Limbic Encephalitis following Allogeneic Hematopoietic Stem Cell Transplantation.

A woman with myelodysplastic syndrome (MDS) was treated with allogeneic hematopoietic stem cell transplantation (allo-HSCT). 65 days after the transplantation, she developed fatigue and central neurological symptoms. Clinical workup including magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) examination revealed findings suspicious for limbic encephalitis (LE), successfully treated with intravenous immunoglobulins and intravenous corticosteroids. Although a rare complication after allo-HSCT, physicians should be aware of neurological symptoms that develop throughout the transplantation course.

Paraneoplastic cerebellar degeneration: Yo antibody alters mitochondrial calcium buffering capacity.

AIM: Neurodegeneration is associated with dysfunction of calcium buffering capacity and thereby sustained cellular and mitochondrial calcium overload. Paraneoplastic cerebellar degeneration (PCD), characterized by progressive Purkinje neurone degeneration following paraneoplastic Yo antibody internalization and binding to cerebellar degeneration-related protein CDR2 and CDR2L, has been linked to intracellular calcium homeostasis imbalance due to calbindin D28k malfunction. Therefore, we hypothesized that Yo antibody internalization affects not only calbindin calcium binding capacity, but also calcium-sensitive mitochondrial-associated signalling, causing mitochondrial calcium overload and thereby Purkinje neurone death. METHODS: Immunohistochemically, we evaluated cerebellar organotypic slice cultures of rat brains after inducing PCD through the application of Yo antibody-positive PCD patient sera or purified antibodies against CDR2 and CDR2L how pharmacologically biased mitochondrial signalling affected PCD pathology. RESULTS: We found that Yo antibody internalization into Purkinje neurons caused depletion of Purkinje neurone calbindin-immunoreactivity, cannabinoid 1 receptor over-activation and alterations in the actions of the mitochondria permeability transition pore (MPTP), voltage-dependent anion channels, reactive oxygen species (ROS) and Na+ /Ca2+ exchangers (NCX). The pathological mechanisms caused by Yo antibody binding to CDR2 or CDR2L differed between the two targets. Yo-CDR2 binding did not alter the mitochondrial calcium retention capacity, cyclophilin D-independent opening of MPTP or activity of NCX. CONCLUSION: These findings suggest that minimizing intracellular calcium overload toxicity either directly with cyclosporin-A or indirectly with cannabidiol or the ROS scavenger butylated hydroxytoluene promotes mitochondrial calcium homeostasis and may therefore be used as future neuroprotective therapy for PCD patients.

Antibody response to seasonal influenza vaccination in patients with multiple sclerosis receiving immunomodulatory therapy.

BACKGROUND AND PURPOSE: We have previously shown that patients with multiple sclerosis receiving immunomodulatory treatment have reduced seroprotection rates after influenza immunization. The aim of this study was to further investigate the influence of immunomodulatory therapies on the antibody response and seroprotection rates in patients immunized with seasonal influenza vaccine in 2012/2013 compared with healthy controls. METHODS: Ninety patients receiving fingolimod, glatiramer acetate, interferon beta-1a/1b, natalizumab or no therapy were compared with 62 healthy controls. All subjects received the inactivated split virus vaccine in 2012 and serum samples were collected pre-vaccination and 3, 6 and 12 months post-vaccination. The vaccine responses were evaluated by the hemagglutination inhibition assay and adjusted for age and gender. RESULTS: No significant differences in rates of protection against H1N1 for interferon beta-1a/1b and glatiramer acetate were observed as compared with controls at 3, 6 and 12 months. Fingolimod provided reduced protection at all time points post-vaccination, whereas natalizumab displayed reduced protection at 3 and 6 months. Patients without immunomodulation did not display protection rates that were significantly different from the controls at 3 and 12 months. CONCLUSION: These findings suggest that patients with multiple sclerosis receiving fingolimod or natalizumab should be considered for a second dose of the vaccine in cases of insufficient protection. Our results further indicate that new immunomodulatory treatment regimens should be systematically evaluated for their influence on influenza-specific vaccine responses.

Assays for Infliximab Drug Levels and Antibodies: A Matter of Scales and Categories.

Immunogenicity is a frequent cause of secondary non-response to tumour necrosis factor (TNF) inhibitors. Drug level measurement and detection of antidrug antibodies have been shown to be cost effective and clinically relevant, and a large number of assays are available for these purposes. It is, however, difficult to compare assays and translate results into clinical meaningful information due to different methodological approaches and a lack of assay standardization. We have analysed infliximab drug levels and antidrug antibodies in 107 patient samples using enzyme-linked immunoassays (ELISA), immunofluorometric assays (IFMA) and reporter-gene assays (RGA). The RGA gave the lowest results for drug levels, whereas the IFMA detected the highest number of antidrug antibody positive sera. Applying individualized therapeutic ranges to each assay resulted in agreement among all three assays in 74% of samples for drug levels and 98% of samples for antidrug antibodies. We found that TNF inhibitor monitoring assays measure on different scales and that the agreement between quantitative results is limited. However, interassay differences can partially be overcome by assay-individualized translations of quantities into categories, which also is necessary for a meaningful clinical application. Our data demonstrate that assays should not be used interchangeably and that direct comparison of quantitative drug levels obtained with different assays should be avoided.

Prostate cancer, Hu antibodies and paraneoplastic neurological syndromes.

Prostate cancer is the most common cancer among American and European men. Nervous system affection caused by local tumor growth or osseous metastases are the main causes of neurological symptoms in prostate cancer patients. Prostate cancer is rarely reported in association with paraneoplastic neurological syndromes (PNS). We have, therefore, studied clinical and paraclinical findings of a series of patients with prostate cancer and PNS, and reviewed cases reported in the literature. Case histories of 14 patients with definite PNS from the PNS Euronetwork database and from the authors' databases were reviewed. A PubMed literature search identified 23 patients with prostate cancer and PNS. Thus, a total of 37 case histories were reviewed with respect to syndrome type, cancer evolution, paraclinical investigations, antibody status, treatment and outcome. The three most frequent isolated PNS were paraneoplastic cerebellar degeneration, paraneoplastic encephalomyelitis (PEM)/limbic encephalitis and subacute sensory neuronopathy (SSN). Onconeural antibodies were detected in 23 patients, in most cases the Hu antibody (17 patients, 74 % of all antibody-positive cases). Other well-characterized onconeural antibodies (Yo, CV2/CRMP5, amphiphysin, VGCC antibodies) were found in a minority. PNS was diagnosed prior to prostate cancer diagnosis in 50 % of the cases. The association of PNS with prostate cancer is quite infrequent, but clinically important. PNS often heralds prostate cancer diagnosis. Syndromes associated with Hu antibodies predominate. Another tumor more prone to associate with PNS should always be excluded.

Ischaemic stroke at a young age is a serious event--final results of a population-based long-term follow-up in Western Norway.

BACKGROUND AND PURPOSE: Our population-based long-term follow-up of young ischaemic stroke patients and controls showed 10-fold increased mortality and fivefold increased arterial event rate nearly 12 years after study inclusion. We now assess memory, anxiety, depression and sleep in relation to employment and functional outcome, treatment goals and results from a last alive-dead survey. METHODS: Patients (n = 232) ≤ 49 years with an index-stroke between 1988 and 1997 were retrospectively selected and compared with age- and sex-matched controls (n = 453). At follow-up from 2004 to 2005, 144 (77%) of 187 patients were clinically examined. Self-assessment information about memory problems, anxiety, depression, sleeping problems, education and employment was compared with answers from standardized questionnaires from 167 controls. Functional outcome was measured by the modified Rankin Scale (mRS). RESULTS: Patients compared with controls had more memory problems (41.0% vs. 5.4%, P < 0.001), anxiety (19.4% vs. 9%, P = 0.009), depression (29.2% vs. 13.2%, P = 0.001) and sleeping problems (36.1% vs. 19.2%, P = 0.001). In the multiple regression analysis male gender (OR 9.3, 95%CI 0.10-0.61, P = 0.002), normal memory (OR 12.7, 95%CI 0.07-0.47, P < 0.001) and mRS 0-1 (OR 15.7, 95%CI 0.002-0.12, P < 0.001) were factors for full-time employment. Blood pressure was < 140/90 mmHg in 39% of patients, 49% stopped smoking and 38.2% used statins. After a mean observation time of 18.3 years, 63 (27.2%) of 232 patients were dead. CONCLUSIONS: Our data show a heterogeneous prognosis and high mortality even for long-time survivors of ischaemic stroke at a young age. Prospective studies of young stroke patients and controls are necessary for direct comparison.

Chronic inflammatory demyelinating polyneuropathy (CIDP).

BACKGROUND: Chronic immune-mediated demyelinating polyneuropathies can often lead to severe neurologic disability. MATERIALS AND METHODS: Literature review and personal experience with these types of neuropathies. CONCLUSIONS: It is important to recognize these immune-mediated neuropathies as they respond to treatment.

Fcγ receptors in Norwegian multiple sclerosis patients and healthy controls.

BACKGROUND: Multiple sclerosis (MS) is an immune-mediated disease of the central nervous system in genetically susceptible persons. Fcγ receptors (FcγR) are involved in autoimmune diseases. PATIENTS AND METHODS: Sixteen Norwegian patients with relapsing-remitting MS (RRMS) were studied to see whether treatment with either interferon-beta (INF-ß) or glatiramer acetate (GA) influenced the proportion of FcγR1a, FcγR2a, and FcγR3b positive monocytes, granulocytes, or lymphocytes or FcγR1a, FcγR2a, and FcγR2b mRNA levels in leukocytes. One hundred and twenty-seven patients with RRMS and 54 Norwegian healthy blood donors were also analyzed for FcγR2b polymorphisms. RESULTS: Interferon-beta or GA treatment initiated an increase in the proportion of FcγR positive lymphocytes, but did not cause major influence of the long-term proportion of FcγR positive leukocytes or their FcγR mRNA levels. No significant differences were observed between RRMS patients and healthy controls for the genotype and allele frequencies of FcγR2b polymorphisms. DISCUSSION: INF-ß or GA treatment probably has no major role in the regulation of FcγRs on immune cells in RRMS. Furthermore, polymorphisms of the inhibitory FcγR2b do not seem to influence the susceptibility for MS.

Onconeural antibodies in patients with neurological symptoms: detection and clinical significance.

BACKGROUND: Onconeural antibodies are strongly associated with cancer and paraneoplastic neurological syndromes (PNS). Most of these antibodies are well-characterized (antibodies against Hu, Yo, Ri, CRMP5, amphiphysin, Ma2 and Tr) and are in common use for the diagnosis of definite PNS. MATERIALS AND METHODS: Literature on detection and clinical significance of onconeural antibodies were identified by using relevant search terms in PubMed and reviewed. CONCLUSIONS: The onconeural antibodies are directed against intracellular antigens and their pathogenic role is still largely unknown. They are highly specific markers of paraneoplastic aetiology in patients with neurological symptoms. Detection of an onconeural antibody in a patient with neurological symptoms should lead to prompt investigation for cancer. However, absence of detectable onconeural antibodies does not exclude the PNS diagnosis. In particular, failure to detect antibodies in patients without classical PNS symptoms may result in less vigorous cancer screening and diagnostic delay. Neuronal antibodies that are directed to synaptic proteins or proteins of the cell membrane are also associated with neurological symptoms, and probably have pathogenic effects. The association between these antibodies and cancer is less robust, and they are usually not included among the onconeural antibodies.

Screening for tumours in paraneoplastic syndromes: report of an EFNS task force.

BACKGROUND: paraneoplastic neurological syndromes (PNS) almost invariably predate detection of the malignancy. Screening for tumours is important in PNS as the tumour directly affects prognosis and treatment and should be performed as soon as possible. OBJECTIVES: an overview of the screening of tumours related to classical PNS is given. Small cell lung cancer, thymoma, breast cancer, ovarian carcinoma and teratoma and testicular tumours are described in relation to paraneoplastic limbic encephalitis, subacute sensory neuronopathy, subacute autonomic neuropathy, paraneoplastic cerebellar degeneration, paraneoplastic opsoclonus-myoclonus, Lambert-Eaton myasthenic syndrome (LEMS), myasthenia gravis and paraneoplastic peripheral nerve hyperexcitability. METHODS: many studies with class IV evidence were available; one study reached level III evidence. No evidence-based recommendations grade A-C were possible, but good practice points were agreed by consensus. RECOMMENDATIONS: the nature of antibody, and to a lesser extent the clinical syndrome, determines the risk and type of an underlying malignancy. For screening of the thoracic region, a CT-thorax is recommended, which if negative is followed by fluorodeoxyglucose-positron emission tomography (FDG-PET). Breast cancer is screened for by mammography, followed by MRI. For the pelvic region, ultrasound (US) is the investigation of first choice followed by CT. Dermatomyositis patients should have CT-thorax/abdomen, US of the pelvic region and mammography in women, US of testes in men under 50 years and colonoscopy in men and women over 50. If primary screening is negative, repeat screening after 3-6 months and screen every 6 months up till 4 years. In LEMS, screening for 2 years is sufficient. In syndromes where only a subgroup of patients have a malignancy, tumour markers have additional value to predict a probable malignancy.

Autoimmune limbic encephalitis.

Autoimmune limbic encephalitis (LE) can arise both by paraneoplastic and non-paraneoplastic mechanisms. Patients with LE usually have a subacute onset of memory impairment, disorientation and agitation, but can also develop seizures, hallucinations and sleep disturbance. The following investigations may aid the diagnosis: analysis of cerebrospinal fluid (CSF), electroencephalography, magnetic resonance imaging, fluorodeoxyglucose positron emission tomography and neuronal antibodies in the serum and CSF. Neuronal antibodies are sometimes, but not always, pathogenic. Autoimmune LE may respond to corticosteroids, intravenous IgG (IVIG) or plasma exchange. The cornerstone of paraneoplastic LE therapy is resection of the tumour and/or oncological treatment. Several differential diagnoses must be excluded, among them herpes simplex encephalitis.

Morphological and immunohistochemical characterization of paraneoplastic cerebellar degeneration associated with Yo antibodies.

INTRODUCTION: Immunohistochemical studies of paraneoplastic cerebellar degeneration (PCD) are rare, and the findings vary. MATERIALS AND METHODS: We performed morphological and immunohistochemical characterization of the brain, medulla and tumour of two patients with PCD, Yo antibodies and ovarian adenocarcinoma. RESULTS: The cerebellum of both patients had extensive loss of Purkinje cells. Microglia activation and T cells were found in the cerebellum, but B cells or deposits of IgG or complement were not detected. Microglia activation was also present in the brain stem and medulla. T cells were found in the ovarian adenocarcinoma. CONCLUSION: PCD is characterized by loss of Purkinje cells and microglia activation, and the presence of T cells indicates cellular immune reactions in PCD and in ovarian cancer.

CRMP5 antibodies found in a patient with limbic encephalitis and myasthenia gravis.

Collapsin response mediator protein 5 (CRMP5) antibodies are often associated with thymoma or small cell lung cancer and paraneoplastic syndromes such as limbic encephalitis (LE). A patient is described with myasthenia gravis who, following thymectomy and immunosuppression, acquired a viral infection and developed LE and increased levels of serum CRMP5 antibodies. The cognitive symptoms improved and CRMP5 antibody levels decreased after plasma exchange, suggesting that CRMP5 antibodies may have contributed to the development of LE.

Ultrasound, atherosclerosis and stroke at a young age: a cross-sectional long-term follow-up in western Norway.

BACKGROUND AND PURPOSE: Previous studies have shown significantly higher mortality and vascular morbidity amongst patients with ischaemic stroke onset at a young age compared with controls after a mean observation time of more than 11 years. METHODS: In the present cross-sectional study, we measured the carotid intima-media thickness (IMT) in 140 (75%) of 187 survivors of ischaemic stroke after a mean observation time of 11.9 years. Their mean age when included was 41.1 years. IMT was measured by B-mode ultrasonography. RESULTS: Total maximum IMT <1.0 mm was found in 34 (24%) patients, [1.0-1.2 mm) in 29 (21%) patients, [1.2-1.5 mm) in 29 (21%) patients and >or=1.5 mm in 48 (34%) patients. Increasing total maximum IMT was related to increasing age, male gender, recurrent ischaemic stroke, coronary atherosclerosis, peripheral atherosclerosis, smoking, hypertension and diabetes mellitus. DISCUSSION: IMT changes confirm increased vascular morbidity in patients who suffered ischaemic stroke at a young age.

Proteasome antibodies in patients with cancer or multiple sclerosis.

Proteasome antibodies were detected by enzyme-linked immunosorbent assay in two of the 45 (4.4%) patients with lung cancer, 0 of the 39 patients with breast cancer and six of the 51 (11.8%) patients with ovarian cancer. Six of the 47 (12.8%) patients with relapsing remitting multiple sclerosis had proteasome antibodies, as well as two of the 100 (2%) blood donors. Significant higher odds ratios compared to the blood donors were found for the patients with ovarian cancer (OR: 6.4; 95% CI: 1.1-68) and multiple sclerosis (OR: 7.1; 95% CI: 1.2-74). There was no association between proteasome antibodies and metastases or onconeural antibodies. The antibodies showed reactivity to 23, 25 and 27 kD proteins of the 20S proteasome using Western blot. The increased prevalence of proteasome antibodies in patients with ovarian cancer or multiple sclerosis may reflect cellular damage and release of intracellular antigens. Whether the antibodies take part in the clearance of released proteasomes and thus participate in the pathogenesis of cancer or autoimmune disease is not known.

Long-term mortality among young ischemic stroke patients in western Norway.

OBJECTIVES: To obtain data on long-term mortality among young ischemic stroke patients compared with controls in this population-based study. MATERIAL AND METHODS: We used Kaplan-Meier survival analysis to compare 232 patients aged 15-49 years with first-ever cerebral infarction in 1988-1997 and 453 controls followed from inclusion to death or 1 August 2005 for 2515 and 5558 person-years respectively. In a subanalysis of 192 patients, we compared risk factor variables using the Kaplan-Meier method and log-rank testing. We applied a Cox proportional hazards model to adjust for multiple risk factors. RESULTS: Forty-five patients and nine controls died during follow-up (P < 0.0005). Independent risk factors for mortality were active tumor disease (P < 0.0005), high consumption of alcohol (P < 0.0005), coronary atherosclerosis (P < 0.001), living alone (P < 0.02), seizures (P < 0.04) and smoking (P = 0.08). CONCLUSIONS: Long-term mortality was significantly increased among young stroke patients, mainly due to such lifestyle factors as high consumption of alcohol and tobacco.

Fc-gamma receptor polymorphisms are not associated with autoimmune Addison's disease.

Polymorphisms in the low-affinity Fcgamma receptors (FcgammaR) modulate their capacity to bind IgG and the subsequent immune response. Different FcgammaR polymorphisms have been reported to be associated with susceptibility and severity of various autoimmune diseases. We wanted to investigate associations between FcgammaR polymorphisms and autoimmune primary adrenal failure (Addison's disease). We have genotyped 149 patients with Addison's disease and 89 healthy controls for common polymorphisms in the genes coding for FcgammaRIIa, FcgammaRIIIa and FcgammaRIIIb using polymerase chain reaction. Patients with Addison's disease and controls showed no differences in genotype distributions of FcgammaRIIa, FcgammaRIIIa and FcgammaRIIIb. The results indicate that different FcgammaR polymorphisms do not have an impact on immune responses involved in the development of autoimmune Addison's disease.

Antibodies to CRMP3-4 associated with limbic encephalitis and thymoma.

We present a case with subacute limbic encephalitis (LE) and thymoma. Neither classical onconeural antibodies nor antibodies to voltage gated potassium channels (VGKC) were detected, but the serum was positive for anti-glutamic acid decarboxylase (GAD). The patient serum also stained synaptic boutons of pyramidal cells and nuclei of granule cells of rat hippocampus. The objective of the study was to identify new antibodies associated with LE. Screening a cDNA expression library identified collapsin response mediator protein 3 (CRMP3), a protein involved in neurite outgrowth. The serum also reacted with both CRMP3 and CRMP4 by Western blot. Similar binding pattern of hippocampal granule cells was obtained with the patient serum and rabbit anti-serum against CRMP1-4. The CRMP1-4 antibodies stained neuronal nuclei of a biopsy from the patient's temporal lobe, but CRMP1-4 expression in thymoma could only be detected by immunoblotting. Absorption studies with recombinant GAD failed to abolish the staining of the hippocampal granule cells. Our findings illustrate that CRMP3-4 antibodies can be associated with LE and thymoma. This has previously been associated with CRMP5.