA 21-1, CEA, Ri, Hu, Yo, MA1, MA2, CV2 and CRMP5 could not be detected in serum. Neuron-specific enolase (NSE) enzyme concentrations were not raised. An extensive cancer search including 18-F-FDG-PET, abdominal ultrasound, X-ray of the chest and bronchoscopy was negative. However, serum glycine receptor (GlyR) antibodies were detected by a cell-based assay (Fig. 1) [2]. Initial lumbar puncture revealed oligoclonal IgG bands and 45 lymphocytes/ll (normal: \4 cells/ll) in the cerebrospinal fluid (CSF). GlyR antibodies could also be found in the patient’s CSF. Gamma-aminobutyric acid (GABA) and glutamate levels in CSF were measured by HPLC, with electrochemical detection after precolumn o-phthaldialdehyde sulphite derivatization, in the patient’s CSF and control samples from 10 subjects (4 males, 6 females); age range 35–83 years (mean 54 years) undergoing diagnostic lumbar puncture as part of their investigations. Their CSF analyses were normal and neurological disorders were excluded. All lumbar punctures were done between 11.00 am and 2.00 pm. Their GABA levels were 42.7 ± 14.2 nmol/l. As shown in Fig. 2, before any treatment the patient’s GABA level was higher (89.0 nmol/l) than upper limit of the control range (mean ? 3SDs, 85.3 nmol/l). Glutamate levels were also lower (initial: 0.33 lmol/l; after 18 months: 0.35 lmol/l) than controls (0.49 ± 0.2 lmol/l) although not significantly different. The neurological symptoms ameliorated after an initial therapy of six plasmaphereses followed by oral corticosteroids (1 mg/kg body weight). The GABAA receptor agonist clonazepam led to a further improvement of muscle stiffness and rigidity. Only a mild pontine symptom with diplopia persisted. CSF GABA levels fell over the treatment period to 28.5 nmol/l (18 months after initial lumbar puncture). GlyR antibody titers also declined but were still just detectable in the serum at 12 months (Fig. 1). Once the improvement had stabilised for 18 months, we tried to wean the steroids. After 2 weeks without steroids the patient developed again neurological symptoms with a left internuclear ophthalmoplegia, and without signs on the MRI. Steroids were therefore increased to 0.5 mg/kg and a steroidsparing drug, azathioprine (2 mg/kg), was introduced. Under this regime the patient is now without symptoms. Up to now, medical examinations are being done every 6 months. A. Piotrowicz (&) A. Thumen A. Moser Neurochemical Research Group, Department of Neurology, University of Lubeck, Ratzeburger Allee 160, 23538 Lubeck, Germany e-mail: agnieszka.piotrowicz@neuro.uni-luebeck.de

Degenerative and inflammatory markers in the cerebrospinal fluid of multiple sclerosis patients with relapsing-remitting course of disease and after clinical isolated syndrome

Background: Literature includes evidence of initial predominance of inflammation and later development of neurodegeneration in the pathogenesis of multiple sclerosis (MS).Objective: To search for differences in inflammatory and degenerative cerebrospinal fluid (CSF) markers between relapsing-remitting MS (RRMS) and the clinical isolated syndrome (CIS).Methods: A total of 148 subjects were evaluated, 65 MS patients (45 RRMS and 20 CIS) and 83 controls. The evaluated parameters included albumin quotient and prealbumin, transferrin, C3 and C4 complement factors, haptoglobin, beta-2-microglobulin, orosomucoid, alpha-1-antitrypsin, apolipoprotein A-I, apolipoprotein B, cystatin C, neuron-specific enolase, tau protein, beta-amyloid, oligoclonal IgG band (OCB), and IgG quotient (QIgG).Results: No differences were found in the inflammatory and degenerative CSF markers between patients with RRMS and CIS. QIgG was higher in RRMS than that in CIS but the number of OCB was higher after CIS. Cystatin C levels were significantly lower in RRMS compared to the other groups. It can be considered an indicator of the demyelination degree. Normal values of beta-amyloid were less frequent in RRMS compared to those in controls.

A new myelin protein, TPPP/p25, reduced in demyelinated lesions is enriched in cerebrospinal fluid of multiple sclerosis

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease with variable extent of remyelination coupled with the differentiation of oligodendrocytes, in which Tubulin Polymerization Promoting Protein/p25 (TPPP/p25) plays a crucial role. Previously we reported that the loss of TPPP/p25-positive oligodendrocytes in demyelinated lesions in the brain of MS patients could be a biomarker for MS [2]. In this work we tested the occurrence of TPPP/p25 in the cerebrospinal fluid (CSF) of MS patients, and by elaborating a sensitive assay for quantification of TPPP/p25 we showed that its level is significantly higher than in the case of non-MS patients. Patients with MS were diagnosed at the Department of Neurology, University of Szeged according to the clinical and laboratory diagnostic criteria of McDonald. In non-MS patients no significant pathological changes were detected on magnetic resonance imaging scans, while in MS patients multiple hyperintense T2 lesions in the white matter were detected. Kurtzke Expanded Disability Status Scale scores as well as IgG level and oligoclonal bands of MS patients were demonstrated. The sensitive assay elaborated in this study is based upon Western blot followed by chemiluminescent detection validated by human recombinant protein. The median TPPP/p25 contents in the CSF were 62.8 and 64.7μg/L for patients with clinically isolated syndromes and relapsing remitting MS, respectively, while this value for non-MS patients was 27.9μg/L. The enrichment of TPPP/p25 was independent of age, gender and the time period between lumbar puncture and relapse/shub. These data suggest that the TPPP/p25-based assay could be a powerful diagnostic test for MS patients.

Isolated progressive cognitive impairment and depression in a patient with neuroradiological features suggestive of multiple sclerosis

We report the case of a woman who started complaining of depression, attention and memory problems at the age of 49. Over the following 6 years, serial neuropsychological assessments showed fluctuating, but overall progressively worsening, performances in tests exploring attention, working memory, language and executive functions. Cerebrospinal fluid (CSF) examination showed identical IgG oligoclonal bands in serum and CSF. Neurological examination, to date, only reveals minimal pyramidal and cerebellar signs. Although typical clinical and laboratory evidence indicating a diagnosis of multiple sclerosis (MS) in this patient is lacking, an extensive diagnostic work-up ruled out many other causes of leukoencephalopathy and neuroradiological features strongly suggest this diagnosis. Multiple sclerosis may present with cognitive or neuropsychiatric symptoms; this should be kept in mind, especially in younger patients, even in the absence of "classical" physical symptoms.

Increased peripheral blood CD5+ B cells predict earlier conversion to MS in high-risk clinically isolated syndromes

Clinically isolated syndrome patients (CIS) with oligoclonal IgG bands (OCGB) are at high risk for clinically definite multiple sclerosis (MS). However, the outcome for individual patients is unpredictable and the search for reliable blood markers predicting early conversion to multiple sclerosis (MS) has clinical relevance. CD5+ B cells (CD5+Bc) are involved in some autoimmune diseases. This study investigated whether high blood CD5+Bc percentage can predict CIS conversion to MS. Fifty-five consecutive CIS showing OCGB were prospectively studied. Every patient underwent a brain MRI study and a flow cytometry analysis of CD5+Bc percentage. Conversion to MS was studied during follow-up. The CD5+Bc percentage was assessed in 40 controls and a cut-off value of 3.5% (mean + 2 SD) was calculated. A blood CD5+Bc percentage above this value predicted earlier conversion to MS in the whole group (hazard ratio [HR]: 3.40; 95% confidence interval [CI]: 1.69–6.68; p = 0.0005) and in CIS patients fulfilling three or more Barkhof–Tintoré criteria plus OCGB, who showed higher risk for MS (HR: 3.79; 95% CI: 1.86–15.32; p = 0.0018). Multivariate analysis also showed a predictive value for high blood CD5+Bc count (HR: 4.3; 95% CI: 1.9–9.5; p < 0.0001). It was concluded that high percentages of CD5+Bc independently associate with increased risk of early conversion to MS in CIS patients with OCGB and Barkhof–Tintoré criteria.

Association of HLA‐DRB1*15 allele and CSF oligoclonal bands in a Spanish multiple sclerosis cohort

The HLA-DRB1*15 allele is consistently associated with multiple sclerosis (MS) susceptibility in most studied populations. This study investigated the association between HLA-DRB1 alleles and the presence of oligoclonal immunoglobulin G bands (OCB) in the cerebrospinal fluid (CSF) in a Spanish population with MS. The HLA-DRB1 typing was performed in 268 patients with sporadic MS and the detection of OCB in CSF. HLA-DRB1 allelic frequencies were compared between OCB-positive and OCB-negative patients, and both groups were also compared with 1088 unrelated healthy controls. Moreover, we correlated the various HLA-DRB1 genotypes, considering all the combinations of both parental alleles found with the presence or absence of OCB. We found 206 OCB-positive and 62 OCB-negative patients. The HLA-DRB1*15 allele in OCB-positive patients had a higher frequency when compared with OCB-negative patients (39.3% in OCB-positive vs. 16.1% in OCB-negative, OR = 1.38 95% CI = 1.18-1.61, P < 0.001). The other alleles did not show differences. When we compared with controls, the HLA-DRB1*15 allele was associated with the disease only in the OCB-positive patients group. None of the 55 genotypes found showed any association with the presence or absence of OCB. HLA-DRB1*15 allele is associated with OCB-positive patients with MS when studying a Spanish MS population.

Brain atrophy and lesion load are related to CSF lipid-specific IgM oligoclonal bands in clinically isolated syndromes

The objective of this work is to study the relationship between the presence of lipid-specific oligoclonal IgM bands (LS-OCMB) in CSF, with both T2 lesion volume (T2LV) accumulation and brain atrophy (percentage change of brain volume-PCBV-and brain parenchyma fraction-BPF) in patients with clinically isolated syndromes (CIS) suggestive of demyelination. Twenty-four CIS patients were included in this prospective study. IgG oligoclonal bands (OCGB) and LS-OCMB were determined in paired serum and CSF samples within 3months since clinical onset. Brain MRI studies were scheduled at baseline, 3months, first and second years after CIS onset. Differences in T2LV, PCBV and BPF between CIS patients according to the type of OCB were studied. Nine patients had no OCB; 15 had only OCGB, and seven had OCGB + LS-OCMB present in the CSF. LS-OCMB were associated with greater T2LV in all scheduled MRI studies. At the end of follow-up (year2), it was threefold higher in patients with these antibodies than in those without LS-OCMB (3.95cm(3) vs. 1.36cm(3), p = 0.001). At that point, brain atrophy was also higher in patients with LS-OCMB (BPF, 0.73 in LS-OCMB+ patients vs. 0.76 in negative ones, p = 0.03). The rate in brain atrophy was higher in the first group of patients as well. Considering only patients with OCGB, the presence of LS-OCMB was also related to greater T2LV, T2LV increase and a trend towards higher atrophy rate. The presence of LS-OCMB in the first event suggestive of demyelination is related to an early increase in lesion load and brain atrophy. These data are in line with prospective studies showing the clinical prognostic value of LS-OCMB.

Repeated Non-enhancing Tumefactive Lesions in a Patient with a Neuromyelitis Optica Spectrum Disorder

A 51-year-old woman had developed fever and consciousness disturbance at 47 years of age. Brain magnetic resonance imaging (MRI) revealed acute disseminating encephalomyelitis (ADEM)-like lesions without gadolinium enhancement (GDE). One year later, she had an episode of bilateral optic neuritis and cerebellar ataxia. Speech deficit and right hand weakness occurred at the age of 51 years. Neurological examination showed motor aphasia, finger agnosia, right-left disorientation, and right hand paresis. Neuromyelitis optica (NMO)-IgG was seropositive. Cerebrospinal fluid examination showed negative results for myelin basic protein and oligoclonal IgG band. The IgG index was normal. Brain MRI revealed a tumefactive lesion in the left temporo-parietal region and conglomerate ovoid lesions in the pericallosal regions. No GDE was found in the brain lesions. Visual evoked potential test showed bilateral prolongation of P100 latencies. She was treated twice with methylprednisolone pulse therapy followed by oral prednisolone, but the motor aphasia did not respond to steroid treatment. She had no prior history of myelitis and was diagnosed as NMO spectrum disorder (NMOSD). Similar to previous studies of NMO-IgG seropositive extensive brain lesions, this patient with NMOSD indicated no GDE in tumefactive lesions at two episodes of encephalopathy. Compared to multiple sclerosis (MS), a high frequency of non-enhancing tumefactive lesions is reported in patients with NMO or NMOSD. The absence of GDE in tumefactive lesions could help to differentiate between NMO and MS.

Late onset multiple sclerosis

Introduction Late onset multiple sclerosis (LOMS) is an unusual entity, poorly characterized and difficult to diagnose. Objective To study a series of patients with LOMS (presentation of the first symptom of disease after the age of 50 years). Patients and methods In this retrospective study we review demographic characteristics, first onset symptom, diagnostic delay, disability at the time of diagnosis (EDSS), disease course and findings in CSF, VEP and MRI studies. Results We included 18 patients (12 F and 6 M) with LOMS (4.8% of the total). The most frequent first symptoms were motor deficits (33%), multisystem deficits (33%) and cerebellum disorder (16%). Clinical course (all the cases with a minimal follow-up of 5 years after the diagnosis): primary progressive-MS (62%), secondary progressive MS (22%), relapsing-remitting MS (16%). The initial EDSS score was higher than 4 points in one third of patients and diagnosis delay was over 5 years in two thirds of cases. The cerebral MRI study was abnormal and compatible with MS in all patients and fulfilled the Barkhof criteria in 12 cases (67%). IgG oligoclonal bands were positive in 64% of patients in the CSF study and VEP were abnormal in 73%. The most frequent wrong diagnoses were cerebrovascular disorders and spondyloarthritic cervical myelopathy. Conclusions LOMS course is often primary, progressive and motor and multisystem symptoms are the most frequent. The diagnosis is usually delayed and when it is made patients have a high disability score. The findings of cerebral and spinal MRI, CSF and VEP studies are of high diagnostic yield. Cerebrovascular disorders and spondyloarthritic cervical myelopathy are the most important entities in the differential diagnosis of LOMS.