Benjamin Berger

Presynaptic opioid receptors on noradrenergic and serotonergic neurons in the human as compared to the rat neocortex

1 Electrically evoked release of [3H]‐noradrenaline ([3H]‐NA) or [3H]‐5‐hydroxytryptamine ([3H]‐5‐HT) in slices of human and the rat neocortex was used to characterize presynaptic opioid receptors. 2 Release of [3H]‐NA in rat neocortical slices was reduced only by the μ‐receptor agonist DAMGO (pIC50: 7.27, CI95: [7.22, 7.32]; Imax: 77.6±1.6%; antagonized by naloxone: pA2: 8.88, CI95: [8.78, 8.98]). 3 Release of [3H]‐NA in human neocortical slices was unaffected by DAMGO, but inhibited by the δ‐receptor agonist DPDPE (Imax: 25.7±2.2%) and the κ‐receptor agonist U‐50,488H (19.7±2.7% inhibition at 1 μM). Both effects were antagonized by naltrindole (1 μM). 4 Release of [3H]‐5‐HT in rat neocortical slices, was inhibited by DAMGO (10 μM) and U‐50,488H (1 and 10 μM) only in the presence of the 5‐HT receptor antagonist methiotepin (1 μM). 5 Release of [3H]‐5‐HT in human neocortical slices was unaffected by DPDPE, but U‐50,488H (Imax: 40.8±8.3%; antagonized by 0.1 μM norbinaltorphimine) and DAMGO (16.4±3.9% inhibition at 1 μM; antagonized by 0.1 μM naloxone) acted inhibitory. 6 Release of [3H]‐5‐HT in human neocortical slices was reduced by nociceptin/orphanin (0.1 and 1 μM). These effects were antagonized by the ORL1 antagonist J‐113397 (1‐[(3R,4R)‐1‐cyclo‐octylmethyl‐3‐hydroxymethyl‐4‐piperidyl]‐3‐ethyl‐1,3‐dihydro‐2H‐benzimidazol‐2‐one; 0.1 μM). 7 This study provides evidence for significant species differences in opioid receptor‐mediated modulation of NA and 5‐HT‐release in human vs rat neocortex. In rats, μ‐opioid receptors modulate NA release, but 5‐HT release is only weakly affected by μ‐ and κ‐opioids. In contrast, NA release in human neocortex is modulated via δ‐opioid receptors, but 5‐HT release mainly via κ‐opioid receptors. In addition also the ORL1 receptor seems to be involved in 5‐HT release modulation.

Severe disease reactivation in four patients with relapsing-remitting multiple sclerosis after fingolimod cessation

OBJECTIVES Fingolimod is a well-established, highly effective immunomodulatory treatment for patients with relapsing-remitting multiple sclerosis (RRMS). However, little is known about disease course after its discontinuation. METHODS This is a case series on four patients with RRMS who had a severe reactivation after fingolimod discontinuation. RESULTS One patient had pretreatment with glatiramer acetate, interferon-β 1b and interferon-β 1a and another with interferon-β 1a, intravenous immunoglobulins and natalizumab whereas the other two were therapy naïve before fingolimod initiation. Patients were treated with fingolimod for two, thirty, forty-five and seventy-eight months, respectively. Fingolimod had to be discontinued because of persisting lymphopenia, severe varicella zoster virus infection, subarachnoid hemorrhage, and increased liver function enzymes, respectively. Between two to four months after fingolimod cessation these patients had a severe relapse. Cerebral magnetic resonance imaging (MRI) at this point revealed multiple new lesions, partially with contrast ring enhancement. Partial recovery was achieved after steroid pulse therapy followed by plasma exchange in two patients. CONCLUSIONS Despite the limited evidence from our case series on potential disease reactivation exceeding pre-fingolimod activity in a subgroup of RRMS patients, particularly patients with previously high disease activity should undergo frequent clinical as well as radiological monitoring after fingolimod discontinuation.

Evidence of cerebrospinal fluid abnormalities in patients with depressive syndromes

BACKGROUND Depression is the most prevalent psychiatric disease. In addition to primary, idiopathic depression, there are multiple secondary organic forms. However, distinguishing the two can be difficult, information about cerebrospinal fluid (CSF) basic findings in patients with depressive syndromes is sparse. Therefore, we investigated CSF alterations in so far the largest sample of patients with depressive syndromes. We hypothesized that increased prevalence of CSF pleocytosis, blood-brain-barrier (BBB) dysfunction, and oligoclonal bands (OCBs) would be observed as possible markers of underlying immunological processes. METHODS From January 2006 until October 2013, we performed CSF basic diagnostics in 125 patients with depressive syndromes. We also performed serum and CSF autoantibody measurements, cerebral magnetic resonance imaging (cMRI) and electroencephalography (EEG). RESULTS Four % of the patients displayed increased CSF white blood cell counts (WBC), 46.4% had increased protein concentrations, and 19.4% had pathological albumin quotients. OCBs in the CSF were detected in 6.5%. Overall, CSF basic diagnostics were abnormal in 56%. Including instrument-based diagnostics, we found alterations in 80.8% of patients. Suicidal tendencies correlated with an increased WBC count (r=0.276, p=0.002). LIMITATIONS In this open, uncontrolled study, we investigated mainly CSF samples of depressive patients with signs of organic features. Therefore, the study cohort is not representative of idiopathic depression. CONCLUSIONS The main findings of this study are the high rates of pathological (although mainly unspecific) CSF findings. We discuss the findings regarding possible immunological mechanisms and the vascular depression hypothesis. If these findings are associated with low-level inflammation of the central nervous system, new treatment alternatives could be considered. More and better controlled research is necessary.

Intrathecal Thyroid Autoantibody Synthesis in a Subgroup of Patients With Schizophreniform Syndromes

Schizophreniform syndromes in combination with autoimmune thyroiditis and increased serum thyroid antibodies lead healthcare practitioners to consider a diagnosis of Hashimotos encephalopathy. To detect specific biomarkers, the authors analyzed whether intrathecal antithyroid antibody synthesis occurred in a subgroup of schizophreniform patients. In doing so, the authors analyzed thyroid antibodies in paired cerebrospinal fluid and serum samples from 100 schizophreniform patients. Increased antibody indices (AIs) for antithyroid peroxidase or antithyroglobulin autoantibodies in 13 schizophreniform patients were found. AIs were increased in 68% of the seropositive patients. These findings support the hypothesis that autoimmune processes may contribute to the pathophysiology in these patients.

Absent anti-N-methyl-D-aspartate receptor NR1a antibodies in herpes simplex virus encephalitis and varicella zoster virus infections

Purpose: A 2012 report and subsequent case series described anti-N-methyl-D-aspartate receptor (NMDAR) antibodies in patients during the acute phase and relapse of herpes simplex virus 1 (HSV1) encephalitis (HSV1E). However, the prevalence of this phenomenon is unknown and systematic studies on other viral infections of the nervous system are missing. Materials and methods: We retrospectively analyzed serial cerebrospinal fluid (CSF) and serum samples of consecutive patients treated for neurological HSV1, HSV2 and varicella zoster virus (VZV) infections in our tertiary care university hospital between 2003 and 2013 for the presence of antibodies directed against the NR1a subunit of the NMDAR using indirect immunofluorescence. Results: In total, 88 patients with the following infections were identified through an electronic database search: HSV1 (24 with encephalitis), HSV2 (6 with meningitis, 3 with encephalitis and 1 with myelitis), or VZV (3 with meningitis, 33 with encephalitis, 17 with radiculitis and 1 with myelitis). Two patients with HSV1E and HSV2E, respectively, experienced a clinical relapse. Clinical follow-up was for up to 85 months, and repetitive serum and CSF analyses for up to 43 months. However, at no time did any of the 88 patients exhibit anti-NMDAR NR1a antibodies. Conclusions: In this study, we did not detect anti-NMDAR NR1a antibodies in serial CSF and serum samples of HSV1E patients or patients with other viral infections (HSV2 and VZV). However, the presence of antibodies directed against other epitopes of the NMDAR and other neuronal cell surface antigens cannot be excluded, necessitating further studies.

Early blood-based microbiological testing is ineffective in severe stroke patients

BACKGROUND AND PURPOSE Patients with severe acute stroke are at high risk for systemic infections which are associated with an increase in morbidity and mortality; nevertheless current guidelines do not recommend prophylactic antibiotic therapy. Sensitive detection of pathogens in the blood is desirable to guide early antibiotic therapy. We studied the yield of blood culture testing and microbiological PCR-based methods for early detection of post-stroke bacteremia. METHODS Serial blood culture tests either during the first fever episode (>38.5°C) or 24h after admission were performed every 12h for up to 96h after admission. Additionally, microbiological PCR-based techniques for the detection of microbiological pathogens were performed once during the first fever episode prior to initiating antibiotic treatment. RESULTS 21 severely affected acute stroke patients deemed at high risk for systemic infections (median (interquartile range (IQR)) at admission NIHSSS 19 (15-30) were enrolled; 20 patients were intubated within 5h after ICU admission. All patients developed clinical signs and laboratory constellations compatible with systemic infections within 36h after admission. However, no patient had pathogenic bacteria either in serial blood culture analyses during the first 96h after admission or by PCR-based techniques. CONCLUSIONS Very early bacteremia seems not to be a feature of severe stroke in patients despite signs of early immune system depression and frequent subsequent evidence of infection including pneumonia. Consequently our data suggests, that routine early blood-based standard or molecular microbiological assays do not reveal bacteremia, this finding questions the usefulness of their routine performance in this context.

Prevalence of anti-SOX1 reactivity in various neurological disorders☆

OBJECTIVES Anti-SOX1 antibodies are associated with small cell lung cancer (SCLC) and predict a paraneoplastic etiology in Lambert-Eaton myasthenic syndrome (LEMS). In 2010, a study described these antibodies in a small cohort of putative non-paraneoplastic, immune-mediated neuropathies. In this respect, we investigated the seroprevalence and specificity of anti-SOX1 antibodies in a large cohort of neurological disorders. METHODS Overall, serum samples of 1493 consecutive patients were screened for anti-SOX1 reactivity by an ELISA: 471 with well-defined neurological disorders (multiple sclerosis, motor neuron disease, Guillain-Barré syndrome, and chronic inflammatory demyelinating polyneuropathy), 185 with polyneuropathy (PNP) of unknown origin, and 837 with neurological syndromes of suspicious paraneoplastic etiology. These were compared to eight positive controls with definite paraneoplastic neurological syndromes (PNS) and 92 healthy individuals. We also collected demographic and clinical data, including well-characterized onconeural antibodies in anti-SOX1-positive patients. RESULTS Fifteen patients (1.0%) showed anti-SOX1 reactivity: two with multiple sclerosis, two with PNP of unknown origin, and 11 suspicious PNS cases. Remarkably, 9/15 anti-SOX1-positive patients had a PNP. However, antibody concentrations were significantly lower compared to positive controls, and none additionally harbored well-characterized onconeural antibodies. During a follow-up of at least four years, only five patients had cancer: one thyroid, one Hodgkin lymphoma, two breast, and one patient had multiple malignancies - prostate, penis, cecum, liver, and non-small cell lung cancer. However, none had SCLC, typically associated with SOX1 antibodies. CONCLUSIONS The seroprevalence of anti-SOX1 antibodies in patients with various neurological disorders is low. These patients predominantly have PNPs, which might represent a group of immune-mediated diseases.

The MRZ reaction helps to distinguish rheumatologic disorders with central nervous involvement from multiple sclerosis

BackgroundSome rheumatologic disorders may initially manifest with central nervous system (CNS) affection, mimicking the clinical, magnetic resonance imaging, and cerebrospinal fluid findings of multiple sclerosis (MS). The MRZ reaction (MRZR), composed of the three respective antibody indices (AIs) against measles, rubella, and varicella zoster virus, has been found positive frequently in MS patients. However, it is unclear whether the MRZR is helpful to distinguish rheumatologic disorders with CNS involvement (RDwCNS) from MS.MethodsThe MRZR was evaluated in patients with RDwCNS (n = 23), MS (n = 46; age and sex matched to patients with RDwCNS), and other inflammatory autoimmune neurological diseases affecting the CNS (OIND; n = 48). Both the stringency levels that have been used in previous MRZR studies, MRZR-1 (≥ 1 of 3 AIs positive) and MRZR-2 (≥ 2 of 3 AIs positive), were applied.ResultsThere was no statistically significant difference in the prevalence of positive MRZR between patients with RDwCNS (MRZR-1: 13.0% and MRZR-2: 8.7%, respectively) and OIND (MRZR-1: 22.9% and MRZR-2: 8.3%, respectively). Compared to these two study cohorts, the MS group exhibited significantly higher prevalences of positive MRZR (MRZR-1: 82.6%, MRZR-2: 63.0%; p < 0.005 each).ConclusionsConsidering the high specificity of MRZR-2 for MS found in this study, MRZR-2 can be a useful diagnostic tool for distinguishing MS from RDwCNS or OIND.

Prevalence of neurofascin-155 antibodies in patients with multiple sclerosis

INTRODUCTION Antibodies against neurofascin, an axo-glial protein located around the node of Ranvier, have been shown to contribute to axonal pathology both in vitro and in experimental autoimmune encephalomyelitis models. Moreover, small case studies have reported anti-NF antibodies in samples from patients with progressive multiple sclerosis (MS). PATIENTS AND METHODS Building up on this observation, we compared the anti-NF reactivity in serum samples from 83 chronic progressive MS (PMS) patients to those with relapsing remitting MS (RRMS, n=159) and 50 healthy controls. Anti-NF seroreactivity was quantified by enzyme-linked immunosorbent assay using recombinant rat neurofascin. In addition, to identify a potential intrathecal anti-NF antibody synthesis, we calculated the specific antibody index in paired cerebrospinal fluid and serum samples from MS patients with positive anti-NF seroreactivity. RESULTS Prevalence of anti-NF seroreactivity in PMS patients (4.8%; all with primary progressive MS) was significantly higher than that detected in RRMS (0.6%; p=0.030). However, we found no significant difference between PMS patients and healthy controls (2.0%; p=0.408). MS patients with positive anti-NF reactivity experienced an above-average progression of disability compared to MS natural-history controls. Anti-NF-specific intrathecal antibody synthesis was not detected in MS patients with positive anti-NF seroreactivity. CONCLUSIONS Although present only in a minor subgroup, seroprevalence of anti-NF reactivity was significantly more frequent in patients with PMS than in those with RRMS, but was also occasionally found in healthy controls. Further prospective studies are warranted to investigate whether anti-NF antibodies anticipate disease progression.

Screening for anti-titin antibodies in patients with various paraneoplastic neurological syndromes

Anti-titin antibodies indicate a paraneoplastic etiology pointing towards a thymoma in myasthenia gravis (MG), but their seroprevalence and potential diagnostic value in patients with other paraneoplastic neurological syndromes (PNS) is unknown. Therefore, we screened the sera of 44 PNS patients with well-characterized onconeural antibodies (anti-Hu, Yo, Ri, CV2/CRMP5, Ma1, Ma2/Ta, or amphiphysin) for anti-titin reactivity. Two patients (4.5%) were positive for anti-titin antibodies: both patients differed regarding the PNS (sensorimotor neuropathy and subacute cerebellar degeneration vs. chorea), well-characterized onconeural antibodies (CV2/CRMP5 vs. Ri), and malignoma (small cell lung cancer vs. breast cancer). However, retrospectively, the patients neither showed any symptoms of MG nor a thymoma on a computed tomographic (CT) scan. The results of this study indicate that anti-titin antibodies without a predictive relevance for MG or thymoma may be present in a small proportion of patients with PNS.