Biomedical subjects

A Pestronk

Publications and source records attributed to A Pestronk.

At least 37 records · Page 2Linked to original sources

PubMed1999

Serum autoantibodies to brain in Landau-Kleffner variant, autism, and other neurologic disorders.

OBJECTIVE: Etiologically unexplained disorders of language and social development have often been reported to improve in patients treated with immune-modulating regimens. Here we determined the frequency of autoantibodies to brain among such children. DESIGN: We collected sera from a cohort of children with (1) pure Landau-Kleffner syndrome (n = 2), (2) Landau-Kleffner syndrome variant (LKSV, n = 11), and (3) autistic spectrum disorder (ASD, n = 11). None had received immune-modulating treatment before the serum sample was obtained. Control sera (n = 71) were from 29 healthy children, 22 with non-neurologic illnesses (NNIs), and 20 children with other neurologic disorders (ONDs). We identified brain autoantibodies by immunostaining of human temporal cortex and antinuclear autoantibodies using commercially available kits. RESULTS: IgG anti-brain autoantibodies were present in 45% of sera from children with LKSV, 27% with ASD, and 10% with ONDs compared with 2% from healthy children and control children with NNIs. IgM autoantibodies were present in 36% of sera from children with ASD, 9% with LKSV, and 15% with ONDs compared with 0% of control sera. Labeling studies identified one antigenic target to be endothelial cells. Antinuclear antibodies with titers >/=1:80 were more common in children with ASD and control children with ONDs. CONCLUSION: Children with LKSV and ASD have a greater frequency of serum antibodies to brain endothelial cells and to nuclei than children with NNIs or healthy children. The presence of these antibodies raises the possibility that autoimmunity plays a role in the pathogenesis of language and social developmental abnormalities in a subset of children with these disorders.

Antibodies, Antinuclear↗

PubMed1999

Mutation analysis in Emery-Dreifuss muscular dystrophy.

The purpose of this study was to search for STA gene defects in three families with clinically typical Emery-Dreifuss muscular dystrophy. Emery-Dreifuss is an X-linked muscular dystrophy with humeroperoneal weakness and life-threatening, but treatable, cardiac abnormalities in male patients and in female carriers. The defect is in the gene coding for emerin, a 254 amino acid protein of unknown function. Complementary and genomic DNA from T lymphocytes from the reported patients and their family members were amplified, cloned, and sequenced. A novel mutation, a 26 base-pair deletion in three brothers and a carrier mother, was detected in one family. A splicing mutation with one base pair insertion and a five base-pair deletion, which have been described previously, were found in the second and third families, respectively. The additional novel mutation detected and the findings of three different mutations in these three families support the idea of genetic heterogeneity of Emery-Dreifuss muscular dystrophy with different mutations in different families.

Adolescent↗

PubMed1999

Distribution of ten laminin chains in dystrophic and regenerating muscles.

Using immunohistochemical methods, we assessed the distribution of all 10 known laminin chains (alpha1-5, beta1-3, gamma1 and gamma2) in skeletal muscles from patients with Duchenne, congenital, limb girdle, or Emery-Dreifuss muscular dystrophies. The alpha2, beta1 and gamma1 chains were abundant in the basal lamina surrounding muscle fibers in normal controls; alpha1, alpha3-alpha5, beta3, and gamma2 were undetectable; and beta2 was present at a low level. Compared to controls, levels of the alpha5 chain were increased in muscles from many dystrophic patients; levels of beta1 were reduced and/or levels of beta2 were increased in a minority. However, these changes were neither specific for, nor consistent within, diagnostic categories. In contrast, levels of alpha4 were increased in muscles from all patients with alpha2 laminin (merosin)-deficient congenital muscular dystrophy. Loss of alpha2 laminin in congenital dystrophy is disease-specific but some other changes in laminin isoform expression in dystrophic muscles could be secondary consequences of myopathy, denervation, regeneration or immaturity. To distinguish among these possibilities, we compared the laminins of embryonic, denervated, regenerating, and mutant mouse muscles with those in normal adult muscle. Embryonic muscle basal lamina contained alpha4 and alpha5 along with alpha2, and regenerating muscle re-expressed alpha5 but not alpha4. Levels of alpha5 but not alpha4 were increased in dystrophin (mdx) mutants and in dystrophin/utrophin double mutants (mdx:utrn -/-), models for Duchenne dystrophy. In contrast, laminin alpha4 was upregulated more than alpha5 in muscles of laminin alpha2 mutant mice (dy/dy; a model for alpha2-deficient congenital dystrophy). Based on these results, we hypothesize that the expression of alpha5 in many dystrophies reflects the regenerative process, whereas the selective expression of alpha4 in alpha2-deficient muscle is a specific compensatory response to loss of alpha2.

Adolescent↗

PubMed1999

Results of transcervical thymectomy for myasthenia gravis in 100 consecutive patients.

OBJECTIVE: To review the results of the authors' most recent 100 consecutive cases of transcervical thymectomy for myasthenia gravis (MG) in terms of complications and outcome in comparison with other reported techniques. SUMMARY BACKGROUND DATA: Myasthenia gravis is believed to be an autoimmune disorder characterized by increasing fatigue with exertion. The role of thymectomy in the management of the disease remains unproven, but there is widespread acceptance of the notion that complete thymectomy improves the course of the disease. Complete excision of the thymus is the goal in all cases; however, the best technique to achieve complete thymectomy remains controversial. The authors favor a transcervical approach through a small collar incision aided by a specially designed sternal retractor. Others prefer a transsternal, a combined transcervical and transsternal ("maximal"), or a video-assisted thoracoscopic surgical approach. METHODS: A retrospective review of the authors' most recent 100 consecutive transcervical thymectomies for nonthymoma-associated MG was performed using medical records and telephone interviews. Patients' symptoms were graded before surgery and at the most recent (within the last 6 months) postoperative time point, using the modified Osserman classification: 0 = asymptomatic, 1 = ocular signs and symptoms, 2 = mild generalized weakness, 3 = moderate generalized weakness, bulbar dysfunction, or both, and 4 = severe generalized weakness, respiratory dysfunction, or both. RESULTS: There were 61 female patients and 39 male patients with a mean age of 38 years (range, 14 to 84). The median hospital stay was 1 day. There were no deaths and no significant complications. Seventy-eight patients who had undergone surgery >12 months ago were available for analysis. In these patients, with a mean follow-up time of 5 years (median 5.3; range, 12 months to 10 years), the median preoperative Osserman grade improved from 3.0 (mean 2.73) before surgery to 1.0 after surgery (mean 0.94). CONCLUSIONS: The transcervical approach for thymectomy for the treatment of MG produces results similar to those of other surgical approaches, with the added benefits of shortened hospital stay, decreased complications, reduced cost, and broader physician and patient acceptance of surgical treatment.

Adolescent↗

PubMed1999

Organ-specific autoantibodies with muscle weakness.

The motor unit includes the anterior horn cell, the motor axon and the muscle fibers it innervates, and the neuromuscular junction. Diseases of the motor unit usually present with weakness. Diagnosis of motor unit disorders involves the history, physical examination, electrophysiologic studies of nerve and muscle, and blood testing for creatine kinase, genetic disorders, and autoantibodies. Antibody testing is often useful for the identification of specific immune-mediated motor unit disorders. Identification of these disorders is important because they are often treatable. Antibodies with disease specificity include those directed against autoantigens with and without organ specificity. Several autoantibodies to non-organ-specific antigens are associated with subgroups of immune myopathies. Organ-specific autoantibodies in motor unit disorders with weakness occur in myasthenia gravis, especially with thymoma, a myopathy associated with Waldenstrom's macroglobulinemia, Lambert-Eaton myasthenic syndrome, and multifocal motor neuropathy.

Autoantibodies↗

PubMed1998

Serum antibodies to heparan sulfate glycosaminoglycans in Guillain-Barré syndrome and other demyelinating polyneuropathies.

We tested for serum antibodies to glycosaminoglycans (GAGs), including heparan sulfate, in patients with Guillain-Barré syndrome (GBS) and other disorders. We used ELISA methods that optimize immunoglobulin binding to carbohydrate antigens to measure serum antibodies to heparan sulfate GAGs in GBS, and control neuromuscular and immune disorders. We found serum IgM or IgG antibodies to heparan sulfate GAGs in 34% of patients with GBS. Serum IgM binding to heparan sulfate GAGs was also found in some chronic demyelinating polyneuropathies, with the highest frequency (33%) in patients with IgM anti-MAG M-proteins. Antibodies to heparan sulfate GAGs were rare (1%) in control serums from patients with other disorders. This result is the first demonstration of high titer serum antibodies to a specific antigen in a substantial group of, and with some specificity for, patients with the classically described GBS syndrome of acute-onset, motor-sensory polyneuropathy with demyelinating features.

Autoantibodies↗

PubMed1998

N lines in a myopathy with myosin loss.

N lines can be seen by electron microscopy within the I band of skeletal muscle, but are poorly visualized in conventional preparations. We present a case of acute quadriplegic myopathy with myosin loss and prominent N lines. The only other reported cases of N lines were also seen in patients with myosin loss from diverse etiologies. Myosin loss and the subsequent detachment of titin from myosin may result in the formation of prominent N lines.

Electrodiagnosis↗

PubMed1998

Primary alpha-sarcoglycan deficiency responsive to immunosuppression over three years.

An 8-year-old girl developed weakness over 2 years and an elevated creatine kinase. The biopsy was most consistent with an active dystrophy with many inflammatory cells present. A trial of immunosuppression was started. In the first 2 months of treatment with prednisone, she had functionally and quantitatively significant improvement in her proximal strength. Over 3 years of treatment she maintained stable strength. Subsequent genetic studies showed that she had primary alpha-sarcoglycan deficiency. The timing and the degree of benefit in strength were similar to that seen in boys with Duchenne muscular dystrophy who are treated with prednisone.

Amino Acid Substitution↗

PubMed1998

Inflammatory myopathy with cytochrome oxidase negative muscle fibers: methotrexate treatment.

Inflammatory myopathy with cytochrome oxidase negative muscle fibers (IM/COX-) is characterized by slowly progressive weakness, most prominent in the quadriceps, muscle fibers with reduced COX staining and mitochondrial DNA mutations, and a poor response to corticosteroid treatment. We reviewed records of quantitative measurements of muscle strength in 7 IM/COX- patients to evaluate the outcomes after treatment with oral, once weekly, methotrexate for an average of 15 months. We compared the results to 6 patients with IM/COX- who received no long-term immunosuppression, and to 4 with inclusion body myositis (IBM) who received methotrexate during the same period. Methotrexate treatment of IM/ COX- was followed by improved muscle strength in 5 of 7 patients, averaging 17+/-5%. In contrast, there was no improvement in the strength of 6 untreated IM/COX- patients (-6+/-4%; P=0.003), or 4 methotrexate-treated IBM patients (1+/-2%; P=0.03). We conclude that, despite clinical similarities to inclusion body myositis, which is usually refractory to immunosuppressive therapy, strength in IM/COX- appears to improve with methotrexate treatment. Biopsy studies of inflammatory myopathies with evaluation of muscle for mitochondrial changes and vacuoles can help to direct the choice of appropriate immunomodulating treatments.

Aged↗

PubMed1998

Clinical correlates of granulomas in muscle.

We evaluated the clinical and myopathological features of all patients with granulomas in muscle biopsy specimens identified over a 5-year period (1992-1996) at the Washington University Medical Center. Ten patients were found to have granulomas in their muscle biopsy specimens. Of these, eight patients had myopathic changes. Seven had dysphagia as a major functional difficulty during the course of their disease. None had elevated levels of serum creatine kinase (CK). Four of the patients with myopathy had systemic sarcoidosis and relatively severe proximal weakness with functional disability. Treatment with corticosteroids was followed by marked improvement in strength and functional disability. The four other patients with myopathy had no systemic signs of sarcoidosis. Weakness was especially prominent distally in three of these patients. The two patients in this group treated with corticosteroids did not improve. The final two patients, who had granulomas in muscle but no myopathic changes, had clinical syndromes of mononeuritis multiplex and eosinophilic fasciitis (Shulman syndrome). We conclude that granulomatous myopathy, in the presence or absence of systemic sarcoidosis, is commonly associated with dysphagia (87%) and a normal serum CK. Clinical features in patients with sarcoidosis included severe proximal weakness with functional disability that often responded to corticosteroid treatment. Granulomatous myopathy without systemic sarcoidosis was associated with milder, but more predominantly distal weakness.

Adult↗

PubMed1998

Steroid-responsive myopathy with deficient chondroitin sulfate C in skeletal muscle connective tissue.

A 71-year-old man developed severe limb, bulbar, and respiratory weakness over 18 months. A muscle biopsy showed only a moderate degree of type 2 atrophy, but immunocytochemistry showed absence of chondroitin sulfate C glycosaminoglycan in the endomysium. Prednisone produced a marked increase in strength. Diffuse loss of endomysial chondroitin sulfate C was a feature of this treatable myopathy with severe weakness, but few pathologic changes.

Aged↗

PubMed1998

Paraneoplastic necrotizing myopathy: clinical and pathological features.

OBJECTIVE: To characterize the clinical features and muscle pathology of paraneoplastic necrotizing myopathy. BACKGROUND: Paraneoplastic syndromes involving many levels of the nervous system are well described, but there are only rare case reports of a necrotizing myopathy associated with cancer. DESIGN: Case series. RESULTS: We identified four patients with paraneoplastic necrotizing myopathy from muscle biopsies done at Washington University over a 10-year period. The patients (aged 38 to 76 years) presented with subacutely evolving, symmetric, proximal weakness. Tumor types included gastrointestinal adenocarcinoma (2 of 4), transitional cell carcinoma, prostatic carcinoma, and non-small cell lung carcinoma. Two patients died. Two others improved after treatment that included corticosteroids and tumor resection. Muscle pathology showed numerous necrotic fibers (8 to 100%) and intense alkaline phosphatase staining of the muscle connective tissue, but little inflammation. CONCLUSIONS: Paraneoplastic necrotizing myopathy is characterized by a rapidly progressive, symmetric, predominantly proximal weakness that produces severe disability. Muscle pathology demonstrates prominent necrosis with alkaline phosphatase staining of connective tissue and little inflammation. Evaluation for cancer is indicated in patients with these clinical and pathologic findings.

Adult↗

PubMed1998

Multifocal motor neuropathy: diagnosis and treatment.

Multifocal motor neuropathy (MMN) and some lower motor neuron syndromes are immune-mediated and treatable. These motor syndromes produce weakness that is typically distal and asymmetric, involves the arms early in the course of disease, and progresses slowly. Electrophysiologic abnormalities often include evidence of demyelination, especially focal conduction block, selectively on motor axons. High titers of serum IgM binding to GM1 ganglioside, alone or in a membrane environment, occur in 80-90% of patients with MMN. Treatments for MMN that commonly produce increased strength include IV human immune globulin (HIG) and cyclophosphamide. After an initial treatment with 2 g/kg of HIG, up to 80% of patients with MMN show short-term improvement. Long-term HIG treatment is useful in 60% of MMN patients and has few side effects but is costly. Intravenous cyclophosphamide treatment is effective in 70% of MMN patients but has significant toxicity, and is reserved for patients who have severe disease and do not respond adequately to HIG.

Antibodies↗

PubMed1997

IgM anti-sulfatide autoantibodies: patterns of binding to cerebellum, dorsal root ganglion and peripheral nerve.

Anti-sulfatide antibodies are associated with polyneuropathies having a prominent sensory component, but with variable degrees of motor and sensory loss, gait dysfunction and demyelination. In this study, we asked whether patterns of IgM binding to neural tissue in anti-sulfatide serums also demonstrated heterogeneity. We used immunocytochemical methods to examine IgM binding to peripheral nerve, dorsal root ganglion, and cerebellum in 41 serums with high titers of IgM anti-sulfatide antibodies. Our results showed that there were several different patterns of IgM binding to neural tissues in anti-sulfatide serums. In peripheral nerve the most common targets of IgM were axons, resident macrophages or Schwann cell cytoplasm. In the cerebellum, IgM bound to neuronal nuclei, white matter, or neuropil in molecular and granule cell layers. There was little binding of IgM to structures in the dorsal root ganglion. Patterns of IgM binding to peripheral nerve and cerebellum were related. Binding to neuronal nuclei in the cerebellum was usually found in serums that recognized peripheral nerve axons or macrophages. Serums with binding of IgM to cerebellar white matter usually recognized Schwann cell cytoplasm. We conclude that IgM anti-sulfatide antibodies may have several different tissue binding patterns in the peripheral and central nervous systems. These differences may be related to the variation in clinical neuropathy syndromes associated with apparently similar anti-sulfatide antibodies.

Antibodies, Blocking↗

PubMed1997

Serum autoantibodies in childhood opsoclonus-myoclonus syndrome: an analysis of antigenic targets in neural tissues.

OBJECTIVE: Opsoclonus-myoclonus (OM) is a rare neurologic syndrome affecting children and adults. In children it occurs as a parainfectious process or a paraneoplastic syndrome in association with neuroblastoma. Evidence for an immune mechanism includes the presence of serum autoantibodies to several neural antigens and improvement of symptoms with immunosuppressive therapy. We studied the neural antigenic targets of serum IgM and IgG autoantibodies from nine children with OM. DESIGN: We studied sera from nine children with OM, three with associated neuroblastoma and six with a prodromal viral illness. Control subjects (n = 77) included four children with neuroblastoma but not OM, 32 children with other neurologic disorders, and 41 with nonneurologic illnesses. We studied the neural antigenic targets of serum IgM and IgG autoantibodies by the following methods: (1) immunostaining of human cerebellar sections and peripheral nerve, and (2) Western blot analysis with human brain fractions including white matter, gray matter, and cerebellar Purkinje cells and nuclei. RESULTS: Sera from all nine children with OM had IgM and IgG binding to the cytoplasm of cerebellar Purkinje cells and to some axons in white matter. In peripheral nerve, IgM and IgG from all nine OM sera bound to large and small axons. Western blot analysis showed a distinctive pattern of binding to several neural proteins, including a 210 kd antigen identified as the high molecular weight subunit of neurofilament. No control serum showed a similar pattern of reactivity. CONCLUSION: Opsoclonus-myoclonus syndrome in childhood is associated with a distinctive pattern of serum IgM and IgG binding to neural tissues and antigens.

Adolescent↗

PubMed1997

Acute immune polyneuropathies: correlations of serum antibodies to Campylobacter jejuni and Helicobacter pylori with anti-GM1 antibodies and clinical patterns of disease.

Antecedent Campylobacter jejuni infection, detected by serologic tests, has been implicated in some acute immune polyneuropathies (AIP). Antibodies to Helicobacter pylori, C. jejuni, and GM1 ganglioside were measured in sera from 35 Chinese patients with AIP. Anti-GM1 antibodies were found in 54% of C. jejuni-seropositive, H. pylori-seronegative patients. In contrast, anti-GM1 antibodies were rare in sera that were either seropositive for both C. jejuni and H. pylori (P = .04) or seronegative for C. jejuni (P = .01). Motor axonal AIP was more common in the C. jejuni-seropositive, H. pylori-seronegative patients (82%) than in the bacterial antibody-negative group (38%). It was concluded that in AIP patients, C. jejuni-positive sera may be polyreactive, in that it may also react with H. pylori. In this situation, the specificity for either infection requires further validation. In contrast, sera with specific C. jejuni seropositivity are associated with both motor axonal AIP and selective serum IgG anti-GM1 antibodies.

Antibodies, Bacterial↗

PubMed1997

Anti-tubulin autoantibodies in acquired demyelinating polyneuropathies.

Selective high-titer anti-tubulin autoantibodies are associated with Guillain-Barré syndrome and chronic inflammatory demyelinating polyneuropathy (CIDP). Low-titer anti-tubulin autoantibodies are a normal component of some human sera. Analysis of 7 human sera with monoclonal anti-tubulin autoantibodies showed that the epitopes recognized by these antibodies are within central, conserved regions of tubulin. Sera from 3 patients with IgM monoclonal antibodies and CIDP reacted to an epitope spanning aa 301-314 of beta-tubulin, which has some sequence homology to several human viruses. Natural polyclonal anti-tubulin antibodies also bind to central regions of tubulin. In contrast, polyclonal tubulin antibodies induced in mice react to epitopes on the amino- or carboxy-terminal. Selective polyclonal anti-tubulin autoantibodies with low reactivity to other neural antigens are found in about one-half of patients with CIDP.

Animals↗

PubMed1997

Polymyositis with cytochrome oxidase negative muscle fibres. Early quadriceps weakness and poor response to immunosuppressive therapy.

We evaluated 10 patients with histologically typical polymyositis except for an excess of muscle fibres with absent cytochrome oxidase (COX) staining. No biopsies had vacuoles or congophilic material in muscle fibres. All patients presented with a history of slowly progressive weakness. The average age of onset was 9 years older than a group of polymyositis patients with normal COX staining of muscle fibres. Selective weakness of knee extension was a prominent and disabling feature in most patients. Serum creatine kinase was usually mildly elevated (363 +/- 115 U/l) but at levels lower than those in other patients with polymyositis. Mitochondrial DNA analysis showed multiple deletions in 90% of muscles from patients with excessive numbers of COX-negative muscle fibres, a prevalence significantly greater than the 22% figure for controls (P = 0.005). As a group, the patients responded poorly to immunosuppressive therapy. We conclude that patients with polymyositis and an excess of COX-negative muscle fibres, but no inclusion bodies, have common features including selective quadriceps weakness, mitochondrial pathology by histochemical and DNA analysis and a poor response to immunosuppressive therapy. Some of these features are shared with inclusion body myositis (IBM) and this entity cannot be entirely excluded as vacuoles may not be present in all muscle tissue in IBM patients. Evaluation of the COX activity in muscle fibres of patients with inflammatory myopathies provides useful prognostic information regarding the likelihood of improved strength after immunosuppressive treatment.

DNA, Mitochondrial↗