Can we face the challenge of expanding use of intravenous immunoglobulin in neurology?

The use of high-dose polyclonal intravenous immunoglobulin (IVIG) in the treatment of autoimmune neurological diseases has expanded over the last decade. Based on controlled clinical trials IVIG can be considered currently as the first-line treatment in Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy and multifocal motor neuropathy, and it may be used as a rescue therapy in worsening myasthenia gravis. IVIG is a second-line therapy in dermatomyositis, stiff-person syndrome and pregnancy-associated or postpartum relapses of multiple sclerosis. Although the biological efficacy of IVIG is due to multiple effects on the immune system, many mechanisms are still unknown. The awareness of risks and complications of IVIG therapy has increased, but severe side effects are still considered rare. Due to increasing costs of this treatment, careful selection of patients who will benefit from IVIG is extremely important.

Elevated cerebrospinal fluid adiponectin and adipsin levels in patients with multiple sclerosis: a Finnish co-twin study.

BACKGROUND AND PURPOSE: The aim of this study was to investigate the levels of three adipocytokines: leptin, adiponectin and adipsin, in serum and cerebrospinal fluid (CSF) of twins discordant for multiple sclerosis (MS). Adipose tissue is an important component connecting immune system and several tissues and organs including CNS. Fat cells produce adipocytokines, which seem to have a role in various autoimmune disorders including MS. METHODS: Plasma samples were collected from twelve twins and CSF samples from four twins discordant for MS. The concentrations of interleukine (IL)-6, adiponectin, adipsin and leptin in plasma and CSF samples were determined by enzyme immuno assay. RESULTS: A significant difference was seen in the adipocytokine levels in CSF samples. Twins with MS had higher concentrations of adiponectin (P = 0.039) and adipsin (P = 0.039), than their asymptomatic co-twins. CONCLUSION: As adiponectin and adipsin levels in CSF did not correlate with their levels in plasma, it seems that there could be a secondary intrathecal synthesis of these adipocytokines in MS.

EFNS guidelines for the use of intravenous immunoglobulin in treatment of neurological diseases: EFNS task force on the use of intravenous immunoglobulin in treatment of neurological diseases.

Despite high-dose intravenous immunoglobulin (IVIG) is widely used in treatment of a number of immune-mediated neurological diseases, the consensus on its optimal use is insufficient. To define the evidence-based optimal use of IVIG in neurology, the recent papers of high relevance were reviewed and consensus recommendations are given according to EFNS guidance regulations. The efficacy of IVIG has been proven in Guillain-Barré syndrome (level A), chronic inflammatory demyelinating polyradiculoneuropathy (level A), multifocal mononeuropathy (level A), acute exacerbations of myasthenia gravis (MG) and short-term treatment of severe MG (level A recommendation), and some paraneoplastic neuropathies (level B). IVIG is recommended as a second-line treatment in combination with prednisone in dermatomyositis (level B) and treatment option in polymyositis (level C). IVIG should be considered as a second or third-line therapy in relapsing-remitting multiple sclerosis, if conventional immunomodulatory therapies are not tolerated (level B), and in relapses during pregnancy or post-partum period (good clinical practice point). IVIG seems to have a favourable effect also in paraneoplastic neurological diseases (good practice point) [corrected],stiff-person syndrome (level A), some acute-demyelinating diseases and childhood refractory epilepsy (good practice point).

Cerebral MRI abnormalities and their association with neuropsychiatric manifestations in SLE: a population-based study.

OBJECTIVE: To evaluate the volumetric brain magnetic resonance imaging (MRI) findings in a population-based sample of systemic lupus erythematosus (SLE) patients and to detect a possible relationship between cerebral MRI abnormalities and specific neuropsychiatric (NP) manifestations. METHODS: The study population consisted of patients with SLE (n = 43) in Pirkanmaa Health Care District, Finland and of a sex- and age-stratified reference group from the general population (n = 43). In addition to a clinical neurological investigation, all subjects received a detailed neuropsychological assessment and an MRI study. Volumetric measures of cerebral atrophy as well as T1- and T2-weighted lesions were obtained. SLE activity was assessed by the European Consensus Lupus Activity Measure (ECLAM) index, and accumulated NP abnormalities were measured by the Systemic Lupus International Collaborating Clinics (SLICC) damage index. A cumulative lifetime dose of glucocorticoids was determined from the patientrecords. RESULTS: Compared with controls, SLE patients had increased volumes of both T1- and T2-weighted lesions (p = 0.019 and p<0.0001, respectively) and increased cerebral atrophy (p<0.001). All the measured MRI parameters were statistically significantly higher in NPSLE than in non-NPSLE patients. In SLE patients, cerebral atrophy was associated with cognitive dysfunction, epileptic seizures, and cerebrovascular disease; T1-weighted lesions were associated with epileptic seizures and T2-weighted lesions with cognitive dysfunction. All MRI parameters correlated significantly with the SLICC index but not with the ECLAM index. A positive correlation was found between a cumulative dose of glucocorticoids and cerebral atrophy in SLE patients. CONCLUSION: MRI abnormalities, including brain atrophy and T1- and T2-weighted lesions, are significantly more common in patients with SLE than in the general population and they are related to specific NP manifestations. Our findings also provide support for the organic aetiology of cognitive dysfunction in SLE.

Validity of the new American College of Rheumatology criteria for neuropsychiatric lupus syndromes: a population-based evaluation.

OBJECTIVE: To assess the validity of the recently developed American College of Rheumatology (ACR) nomenclature for neuropsychiatric systemic lupus erythematosus (NPSLE). METHODS: We conducted a cross-sectional, population-based study covering an area with 440,000 people. A total of 46 patients aged 16 to 65 years fulfilled the criteria for a definite diagnosis of SLE. One control for each patient matched by age, sex, education, and place of residence was randomly identified from the population register. All patients and controls underwent a clinical neurologic examination and neuropsychological testing. The data were analyzed using conditional logistic regression methods. RESULTS: Forty-two patients (91%) and 25 controls (56%) fulfilled at least one of the ACR NPSLE criteria, which gave an odds ratio (OR) of 9.5 (95% confidence interval [CI] 2.2-40.8) but low specificity (0.46). Cognitive dysfunction was the most common syndrome detected in 37 patients (80%). A revised set of 16 criteria excluding the syndromes without evidence for neuronal damage resulted in improved specificity (OR 7.0, 95% CI 2.1-23.5, specificity 0.93). CONCLUSION: The proposed 19 ACR criteria did not differentiate SLE patients from controls, nor NPSLE patients from other SLE patients. The revised NPSLE criteria proposed by us performed well in our population but should be evaluated in a larger patient population.

The prevalence of neuropsychiatric syndromes in systemic lupus erythematosus.

OBJECTIVE: To describe the prevalence of neuropsychiatric (NP) syndromes in a Finnish population of patients with systemic lupus erythematosus (SLE) and to classify them according to the recently developed American College of Rheumatology (ACR) nomenclature and case definitions for NPSLE. METHODS: Cross-sectional, population-based study covering an area with 440,000 people. A total of 58 patients with a definite diagnosis of SLE and aged 16 to 65 years were found in the computerized database of the area hospitals. Of these, 46 (79%) agreed to participate. The diagnosis of various NP syndromes was based on clinical impression (H.A.) following history, examination, review of medical records, and neuropsychologic testing. RESULTS: At least one NP syndrome was identified in 42 patients (91%). The most frequent manifestation was cognitive dysfunction (n = 37; 81%), followed by headache (n = 25; 54%) and mood disorder (n = 20; 43%). When mild NP syndromes (mild cognitive deficit, headache, mild depression, anxiety, electroneuromyography-negative polyneuropathy) were excluded, the prevalence of NPSLE dropped to 46%. CONCLUSIONS: According to the ACR nomenclature, there is a high prevalence of NP manifestations in a population-based sample of patients with SLE. Most NP syndromes were classified as minor; if they were excluded, the 46% prevalence of NPSLE would be slightly less than estimated in previous studies.

The coexistence of systemic lupus erythematosus and multiple sclerosis in a mother and daughter.

The occurrence of both multiple sclerosis (MS) and systemic lupus erythematosus (SLE) has previously been described in several members within the same family and in twins of successive generations, but the finding of both diseases in one patient is a great rarity. We here report on a rare coexistence of MS and SLE both in mother and daughter. Both patients fulfill the diagnostic criteria of primary-progressive subtype of MS as well as SLE. The finding constitutes supporting evidence of a common genetic background for these two autoimmune disorders.

Chronic neuropathic pain in treated leprosy.

The existence of chronic neuropathic pain in treated leprosy has received scant attention. We describe the clinical findings of 16 patients with multibacillary leprosy who had chronic stimulus-independent pain despite finishing their treatment. With confirmation, our results could be of importance in the establishment of "care after cure" programmes for patients with leprosy.

Reversible posterior leukoencephalopathy after combination chemotherapy.

We describe a young woman with Burkitt's lymphoma, treated with intravenous adriamycine and cyclophosphamide and intrathecal cytarabine. She developed a reversible posterior leukoencephalopathy syndrome (RPLS) with typical MRI findings. Diffusion-weighted images during the first days after the onset of symptoms predicted a small irreversible lesion in the frontal lobe, verified on T2-weighted images 1 month later. The patient showed full recovery after high-dose steroid treatment.

A reversible neuronal antibody (anti-Tr) associated paraneoplastic cerebellar degeneration in Hodgkin's disease.

Paraneoplastic cerebellar degeneration (PCD) has been associated with a variety of neoplasms, most commonly with gynecologic tumors, breast cancer, small cell lung cancer, and Hodgkin's disease (HD). In some patients PCD is associated with circulating antineuronal antibodies like anti-Hu, anti-Yo or anti-Ri. Previously, only 5 patients with a new antineuronal antibody called anti-Tr, proposed to be specific for HD, have been reported. We describe 1 further patient with HD and reversible PCD with a decline in anti-Tr antibody titers in cerebrospinal fluid and serum corresponding to the improvement of clinical symptoms. At the present time the immunoreactive pattern observed in rat cerebellum is the only way to identify anti-Tr antibodies and differentiate them from other antibodies that immunoreact with the Purkinje cells.

Association of HLA antigens with anti-Scl-70-antibodies and clinical manifestations of systemic sclerosis (scleroderma)

Thirty patients with systemic sclerosis (scleroderma) and 188 healthy controls were studied for class I and class II MHC antigens. All patients with scleroderma fulfilled the ARA preliminary criteria for systemic sclerosis. The frequencies of HLA antigens B8, DR3 and DR52 were higher in patients with scleroderma as compared with controls. Ten patients had anti-Scl-70 antibodies, and four of them (40%) had HLA-DR5 antigen compared to 19 of 188 controls (10%), P = 0.013. The relative risk for DR5 in anti-Scl-70-positive patients was 3.6 compared to 1.6 of DQ3 suggesting the primary significance of DR5 compared to DQ related factors. Patients with neurological manifestations had higher frequencies of B8 and DR3 than those with no neurological manifestations of scleroderma. Our results support the view that immunogenetic background is associated with different clinical subsets of systemic sclerosis.

Association of anti-U1RNP- and anti-Scl-70-antibodies with neurological manifestations in systemic sclerosis (scleroderma).

Thirty-one patients with SSc were studied. Eleven patients had anti-Scl-70-, six had anti-U1RNP-, three had anticentromere antibodies, and one both anti-Scl-70- and anticentromere antibodies. Eleven patients (35%) had neurological findings (trigeminal neuropathy, polyneuropathy, in some with myopathy). Eight of these patients (73%) had either anti-U1RNP- or anti-Scl-70-antibodies in their serum. These findings suggest that neurological manifestations are not as uncommon in SSc as previously reported. There are probably subgroups of patients who are more prone to neurological manifestations of scleroderma (mostly patients with anti-U1RNP and possibly those with anti-Scl-70 antibodies).

Peripheral neuromuscular manifestations in systemic sclerosis (scleroderma).

Systemic sclerosis (scleroderma) is thought to be the least likely of the collagen vascular disorders to cause nervous system damage. We evaluated the peripheral neuromuscular manifestations in 32 patients with scleroderma. A clinically defined peripheral nervous system (PNS) lesion was manifest in 5 of 32 patients (16%), including 2 patients with trigeminal neuropathy and single cases of polyneuropathy, brachial plexopathy, and lumbosacral radiculopathy. Neurophysiological studies suggested subclinical PNS involvement in 6 additional patients (3 with distal axonal polyneuropathy, 1 with probable myopathy and superimposed polyneuropathy, 1 with trigeminal neuropathy, and 1 with focal ulnar neuropathy). Even though subjective muscular complaints were numerous (16 patients, 50%), a defined primary muscular disease could be demonstrated only in 5 patients (16%). Our results indicate that peripheral neuropathy in scleroderma is not as uncommon as previously estimated.

Nervous system involvement in systemic lupus erythematosus, Sjögren syndrome and scleroderma.

INTRODUCTION: The purpose of this study was to determine, whether there are any differences in the occurrence of nervous system involvement in different systemic rheumatic diseases. The further aim of the present study was to identify and distinguish primary involvement of the nervous system by these diseases and involvement that may be secondary to confounding factors. MATERIAL AND METHODS: The patient population consisted of 122 patients with a connective tissue disease (42 with systemic lupus erythematosus (SLE), 48 with Sjögren's syndrome and 32 with scleroderma). The methods included neurological examination and standard electrophysiological tests. RESULTS: At least one neurological defect was diagnosed in 69% of SLE patients, in 71% of Sjögren's syndrome patients and in 66% of scleroderma patients. Secondary factors might have contributed to the pathogenesis of neurological symptoms and signs in up to 25-34% of events. CONCLUSION: No significant differences were noted in the occurrence of neurological events in patients with SLE, Sjögren's syndrome and scleroderma. The necessity to differentiate between neurological phenomena directly attributed to the systemic rheumatic disease and those which are totally unrelated or secondary events resulting indirectly from involvement of other organ systems is emphasized.

Central nervous system involvement and psychiatric manifestations in systemic sclerosis (scleroderma): clinical and neurophysiological evaluation.

We evaluated central nervous system and psychiatric involvement in a clinical sample of 32 patients with systemic sclerosis (SSc) (scleroderma). All patients underwent clinical neurological examination. Electroencephalography (EEG) and visual evoked potentials (VEPs) were also recorded. Prominent central nervous system (CNS) or psychiatric symptoms were present in 5 patients (16%), including encephalopathy, psychosis, anxiety disorder, grand mal seizures and transient ischemic attack. In addition, abnormal VEPs were recorded from 5/32 patients (16%), suggesting optic neuropathy. EEGs were mainly normal or showed only slight, nonspecific changes. Primary CNS involvement in scleroderma, however, could not be shown in any of the 5 cases with neuropsychiatric symptoms. Our results suggest that neuropsychiatric symptoms in SSc are, if not coincidental, indirectly caused by internal organ involvement of SSc or by possible overlapping connective tissue diseases. On the other hand, optic neuropathy might be a primary complication of SSc.

Nervous system disease, immunological features, and HLA phenotype in Sjögren's syndrome.

Twenty seven patients with primary or possible Sjögren's syndrome with neurological manifestations were compared immunologically with 21 patients with Sjögren's syndrome with an intact nervous system. Patients with Sjögren's syndrome were divided into seropositive and seronegative subgroups with respect to the occurrence of one or more autoantibodies (antinuclear antibodies, rheumatoid factor, antibodies to SS-B) in their serum samples. This study of 48 patients indicates that the spectrum of nervous system disease in seronegative and seropositive subgroups is almost indistinguishable. No significant differences were found in the occurrence of circulating immune complexes, the levels of serum complement C3 and C4, or serum IgA, IgM, and beta 2 microglobulin with respect to the neurological manifestations. The serum IgG level, however, was significantly higher in the patients with Sjögren's syndrome with intact nervous systems than in those with neurological manifestations. No significant association was found between the HLA phenotype and nervous system disease. The occurrence of HLA-B8 and DR3 antigens was, however, significantly higher in those patients with antibodies to SS-B than in those without. This finding supports the suggestion that HLA-B8/DR3 may modulate autoantibody responses rather than disease expression in Sjögren's syndrome.