Christian Jacobi

Frequency and syndrome specificity of antibodies to aquaporin-4 in neurological patients with rheumatic disorders

Background: A new autoantibody (termed NMO-IgG, or AQP4-Ab) has recently been described in patients with neuromyelitis optica (NMO) and its formes frustes, longitudinally extensive transverse myelitis (LETM) and recurrent optic neuritis (rON). However, AQP4-Ab has been found also in patients with co-existing rheumatic diseases such as systemic lupus erythematosus (SLE) or Sjögren’s syndrome (SS), conditions which are characterized by broad, polyspecific B cell activation. Objectives: In this study, we aimed at evaluating the syndrome specificity and frequency of AQP4-Ab in patients with rheumatic diseases and neurological symptoms. Methods: For this purpose, serum samples from 109 neurological patients with established connective tissue disorders (CTD) (n = 54), possible CTD (n = 42), or vasculitis (n = 13) were analysed for the presence of AQP4-Ab by a cell-based assay employing recombinant human AQP4. Results: AQP4-Ab was detectable in 31/40 (78%) patients with CTD and NMO spectrum disorders (median titre, 1:1000) but in none of the samples obtained from patients with CTD or vasculitis and neurological disorders other than NMO, LETM, or rON (n = 69). Conclusion: The high syndrome specificity of the antibody for neuromyelitis optica spectrum disorders (NMOSDs) in patients with CTD supports the concept of AQP4-Ab being involved in the pathogenesis of these neurological conditions, and argues against AQP4-Ab simply being part of the polyclonal B cell activation generally associated with rheumatic diseases. Moreover, the finding that AQP4-Ab is present in patients with CTD and co-existing NMOSD with approximately the same frequency as in patients without CTD strengthens the case of CTD and AQP4-Ab positive NMOSD representing two co-existing yet distinct entities in the majority of patients.

The intrathecal, polyspecific antiviral immune response: Specific for MS or a general marker of CNS autoimmunity?

BACKGROUND 80-100% of patients with multiple sclerosis (MS) display a polyspecific, intrathecal humoral immune response against a broad panel of viral agents including antibodies to measles, rubella and varicella zoster virus as its three most abundant components (called MRZ reaction [MRZR]). However, a positive MRZR reaction can also be found in some patients with CNS vasculitis, another rare autoimmune condition, raising the question whether this marker is really of high specificity for MS as previously claimed or whether it just represents a non-specific marker of CNS autoimmunity. Besides MS and CNS vasculitis, paraneoplastic neurological disorders (PND) represent the best recognized models of CNS autoimmunity. OBJECTIVE To investigate MRZR for the first time in patients with PND. PATIENTS AND METHODS Forty-two patients with MS and 34 with PND were compared in this study. The intrathecal synthesis of antibodies against measles, rubella, and varicella zoster virus was detected by calculation of the respective antibody indices (AI). RESULTS A positive MRZ reaction as defined by a combination of at least two positive AIs was present in 37/42 patients with MS, but in none of the patients with PND (p < 0.0001). Median AI values differed significantly between groups (p < 0.0005). CONCLUSIONS Our results confirm that MRZR is not a general marker of CNS autoimmunity. Taking into account the very rarity of CNS vasculitis as well the lack of MRZR positivity in infectious inflammatory CNS conditions as previously demonstrated, MRZR might indeed be a promising marker of MS. Further investigations on MRZR in more rare autoimmune conditions, which were not available for analysis in this study, are now warranted to refine further the specificity of this parameter.

Intrathecal antibody production against Epstein-Barr and other neurotropic viruses in pediatric and adult onset multiple sclerosis

Epstein-Barr virus (EBV) has been implicated in the pathogenesis of multiple sclerosis (MS). Recent reports proposed an increased EBV-targeted humoral immune response in MS, which appears to be more pronounced in pediatric patients. However, little is known about the CNS-derived antibody production against EBV in patients with MS. The objective of this study was to assess the frequency and intensity of intrathecal antibody production against EBV as compared to other neurotropic viruses in pediatric and adult onset MS. In cohorts of 43 childhood, 50 adult onset MS patients, 20 children and 12 adults with other CNS disorders, paired CSF and serum samples were studied. Frequency and intensity of intrathecal antibody production against EBV as compared to measles, rubella, varicella zoster (VZV) and herpes simplex virus (HSV) were analyzed by determination of virus-specific CSF-to-serum Antibody Indices (AI). Intrathecally synthesized EBV antibodies were detectable in 26% pediatric and 10% adult onset MS patients, compared to frequencies ranging in both groups from 10 to 60% for the other viruses. Median AIs for EBV were lower than those for all other viruses, with more than twofold higher median AI for measles, rubella and VZV. The EBV-targeted humoral immune response in the CNS is only part of the intrathecal polyspecific antibody production in MS, directed against various neurotropic viruses. Our results do not rule out the possibility that EBV is involved in the pathogenesis of MS by triggering diverse cellular immune mechanisms, but they argue against a direct pathogenic role of EBV-targeted humoral immune response within the CNS.

Aquaporin-4 antibody positive longitudinally extensive transverse myelitis following varicella zoster infection

Longitudinally extensive transverse myelitis (LETM) is a condition shown to confer high risk of conversion into neuromyelitis optica (NMO). Increasing evidence from immunological and histopathological studies suggests that LETM is an autoimmune disorder caused by pathogenic antibodies to aquaporin-4 (AQP4-Ab), the most abundant water channel in the CNS, at least in a subset of patients. However, cases of infectious or parainfectious NMO/LETM (mostly associated with herpes zoster) have been repeatedly reported in the previous literature, raising the question of aetiological diversity in NMO/LETM. Here we present a case of acute LETM in a 63-year-old patient occurring two weeks after reactivation of varicella zoster virus (VZV). Serological testing revealed antibodies to AQP4. Plasma exchange was paralleled by disappearance of AQP4-Ab and sustained clinical improvement. Our observations provide further evidence for a pathogenic role of AQP4-Ab in LETM and suggest that AQP4-Ab associated auto-immunity should be considered also in apparently infectious/parainfectious settings.

Disgust and fear recognition in paraneoplastic limbic encephalitis

Paraneoplastic limbic encephalitis (PNLE) affects limbic portions of the brain associated with recognition of social signals of emotions. Yet it is not known whether this perceptual ability is impaired in individuals with PNLE. We therefore conducted a single case study to explore possible impairments in recognising facially, vocally and bodily expressed emotions, using standardised emotion recognition tests. Facial expression recognition was tested with two forced-choice emotion-labelling tasks using static faces with either prototypical or morphed blends of basic emotions. Recognition of vocally and bodily expressed emotions was also tested with forced-choice labelling tasks, one based on prosodic cues, the other on whole-body movement cues. We found a deficit in fear and disgust recognition from both face and voice, while recognition of bodily expressed emotions was unaffected. These findings are consistent with data from previous studies demonstrating critical roles for certain brain regions - particularly the amygdala and insular cortex - in processing facially and vocally displayed basic emotions, and furthermore, suggest that recognition of bodily expressed emotions may not depend on neural structures involved in facial and vocal emotion recognition. Impaired facial and vocal emotion recognition may form a further neuropsychological marker of limbic encephalitis, in addition to the already well-described mnestic deficits.

Exposure of NK cells to intravenous immunoglobulin induces IFNγ release and degranulation but inhibits their cytotoxic activity

The mechanisms underlying the modulation of Natural Killer (NK) cell functions by intravenous immunoglobulin (IVIg) are poorly understood. Using an ex vivo whole blood assay system we demonstrate that IVIg suppresses NK cell cytotoxicity. This was paralleled by IVIg-induced degranulation of CD56(bright), CD16(positive) NK cells, reduced expression of CD16 and elevated IFN gamma release. To assess whether these findings also occur in vivo we analyzed whole blood before and after IVIg therapy of patients. Following IVIg treatment the number of NK cells in peripheral blood dropped significantly. We observed reduced CD16 expression, elevated IFN gamma-amounts in plasma, reduced NK cell cytotoxicity, and granzyme B release into the plasma, confirming our in vitro data. These effects on the functions of NK cells describe a novel immunomodulatory effect of IVIg. The in vitro assays employed here could represent informative test systems to monitor effects of in vivo IVIg treatment at an individual level.

Mononeuropathy multiplex as a result of treatment with interferon-α and ribavirin in a patient with hepatitis C

Hepatitis C may be complicated by systemic mixed cryoglobulinemic (MC) vasculitis, and in some cases by a polyarteritis nodosa (PAN)-type non-cryoglobulinemic vasculitis [1]. Treatment with interferon-a (IFN-a) and ribavirin mostly is associated with an improvement of vasculitic symptoms. In some cases, exacerbation and rarely new onset of vasculitis of the peripheral nervous system have been described [2–5]. So far, only one patient with hepatitis C, who developed MC-vasculitic bilateral and predominantly sensory axonal neuropathy under treatment with the polyethylene glycol (PEG)-conjugated form of IFN-a (PEG-IFN-a) and ribavirin [2] has been published. On the other hand, a recent study revealed no signs of peripheral neurotoxicity in PEGIFN-a treated hepatitis C patients [6]. Here, we report a 43-year-old male patient, who was diagnosed with hepatitis C type 1 and treated with ribavirin and PEG-IFN-a 5 years later because of an excessive viral load (180 lg s.c., every week). At this time, the patient had no neurological symptoms and liver enzymes were normal. There was also no evidence of a systemic autoimmune disease. Two weeks after initiation of therapy, he experienced paraesthesias in the right hand and both legs rapidly followed by weakness of the right abductor pollicis brevis muscle. Nerve conduction velocity of the median nerve was reduced on the right side and electromyography showed a neurogenic pattern. Hepatitis C viral load was not tested at this time. After 4 weeks of PEGIFN-a and ribavirin treatment hepatitis C virus was undetectable. Two weeks later, the patient suffered from intensive pain of the right arm and sudden weakness of both arms and both legs. On neurological examination, he had severe motor and sensory dysfunction affecting the territories of the right median, left ulnar, left peroneal and right tibial nerves. Laboratory tests revealed monoclonal gammopathy of IgM kappa type with Bence-Jones protein in urine and an increased rheumatoid factor (RF). Cerebrospinal fluid was normal. Mononeuropathy multiplex (MMp) was diagnosed and PEG-IFN-a and ribavirin treatment was stopped immediately. The patient was treated with intravenous immunoglobulin (IVIG) (initially 60 g, followed by 40 g i.v. every 6 weeks) and pregabaline (600 mg daily) against the neuropathic pain. Six months after initiation of PEGIFN-a and ribavirin treatment, the patient was clinically stabilized but still had weakness of the right arm, both hands and a hypoesthesia in the territories of the left ulnar nerve, right median nerve and both legs. Motor and sensory nerve conduction

Prospective combined brain and spinal cord MRI in clinically isolated syndromes and possible early multiple sclerosis: impact on dissemination in space and time

Background:  The diagnosis of multiple sclerosis (MS) is based on dissemination in space (DIS) and time (DIT). The aim of the study was to assess the impact of spinal cord (SC) imaging on the evidence of DIS and DIT.

Rippling muscle disease: Variable phenotype in a family with five afflicted members

We report a family with rippling muscle disease (RMD) who had an autosomal dominant mode of inheritance. The father, mother, and one daughter proved to be heterozygous, and two sons were homozygous for the A92T mutation of the caveolin‐3 gene. The cardinal features of RMD, particularly percussion‐induced rapid contractions, muscle mounding, and muscle rippling, varied considerably among these subjects. Moreover, all examined individuals showed muscle weakness; however, the patterns were inconsistent. Muscle Nerve, 2010

Prolonged Low-Dose Intravenous Thrombolysis in a Stroke Patient With Distal Basilar Thrombus

Background and Purpose— Patients with high-grade basilar artery stenosis secondary to thromboembolism are at high risk of developing subsequent vessel occlusion. Optimal medical management of this condition is unclear. Summary of Case— We present a patient with a small subacute brain stem infarction and filiform distal basilar residual lumen attributable to arterioarterial or cardiogenic embolism. Beginning 3 days after symptom onset, low-dose intravenous thrombolysis with 0.125 mg/kg recombinant tissue plasminogen activator was continuously infused for 48 hours. Follow-up magnetic resonance angiography revealed complete resolution of the embolus. No further cerebral ischemic episodes occurred during 3-month follow-up, and the basilar artery remained patent. Conclusion— Our observation suggests a potential for prolonged low-dose intravenous thrombolysis in basilar artery embolism, but further data are needed to judge the effectiveness and risk of this intervention.