Long lasting trigeminal neuropathy, limbic encephalitis and abdominal ganglionitis without primary cancer: An atypical case of Hu-antibody syndrome.

OBJECTIVES: Anti-Hu antibodies (Hu-Abs) are the most frequent onconeural antibodies associated with paraneoplastic neurologic syndromes (PNS). PNS include a variety of neurological syndromes, affecting less than 1/10,000 patients with cancer. In the majority of cases, PNS will manifest before the malignancy is diagnosed. We found a case in which PNS was diagnosed without finding a primary malignancy after extensive work-up and even post-mortem autopsy. PATIENT AND METHODS: We present a case report of a 58-year-old man. This article includes extensive clinical work-up, full-body autopsy and brain autopsy with classical histochemical and myelin stainings and immunohistochemistry was performed. RESULTS: The patient developed a progressive trigeminal neuropathy over a period of 5 years, in combination with cerebellar degeneration, asymmetrical brainstem and limbic encephalitis. Serum showed repeatedly high anti-Hu antibodies. Comprehensive cancer screening could not demonstrate any primary malignancy. Therapy with corticosteroids, plasma exchange, cyclophosphamide and rituximab showed no beneficial effect. He died from the complications of enteric ganglionitis 5 years after onset of the first symptoms. A postmortem autopsy could not detect a primary malignancy either. Brain morphology is described in detail. CONCLUSION: Paraneoplastic anti-Hu encephalitis cases associated with SCLC or other primary neoplasms are well known. An adult with a progressive multifocal neurological syndrome in the presence of positive anti-Hu antibodies, but without any primary neoplasm after a follow-up over 5 years is unusual.

Necrotizing myopathy as a paraneoplastic syndrome associated with renal cell carcinoma.

We report a 49-year-old patient with necrotizing myopathy and a right renal mass. After laparoscopic radical nephrectomy, a remission of myopathy was seen. Pathologic evaluation of the nephrectomy specimen revealed a clear cell renal cell carcinoma. Relapse of myopathy 6 months postoperatively coincided with the diagnosis of the appearance of liver metastatic disease. After initiation of treatment with an mTOR-inhibitor, myopathy became less active requiring smaller amounts of corticosteroids with a complete remission of myopathy after 3 months of systemic treatment for metastatic renal cell cancer.

Dermatomyositis and polymyositis: new treatment targets on the horizon.

Polymyositis (PM) and dermatomyositis (DM) are rare idiopathic inflammatory myopathies (IIM) with a presumed autoimmune pathogenesis. Typical features are subacute onset, proximal, symmetric muscle weakness, elevated serum creatine kinase, and mononuclear cell infiltrates in the muscle biopsy. Strong support for an autoimmune pathogenesis comes from histopathological findings in biopsies of affected muscles. Furthermore, the association with autoantibodies supports the notion that immune-mediated inflammation is involved. PM and DM may occur in isolation or in connection with a connective tissue disease or cancer. The current treatment for IIM consists of first-line high-dose steroids and various conventional second-line treatments. Improvements in treatment for IIM are hampered by difficulties in the design of trials and the low incidence and prevalence of the disease. Cytokines and chemokines are factors involved in the inflammatory process in IIM, and are candidates for future therapeutic targets. Preliminary data with anti-tumour necrosis factor therapy are not very promising, but results of blockers of the lymphotoxin signalling pathway are to be awaited. Anti-B cell therapy may be a valuable therapeutic option for treatment of refractory IIM. The effects of anti-interferon-alpha in IIM are to be awaited, as are results of other anti-cytokine therapies and anti-chemokine therapy. Outcome measures to be used in clinical trials in II M include at present the core sets of outcome proposed by the International Myositis Assessment Clinical Study Group (IMACS).

Progressive myoclonic epilepsy as an adult-onset manifestation of Leigh syndrome due to m.14487T>C.

BACKGROUND: m.14487T>C, a missense mutation (p.M63V) affecting the ND6 subunit of complex I of the mitochondrial respiratory chain, has been reported in isolated childhood cases with Leigh syndrome (LS) and progressive dystonia. Adult-onset phenotypes have not been reported. OBJECTIVES: To determine the clinical-neurological spectrum and associated mutation loads in an extended m.14487T>C family. METHODS: A genotype-phenotype correlation study of a Belgian five-generation family with 12 affected family members segregating m.14487T>C was carried out. Clinical and mutation load data were available for nine family members. Biochemical analysis of the respiratory chain was performed in three muscle biopsies. RESULTS: Heteroplasmic m.14487T>C levels (36-52% in leucocytes, 97-99% in muscle) were found in patients with progressive myoclonic epilepsy (PME) and dystonia or progressive hypokinetic-rigid syndrome. Patients with infantile LS were homoplasmic (99-100% in leucocytes, 100% in muscle). We found lower mutation loads (between 8 and 35% in blood) in adult patients with clinical features including migraine with aura, Leber hereditary optic neuropathy, sensorineural hearing loss and diabetes mellitus type 2. Despite homoplasmic mutation loads, complex I catalytic activity was only moderately decreased in muscle tissue. INTERPRETATION: m.14487T>C resulted in a broad spectrum of phenotypes in our family. Depending on the mutation load, it caused severe encephalopathies ranging from infantile LS to adult-onset PME with dystonia. This is the first report of PME as an important neurological manifestation of an isolated mitochondrial complex I defect.

Open-label trial of anti-TNF-alpha in dermato- and polymyositis treated concomitantly with methotrexate.

BACKGROUND/AIMS: To determine the efficacy of infliximab combined with weekly methotrexate in drug-naive recent-onset dermatomyositis and polymyositis. METHODS: A multicentre open-label controlled trial was conducted. Disease activity was assessed using patient's and physician's disease activity assessment, manual muscle testing (MMT), handheld dynamometry, and serum CK. The primary objective was to assess the efficacy using MMT after a period of 26 weeks. RESULTS: The study was terminated prematurely because of a low inclusion rate and a high drop-out rate due to disease progression and the occurrence of an infusion reaction. The few patients who did reach the primary endpoint showed improvement in all aspects studied. CONCLUSION: Infliximab combined with weekly methotrexate might be safe and well tolerated in a small subgroup of patients with drug-naive recent-onset myositis. At present, we do not advocate the use of this treatment because treatment response cannot be predicted beforehand.

Post-traumatic spontaneous recurrent hypothermia: a variant of Shapiro's syndrome.

A 49-year-old man presented with episodic hypothermia many years after sustaining a contusional brain injury. Brain magnetic resonance imaging demonstrated the destruction of the anterior parts of the corpus callosum without hypothalamic lesions. Nevertheless, delayed hypothalamic dysfunction at the neurotransmitter level is the probable pathophysiological key factor. Clomipramine treatment was beneficial. This case expands the spectrum of Shapiro's syndrome.

Role of tumour necrosis factor-alpha receptor p75 in cigarette smoke-induced pulmonary inflammation and emphysema.

Chronic obstructive pulmonary disease (COPD) is characterised by a local pulmonary inflammatory response to respiratory pollutants and by systemic inflammation. Tumour necrosis factor (TNF)-alpha has been implicated in systemic effects of COPD and operates by binding the p55 (R1) and p75 (R2) TNF-alpha receptors. To investigate the contribution of each TNF-alpha receptor in the pathogenesis of COPD, the present study examined the effects of chronic air or cigarette smoke (CS) exposure in TNF-alpha R1 knockout (KO) mice, TNF-alpha R2 KO mice and wild type (WT) mice. CS was found to significantly increase the protein levels of soluble TNF-alpha R1 (by four-fold) and TNF-alpha R2 (by 10-fold) in the bronchoalveolar lavage of WT mice. After 3 months, CS induced a prominent pulmonary inflammatory cell influx in WT and TNF-alpha R1 KO mice. In TNF-alpha R2 KO mice, CS-induced pulmonary inflammation was clearly attenuated. After 6 months, no emphysema was observed in CS-exposed TNF-alpha R2 KO mice in contrast to WT and TNF-alpha R1 KO mice. CS-exposed WT and TNF-alpha R1 KO mice failed to gain weight, whereas the body mass of TNF-alpha R2 KO mice was not affected. These current findings suggest that both tumour necrosis factor-alpha receptors contribute to the pathogenesis of chronic obstructive pulmonary disease, but tumour necrosis factor-alpha receptor-2 is the most active receptor in the development of inflammation, emphysema and systemic weight loss in this murine model of chronic obstructive pulmonary disease.

The genetic causes of basal ganglia calcification, dementia, and bone cysts: DAP12 and TREM2.

BACKGROUND: Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL), or Nasu-Hakola disease, is a presenile dementia associated with loss of myelin, basal ganglia calcification, and bone cysts. It is caused by recessively inherited mutations in two genes encoding subunits of a cell membrane-associated receptor complex: TREM2 and DAP12. The clinical course of PLOSL has not been characterized in a series of patients with TREM2 mutations. METHODS: The authors compare neurologic and neuroradiologic follow-up data of six patients carrying TREM2 mutations with PLOSL due to defective DAP12 genes. The authors review the known mutations in these two genes. RESULTS: Mutations in DAP12 and TREM2 result in a uniform disease phenotype. In Finnish and Japanese patients with PLOSL, DAP12 mutations predominate, whereas TREM2 is mutated more frequently elsewhere. CONCLUSIONS: Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy should be considered in adult patients under age 50 years with dementia and basal ganglia calcification. Radiographs of ankles and wrists, and DNA test in uncertain cases, confirm the diagnosis.

Immunolocalization of FAS and FAS ligand in inflammatory myopathies.

Fas/Fas ligand (FasL) interaction can induce apoptosis, have a costimulatory role or act as a mechanism by which cytotoxic T cells produce target cell lysis. We used several commercially available antibodies to study Fas and FasL expression in polymyositis (PM), inclusion body myositis (IBM), dermatomyositis (DM) and normal controls. A strong Fas signal occurred on the sarcolemma, and to a lesser extent in the sarcoplasm of neural cell adhesion molecule (NCAM)-positive or developmental myosin heavy chain-positive regenerating muscle fibers and of injured fibers with presumed abortive regenerative activity, including some nonnecrotic invaded fibers in PM and IBM and some of the atrophic perifascicular fibers in DM. Most fibers within groups of atrophic fibers in IBM were strongly Fas-positive, and statistically more muscle fibers were Fas-positive in IBM compared to PM. A subset of the actively invading CD8+ T cells in nonnecrotic muscle fibers in PM and IBM, and scattered CD4+ cells in each inflammatory myopathy, had up-regulated Fas expression, probably reflecting costimulation. No FasL antibody consistently labeled the positive control tissue (testis) or intramuscular elements in control or inflammatory myopathy specimens. Our study identifies regenerating muscle fibers as the main site of Fas immunoreactivity in inflammatory myopathies, and Fas expression may be part of an activated or reactivated developmental program of new gene expression in regenerating or denervated muscle fibers. Our data plead against a specific role of Fas/FasL interaction in the immunopathogenesis of the inflammatory myopathies.

Immunolocalization of tumor necrosis factor-alpha and its receptors in inflammatory myopathies.

Adhesion molecule upregulation occurs in inflammatory myopathies, and is one of the myriad functions of tumor necrosis factor-alpha (TNF-alpha). TNF-alpha acts via two different receptors of 55 (TNF-R55) and 75 kD (TNF-R75). We immunolocalized TNF-alpha and its receptors in polymyositis, inclusion body myositis and dermatomyositis. In each myopathy, TNF-alpha was detected in macrophages, in myonuclei in regenerating muscle fibers, and freely dispersed in endomysial or perimysial connective tissue. Many endothelial cells in dermatomyositis expressed TNF-alpha. TNF-R55 was strongly expressed on myonuclei of regenerating muscle fibers. TNF-R75 was increased on endothelial cells in the midst of inflammatory infiltrates in each myopathy, and on perifascicular and perimysial endothelia, remote from inflammatory foci in dermatomyositis. Possible TNF-alpha-mediated effects include: increased transendothelial cell trafficking, activation of T/B cells and macrophages, induction of MHC-I gene products, and focal muscle fiber atrophy. In dermatomyositis, the upregulated TNF-R75, via its consensus elements for transcription factors, may be involved in endothelial cell degeneration. Strong TNF-R55 expression on regenerating myonuclei is consistent with a role of TNF-alpha and TNF-R55 in muscle regeneration.

Quinidine prevents paraoxon-induced necrotizing myopathy in rats.

Acute organophosphorus anticholinesterase poisoning induces a necrotizing end-plate myopathy in rats and patients. Acetylcholine (ACh) excess leads to prolonged synaptic currents and increased influx of cations including calcium through the postsynaptic ACh receptor channels with prolonged muscle membrane depolarization, excess calcium influx into the sarcoplasm, and ultimately muscle fiber necrosis. Quinoline derivatives such as quinidine induce or worsen pre- and postsynaptic disorders of neuromuscular transmission in humans, and are beneficial in patients suffering from a rare congenital myasthenic syndrome called the slow channel congenital myasthenic syndrome. These drugs correct the prolonged opening times of the mutated acetylcholine receptor channels in this myasthenic syndrome. We treated paraoxon-poisoned rats with 4 x 10 or 4 x 50 mg/kg of quinidine and assessed the severity of the necrotizing myopathy in gastrocnemius and diaphragm muscle biopsies. Fasciculations were decreased and the necrotizing myopathy was prevented in most treated rats, with absence of necrotic muscle fibers in most animals in the high-dose group. Survival was not different from untreated poisoned animals. A number of physiological mechanisms, including blocking of presynaptic voltage-gated sodium or calcium channels or inhibition of the postsynaptic ACh receptors channels may have contributed to the attenuation of the myonecrosis. The optimal dose and the drug of choice amongst the clinically available quinoline derivatives remains to be determined.

Patterns of abnormal protein expression in target formations and unstructured cores.

Streaming of Z-disks and focal myofibrillar degeneration occur in target formations (TF) and unstructured cores (UC). Similar myofibrillar alterations are also part of the spectrum of ultrastructural reactions that can occur in the myopathies associated with myofibrillar degeneration and abnormal foci of desmin positivity. In the latter disorders, there is ectopic overexpression of dystrophin, neural cell adhesion molecule (NCAM), gelsolin, beta-amyloid precursor protein (beta APP) epitopes, alpha 1-antichymotrypsin (alpha 1-ACT), and many abnormal fiber regions are also strongly congophilic. Therefore, we searched for similar abnormalities in TF and UC. The UC and the center of TF show increased immunoreactivity for actin, alpha-actinin, gelsolin, dystrophin, beta APP epitopes, alpha 1-ACT, beta 2-microglobulin, desmin, and NCAM, but minimal or no congophilia. The periphery of the TF reacts strongly for nebulin but not for actin. The observed immunocytochemical alterations in TF and UC may represent a stereotyped cellular response associated with myofibrillar degeneration due to any cause. However, the three-dimensional profile of the TF and UC as well as their fiber-type specificity distinguish them from lesions that have similar immunocytochemical profiles in other myopathies.

Peripheral lymphoid tissue-like adhesion molecule expression in nodular infiltrates in inflammatory myopathies.

Non-granulomatous nodular accumulations of inflammatory cells in inflammatory myopathies were studied to characterize adhesion mechanisms used for leukocyte recruitment. The nodules had a B-cell-rich center surrounded by a helper T-cell-rich peripheral zone, resembling lymph nodes. The T-cell-rich zones harbored high-walled venules resembling high endothelial venules (HEV), whose endothelia frequently expressed ICAM-1, VCAM-1, and less constantly E-selectin. This endothelial adhesion molecule profile differs from that found in polymyositis, inclusion body myositis, or dermatomyositis, but resembles that in lymphoid tissues. Also, the peripheral lymph node addressin, a vascular addressin specific for peripheral lymphoid tissue HEV, was present on many HEV. This adhesion system is probably responsible for the excessive lymphocyte recruitment. The similar cellular organization and lymphocyte recirculation mechanisms of the nodular infiltrates in muscle and of lymph nodes suggest that the former may also produce antibodies.

Myofibrillar myopathy with abnormal foci of desmin positivity. II. Immunocytochemical analysis reveals accumulation of multiple other proteins.

The two major types of lesions in myofibrillar myopathy consist of hyaline spheroidal structures composed of compacted myofibrillar residues, and nonhyaline lesions that comprise foci of myofibrillar destruction. We employed immunocytochemical analysis to further characterize these abnormalities. The nonhyaline lesions are depleted of actin, alpha-actinin, myosin, and, less consistently, of titin and nebulin. Thus, each major component of the myofibrils is lost or decreased. These lesions also react strongly for both NCAM and desmin. By contrast, the hyaline structures are highly enriched in actin, are immunoreactive for fast and slow myosin, and show increased expression of titin, nebulin, and alpha-actinin. They fail to react for NCAM and react variably for desmin. Both types of lesion react, but with differing intensities, for gelsolin, dystrophin, beta-amyloid precursor protein (beta APP) epitopes amino-terminal to the alpha-secretase site, alpha 1-antichymotrypsin, and ubiquitin, and both can be congophilic. The increased expressions of desmin, dystrophin and gelsolin in muscle are also confirmed by immunoblot studies. The results, in harmony with the ultrastructural findings described in the companion paper, suggest that myofibrillar myopathy is conditioned by abnormal activation of a degradative process that primarily affects the myofibrils. A structural abnormality of desmin alone may not be sufficient to disrupt the myofibrillar architecture, but abnormal activation of a phosphorylating process could account for dissolution of the myofibrils. The cause and significance of the ectopic overexpression of desmin, dystrophin, NCAM, and beta APP components, and the chemical basis of the congophilia remain unknown.

Immunocytochemical study of CD45 T cell isoforms in inflammatory myopathies.

The CD45RO and CD45RA antigens subdivide the CD8+ and the CD4+ T cells into primed memory cells and unprimed virgin T cells, respectively. To assess the relative abundance of the CD8+ and the CD4+ T cells expressing the two CD45 isoforms in the major inflammatory myopathies, we immunophenotyped T cells in muscle specimens from patients with inclusion body myositis, polymyositis (PM), and dermatomyositis. The analysis was according to diagnosis and sites of cell accumulation: endomysial inflammatory cells focally surrounding and invading nonnecrotic fibers were analyzed in inclusion body myositis and PM and perivascular infiltrates in PM and dermatomyositis. In all diseases and at all sites of accumulation, the CD45RO+ memory T cells were predominant and the CD45RO/CD45RA ratio exceeded that in normal blood. In PM and inclusion body myositis, the marked enrichment of endomysial T cells in memory cells implicates these cells in the pathogenesis. The enrichment of perivascular T cells in dermatomyositis and PM in memory cells may be a result of enhanced transendothelial migratory capacity of these cells; alternatively, the virgin-to-memory cell conversion may occur after diapedesis.

The intermediate syndrome in organophosphate poisoning: an overview of experimental and clinical observations.

The intermediate syndrome of organophosphate poisoning arises in the time interval between the acute cholinergic crisis of fasciculations and muscle weakness and the delayed neuropathy attributed to inhibition of the neuropathy target esterase. The conclusions derived from salient experimental and clinical studies are that intermediate syndrome relates to the severity of poisoning not the specific organophosphate and to prolonged inhibition of acetylcholinesterase activity of the erythrocytes, brain and muscle endplate with pre and post synaptic impairment of neuromuscular transmission. It is not related to delayed neuropathy.

Expression of cell adhesion molecules in inflammatory myopathies and Duchenne dystrophy.

Cell adhesion molecules participate in target-effector cell interactions in cell-mediated cytotoxicity and in leukodiapedesis in inflammatory diseases. Two ligand-receptor pairs may play a role in the adhesion of cytotoxic T cells to their targets: 1) intercellular adhesion molecule-1 (ICAM-1) and lymphocyte function-associated antigen-1 (LFA-1), and 2) LFA-3 and CD2. We therefore immunolocalized these molecules in myopathies where there is evidence for T cell-mediated myocytotoxicity, namely inclusion body myositis, polymyositis, and Duchenne dystrophy. Autoaggressive inflammatory cells close to invaded muscle fibers showed an increased expression of ICAM-1 and LFA-1. The nonnecrotic muscle fibers invaded by autoaggressive cells expressed ICAM-1 where their surfaces faced the invading cells. That immunoreactivity for ICAM-1 on the invading cells was distinct from that on the opposite muscle fiber surface was established by colocalization of ICAM-1 with the sarcolemmal marker dystrophin (or beta-spectrin) and was also confirmed by confocal microscopy. Leukodiapedesis in inflamed tissues is mediated by ICAM-1, LFA-3, vascular cell adhesion molecule-1 (VCAM-1), and E-selectin associated with endothelial cells. In dermatomyositis ICAM-1 was strongly expressed on endothelial cells of perimysial arterioles and venules and on some perifascicular capillaries. In all the other myopathies ICAM-1 and LFA-3 expressions were increased on endothelia of capillaries surrounded by inflammatory cells. VCAM-1 was detected in few arterioles in all diseases. E-selectin was not detected at any site in any disorder.(ABSTRACT TRUNCATED AT 250 WORDS)