[Intravenous immunoglobulins in multiple sclerosis. An update]. / Intravenöse Immunglobuline bei Multipler Sklerose. Eine Standortbestimmung.

In MS patients with contraindications, intolerance, or failure of established immunomodulatory drugs, intravenous immunoglobulins (IVIG) are increasingly being administered. Several clinical studies recently showed that IVIG are generally safe, well tolerated and only occasionally have serious side effects. While some studies indicated beneficial effects from IVIG in relapsing-remitting MS, the recently published PRIVIG study failed to show any clinical benefit. Although pregnancy and the post-partum period appear to be interesting potential indications for IVIG, since under those conditions all other immunomodulatory drugs except for corticosteroids are not indicated, there are no data from adequate studies to support the use of IVIG in this patient group. For other indications in MS patients, study results are either negative or lacking. Overall IVIG may be considered a safe second-line compound in patients with relapsing-remitting MS. However, efficacy, long-term consequences, and optimal dosage of IVIG have not been unequivocally ascertained as yet.

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. METHODS: Thirty-five treatment-naive patients with a first clinical symptom suggestive of MS were examined in a 2-year prospective longitudinal follow-up assessment. Brain and SC magnetic resonance imaging (MRI), Expanded Disability Status Scale and multiple sclerosis functional composite were analysed at baseline and after 1 and 2 years. RESULTS: At study entry, 21 patients were classified as clinically isolated syndrome suggestive of MS (CIS) and 14 patients as possible early MS. SC lesions were detected at baseline in 14 CIS patients (67%, median: 1.0, enhancing 29%) and in 11 patients with possible early MS (79%, median: 2.0, enhancing 29%). DIS as depicted by additive SC imaging was detected in two additional individuals according to the revised versus the 2001 McDonald criteria. All patients with emerging cord lesions showed new brain lesions. Five individuals developed clinically asymptomatic cord lesions. CONCLUSIONS: Spinal cord abnormalities are frequent in CIS patients and in patients with possible early MS. SC imaging slightly improved the establishment of DIS, but had no impact on the evidence of DIT.

Interferon as a treatment for uveitis associated with multiple sclerosis.

AIM: In addition to optic neuritis (ON), multiple sclerosis (MS) may also involve the eye with a typically bilateral intermediate uveitis. The aim of this pilot study was to evaluate the efficacy of type I interferons (IFN) for the treatment of MS associated uveitis. METHODS: In this non-randomised, retrospective observational case series 13 patients (eight female, five male) with proved MS and associated uveitis from five uveitis centres who were treated with interferon beta1a were included. Visual acuity (VA), cell count in the aqueous humour and vitreous, as well as the presence of cystoid macula oedema (CMO) were observed. RESULTS: All except one patient had a bilateral form of intermediate uveitis (total of 24 eyes). Seven patients had documented CMO before IFN treatment (n = 13 eyes). Median duration of treatment was 24.6 months (range 7.9-78.7). VA improved in 17 eyes (comparing VA before therapy and at last follow up); while 10 eyes (36%) improved >or=3 Snellen lines. Aqueous cell count improved by 1.2 (SD 1.1) grades in all eyes. Vitreous cell count improved by 1.7 (1.4) in all eyes. Only two patients still had minimal CMO on last follow up angiographically. CMO resolved after or during IFN treatment in nine eyes. CONCLUSIONS: IFN has been shown to have beneficial effects in patients with MS and/or ON. As shown in the models of experimental allergic encephalomyelitis (EAE) and uveitis, the neurological and ophthalmological manifestations seem to share similar pathogenic mechanisms. Treatment of MS associated uveitis with IFN appears to have beneficial effects on VA, intraocular inflammation activity, and the presence of CMO.

[Infectious diseases of brain parenchyma in adults: imaging and differential diagnosis aspects]. / Infektiöse Erkrankungen des Hirnparenchyms bei Erwachsenen: Bildgebung und differenzialdiagnostische Aspekte.

Infectious diseases of the central nervous system have often to be considered in differential diagnosis, particularly in immunocompromised persons. Neuroimaging, specifically advanced techniques such as diffusion-weighted MRI and perfusion MRI contribute much to the differentiation of various brain infections and to delineation of brain infections from other, for instance, neoplastic diseases. In this review we present the imaging criteria for the most important brain infections in adults and discuss in detail differential diagnostic aspects.

Quantitation of HIV-1 proviral DNA in cells from cerebrospinal fluid.

The number of proviral copies in the cerebrospinal fluid of 13 patients in various stages of HIV-1 infection was determined using the polymerase chain reaction. HIV-1 proviral DNA was detected at a median value of 1 provirus per 300 cells with a range from 1 per 20 to 1 per 2,400 cells and a mean value of 1 provirus per 570 cells. Interestingly, this indicates a higher proportion of infected cells in cerebrospinal fluid than is reported to be the case for blood mononuclear cells. However, a clear correlation of these findings to the CDC stage or to neurologic complications was not obvious.

Diagnosis of cytomegalovirus encephalitis in patients with AIDS by quantitation of cytomegalovirus genomes in cells of cerebrospinal fluid.

A nested polymerase chain reaction (PCR) assay was used to determine the levels of cytomegalovirus (CMV) genomes in cells of CSF from 19 patients with AIDS and 12 human immunodeficiency virus type I (HIV-1) seronegative individuals with various neurologic disorders. Five AIDS patients had autopsy-proven CMV encephalitis (CMVE) and 14 patients had no evidence of CMV-related CNS manifestations. CSF cells from AIDS patients with confirmed CMVE harbored viral genomes at a median value of 3,333/10(5) cells (range, 1,667 to 5,333/10(5) cells; mean, 3,558/10(5) cells) compared with a median value of 125/10(5) cells (range, 9 to 1,000/10(5) cells; mean, 281/10(5) cells) for AIDS patients with CMV-unrelated symptoms and a median value of 1.9/10(5) cells (range, 0 to 562/10(5) cells; mean, 52/10(5) cells) for HIV-1 seronegative control subjects. A subset of CSF samples was assessed using a modified single round amplification PCR with a detection limit of 500 viral copies. CMV DNA was detected in all four specimens from AIDS patients with proven CMVE, in two of five AIDS patients without CMVE, and in none of five seronegative control subjects. Quantitation of CMV genomes in CSF cells is indicative of latent or productive CMV infection and is a reliable means for diagnosis of CMVE in patients with AIDS. Detection of a cutoff value of cellular CMV genomes by means of nonquantitative PCR may identify patients at risk for CMV infection of the CNS.

Acute disseminated encephalomyelitis: a follow-up study of 40 adult patients.

OBJECTIVES: To describe the clinical, CSF, and radiologic findings and long-term follow-up in a cohort of patients with acute disseminated encephalomyelitis (ADEM), and to determine possible prognostic factors for progression to MS. METHODS: Forty adults (28 women, mean age 33.5 years) diagnosed with ADEM were analyzed. Clinical symptoms, cranial MRI and CSF findings, and the response to a standardized treatment during the acute phase of the disease were analyzed by chart review. The final diagnosis of ADEM or clinically definite MS was established upon follow-up examination after 8 to 137 months. The patients with ADEM and MS were compared to detect differences between the two groups. RESULTS: Fifteen patients had a preceding infection (n = 14) or immunization (n = 1). The most frequent clinical signs were motor deficit (80%), followed by sensory deficits, brainstem signs, and ataxia. CSF findings were highly variable; normal results were present in 20% of patients. Oligoclonal bands were positive in 65% of patients. Ninety-five percent of all patients improved during the acute phase of the disease. Upon follow-up, 14 patients had developed clinically definite MS. Of the 26 patients with the final diagnosis of ADEM, two patients had died, nine had minor deficits, three had moderate deficits, and 12 patients had no remaining symptoms. Patients with the final diagnosis of ADEM were older, and more often had a preceding infection, clinical signs of brainstem involvement, a higher CSF albumin fraction, and infratentorial lesions. CONCLUSIONS: Many patients initially diagnosed with ADEM develop clinically definite MS upon long-term follow-up. The authors found no useful diagnostic criteria for the differentiation of a first episode of MS from monophasic ADEM. The term ADEM may still be employed as a description of a clinical syndrome, but should not be used as a distinct entity until reliable diagnostic criteria have been developed.

Quantitation of herpes simplex virus type 1 DNA in cells of cerebrospinal fluid of patients with herpes simplex virus encephalitis.

We used a nested polymerase chain reaction assay to quantitate the number of viral copies in cells of CSF of eight patients with herpes simplex virus encephalitis (HSVE). The viral load was monitored in serial CSF samples during the course of disease and correlated to clinical symptoms, radiologic manifestations, efficacy of acyclovir treatment, and overall clinical outcome. Before treatment, HSV type 1 (HSV-1) copies were detected at a mean value of 1,786/10(5) (range, 5 to 8,333/10(5) cells; median, 81/10(5) cells). During therapy, HSV-1 DNA decreased gradually to a mean value of 6 copies/10(5) cells (range, 0 to 33 copies/10(5) cells; median, 0 copies/10(5) cells) within 6 to 21 days and disappeared or was barely detectable before treatment completion in most cases. The HSV-1 burden in the CSF did not clearly correlate with the severity of clinical signs or the degree of cranial imaging findings and overall outcome. Quantitation of HSV-1 copies allows rapid and reliable monitoring of antiviral therapy. The absence of a clear correlation between viral load in the CSF and morbidity may suggest a role for indirect mechanisms of brain injury in HSVE.

In vivo comparison of zidovudine resistance mutations in blood and CSF of HIV-1-infected patients.

Several mutations are associated with resistance to zidovudine (3'-azido-3'-deoxythymidine, AZT) in cultured human immunodeficiency virus type 1 (HIV-1) isolates. Little is known as to what extent drug resistance occurs in vivo and whether its development within the CNS differs from that in peripheral blood. We therefore performed comparative nucleotide sequence analysis of the HIV-1 reverse transcriptase (RT) gene in proviral DNA obtained from blood and CSF of three patients, all of whom had progressed to AIDS under long-term zidovudine treatment. Six to 11 individual proviral copies per patient and compartment were analyzed by polymerase chain reaction (PCR)-mediated direct sequencing. In all samples, mutations associated with zidovudine resistance could be identified. They occurred in multiple HIV-1 copies in both blood and CSF, indicating that molecular determinants of resistance are reflected in most individual proviruses in vivo. Comparable positions and frequencies of mutations in isolates derived from both compartments do not argue for independent development of zidovudine resistance in CSF.

Independent HIV replication in paired CSF and blood viral isolates during antiretroviral therapy.

BACKGROUND: The goal of highly active antiretroviral therapy in HIV-infected patients is to reduce plasma viral load (VL) below quantifiable levels. Mutations associated with drug resistance within the HIV-1 genome can limit therapeutic success. Low VL implicates a low risk of emergence of resistant mutants. Whether there is divergent development of HIV strains in different biologic compartments is not understood. METHODS: The authors studied VL and the occurrence of mutations conferring resistance in viral genomes isolated from blood and CSF samples of 23 HIV-infected patients. They determined sequences of HIV-1 RNA by reverse transcriptase PCR amplification and direct sequencing. They measured resistance to antiretroviral drugs genotypically by detection of drug-related point mutations and VL by a branched-DNA assay. RESULTS: Amplification of HIV was successful even in patients with plasma or CSF VL below detection limit. VL was considerably lower in CSF as compared with blood (p < 0.0001). There was no correlation between CSF and plasma VL. The mutational pattern in viral copies derived from blood and CSF was not identical. Ten (9%) of the total number of 118 mutations associated with drug resistance occurred in blood isolates only; 14 (11%) were detected exclusively in CSF strains. CONCLUSION: There is evidence for viral replication at HIV RNA levels less than 50/mL. The results suggest divergent evolution of HIV-1 in different biologic compartments. The presence of resistant mutants in the CSF may escape regular diagnostic in blood. Therapeutic success may fail after adapting therapy to genotypic resistance patterns detected in one compartment only.

Distinct populations of human immunodeficiency virus type 1 in blood and cerebrospinal fluid.

The nucleotide sequence of the gp41 transmembrane protein coding region of human immunodeficiency virus type 1 (HIV-1) proviral DNA obtained from blood and cerebrospinal fluid (CSF) from 6 individuals was determined by direct sequencing of polymerase chain reaction (PCR)-amplified DNA. The direct sequencing approach was performed to avoid errors introduced by Taq polymerase during the amplification reaction. In 3 of 6 paired samples distinct sequence differences between proviral DNA from blood and CSF, ranging from 0.64% to 1.73%, were detected. The greatest diversity (4.2% different amino acids) was found between paired samples of a patient suffering from AIDS encephalopathy, with most of the differences clustering near the carboxy-terminal end of gp41. The results demonstrate that genetically different populations of HIV-1 may be present in different biological compartments and specific neurotropic HIV variants may exist.

Rapid distinction of acute demyelinating disorders and central nervous system lymphoma by molecular analysis of cerebrospinal fluid cells.

Polymerase chain reaction (PCR) based automated high-resolution fragment analysis of rearranged immunoglobulin heavy-chain genes is a highly sensitive means for identifying clonal B-cell responses. We used this technique to distinguish polyclonal inflammatory from monoclonal neoplastic B-cell populations in the cerebrospinal fluid (CSF) of three patients with acute demyelinating disorders of the central nervous system whose clinical, magnetic resonance imaging (MRI) and CSF features did not permit unequivocal exclusion of primary central nervous system lymphoma (pC-NSL). This approach is highly suitable for detecting CNS inflammation particularly when lymphomatous involvement cannot be ruled out by noninvasive diagnostic procedures alone.

Acyclovir treatment of experimentally induced herpes simplex virus encephalitis: monitoring the changes in immunologic NO synthase expression and viral load within brain tissue of SJL mice.

The effect of acyclovir treatment on viral burden and the expression of immunologic nitric oxide synthase (iNOS) within brains of 42 HSV-1 F infected mice was studied by using a titration PCR assay for HSV-1 DNA and a semiquantitative RT-PCR for iNOS mRNA. iNOS mediated NO-production may possibly be involved in secondary mechanisms of brain injury following virus infection, which may account for treatment failures in human herpes simplex virus encephalitis (HSVE). Following infection, a parallel increase of iNOS mRNA and HSV-1F-DNA occurred with peaks after 7 days that were both significantly lower under acyclovir treatment. Six months post infection viral load had declined, but iNOS mRNA expression in both treated and untreated mice was still enhanced as compared with mock infected controls. This suggests that acyclovir decreases iNOS expression via inhibition of viral replication shortly after infection but fails to influence elevated iNOS within the brain late in the course of experimental HSVE.

Herpes simplex virus encephalitis: long-term comparative study of viral load and the expression of immunologic nitric oxide synthase in mouse brain tissue.

In the brain tissue of 21 mice infected with herpes simplex virus type 1 (HSV-1) strain F we determined the expression of immunologic nitric oxide synthase (iNOS) as a potential mediator of neuronal injury with a semiquantitative reverse transcription polymerase chain reaction. Viral burden in brain tissue was quantitated with a dilutional polymerase chain reaction assay. Viral burden and iNOS-expression peaked at day 7 following infection. Thereafter viral burden declined to a low baseline value at 6 months following infection, whereas iNOS-expression was still 4-fold increased compared to baseline levels. In experimental herpes simplex virus encephalitis iNOS, as one potent mediator of neuronal injury, is upregulated in the acute and chronic disease. In future, in addition to antiviral treatment, inhibitors of iNOS might offer new therapeutic strategies in herpes simplex virus encephalitis.

Inflammatory autoimmune neuropathy, presumably induced by bortezomib, in a patient suffering from multiple myeloma.

Bortezomib is a proteasome inhibitor demonstrating substantial activity in multiple myeloma. One of its key toxicities is peripheral neuropathy, which is reversible in most patients. The possibility that bortezomib might in rare cases induce severe neuropathies by auto-inflammatory mechanisms remains controversial. We report here the case of a 65-year-old female myeloma patient who was initially treated with bortezomib, doxorubicin, and dexamethasone (PAD). At the end of the second cycle of PAD, the patient presented with a rapid and severe onset of paresis of the left arm, accompanied by progressive sensory neuropathy and increasing neuropathic pain. After an extensive neurological work-up, including electrophysiological and laboratory evaluations as well as magnet resonance tomography imaging, we diagnosed an inflammatory autoimmune neuropathy, presumably induced by bortezomib, with accentuation of the left arm nerve plexus. We subsequently initiated regular treatment with polyvalent immunoglobulins, which gradually improved the neurological symptoms. In conclusion, the identification of an inflammatory autoimmune neuropathy, presumably associated with bortezomib, is a rare but important complication. An extensive neurological examination should be performed in patients who develop severe or unusual sensory or motor deficits under therapy with bortezomib, so as to differentiate autoimmune from toxic neuropathies, as therapeutic strategies differ for each.

Fulminant onset of cerebral immunocomplex vasculitis as first manifestation of neuropsychiatric systemic lupus erythematosus (NPSLE).

Fulminant onset of neuropsychiatric symptoms as first manifestation of neuropsychiatric systemic lupus erythematosus (NPSLE) is rare and diagnosis is difficult if only one organ is involved. Here, we report the case of a previously healthy woman who presented with a clinical syndrome most compatible with acute onset of NPSLE. However, American College of Rheumatology (ACR) criteria were not sufficiently met. Brain biopsy showed an autoimmune complex vasculitis consistent with central nervous system (CNS) lupus. Because the prognosis of SLE-related CNS involvement is poor, aggressive immunosuppressive treatment was initiated using methylprednisolone in combination with cyclophosphamide.

Subarachnoid hemorrhage due to Borrelia burgdorferi-associated vasculitis.

We report the case history of a patient who suffered a subarachnoid hemorrhage (SAH) in association with early Lyme neuroborreliosis. After a tick bite, this patient developed erythema chronicum migrans and complained of stinging radicular pain in both legs. A computed tomography (CT) scan was performed because of acute headache and nuchal rigidity, which revealed an occipital SAH. Cerebrospinal fluid analysis provided further evidence of acute neuroborreliosis. Digital substraction angiography showed irregularities in the right posterior cerebral artery, which might be due to vasculitis, but no aneurysms.

Neuromyelitis optica (Devic's syndrome) as first manifestation of systemic lupus erythematosus.

Neurologic symptoms rarely occur as presenting feature of systemic lupus erythematosus (SLE). We describe a 37-year old woman who presented with several episodes of transverse myelitis and optic neuritis. Clinical, radiologic and laboratory findings were compatible with neuromyelitis optica (NMO). Seven years after disease onset clinical and laboratory findings were diagnostic for SLE. This case illustrates that NMO may represent a first manifestation of SLE for many years.

[Leptomeningeal tumor cell infiltrations as a first manifestation of an immunocytoma (Waldenstrom's macroglobulinemia)]. / Leptomeningeale Tumorzellinfiltration als Erstmanifestation eines Immunozytoms (M. Waldenström).

Immunocytoma (Waldenstrom's macroglobulinemia) is a rare chronic lymphoproliferative disorder of B-cell origin. It is characterized by the presence of large amounts of circulating monoclonal immunoglobulin M (IgM) and lymphoplasmocytoid bone marrow infiltration. Affection of the peripheral nervous system is common and causes polyneuropathy (5-10%). An isolated leptomeningeal infiltration by neoplastic cells is very rare and has been reported in few cases only. The diagnosis is difficult, in particular if cerebrospinal fluid (CSF) cytology is inconclusive. We present the case of a patient who developed a personality disorder and cognitive impairment. Initial CSF findings were compatible with chronic lymphocytic (aseptic) meningitis. The serologic detection of IgM paraproteinemia and bone marrow cytology suggested immunocytoma. The selective analysis of B-cell clonality in both whole CSF cell lysates and individual CSF cells using polymerase chain reaction (PCR) based amplification of the rearranged CDR3 region of the IgH gene revealed the presence of a monoclonal B-cell population and was diagnostic for leptomeningeal tumor cell infiltration by immunocytoma.

Differentiation of multiple sclerosis plaques, subacute cerebral ischaemic infarcts, focal vasogenic oedema and lesions of subcortical arteriosclerotic encephalopathy using magnetisation transfer measurements.

Although multiple sclerosis (MS) plaques, subacute cerebral ischaemic infarcts, focal vasogenic brain oedema, and subcortical arteriosclerotic encephalopathy (SAE) often have typical radiological patterns, they are sometimes difficult to distinguish from each other. Our aim was to determine whether they can be differentiated by magnetisation transfer (MT) measurements. We measured MT ratios (MTR) in ten patients with plaques of MS, 11 with subacute ischaemic infarcts, 12 with focal vasogenic oedema, and ten with lesions of SAE and compared the mean MTRs statistically. The MTR of normal white matter was 47.3%; the lowest MTR was found in plaques of MS (mean 26.4%). With the exception of vasogenic oedema and subacute cerebral ischaemic infarcts the mean MTRs were significantly different between all groups. MT measurements can provide additional information for the differentiation of these conditions, but we could not distinguish vasogenic oedema from subacute cerebral ischaemic infarcts.