Interferon alpha and neuromuscular disorders.

Interferon-alpha (IFNalpha) is a potent extracellular protein mediator of host defense and homeostasis. IFNalpha has well-established direct antiviral, antiproliferative and immunomodulatory properties. The worldwide, increasing and long-term use of IFNalpha, particularly for the treatment of chronic hepatitis C virus infection, has drawn attention to the development or exacerbation of numerous autoimmune phenomena, including a variety of neuropathy syndromes, neuromuscular junction disorders and myopathies. Management entailed withdrawal of IFNalpha therapy with supportive, immunomodulatory, and symptomatic treatment as clinically indicated. The mechanisms of IFNalpha-induced autoimmunity are incompletely understood, and likely vary depending on the inherent differences in the pathogenesis of the immune disorder on a background of patient genetic susceptibility. In addition, there is preliminary evidence from case reports and open-label studies that the immunomodulatory effects of IFNalpha may have potential as a treatment option for a spectrum of immune-mediated neuromuscular diseases, but further studies are needed.

B cell-targeted therapy with rituximab and autoimmune neuromuscular disorders.

B lymphocytes play a central role in the pathogenesis of autoimmunity, so that B cell suppression is considered a potential treatment option for immune-mediated diseases. Rituximab, a chimeric anti-human CD20 antibody, is the only anti-B cell biological agent presently under study for the treatment of autoimmune neuromuscular diseases. Isolated case histories and series, pilot and retrospective studies report on the experimental administration of rituximab as treatment of a variety of immune-mediated neuropathy syndromes, treatment-refractory myasthenia gravis and inflammatory myopathies. Rituximab was used as monotherapy or in combination with other types of immunomodulation, and was well tolerated. The mechanism whereby B cell depletion shows benefit is uncertain and may vary depending on the inherent differences in the pathogenesis of various autoimmune neuromuscular disorders.

Rigid spine syndrome: vacuolar variant multimodal evoked potentials.

BACKGROUND: Overt or covert central nervous system (CNS) abnormalities have been reported in various primary muscle diseases, including congenital muscular dystrophies. PURPOSE: To ascertain by neurophysiologic techniques evidence of CNS dysfunction in a relatively large, homogeneous group of patients with the "vacuolar variant" of the rigid spine syndrome (RSS). METHODS: Standard evoked potential (EP) techniques were used to study the visual, auditory and somatosensory pathways in patients with RSS. RESULTS: Abnormal values were recorded in 78% (7/9) of patients, specifically of visual pathways (2/9), brainstem auditory pathways (2/9), and somatosensory pathways (5/9), and the retina (1/9). Abnormal findings were not correlated with clinical measures of patient age, disease duration nor degree of weakness. CONCLUSION: Electrophysiological studies showed that the CNS is not primarily involved in any disease process that underlies this congenital myopathy. There were reasonable other explanations for most abnormal measurements.

Juvenile dermatomyositis/polymyositis and lymphoma.

In patients with juvenile dermatomyositis/polymyositis (JDM/PM), malignancy is a rare phenomenon. An extensive workup for neoplastic disease is not routinely indicated, but should be considered if unusual physical findings are noted at JDM/PM diagnosis or during follow-up period. The objective of this literature review was to assess for any association between, and disease profile of, JDM/PM and lymphoma in childhood. Risk determinants of the possible development of lymphoma in the pediatric population with JDM/PM appear to be the degree and duration of inflammatory activity with chronic B-cell activation and/or antigen stimulation; a paraneoplastic relationship is unlikely.

Inflammatory myopathies and lymphoma.

The inflammatory myopathies comprise a group of immune-mediated muscle diseases. Lymphoma is a term for a variety of lymphatic system malignancies. Autoimmune diseases and lymphoproliferative malignancies share a complex bidirectional relationship. A causal relationship between inflammatory mypathies and lymphoma has not been established. The diagnosis/treatment of inflammatory myopathy usually precedes the detection/diagnosis of lymphoma. Immune system dysregulation presumably underlies the evolution of lymphoma in patients with inflammatory myopathies. Inflammatory activity with chronic B-cell activation and/or antigen stimulation is deemed the major risk factor for lymphoma in patients with autoimmunity. A "paraneoplastic" phenomenon or the effects of immunosuppressive therapy may be alternative immune-based mechanisms. In chronic lymphocytic leukemia immune system disturbance rarely results in non-hematological autoimmune disease, including inflammatory myopathies.

Autoantibody-Mediated Sensory Polyneuropathy Associated with Indolent B-Cell Non-Hodgkin's Lymphoma: A Report of Two Cases.

BACKGROUND AND PURPOSE: Abnormalities of the peripheral nervous system occur in 5% of patients with lymphoma. Polyneuropathy has not been described in patients with mantle-cell and marginal-zone B-cell lymphomas. CASE REPORT: Two elderly patients with indolent non-Hodgkin's lymphoma developed a progressive sensory polyneuropathy that was associated with serum autoantibodies directed against asialosyl/sialosyl gangliosides and myelin-associated glycoprotein/sulfated glucuronyl paragloboside, respectively, which are peripheral-nerve antigens. The oligoclonal pattern of these antibodies hinted at a lymphoma-induced immune dysregulation. The neuropathy stabilized clinically during treatment with intravenous immunoglobulin G. B-cell lymphoma was managed with a "watchful waiting" approach. CONCLUSIONS: The concept of antigen-specific, immune-mediated neuropathy associated with slow-growing lymphoma of mature B-cells may be underrecognized. The principle of treating the illness underlying neuropathy may not be always indicated or necessary if risk-benefit and cost-benefit analyses are taken into account.

Lymphoma-associated dysimmune polyneuropathies.

Lymphoma consists of a variety of malignancies of lymphocyte origin. A spectrum of clinical peripheral neuropathy syndromes with different disease mechanisms occurs in about 5% of lymphoma patients. There exists a complex inter-relationship between lymphoproliferative malignancies and autoimmunity. An imbalance in the regulation of the immune system presumably underlies various immune-mediated neuropathies in patients with lymphoma. This article reviews lymphoma and more-or-less well-defined dysimmune neuropathy subgroups that are caused by humoral and/or cell-mediated immune disease mechanisms directed against known or undetermined peripheral nerve antigens.

A review on the association between inflammatory myopathies and vaccination.

Several viruses and vaccines are among the environmental factors implicated as triggers of autoimmune inflammatory myopathies. Case histories report on the onset of dermatomyositis/polymyositis after immunization with various vaccines of patients with probable genetic predisposition. However, retrospective and epidemiological studies failed to ascertain an association between DM/PM and vaccines: no significant increase in the incidence of DM/PM was reported after large vaccination campaigns. The risk for vaccine-induced adverse events may be enhanced by adjuvants. Macrophagic myofasciitis is a novel inflammatory myopathy ascribed to an ongoing local immune reaction to a vaccine adjuvant. Isolated prospective studies showed that the administration of unadjuvanted, non-live vaccine to patients with DM/PM caused no short-term harmful effects to DM/PM immune processes. However, more research is warranted to clarify the incidence of vaccine-preventable infections, harmful effects of vaccination, and the influence of any immunomodulating agents on vaccination efficacy. Vaccination is an important disease prevention tool in modern medicine. This review does not address risk-benefit or cost-benefit analyses, and does not advocate the use of specific vaccines or vaccination programs. Despite a great deal of scientific uncertainty, the concept of a possible causal link between immunization and inflammatory myopathies should not be totally rejected.

A literature review on optic neuritis following vaccination against virus infections.

Optic neuritis (ON) is a primary inflammation of the optic nerve. ON is mostly idiopathic, and infrequently occurs on the background of systemic autoimmune disease, recent infectious disease or inoculation with mostly adjuvanted vaccines. Published case histories, retrospective reviews and analyses of epidemiological data report on the onset of immune-mediated ON (and other autoimmune disorders) within a defined period (days to weeks) after immunization of patients with probable genetic predisposition. After vaccination, there exists no long-term increased risk to develop ON. The risk for these vaccine-induced adverse events may be enhanced by adjuvants. Patient age distribution reflected immunization schedules and advisories, or patient age groups studied. Vaccination is one of the most important prevention tools in modern medicine, and a discussion on risk-benefit or cost-benefit analysis, and advisory on individual vaccines or vaccination programs falls outside the scope of this review. Despite a great deal of scientific uncertainty, the existence of a possible causal link between vaccines and acute ON should not be totally disregarded.

Targeted immunotherapy trials for idiopathic inflammatory myopathies.

The idiopathic inflammatory myopathies (IIM) are a group of muscle diseases with complex immunopathogenesis that varies between disease subgroups, and possibly between patients within the same subgroup. There exists no universal consensus on optimum management, so that no "standard" therapy has been developed. Treatment-refractive IIM remains a clinical challenge. Progress in the development and application of molecular biology techniques and biological therapeutics are evolving into a new scientific frontier in the management of autoimmune diseases. This review offers an update on those components of the humoral and cellular immunity deemed potential targets for biological therapeutics (monoclonal antibodies and fusion proteins) that have been approved by the US FDA for treatment of immunological disorders. A futuristic approach is envisioned in which each individual will receive targeted therapy tailored to patient-specific immune mechanisms. Risk-benefit and cost analyses should determine whether such targeted therapy is appropriate and feasible for refractive and/or newly diagnosed disease.

A review of the use of biological agents for chronic inflammatory demyelinating polyradiculoneuropathy.

Chronic inflammatory demyelinating polyneuropathy (CIDP) is a group of idiopathic, acquired, immune-mediated inflammatory demyelinating diseases of the peripheral nervous system. A majority of patients with CIDP respond to "first-line" treatment with IVIG, plasmapheresis and/or corticosteroids. There exists insufficient evidence to ascertain the benefit of treatment with "conventional" immunosuppressive drugs. The inconsistent efficacy, long-term financial burden and health risks of non-specific immune altering therapy have drawn recurrent attention to the possible usefulness of a variety of biological agents that target key aspects in the CIDP immunopathogenic pathways. This review aims to give an updated account of the scientific rationale and potential use of biological therapeutics in patients with CIDP. No specific treatment recommendations are given. The discovery, development and application of biological markers by modern molecular diagnostic techniques may help identify drug-naïve or treatment-resistant CIDP patients most likely to respond to targeted immunotherapy.

Immune-mediated myelitis following hepatitis B vaccination.

The hepatitis B virus (HBV) is an important international cause of infectious acute and chronic liver diseases. HBV vaccines were developed to combat the potential life-threatening effects of HBV infection. Published case histories, retrospective reviews and analyses of epidemiological data report on the onset of immune-mediated myelitis after recombinant HBV vaccination, mostly in adults with a presumed genetic/immunologic predisposition. However, HBV vaccination has not borne out to be a significant trigger of serious autoimmune events, including acute myelitis, in populations at large over prolonged observation periods after immunization. Published study methods lack the sensitivity to categorically establish a causal relationship between exposure to HBV vaccine components and immune mediated myelitis, but in practice the faint possibility of such a link should not be totally rejected.

Posterior reversible encephalopathy syndrome (PRES) after granulocyte-colony stimulating factor (G-CSF) therapy: a report of 2 cases.

Two patients with recurrent lymphoma developed an acute, transient encephalopathy following administration of recombinant human granulocyte-colony stimulating factor (rhG-CSF), filgrastim, in anticipation of leukapheresis for hematopoietic stem cell transplantation. Head magnetic resonance imaging showed evidence of blood-brain barrier (BBB) breakdown, compatible with posterior reversible encephalopathy syndrome (PRES). The proposed pathogenesis of PRES was rhG-CSF-induced neutrophil mobilization and activation with the release of inflammatory mediators, resulting in transient alteration of barrier permeability and capillary leakage.

Tumor necrosis factor-alpha as a potential therapeutic target in idiopathic inflammatory myopathies.

The cytokine, tumor necrosis factor alpha (TNFα), has been implicated in many aspects of immune system development, immune response regulation, and T cell-mediated tissue injury. TNFα plays a less well-defined role in the pathogenesis of the idiopathic inflammatory myopathy (IIM) group of disorders, and has been considered a potential therapeutic target. Observational studies of TNFα-blockade in (mostly refractory) IIM have yielded inconsistent beneficial results so that administration of these biological agents is presently deemed an unreliable alternative treatment strategy. Moreover, anti-TNFα therapy has the rare potential to trigger myositis in patients with rheumatoid arthritis, hinting at a pre-existing "overlap disorder". The full potential of TNFα-antagonism will be realized only if randomized controlled trials ascertain appropriate treatment regimens and identify patient subgroups most likely to benefit from such therapy.

Neuromuscular complications of hepatitis A virus infection and vaccines.

The hepatitis A virus (HAV) infects millions of people worldwide every year. Case histories report on various acute neuropathy syndromes in the context of acute HAV infection, but any causal link has not been established. Epidemiological data also cast doubt on the importance of HAV as a trigger for Guillain-Barré syndrome. The virtual absence of a chronic HAV-infected state likely explains the rare occurrence of extrahepatic immune-mediated diseases, including an absence of chronic autoimmune neuromuscular disorders. Several vaccines against HAV provide effective protection against natural infection. Isolated case histories report on an unconvincing association between HAV vaccination and neuropathy. Medical and epidemiological data show insufficient evidence to support a causal relationship between HAV vaccines and neuropathy syndromes. Aluminum hydroxide, a HAV vaccine adjuvant, is considered a trigger of the macrophagic myofasciitis syndrome. This review concludes that it seems unnecessary to routinely consider HAV infection or vaccination as triggers of neuromuscular diseases.

Drug-induced dysimmune demyelinating neuropathies.

Drug-induced peripheral neurotoxicity usually manifests as a length-dependent, "dying back" axonal, predominantly sensory polyneuropathy. Rarely, immune-mediated demyelinating neuropathies occur during initial or maintenance treatment with immunomodulatory, immunosuppressive or antineoplastic agents. Medication-induced immune perturbation presumably triggers a dysimmune attack directed at unidentified peripheral nerve myelin epitopes; true peripheral nerve toxicity (i.e., dependent on accumulative dose or serum level) plays no identified role. The mechanisms that underlie a paradoxical and unpredictable immune exacerbation are unclear, and may depend on patient age, drug dosage and schedule, time of treatment relative to disease course, and host genetic factors. Suspicion and recognition of a non-toxic, immune-mediated demyelinating process has management (targeted immunotherapy) and prognostic (mostly favorable) implications.

Unilateral macroglossia as sole presenting manifestation of internal carotid artery dissection.

A patient presented with acute-onset, painless, unilateral enlargement of the tongue. Steroid treatment for angioedema was ineffective, and a biopsy of an apparent mass of the tongue base showed normal tissue. Subsequent magnetic resonance imaging showed enlargement, enhancement, asymmetric T2 hyperintensity of the left half of the tongue, and dissection of the left cervical internal carotid artery (ICA) at the skull base. Unilateral enlargement of the tongue due to acute neurogenic denervation may be the sole clinical presentation of a spontaneous arterial dissection at the skull base. The hypoglossal neuropathy resulted from compression by the pseudoaneurysmal ICA dilatation or ischemia from interruption of the vasa nervorum.

Immune-mediated myelitis associated with hepatitis virus infections.

Virus-induced spinal cord damage results from a cytolytic effect on anterior horn cells or from predominantly cellular immune-mediated damage of long white matter tracts. Infection with the hepatitis virus group, most notably hepatitis C virus, has infrequently been associated with the occurrence of myelitis. The pathogenesis of hepatitis virus-associated myelitis has not been clarified: virus-induced autoimmunity (humoral or cell-mediated, possibly vasculitic) seems the most likely disease mechanism. Limited available information offers no evidence of direct hepatitis virus infection of the spinal cord. Virus neuropenetration may occur after virus-infected mononuclear cells penetrate the blood-brain barrier, but a true neurolytic effect has not been demonstrated. Attacks of acute myelitis usually respond favorably to immunomodulatory therapy. Antiviral therapy plays no confirmed role in the treatment of acute bouts of myelitis, but may limit the relapsing course of HCV-associated myelitis.

Neuromuscular diseases associated with chronic hepatitis C virus infection.

Hepatitis C virus (HCV) infection is a growing international health problem, and more than 170 million people are chronic carriers. Up to 50% of HCV-positive patients develop at least one extrahepatic manifestation during the course of disease. To varying degrees of certainty, there is evidence of an association between chronic HCV infection and a variety of neuromuscular diseases. The pathogenesis of most extrahepatic diseases remains unclear but possibly includes HCV lymphotropism and/or HCV-induced autoantibodies. The therapeutic approach to HCV-associated autoimmune disorders entails eradication of HCV with one of the recombinant interferon-alpha preparations with or without additional immunosuppressive drugs.

Neuromuscular disorders associated with hepatitis B virus infection.

Approximately 400 million worldwide are chronically infected with the hepatitis B virus (HBV). During the course of illness, approximately 20% of patients develop disease manifestations outside the liver. Neuropathy develops in approximately 5% of patients with chronic HBV infection and rarely during acute HBV infection. The pathogenesis of the various HBV-associated neuropathy syndromes possibly involves deposition of immune complexes in nerves or blood vessel walls. Direct viral infection of nerves has not been demonstrated. Management entailed supportive care with antiviral and immunomodulatory treatment as clinically indicated. Rare cases of muscle disease, mostly inflammatory myopathy, have been associated with HBV infection. Presumably, HBV-associated antigens trigger immune mechanisms directed against components of muscle tissue. There is no evidence of replicative virus infection of muscle fibers. Management entailed immunomodulatory treatment, occasionally with anti-HBV therapy. Physicians should be aware that HBV infection has the potential to trigger presumed immune-mediated neuromuscular syndromes.