Single-fiber electromyography in the orbicularis oculi muscle in patients with ocular myasthenia gravis symptoms: does abnormal jitter predict response to treatment?

BACKGROUND: Seronegative ocular myasthenia gravis (OMG) is diagnosed by ocular symptoms with supporting SFEMG, typically of frontalis or extensor digitorum muscles. We aimed to determine the sensitivity and specificity of orbicularis oculi SFEMG to diagnose and exclude myasthenia gravis and predict response to therapy. METHODS: Orbicularis oculi SFEMG studies were conducted in 142 consecutive patients with symptoms and/or findings of OMG and negative AChR antibody during the period of 5 years. Retrospective chart review was conducted 2 years after the SFEMG to determine whether treatments were given and responses to treatment. RESULTS: Orbicularis oculi SFEMG was abnormal in 31 patients and normal in 111 patients. Twenty-nine patients with abnormal SFEMG were treated, and 25 had a good response. Twenty-four patients with normal SFEMG received treatment; none responded to treatment or developed generalized myasthenia. CONCLUSION: An abnormal orbicularis oculi SFEMG in patients with seronegative OMG has a high predictive value for response to therapy. Our study findings may affect the treatment decisions in practice and aid better management of myasthenic patients.

Propofol as a Risk Factor for ICU-Acquired Weakness in Septic Patients with Acute Respiratory Failure.

BACKGROUND: Critical illness polyneuropathy (CIN) and critical illness myopathy (CIM), together "ICU-Acquired weakness (ICUAW)," occur frequently in septic patients. One of the proposed mechanisms for ICUAW includes prolonged inactivation of sodium channels. Propofol, used commonly in patients with acute respiratory failure (ARF), primarily acts via enhancement of GABAergic transmission but may also increase sodium channel inactivation, suggesting a potential interaction. METHODS: Electronic medical records and EMG reports of patients with ICUAW and a diagnosis of either sepsis, septicaemia, severe sepsis, or septic shock, concurrent with a diagnosis of acute respiratory failure (ARF), were retrospectively analyzed in a single center university hospital. RESULTS: 74 cases were identified (50.0% men, age 58±14 years), and compared to age- and sex-matched controls. Of these, 51 (69%) had CIN, 19 (26%) had CIM, and 4 (5%) had both. Propofol exposure was significantly higher in patients with ICUAW compared to controls (63.5% vs. 33.8%, p<0.001). The odds ratio of developing ICUAW with propofol exposure was 3.4 (95% CI:1.7-6.7, p<0.001). Patients with ICUAW had significantly more days in hospital (59±44 vs. 30±23) and ICU (38±26 vs. 17±13), days dependent on mechanical ventilation (27±21 vs. 13±16), and rates of tracheostomy (79.7% vs. 36.5%) and gastrostomy (75.7% vs. 25.7%) (all p<0.001). They also received a significantly higher number of distinct intravenous antibiotics, cumulative days of antibiotic therapy, and exposure to vasopressors and paralytics. CONCLUSIONS: Propofol exposure may increase the risk of ICUAW in septic patients. An interaction through sodium channel inactivation is hypothesized.

Parallel targeted next generation sequencing of childhood and adult acute myeloid leukemia patients reveals uniform genomic profile of the disease.

The age-specific differences in the genetic mechanisms of myeloid leukemogenesis have been observed and studied previously. However, NGS technology has provided a possibility to obtain a large amount of mutation data. We analyzed DNA samples from 20 childhood (cAML) and 20 adult AML (aAML) patients, using NGS targeted sequencing. The average coverage of high-quality sequences was 2981 × per amplicon. A total of 412 (207 cAML, 205 aAML) variants in the coding regions were detected; out of which, only 122 (62 cAML and 60 aAML) were potentially protein-changing. Our results confirmed that AML contains small number of genetic alterations (median 3 mutations/patient in both groups). The prevalence of the most frequent single gene AML associated mutations differed in cAML and aAML patient cohorts: IDH1 (0 % cAML, 5 % aAML), IDH2 (0 % cAML, 10 % aAML), NPM1 (10 % cAML, 35 % aAML). Additionally, potentially protein-changing variants were found in tyrosine kinase genes or genes encoding tyrosine kinase associated proteins (JAK3, ABL1, GNAQ, and EGFR) in cAML, while among aAML, the prevalence is directed towards variants in the methylation and histone modifying genes (IDH1, IDH2, and SMARCB1). Besides uniform genomic profile of AML, specific genetic characteristic was exclusively detected in cAML and aAML.

Gene Mutation Profiles in Primary Diffuse Large B Cell Lymphoma of Central Nervous System: Next Generation Sequencing Analyses.

The existence of a potential primary central nervous system lymphoma-specific genomic signature that differs from the systemic form of diffuse large B cell lymphoma (DLBCL) has been suggested, but is still controversial. We investigated 19 patients with primary DLBCL of central nervous system (DLBCL CNS) using the TruSeq Amplicon Cancer Panel (TSACP) for 48 cancer-related genes. Next generation sequencing (NGS) analyses have revealed that over 80% of potentially protein-changing mutations were located in eight genes (CTNNB1, PIK3CA, PTEN, ATM, KRAS, PTPN11, TP53 and JAK3), pointing to the potential role of these genes in lymphomagenesis. TP53 was the only gene harboring mutations in all 19 patients. In addition, the presence of mutated TP53 and ATM genes correlated with a higher total number of mutations in other analyzed genes. Furthermore, the presence of mutated ATM correlated with poorer event-free survival (EFS) (p = 0.036). The presence of the mutated SMO gene correlated with earlier disease relapse (p = 0.023), inferior event-free survival (p = 0.011) and overall survival (OS) (p = 0.017), while mutations in the PTEN gene were associated with inferior OS (p = 0.048). Our findings suggest that the TP53 and ATM genes could be involved in the molecular pathophysiology of primary DLBCL CNS, whereas mutations in the PTEN and SMO genes could affect survival regardless of the initial treatment approach.

Molecular treatment effects of alemtuzumab in skeletal muscles of patients with IBM.

BACKGROUND: Mechanisms of inflammation and protein accumulation are crucial in inclusion body myositis (IBM). Recent evidence demonstrated that intravenous immunoglobulin failed to suppress cell-stress mediators in IBM. Here we studied the molecular changes in skeletal muscle biopsies from patients with IBM before and after treatment with alemtuzumab. METHODS: Relevant inflammatory and degeneration-associated markers were assessed by quantitative-PCR and immunohistochemistry in repeated muscle biopsy specimens from patients with IBM, which had been treated in a previously published uncontrolled proof-of-concept trial with alemtuzumab. RESULTS: There were no significant changes of the mRNA expression levels of the pro-inflammatory chemokines CXCL-9, CCL-4, and the cytokines IFN-γ, TGF-ß, TNF-α, and IL-1ß. Similarly, the degeneration-associated molecules ubiquitin, APP and αB-crystallin did not substantially change. Although no overall beneficial treatment effect was noted except for a 6-month stabilization, some patients experienced a transient improvement in muscle strength. In such responders, a trend towards reduced expression of inflammatory markers was noted. In contrast, the expression remained unchanged in the others who did not experience any change. The expression levels of IL-1ß and MHC-I correlated with the positive clinical effect. By immunohistochemistry, some inflammatory mediators like CD8, CXCL-9, and MHC-I were downmodulated. However, no consistent changes were noted for ubiquitin, nitrotyrosin and ß-amyloid. CONCLUSIONS: Alemtuzumab showed a trend towards downregulation of the expression of some inflammatory molecules in skeletal muscle of IBM patients but has no effect on several crucial markers of cell stress and degeneration. The data are helpful to explain the molecular treatment effects of future lymphocyte-targeted immunotherapies in IBM.

Severe acute inflammatory demyelinating polyradiculoneuropathy with persistent weakness associated with tumor-like nerve root enlargement.

We report a 23-year-old woman with rapid onset of proximal and distal limb weakness and areflexia, associated with tumor-like spinal nerve root enlargement and markedly elevated cerebrospinal fluid protein. Our patient developed the inability to walk within days, without preceding illness. Within two weeks, she had near-complete bilateral wrist and foot drop. Her cranial nerves and respiratory function remained intact. She received intravenous immunoglobulin early on for suspected Guillain-barre syndrome but remained wheelchair-bound until 6 Plasma exchange sessions were completed. After that, she continued to improve with intravenous immunoglobulin dosed every 3-4 weeks. Prominent demyelinating features were found on NCS, with cerebrospinal fluid protein of 415 mg/dL. Comprehensive infectious work-up was negative. Magnetic resonance imaging of lumbosacral and cervical spine showed tumor-like masses mistaken for neurofibromatosis (axial diameter, 7.5-10 mm). Repeated magnetic resonance imaging 6 months later showed persistent nerve root enlargement, despite the patient's improved functional status.

Autoimmune stiff person syndrome and related myelopathies: understanding of electrophysiological and immunological processes.

Stiff person syndrome (SPS) is a disabling autoimmune central nervous system disorder characterized by progressive muscle rigidity and gait impairment with superimposed painful spasms that involve axial and limb musculature, triggered by heightened sensitivity to external stimuli. Impaired synaptic GABAergic inhibition resulting from intrathecal B-cell-mediated clonal synthesis of autoantibodies against various presynaptic and synaptic proteins in the inhibitory neurons of the brain and spinal cord is believed to be an underlying pathogenic mechanism. SPS is most often idiopathic, but it can occur as a paraneoplastic condition. Despite evidence that anti-GAD and related autoantibodies impair GABA synthesis, the exact pathogenic mechanism of SPS is not fully elucidated. The strong association with several MHC-II alleles and improvement of symptoms with immune-modulating therapies support an autoimmune etiology of SPS. In this review, we discuss the clinical spectrum, neurophysiological mechanisms, and therapeutic options, including a rationale for agents that modulate B-cell function in SPS.

Rituximab induces sustained reduction of pathogenic B cells in patients with peripheral nervous system autoimmunity.

The B cell-depleting IgG1 monoclonal antibody rituximab can persistently suppress disease progression in some patients with autoimmune diseases. However, the mechanism underlying these long-term beneficial effects has remained unclear. Here, we evaluated Ig gene usage in patients with anti-myelin-associated glycoprotein (anti-MAG) neuropathy, an autoimmune disease of the peripheral nervous system that is mediated by IgM autoantibodies binding to MAG antigen. Patients with anti-MAG neuropathy showed substantial clonal expansions of blood IgM memory B cells that recognized MAG antigen. The group of patients showing no clinical improvement after rituximab therapy were distinguished from clinical responders by a higher load of clonal IgM memory B cell expansions before and after therapy, by persistence of clonal expansions despite efficient peripheral B cell depletion, and by a lack of substantial changes in somatic hypermutation frequencies of IgM memory B cells. We infer from these data that the effectiveness of rituximab therapy depends on efficient depletion of noncirculating B cells and is associated with qualitative immunological changes that indicate reconfiguration of B cell memory through sustained reduction of autoreactive clonal expansions. These findings support the continued development of B cell-depleting therapies for autoimmune diseases.

Effect of Alemtuzumab (CAMPATH 1-H) in patients with inclusion-body myositis.

Sporadic inclusion-body myositis (sIBM) is the most common disabling, adult-onset, inflammatory myopathy histologically characterized by intense inflammation and vacuolar degeneration. In spite of T cell-mediated cytotoxicity and persistent, clonally expanded and antigen-driven endomysial T cells, the disease is resistant to immunotherapies. Alemtuzumab is a humanized monoclonal antibody that causes an immediate depletion or severe reduction of peripheral blood lymphocytes, lasting at least 6 months. We designed a proof-of-principle study to examine if one series of Alemtuzumab infusions in sIBM patients depletes not only peripheral blood lymphocytes but also endomysial T cells and alters the natural course of the disease. Thirteen sIBM patients with established 12-month natural history data received 0.3 mg/kg/day Alemtuzumab for 4 days. The study was powered to capture > or =10% increase strength 6 months after treatment. The primary end-point was disease stabilization compared to natural history, assessed by bi-monthly Quantitative Muscle Strength Testing and Medical Research Council strength measurements. Lymphocytes and T cell subsets were monitored concurrently in the blood and the repeated muscle biopsies. Alterations in the mRNA expression of inflammatory, stressor and degeneration-associated molecules were examined in the repeated biopsies. During a 12-month observation period, the patients' total strength had declined by a mean of 14.9% based on Quantitative Muscle Strength Testing. Six months after therapy, the overall decline was only 1.9% (P < 0.002), corresponding to a 13% differential gain. Among those patients, four improved by a mean of 10% and six reported improved performance of daily activities. The benefit was more evident by the Medical Research Council scales, which demonstrated a decline in the total scores by 13.8% during the observation period but an improvement by 11.4% (P < 0.001) after 6 months, reaching the level of strength recorded 12 months earlier. Depletion of peripheral blood lymphocytes, including the naive and memory CD8+ cells, was noted 2 weeks after treatment and persisted up to 6 months. The effector CD45RA(+)CD62L(-) cells, however, started to increase 2 months after therapy and peaked by the 4th month. Repeated muscle biopsies showed reduction of CD3 lymphocytes by a mean of 50% (P < 0.008), most prominent in the improved patients, and reduced mRNA expression of stressor molecules Fas, Mip-1a and alphaB-crystallin; the mRNA of desmin, a regeneration-associated molecule, increased. This proof-of-principle study provides insights into the pathogenesis of inclusion-body myositis and concludes that in sIBM one series of Alemtuzumab infusions can slow down disease progression up to 6 months, improve the strength of some patients, and reduce endomysial inflammation and stressor molecules. These encouraging results, the first in sIBM, warrant a future study with repeated infusions

Inclusion body myositis with human immunodeficiency virus infection: four cases with clonal expansion of viral-specific T cells.

OBJECTIVE: Sporadic inclusion body myositis (sIBM), a common adult-onset myositis, is characterized by an antigen-driven inflammatory response and vacuolar degeneration. The cause is unknown. We report the association of sIBM with human immunodeficiency virus (HIV) infection and explore the clonality and viral specificity of the autoinvasive T cells. METHODS: Clinicopathological studies in four HIV-infected patients with IBM were performed. The clonal restriction of endomysial T cells, compared with peripheral blood, was examined by spectratyping. Immunohistochemical studies using human leukocyte antigen-A* 0201-gag tetramers and the most dominant Vb families were performed in serial muscle biopsy sections to examine whether clonally expanded autoinvasive T cells are viral specific and invade muscle fibers expressing the allele-specific monomorphic major histocompatibility complex class I antigen. RESULTS: Prominent clonal restriction of certain Vb families was noted among the endomysial T cells with evidence of in situ expansion. Approximately 10% of the autoinvasive CD8(+) cells were human leukocyte antigen-A* 0201-HIV-gag specific and invaded muscle fibers expressing the specific human leukocyte antigen-A* 0201 allele. These cells belonged to restricted Vb families. The HIV gag antigen was present on several endomysial macrophages but not within the muscle fibers. INTERPRETATION: sIBM develops in patients who harbor HIV. In HIV-IBM, a subset of CD8(+) T cells surrounding muscle fibers are viral specific and may play a role in the disease mechanism by cross-reacting with antigens on the surface of muscle fibers. This study provides a paradigm that a chronic viral infection in genetically susceptible individuals can trigger viral specific T cell clones that persist within the muscle and lead to development of sIBM.

Bilateral pallidotomy for severe dystonia in an 18-month-old child with glutaric aciduria.

Glutaric aciduria type 1 is an inborn error of metabolism due to deficiency of glutaryl-CoA dehydrogenase. This disorder mainly affects children. The majority of patients develop a dystonic-dyskinetic syndrome. The dystonia is painful and can cause significant disability. This report documents an 18-month-old child, the youngest reported, who underwent pallidotomy for disabling dystonia. The surgery improved dystonic symptoms, especially pain in this child with minor complications related to the procedure. Pallidotomy is a reasonable option for children with dystonic symptoms secondary to glutaric aciduria.

Myasthenia gravis, thymoma, and intestinal pseudo-obstruction: a case report and review.

We report a 28-year-old man who presented with intestinal pseudo-obstruction as the initial manifestation of thymoma, myasthenia gravis, and dysautonomia. The patient's autoantibody profile was characteristic of this constellation of disorders, being positive for both muscle and ganglionic nicotinic acetylcholine receptor antibodies and striational antibody. Inflammatory cell infiltrates were found in the myenteric plexus of the stomach and small intestine. Review of 12 previously reported cases suggests that patients with both myasthenia gravis and dysautonomia in the context of thymoma respond poorly to therapy.