Janice Massey - Independent Researcher (original) (raw)

Papers by Janice Massey

Pregnancy in MuSK‐positive myasthenia gravis: A single‐center case series

Muscle & Nerve, May 7, 2023

Introduction/AimsMyasthenia gravis (MG) with muscle‐specific tyrosine kinase (MuSK) antibodies (M... more Introduction/AimsMyasthenia gravis (MG) with muscle‐specific tyrosine kinase (MuSK) antibodies (MMG) is predominantly seen in women of childbearing age. Our objective in this study was to describe the course of MMG during pregnancy and within 6 months postpartum, and to document any effect on fetal health.MethodsA retrospective review was performed of medical records of patients with MMG seen in the Duke Myasthenia Gravis Clinic from 2003 to 2022. MMG patients with onset of MMG symptoms before or during pregnancy as well as within 6 months postpartum were reviewed.ResultsA total of 14 pregnancies in 10 patients were included in our study cohort. Initial MG symptoms developed during pregnancy or within 6 months postpartum in six patients. Four patients had two pregnancies, three of whom developed MG during their first pregnancy. In the patients diagnosed before pregnancy, MG symptoms increased in five of eight patients during pregnancy or postpartum. Four patients required rescue therapy with plasma exchange or intravenous immunoglobulin during pregnancy or postpartum. One patient had a cesarean section after prolonged labor due to failure of progression. There were no other complications of pregnancy or delivery, and all infants were healthy at delivery.DiscussionAs in non‐MuSK MG, women with MMG may also have worsening or may develop initial MG symptoms during pregnancy or within 6 months postpartum. More aggressive medical therapy may be required for pregnant patients with MMG. Further study is needed to identify the mechanism and risk of worsening of MMG during pregnancy or postpartum.

Muscle specific tyrosine kinase antibody positive myasthenia gravis (MuSK-MG) is characterized by... more Muscle specific tyrosine kinase antibody positive myasthenia gravis (MuSK-MG) is characterized by autoantibodies against the MuSK protein of the neuromuscular junction resulting in weakness of bulbar and proximal muscles. We previously demonstrated that patients with MuSK-MG have increased pro-inflammatory Th1 and Th17 responses. Tacrolimus, an immunosuppressant used in AChR-MG and transplantation patients, inhibits T cell responses through interference with IL-2 transcription. The therapeutic efficacy and immunological effect of tacrolimus in MuSK-MG is unclear. In the current study we examined the proliferation, phenotype and cytokine production of CD4+ and CD8+ T cells in peripheral blood mononuclear cells of MuSK-MG following a 3-day in vitro culture with or without tacrolimus. We determined that tacrolimus profoundly suppressed CD4 and CD8 T cell proliferation and significantly suppressed Th1 and Th17 responses, as demonstrated by a reduced frequency of IFN-γ, IL-2, and IL-17 producing CD4 T cells and reduced frequencies of IFN-γ and IL-2 producing CD8 T cells. Tacrolimus also inhibits pathogenic Th17 cells coproducing IL-17 and IFN-γ. In addition, tacrolimus suppressed follicular T helper cell (Tfh) and regulatory T helper cell (Treg) subsets. These findings provide preliminary support for tacrolimus as a potential alternative immunosuppressive therapy for MuSK-MG.

Lambert-Eaton Myasthenia With and Without Cancer: Clinical Characteristics and Long-term Survival (P6.444)

Neurology, Apr 10, 2018

Objective: To describe clinical characteristics and long-term survival in LEM patients seen in th... more Objective: To describe clinical characteristics and long-term survival in LEM patients seen in the Duke Myasthenia Gravis (MG) Clinic. Background: Lambert-Eaton Myasthenia (LEM) is an autoimmune disease associated with pre-synaptic P/Q-type calcium channel antibodies. Approximately 50–60% of LEM patients have cancer (CA-LEM). Few studies report long-term survival of LEM patients without cancer (NCA-LEM). Design/Methods: LEM patients seen between January 1980 and December 2015 were identified by review of the Duke MG Clinic Database. Results: Of 126 LEM patients, 71 (56%) were NCA-LEM. 58% of NCA-LEM and 49% of CA-LEM patients were female (p=0.34); the mean age of symptom onset was 48 and 63 years, respectively, in the 2 groups (p At 5, 10, 15, and 20 years, the survival probabilities of NCA-LEM patients were similar to those from the 2013 National Vital Statistics Report (p=0.07). Log-rank analysis of the unadjusted survival probabilities revealed a significant difference between LEM patients with and without cancer (p Conclusions: In a large longitudinal cohort, compared to LEM patients with cancer, a slightly higher proportion of those without cancer were female; they were also younger at onset, less likely to smoke tobacco, and had longer survival. Although virtually all patients with cancer had a history of smoking, a smoking history did not significantly affect long-term survival in LEM patients without cancer. LEM patients with and without cancer had a similar prevalence of coincidental autoimmune conditions. LEM did not significantly affect long-term survival in patients without cancer. Disclosure: Dr. Raja has nothing to disclose. Dr Juel has nothing to disclose. Dr. Massey has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Revance, Quatrobio. Dr. Hobson-Webb has nothing to disclose. Dr. Guptill has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Alexion, Argen-X, Becton Dickinson, and Grifols. Dr. Gable has nothing to disclose. Dr. Sanders has nothing to disclose.

Effects of Therapeutic Plasma Exchange on Myasthenic Outcome Measures (P3.172)

Objective: To demonstrate correlations between the effects of therapeutic plasma exchange (TPE) a... more Objective: To demonstrate correlations between the effects of therapeutic plasma exchange (TPE) and commonly used outcome measures of myasthenic response. Background: The MG Activities of Daily Living (MG-ADL), Quality of Life (MG-QOL15, Manual Muscle Testing (MG-MMT) and Composite (MGC) Scores are validated measures of myasthenic response to treatment that have not been examined in a prospective trial of therapeutic plasma exchange. Methods: TPE was performed according to institutional practice and patients were profiled for up to 12 weeks. Immunosuppressive medications were kept as constant as possible. We quantitated MG-ADL, MG-QOL15, MG-MMT and MGC Scores at 8 visits; screening, initiation and end of TPE, and at weeks 1, 2, 3, 6, 12 post procedure. Results: Ten patients (mean age=68 years; baseline MG-ADL=8.7, MG-QOL15=28.8, MG-MMT=29.5, MG-Composite=20.7) received a median of 6 TPE treatments during their first course; all improved. Three patients received more than one course of TPE. Rapid improvement was seen in all outcome measures although there was some variation in the degree of change between outcome measures in a given patient. Maximal improvement was achieved in most patients by Visit 6 or 7. No single outcome measure was more reliable than another although MG-QOL was the least reliable measure of improvement. Conclusions: This pilot study demonstrates that currently available validated myasthenic outcome measures can serve as primary and secondary outcome measure for studies using therapeutic apheresis in myasthenia gravis. Disclosure: Dr. Guptill has received personal compensation for activities with Jacobus Pharmaceuticals, Marinus, Momenta, Serimmune, and UCB Pharma, Inc for consulting services and from Grifols for educational activities. Dr. Guptill has received research support fro Dr. Juel has received research support from Alexion Pharmaceuticals. Dr. Massey has received research support from Allergan and Merz Pharmaceuticals. Dr. Chopra has nothing to disclose. Dr. Howard holds stock and/or stock options in Pfizer, Johnson & Johnson, and General Electric.

Annals of the New York Academy of Sciences, Sep 1, 2003

Is the Decremental Pattern in Lambert-Eaton Myasthenic Syndrome Different from That in Myasthenia Gravis? (P2.080)

OBJECTIVE: To determine if the decremental pattern to low-frequency repetitive nerve stimulation ... more OBJECTIVE: To determine if the decremental pattern to low-frequency repetitive nerve stimulation (LF-RNS) distinguishes between myasthenia gravis (MG) and the Lambert-Eaton myasthenic syndrome (LEMS). BACKGROUND: Decremental responses to LF-RNS are seen in MG and LEMS, but a “U-shaped” or non-progressive pattern has been said to be characteristic of MG. METHODS: RNS studies performed at 3/sec were retrospectively reviewed from 58 muscles in 34 LEMS patients and 54 muscles in 44 patients with MG, 38 of whom had acetylcholine receptor antibodies (AChR-ab), 4 had MuSK antibodies, and 2 had neither antibody. In each train, we calculated the percent fall in negative peak compound muscle action potential (CMAP) amplitude from the first to the 4th or 5th CMAP (“early decrement”) and from the 1st to the 9th or 10th CMAP (“late decrement”), and the ratio between the early and late decrement (“Late/Early%”). Receiver-operator characteristic (ROC) curves were calculated to determine the Late/Early% value that best distinguished between LEMS and MG. Positive and negative predictive values for each disease were calculated for this optimum Late/Early% value. RESULTS: T-test showed significant differences between Late/Early% values in LEMS and MG (p<0.0001): late decrement was greater than early decrement in LEMS (mean Late/Early% = 118%) and the converse was true in MG (mean Late/Early% = 85%), but there was considerable overlap in individual values. ROC curves showed that a Late/Early% of 102% discriminated between LEMS and MG in 89% of studies. The decremental pattern in MuSK MG patients resembled that in LEMS. CONCLUSIONS: These findings indicate that when the decrement becomes progressively greater during LF-RNS, the patient is more likely to have LEMS than MG, and in MG, is more likely to have MuSK antibodies. This LF-RNS pattern should prompt further electrophysiologic, serological and clinical evaluations to clarify the diagnosis. Disclosure: Dr. Sanders has received personal compensation for activities with Athena Diagnostics as a speaker, and with Accordant Health Services, Jacobus Pharmaceuticals, CytoKinetics, GlaxoSmithKline Inc., Alexion, and UCB Pharma as a consultant. Dr. Cao has nothing to disclose. Dr. Massey has received personal compensation for activities with Allergan, Inc. Dr. Massey has received research support from Cytokinetics, the National Institutes of Health, Allergan, Inc., and Merz Pharma. Dr. Juel has received research support from Jacobus Pharmaceuticals and the U.S Food and Drug Administration. Dr. Hobson-Webb has nothing to disclose. Dr. Guptil has received personal compensation for activities with UCB Pharma as a consultant, and Grifols as a scientific advisory board member.

Inhibition of the transcription factor ROR-γ reduces pathogenic Th17 cells in acetylcholine receptor antibody positive myasthenia gravis

Experimental Neurology, Mar 1, 2020

IL-17 producing CD4 T cells (Th17) cells increase significantly with disease severity in myasthen... more IL-17 producing CD4 T cells (Th17) cells increase significantly with disease severity in myasthenia gravis (MG) patients. To suppress the generation of Th17 cells, we examined the effect of inhibiting retinoic acid receptor-related-orphan-receptor-C (RORγ), a Th17-specific transcription factor critical for differentiation. RORγ inhibition profoundly reduced Th17 cell frequencies, including IFN-γ and IL-17 co-producing pathogenic Th17 cells. Other T helper subsets were not affected. In parallel, CD8 T cell subsets producing IL-17 and IL-17/IFN-γ were increased in MG patients and inhibited by the RORγ inhibitor. These findings provide rationale for exploration of targeted Th17 therapies, including ROR-γ inhibitors, to treat MG patients.

Journal of Neuroimmunology, Dec 1, 2018

Muscle-specific tyrosine-kinase-antibody positive myasthenia gravis (MuSK+ MG) is an immunologica... more Muscle-specific tyrosine-kinase-antibody positive myasthenia gravis (MuSK+ MG) is an immunological subtype with distinctive pathogenic mechanisms and clinical features. The aim of this study was to analyze the circulating plasma microRNA profile of patients with MuSK+ MG. From the discovery cohort miR-210-3p, miR-324-3p and miR-328-3p were further analyzed in the validation cohort. We found a distinct plasma profile of miR-210-3p and miR-324-3p that were significantly decreased in MuSK+ MG patients compared to healthy controls (4.1 ± 1.4 vs 5.1 ± 1.4, p=0.006 and 4.7 ± 1.0 vs 5.4 ± 1.3, p=0.02). These findings reveal a distinct plasma miRNA profile in MuSK+ MG.

Experimental Neurology, Feb 1, 2019

Muscle specific tyrosine kinase antibody positive myasthenia gravis (MuSK-MG) is characterized by... more Muscle specific tyrosine kinase antibody positive myasthenia gravis (MuSK-MG) is characterized by autoantibodies against the MuSK protein of the neuromuscular junction resulting in weakness of bulbar and proximal muscles. We previously demonstrated that patients with MuSK-MG have increased pro-inflammatory Th1 and Th17 responses. Tacrolimus, an immunosuppressant used in AChR-MG and transplantation patients, inhibits T cell responses through interference with IL-2 transcription. The therapeutic efficacy and immunological effect of tacrolimus in MuSK-MG is unclear. In the current study we examined the proliferation, phenotype and cytokine production of CD4+ and CD8+ T cells in peripheral blood mononuclear cells of MuSK-MG following a 3-day in vitro culture with or without tacrolimus. We determined that tacrolimus profoundly suppressed CD4 and CD8 T cell proliferation and significantly suppressed Th1 and Th17 responses, as demonstrated by a reduced frequency of IFN-γ, IL-2, and IL-17 producing CD4 T cells and reduced frequencies of IFN-γ and IL-2 producing CD8 T cells. Tacrolimus also inhibits pathogenic Th17 cells coproducing IL-17 and IFN-γ. In addition, tacrolimus suppressed follicular T helper cell (Tfh) and regulatory T helper cell (Treg) subsets. These findings provide preliminary support for tacrolimus as a potential alternative immunosuppressive therapy for MuSK-MG.

Can Mycophenolate Mofetil Be Successfully Tapered in Myasthenia Gravis? (P05.172)

Neurology, Apr 22, 2012

Objective: To determine if mycophenolate mofetil (MMF) can be tapered without worsening in patien... more Objective: To determine if mycophenolate mofetil (MMF) can be tapered without worsening in patients with myasthenia gravis (MG). Background MMF is frequently used in the treatment of MG, but no studies address long term management. Design/Methods: The Duke MG Patient Database was reviewed to identify all patients who were prescribed MMF from 1999-2011. Two hundred fifty-seven patients with adequate data were identified and 147 reached Minimal Manifestation Status (MMS) or Pharmacologic Remission (PR) after starting MMF. Their records were reviewed to determine if a taper of MMF had been attempted and were analyzed for factors including initial and worst MGFA scores, duration of MG prior to starting MMF, MMF dose, and concurrent therapies. If MG symptoms recurred after the dose of MMF was tapered, the dose at which relapse occurred and the subsequent clinical course were recorded. Patients were required to be on a stable lower dose of MMF for 6 months for a taper to be deemed successful. Results: MMF taper or discontinuation was attempted in 60 of 147 patients. Forty-four attempts (73%) were successful. No significant differences were found between the taper success and failure groups, other than an increased rate of prednisone use in the relapsing group (42% vs 14%). In the sixteen patients who failed attempts at an MMF taper, most developed only ocular symptoms and 69% again achieved MMS or PR after the prior dose was restored. The mean dose at which relapse occurred was 1066 mg/day (mean starting dose 2375 mg/day). Only one patient required addition of therapy (prednisone). Conclusions: In this retrospective analysis, 73% of MG patients tolerated MMF dose reduction without worsening. Concurrent prednisone use was associated with a higher rate of taper failure. In patients who did relapse, their symptoms were minor and most improved after the prior dose was restored. Disclosure: Dr. Hobson-Webb has received personal compensation for activities with Frederick O9Connor Medical Consultants as a consultant.Dr. Hobson-Webb has received research support from Genzyme Corporation. Dr. Juel has nothing to disclose. Dr. Guptill has nothing to disclose. Dr. Massey has nothing to disclose. Dr. Sanders has received personal compensation for activities with Athena Diagnostics, Accordant Health Services, Jacobus Pharmaceuticals, CytoKinetics, Bayhill Therapeutics, and GlaxoSmithKline, Inc.

Reply to “Diagnostic value of wrist median nerve cross sectional area versus wrist-to-forearm ratio in carpal tunnel syndrome”

Clinical Neurophysiology, Dec 1, 2008

Beekman R, Visser LH. Sonography in the diagnosis of carpal tunnel syndrome: a critical review of... more Beekman R, Visser LH. Sonography in the diagnosis of carpal tunnel syndrome: a critical review of the literature. Muscle Nerve 2003;27(1):26–33. Buchberger W, Judmaier W, Birbamer G, Lener M, Schmidauer C. Carpal tunnel syndrome: diagnosis with high-resolution sonography. AJR Am J Roentgenol 1992;159(4):793–8. Hobson-Webb LD, Massay JM, Juel VC, Sanders DB. The ultrasonographic wrist-toforearm median nerve area ratio in carpal tunnel syndrome. Clin Neurophysiol 2008;119:1353–7. Visser LH, Smidt MH, Lee ML. High-resolution sonography versus EMG in the diagnosis of carpal tunnel syndrome. J Neurol Neurosurg Psychiatry 2008;79:63–7.

Do Clinical Characteristics Predict Response to Mycophenolate Mofetil in Myasthenia Gravis? (P05.171)

Neurology, Apr 22, 2012

Muscle & Nerve, Feb 4, 2013

Introduction: Diabetic polyneuropathy (DPN) is increasingly prevalent in the USA, but nerve ultra... more Introduction: Diabetic polyneuropathy (DPN) is increasingly prevalent in the USA, but nerve ultrasound (US) findings have not been assessed systematically. Our aim was to establish the sonographic characteristics of lower extremity nerves in DPN and correlate them with electrodiagnostic (EDx) findings. Methods: Consecutive patients (n ¼ 25) with evidence of DPN and 25 patient controls without DPN underwent blinded US imaging of the fibular and sural nerves. Nerve cross-sectional area (CSA), diameter and echogenicity were recorded. Results: There were no differences in fibular or sural nerve CSA, diameter, or echogenicity between the 2 groups. No correlations between nerve CSA and EDx studies were found. In DPN, there were moderate inverse correlations with age (r ¼ À0.44 sural ankle, r ¼ À0.39 sural leg, r ¼ À0.45 fibular ankle). Conclusions: US measurements of lower extremity nerves in DPN do not differ from controls or correlate with EDx findings. Novel US techniques and/or pedal nerve US may be necessary to detect differences.

A Retrospective study of complications of therapeutic plasma exchange in myasthenia

Muscle & Nerve, Nov 21, 2012

Venous access for therapeutic plasma exchange (TPE) in myasthenia gravis (MG) can be achieved by ... more Venous access for therapeutic plasma exchange (TPE) in myasthenia gravis (MG) can be achieved by central venous catheters (CVC) or peripheral veins (PV), and the preferred method varies among providers. We evaluated our institutional experience with TPE venous access method and complications. We reviewed all TPE-treated MG patients (2005-2010) through blinded chart review. TPE complications were categorized as serious or minor. Serious complications ended the procedure and/or were potentially life-threatening. A total of 134 MG patients received 230 TPE courses; 56% were outpatient procedures. Whenever feasible, TPE was performed by PV access, which was successful in 75% of courses. Over 90% in both groups improved after TPE. Compared with PV access, CVCs were associated with more total (68% vs. 35%) and serious complications (41% vs. 4%), including 2 deaths. PV access for TPE can be used successfully in most MG patients and may reduce morbidity of the procedure.

Carolina Digital Repository (University of North Carolina at Chapel Hill), 2016

An integrated understanding of therapeutic plasma exchange (TPE) effects on immunoglobulins, auto... more An integrated understanding of therapeutic plasma exchange (TPE) effects on immunoglobulins, autoantibodies, and natural or acquired (vaccine) protective antibodies in patients with autoimmune myasthenia gravis (MG) is lacking. Prior studies measured TPE effects in healthy volunteers or heterogeneous autoimmune diseases populations. We prospectively profiled plasma IgA, IgM, IgG, IgG subclasses (IgG1-4), acetylcholine receptor autoantibodies (AChR+), and protective antibodies in patients with AChR+ MG receiving TPE for an exacerbation. TPE was performed according to institutional practice and patients were profiled for up to 12 weeks. Ten patients were enrolled (median age=72.9 years; baseline MG-Composite=21; median TPE treatments=6 during their first course) and all improved. The maximum decrease in all immunoglobulins, including AChR autoantibodies, was achieved on the final day of the first TPE course (approximately 60-70% reduction). Three weeks post-TPE mean AChR autoantibody, total IgG, IgG1 and IgG2 titers were below the reference range and had not recovered to within 20% of baseline, whereas other measured immunoglobulins approached baseline values. We did not generally observe an "overshoot" of immunoglobulins above pre-TPE levels or accelerated recovery of pathologic AChR autoantibodies. Protective antibody profiles showed similar patterns

The D uke myasthenia gravis clinic registry: I . D escription and demographics

Muscle & Nerve, Dec 5, 2020

IntroductionThe Duke Myasthenia Gravis (MG) Clinic Registry is a disease‐specific database contai... more IntroductionThe Duke Myasthenia Gravis (MG) Clinic Registry is a disease‐specific database containing physician‐derived data from patients seen in the Duke MG Clinic since 1980.MethodsData from 1060 MG patients initially seen between 1980 and 2008 were reviewed.ResultsFifty‐four percent were male. Symptoms began after age 50 in 66% of males and 42% of females. Peak onset age in males was in their 60's; females had no predominant onset age. Onset age for both sexes increased from 1980 to 2008. Thymoma was present in 8.5%. Weakness was limited to ocular muscles for at least 2 y in 22% and became generalized later in 8.3% of these. Acetylcholine receptor antibodies were present in 78% overall, 82% with generalized MG and 52% with ocular MG (OMG). The distribution of MG disease class was similar in males and females, except that a greater proportion of women experienced myasthenic crisis and men were more likely to have OMG.DiscussionData in the Registry permit comprehensive and longitudinal analysis of a validated MG population. Analysis of Registry data shows that the frequency of AChR antibody negative MG, ocular MG, and thymoma are similar to other reports, but the onset age and proportion of males have progressively increased compared to studies published more than 20 y ago. These observations demonstrate the value of collecting comprehensive clinical information and comparing historic and contemporary populations. Other potential uses of Registry data include comparison of outcome measures in different disease subgroups and the response to specific treatments.

Annals of clinical and translational neurology, Sep 27, 2019

Our objective is to report longitudinal results of the MG-ADL, MG-Composite, MG-MMT, and MG-QoL15... more Our objective is to report longitudinal results of the MG-ADL, MG-Composite, MG-MMT, and MG-QoL15 in an open-label trial of therapeutic plasma exchange in myasthenia gravis. Ten MG patients experiencing exacerbation had assessments prior to, immediately following, and at selected time points post-TPE. Changes from baseline to 2 weeks post-TPE were: MG-ADL median À5.0, P < 0.0033, MG-QoL15 median À13.0, P < 0.001, MG-MMT median À10.0, P < 0.0001, and MG-Composite median À10.0, P < 0.005. TPE produced a rapid, clinically significant change in all instruments, indicating these outcome measures are robust endpoints for clinical trials of rapidly efficacious MG therapies.

Journal of Autoimmunity, Aug 1, 2014

Muscle specific tyrosine kinase myasthenia gravis (MuSK MG) is a form of autoimmune MG that predo... more Muscle specific tyrosine kinase myasthenia gravis (MuSK MG) is a form of autoimmune MG that predominantly affects women and has unique clinical features, including prominent bulbar weakness, muscle atrophy, and excellent response to therapeutic plasma exchange. Patients with MuSK MG have predominantly IgG4 autoantibodies directed against MuSK on the postsynaptic muscle membrane. Lymphocyte functionality has not been reported in this condition. The goal of this study was to characterize T cell responses in patients with MuSK MG. Intracellular production of IFN-gamma, TNF-alpha, IL-2, IL-17, and IL-21 by CD4þ and CD8þ T cells was measured by polychromatic flow cytometry in peripheral blood samples from 11 Musk MG patients and 10 healthy controls. Only one MuSK MG patient was not receiving immunosuppressive therapy. Regulatory T cells (Treg) were also included in our analysis to determine if changes in T cell function were due to altered Treg frequencies. CD8þ T cells from MuSK MG patients had higher frequencies of polyfunctional responses than controls, and CD4þ T cells had higher IL-2, TNF-alpha, and IL-17. MuSK MG patients had a higher percentage of CD4þ T cells producing combinations of IFN-gamma/IL-2/TNF-gamma, TNF-alpha/IL-2, and IFN-gamma/TNF-alpha. Interestingly, Treg numbers and CD39 expression were not different from control values. MuSK MG patients had increased frequencies of Th1 and Th17 cytokines and were primed for polyfunctional proinflammatory responses that cannot be explained by a defect in CD39 expression or Treg number.

Clinical Neurophysiology, Jun 1, 2008

Objective: Peripheral nerve ultrasound is an emerging tool in the diagnosis of carpal tunnel synd... more Objective: Peripheral nerve ultrasound is an emerging tool in the diagnosis of carpal tunnel syndrome (CTS). Although numerous publications have cited an increased median nerve area at the wrist to be the diagnostic of CTS, there has been considerable variability in the published normal values for this measurement. Our objective is to collect data on the wrist-to-forearm ratio (WFR) of median nerve area in patients with CTS and healthy controls. Methods: Patients with electrodiagnostically proven CTS underwent ultrasonography of the median nerve at the wrist and forearm. The median nerve area was measured at these points and compared to values from asymptomatic volunteers. Results: The WFR of median nerve area in asymptomatic volunteers was 1.0 ± 0.1. The WFR in patients presenting with CTS was 2.1 ± 0.5. Conclusions: The WFR in patients with CTS is elevated as compared to asymptomatic controls. A WFR of P1.4 gave 100% sensitivity for detecting patients with CTS while using only median nerve area at the wrist resulted in a sensitivity of 45-93%, depending on the cutoff value used. Significance: The WFR of median nerve area promises to be a valid means of diagnosing CTS, and may be superior to measuring median nerve area at the wrist alone.

Journal of Neuroimmunology, Aug 1, 2020

A detailed understanding of the role of Tfh cells in MuSK-antibody positive myasthenia gravis (Mu... more A detailed understanding of the role of Tfh cells in MuSK-antibody positive myasthenia gravis (MuSK-MG) is lacking. We characterized phenotype and function of Tfh cells in MuSK-MG patients and controls. We found similar overall Tfh and follicular regulatory (Tfr) T cell frequencies in MuSK-MG and healthy controls, but MuSK-MG patients exhibited higher frequencies of Tfh17 cells and a higher ratio of Tfh:Tfr cells. These results suggest imbalanced Tfh cell regulation, further supported by increased frequencies of CD4 T cells co-producing IL-21/IL-17 and IL-17/IFN-γ, and increased Tfh-supported IgG production. These results support a role for Tfh cell dysregulation in MuSK-MG immunopathology.

Pregnancy in MuSK‐positive myasthenia gravis: A single‐center case series

Muscle & Nerve, May 7, 2023

Introduction/AimsMyasthenia gravis (MG) with muscle‐specific tyrosine kinase (MuSK) antibodies (M... more Introduction/AimsMyasthenia gravis (MG) with muscle‐specific tyrosine kinase (MuSK) antibodies (MMG) is predominantly seen in women of childbearing age. Our objective in this study was to describe the course of MMG during pregnancy and within 6 months postpartum, and to document any effect on fetal health.MethodsA retrospective review was performed of medical records of patients with MMG seen in the Duke Myasthenia Gravis Clinic from 2003 to 2022. MMG patients with onset of MMG symptoms before or during pregnancy as well as within 6 months postpartum were reviewed.ResultsA total of 14 pregnancies in 10 patients were included in our study cohort. Initial MG symptoms developed during pregnancy or within 6 months postpartum in six patients. Four patients had two pregnancies, three of whom developed MG during their first pregnancy. In the patients diagnosed before pregnancy, MG symptoms increased in five of eight patients during pregnancy or postpartum. Four patients required rescue therapy with plasma exchange or intravenous immunoglobulin during pregnancy or postpartum. One patient had a cesarean section after prolonged labor due to failure of progression. There were no other complications of pregnancy or delivery, and all infants were healthy at delivery.DiscussionAs in non‐MuSK MG, women with MMG may also have worsening or may develop initial MG symptoms during pregnancy or within 6 months postpartum. More aggressive medical therapy may be required for pregnant patients with MMG. Further study is needed to identify the mechanism and risk of worsening of MMG during pregnancy or postpartum.

Muscle specific tyrosine kinase antibody positive myasthenia gravis (MuSK-MG) is characterized by... more Muscle specific tyrosine kinase antibody positive myasthenia gravis (MuSK-MG) is characterized by autoantibodies against the MuSK protein of the neuromuscular junction resulting in weakness of bulbar and proximal muscles. We previously demonstrated that patients with MuSK-MG have increased pro-inflammatory Th1 and Th17 responses. Tacrolimus, an immunosuppressant used in AChR-MG and transplantation patients, inhibits T cell responses through interference with IL-2 transcription. The therapeutic efficacy and immunological effect of tacrolimus in MuSK-MG is unclear. In the current study we examined the proliferation, phenotype and cytokine production of CD4+ and CD8+ T cells in peripheral blood mononuclear cells of MuSK-MG following a 3-day in vitro culture with or without tacrolimus. We determined that tacrolimus profoundly suppressed CD4 and CD8 T cell proliferation and significantly suppressed Th1 and Th17 responses, as demonstrated by a reduced frequency of IFN-γ, IL-2, and IL-17 producing CD4 T cells and reduced frequencies of IFN-γ and IL-2 producing CD8 T cells. Tacrolimus also inhibits pathogenic Th17 cells coproducing IL-17 and IFN-γ. In addition, tacrolimus suppressed follicular T helper cell (Tfh) and regulatory T helper cell (Treg) subsets. These findings provide preliminary support for tacrolimus as a potential alternative immunosuppressive therapy for MuSK-MG.

Lambert-Eaton Myasthenia With and Without Cancer: Clinical Characteristics and Long-term Survival (P6.444)

Neurology, Apr 10, 2018

Objective: To describe clinical characteristics and long-term survival in LEM patients seen in th... more Objective: To describe clinical characteristics and long-term survival in LEM patients seen in the Duke Myasthenia Gravis (MG) Clinic. Background: Lambert-Eaton Myasthenia (LEM) is an autoimmune disease associated with pre-synaptic P/Q-type calcium channel antibodies. Approximately 50–60% of LEM patients have cancer (CA-LEM). Few studies report long-term survival of LEM patients without cancer (NCA-LEM). Design/Methods: LEM patients seen between January 1980 and December 2015 were identified by review of the Duke MG Clinic Database. Results: Of 126 LEM patients, 71 (56%) were NCA-LEM. 58% of NCA-LEM and 49% of CA-LEM patients were female (p=0.34); the mean age of symptom onset was 48 and 63 years, respectively, in the 2 groups (p At 5, 10, 15, and 20 years, the survival probabilities of NCA-LEM patients were similar to those from the 2013 National Vital Statistics Report (p=0.07). Log-rank analysis of the unadjusted survival probabilities revealed a significant difference between LEM patients with and without cancer (p Conclusions: In a large longitudinal cohort, compared to LEM patients with cancer, a slightly higher proportion of those without cancer were female; they were also younger at onset, less likely to smoke tobacco, and had longer survival. Although virtually all patients with cancer had a history of smoking, a smoking history did not significantly affect long-term survival in LEM patients without cancer. LEM patients with and without cancer had a similar prevalence of coincidental autoimmune conditions. LEM did not significantly affect long-term survival in patients without cancer. Disclosure: Dr. Raja has nothing to disclose. Dr Juel has nothing to disclose. Dr. Massey has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Revance, Quatrobio. Dr. Hobson-Webb has nothing to disclose. Dr. Guptill has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Alexion, Argen-X, Becton Dickinson, and Grifols. Dr. Gable has nothing to disclose. Dr. Sanders has nothing to disclose.

Effects of Therapeutic Plasma Exchange on Myasthenic Outcome Measures (P3.172)

Objective: To demonstrate correlations between the effects of therapeutic plasma exchange (TPE) a... more Objective: To demonstrate correlations between the effects of therapeutic plasma exchange (TPE) and commonly used outcome measures of myasthenic response. Background: The MG Activities of Daily Living (MG-ADL), Quality of Life (MG-QOL15, Manual Muscle Testing (MG-MMT) and Composite (MGC) Scores are validated measures of myasthenic response to treatment that have not been examined in a prospective trial of therapeutic plasma exchange. Methods: TPE was performed according to institutional practice and patients were profiled for up to 12 weeks. Immunosuppressive medications were kept as constant as possible. We quantitated MG-ADL, MG-QOL15, MG-MMT and MGC Scores at 8 visits; screening, initiation and end of TPE, and at weeks 1, 2, 3, 6, 12 post procedure. Results: Ten patients (mean age=68 years; baseline MG-ADL=8.7, MG-QOL15=28.8, MG-MMT=29.5, MG-Composite=20.7) received a median of 6 TPE treatments during their first course; all improved. Three patients received more than one course of TPE. Rapid improvement was seen in all outcome measures although there was some variation in the degree of change between outcome measures in a given patient. Maximal improvement was achieved in most patients by Visit 6 or 7. No single outcome measure was more reliable than another although MG-QOL was the least reliable measure of improvement. Conclusions: This pilot study demonstrates that currently available validated myasthenic outcome measures can serve as primary and secondary outcome measure for studies using therapeutic apheresis in myasthenia gravis. Disclosure: Dr. Guptill has received personal compensation for activities with Jacobus Pharmaceuticals, Marinus, Momenta, Serimmune, and UCB Pharma, Inc for consulting services and from Grifols for educational activities. Dr. Guptill has received research support fro Dr. Juel has received research support from Alexion Pharmaceuticals. Dr. Massey has received research support from Allergan and Merz Pharmaceuticals. Dr. Chopra has nothing to disclose. Dr. Howard holds stock and/or stock options in Pfizer, Johnson & Johnson, and General Electric.

Annals of the New York Academy of Sciences, Sep 1, 2003

Is the Decremental Pattern in Lambert-Eaton Myasthenic Syndrome Different from That in Myasthenia Gravis? (P2.080)

OBJECTIVE: To determine if the decremental pattern to low-frequency repetitive nerve stimulation ... more OBJECTIVE: To determine if the decremental pattern to low-frequency repetitive nerve stimulation (LF-RNS) distinguishes between myasthenia gravis (MG) and the Lambert-Eaton myasthenic syndrome (LEMS). BACKGROUND: Decremental responses to LF-RNS are seen in MG and LEMS, but a “U-shaped” or non-progressive pattern has been said to be characteristic of MG. METHODS: RNS studies performed at 3/sec were retrospectively reviewed from 58 muscles in 34 LEMS patients and 54 muscles in 44 patients with MG, 38 of whom had acetylcholine receptor antibodies (AChR-ab), 4 had MuSK antibodies, and 2 had neither antibody. In each train, we calculated the percent fall in negative peak compound muscle action potential (CMAP) amplitude from the first to the 4th or 5th CMAP (“early decrement”) and from the 1st to the 9th or 10th CMAP (“late decrement”), and the ratio between the early and late decrement (“Late/Early%”). Receiver-operator characteristic (ROC) curves were calculated to determine the Late/Early% value that best distinguished between LEMS and MG. Positive and negative predictive values for each disease were calculated for this optimum Late/Early% value. RESULTS: T-test showed significant differences between Late/Early% values in LEMS and MG (p<0.0001): late decrement was greater than early decrement in LEMS (mean Late/Early% = 118%) and the converse was true in MG (mean Late/Early% = 85%), but there was considerable overlap in individual values. ROC curves showed that a Late/Early% of 102% discriminated between LEMS and MG in 89% of studies. The decremental pattern in MuSK MG patients resembled that in LEMS. CONCLUSIONS: These findings indicate that when the decrement becomes progressively greater during LF-RNS, the patient is more likely to have LEMS than MG, and in MG, is more likely to have MuSK antibodies. This LF-RNS pattern should prompt further electrophysiologic, serological and clinical evaluations to clarify the diagnosis. Disclosure: Dr. Sanders has received personal compensation for activities with Athena Diagnostics as a speaker, and with Accordant Health Services, Jacobus Pharmaceuticals, CytoKinetics, GlaxoSmithKline Inc., Alexion, and UCB Pharma as a consultant. Dr. Cao has nothing to disclose. Dr. Massey has received personal compensation for activities with Allergan, Inc. Dr. Massey has received research support from Cytokinetics, the National Institutes of Health, Allergan, Inc., and Merz Pharma. Dr. Juel has received research support from Jacobus Pharmaceuticals and the U.S Food and Drug Administration. Dr. Hobson-Webb has nothing to disclose. Dr. Guptil has received personal compensation for activities with UCB Pharma as a consultant, and Grifols as a scientific advisory board member.

Inhibition of the transcription factor ROR-γ reduces pathogenic Th17 cells in acetylcholine receptor antibody positive myasthenia gravis

Experimental Neurology, Mar 1, 2020

IL-17 producing CD4 T cells (Th17) cells increase significantly with disease severity in myasthen... more IL-17 producing CD4 T cells (Th17) cells increase significantly with disease severity in myasthenia gravis (MG) patients. To suppress the generation of Th17 cells, we examined the effect of inhibiting retinoic acid receptor-related-orphan-receptor-C (RORγ), a Th17-specific transcription factor critical for differentiation. RORγ inhibition profoundly reduced Th17 cell frequencies, including IFN-γ and IL-17 co-producing pathogenic Th17 cells. Other T helper subsets were not affected. In parallel, CD8 T cell subsets producing IL-17 and IL-17/IFN-γ were increased in MG patients and inhibited by the RORγ inhibitor. These findings provide rationale for exploration of targeted Th17 therapies, including ROR-γ inhibitors, to treat MG patients.

Journal of Neuroimmunology, Dec 1, 2018

Muscle-specific tyrosine-kinase-antibody positive myasthenia gravis (MuSK+ MG) is an immunologica... more Muscle-specific tyrosine-kinase-antibody positive myasthenia gravis (MuSK+ MG) is an immunological subtype with distinctive pathogenic mechanisms and clinical features. The aim of this study was to analyze the circulating plasma microRNA profile of patients with MuSK+ MG. From the discovery cohort miR-210-3p, miR-324-3p and miR-328-3p were further analyzed in the validation cohort. We found a distinct plasma profile of miR-210-3p and miR-324-3p that were significantly decreased in MuSK+ MG patients compared to healthy controls (4.1 ± 1.4 vs 5.1 ± 1.4, p=0.006 and 4.7 ± 1.0 vs 5.4 ± 1.3, p=0.02). These findings reveal a distinct plasma miRNA profile in MuSK+ MG.

Experimental Neurology, Feb 1, 2019

Muscle specific tyrosine kinase antibody positive myasthenia gravis (MuSK-MG) is characterized by... more Muscle specific tyrosine kinase antibody positive myasthenia gravis (MuSK-MG) is characterized by autoantibodies against the MuSK protein of the neuromuscular junction resulting in weakness of bulbar and proximal muscles. We previously demonstrated that patients with MuSK-MG have increased pro-inflammatory Th1 and Th17 responses. Tacrolimus, an immunosuppressant used in AChR-MG and transplantation patients, inhibits T cell responses through interference with IL-2 transcription. The therapeutic efficacy and immunological effect of tacrolimus in MuSK-MG is unclear. In the current study we examined the proliferation, phenotype and cytokine production of CD4+ and CD8+ T cells in peripheral blood mononuclear cells of MuSK-MG following a 3-day in vitro culture with or without tacrolimus. We determined that tacrolimus profoundly suppressed CD4 and CD8 T cell proliferation and significantly suppressed Th1 and Th17 responses, as demonstrated by a reduced frequency of IFN-γ, IL-2, and IL-17 producing CD4 T cells and reduced frequencies of IFN-γ and IL-2 producing CD8 T cells. Tacrolimus also inhibits pathogenic Th17 cells coproducing IL-17 and IFN-γ. In addition, tacrolimus suppressed follicular T helper cell (Tfh) and regulatory T helper cell (Treg) subsets. These findings provide preliminary support for tacrolimus as a potential alternative immunosuppressive therapy for MuSK-MG.

Can Mycophenolate Mofetil Be Successfully Tapered in Myasthenia Gravis? (P05.172)

Neurology, Apr 22, 2012

Objective: To determine if mycophenolate mofetil (MMF) can be tapered without worsening in patien... more Objective: To determine if mycophenolate mofetil (MMF) can be tapered without worsening in patients with myasthenia gravis (MG). Background MMF is frequently used in the treatment of MG, but no studies address long term management. Design/Methods: The Duke MG Patient Database was reviewed to identify all patients who were prescribed MMF from 1999-2011. Two hundred fifty-seven patients with adequate data were identified and 147 reached Minimal Manifestation Status (MMS) or Pharmacologic Remission (PR) after starting MMF. Their records were reviewed to determine if a taper of MMF had been attempted and were analyzed for factors including initial and worst MGFA scores, duration of MG prior to starting MMF, MMF dose, and concurrent therapies. If MG symptoms recurred after the dose of MMF was tapered, the dose at which relapse occurred and the subsequent clinical course were recorded. Patients were required to be on a stable lower dose of MMF for 6 months for a taper to be deemed successful. Results: MMF taper or discontinuation was attempted in 60 of 147 patients. Forty-four attempts (73%) were successful. No significant differences were found between the taper success and failure groups, other than an increased rate of prednisone use in the relapsing group (42% vs 14%). In the sixteen patients who failed attempts at an MMF taper, most developed only ocular symptoms and 69% again achieved MMS or PR after the prior dose was restored. The mean dose at which relapse occurred was 1066 mg/day (mean starting dose 2375 mg/day). Only one patient required addition of therapy (prednisone). Conclusions: In this retrospective analysis, 73% of MG patients tolerated MMF dose reduction without worsening. Concurrent prednisone use was associated with a higher rate of taper failure. In patients who did relapse, their symptoms were minor and most improved after the prior dose was restored. Disclosure: Dr. Hobson-Webb has received personal compensation for activities with Frederick O9Connor Medical Consultants as a consultant.Dr. Hobson-Webb has received research support from Genzyme Corporation. Dr. Juel has nothing to disclose. Dr. Guptill has nothing to disclose. Dr. Massey has nothing to disclose. Dr. Sanders has received personal compensation for activities with Athena Diagnostics, Accordant Health Services, Jacobus Pharmaceuticals, CytoKinetics, Bayhill Therapeutics, and GlaxoSmithKline, Inc.

Reply to “Diagnostic value of wrist median nerve cross sectional area versus wrist-to-forearm ratio in carpal tunnel syndrome”

Clinical Neurophysiology, Dec 1, 2008

Beekman R, Visser LH. Sonography in the diagnosis of carpal tunnel syndrome: a critical review of... more Beekman R, Visser LH. Sonography in the diagnosis of carpal tunnel syndrome: a critical review of the literature. Muscle Nerve 2003;27(1):26–33. Buchberger W, Judmaier W, Birbamer G, Lener M, Schmidauer C. Carpal tunnel syndrome: diagnosis with high-resolution sonography. AJR Am J Roentgenol 1992;159(4):793–8. Hobson-Webb LD, Massay JM, Juel VC, Sanders DB. The ultrasonographic wrist-toforearm median nerve area ratio in carpal tunnel syndrome. Clin Neurophysiol 2008;119:1353–7. Visser LH, Smidt MH, Lee ML. High-resolution sonography versus EMG in the diagnosis of carpal tunnel syndrome. J Neurol Neurosurg Psychiatry 2008;79:63–7.

Do Clinical Characteristics Predict Response to Mycophenolate Mofetil in Myasthenia Gravis? (P05.171)

Neurology, Apr 22, 2012

Muscle & Nerve, Feb 4, 2013

Introduction: Diabetic polyneuropathy (DPN) is increasingly prevalent in the USA, but nerve ultra... more Introduction: Diabetic polyneuropathy (DPN) is increasingly prevalent in the USA, but nerve ultrasound (US) findings have not been assessed systematically. Our aim was to establish the sonographic characteristics of lower extremity nerves in DPN and correlate them with electrodiagnostic (EDx) findings. Methods: Consecutive patients (n ¼ 25) with evidence of DPN and 25 patient controls without DPN underwent blinded US imaging of the fibular and sural nerves. Nerve cross-sectional area (CSA), diameter and echogenicity were recorded. Results: There were no differences in fibular or sural nerve CSA, diameter, or echogenicity between the 2 groups. No correlations between nerve CSA and EDx studies were found. In DPN, there were moderate inverse correlations with age (r ¼ À0.44 sural ankle, r ¼ À0.39 sural leg, r ¼ À0.45 fibular ankle). Conclusions: US measurements of lower extremity nerves in DPN do not differ from controls or correlate with EDx findings. Novel US techniques and/or pedal nerve US may be necessary to detect differences.

A Retrospective study of complications of therapeutic plasma exchange in myasthenia

Muscle & Nerve, Nov 21, 2012

Venous access for therapeutic plasma exchange (TPE) in myasthenia gravis (MG) can be achieved by ... more Venous access for therapeutic plasma exchange (TPE) in myasthenia gravis (MG) can be achieved by central venous catheters (CVC) or peripheral veins (PV), and the preferred method varies among providers. We evaluated our institutional experience with TPE venous access method and complications. We reviewed all TPE-treated MG patients (2005-2010) through blinded chart review. TPE complications were categorized as serious or minor. Serious complications ended the procedure and/or were potentially life-threatening. A total of 134 MG patients received 230 TPE courses; 56% were outpatient procedures. Whenever feasible, TPE was performed by PV access, which was successful in 75% of courses. Over 90% in both groups improved after TPE. Compared with PV access, CVCs were associated with more total (68% vs. 35%) and serious complications (41% vs. 4%), including 2 deaths. PV access for TPE can be used successfully in most MG patients and may reduce morbidity of the procedure.

Carolina Digital Repository (University of North Carolina at Chapel Hill), 2016

An integrated understanding of therapeutic plasma exchange (TPE) effects on immunoglobulins, auto... more An integrated understanding of therapeutic plasma exchange (TPE) effects on immunoglobulins, autoantibodies, and natural or acquired (vaccine) protective antibodies in patients with autoimmune myasthenia gravis (MG) is lacking. Prior studies measured TPE effects in healthy volunteers or heterogeneous autoimmune diseases populations. We prospectively profiled plasma IgA, IgM, IgG, IgG subclasses (IgG1-4), acetylcholine receptor autoantibodies (AChR+), and protective antibodies in patients with AChR+ MG receiving TPE for an exacerbation. TPE was performed according to institutional practice and patients were profiled for up to 12 weeks. Ten patients were enrolled (median age=72.9 years; baseline MG-Composite=21; median TPE treatments=6 during their first course) and all improved. The maximum decrease in all immunoglobulins, including AChR autoantibodies, was achieved on the final day of the first TPE course (approximately 60-70% reduction). Three weeks post-TPE mean AChR autoantibody, total IgG, IgG1 and IgG2 titers were below the reference range and had not recovered to within 20% of baseline, whereas other measured immunoglobulins approached baseline values. We did not generally observe an "overshoot" of immunoglobulins above pre-TPE levels or accelerated recovery of pathologic AChR autoantibodies. Protective antibody profiles showed similar patterns

The D uke myasthenia gravis clinic registry: I . D escription and demographics

Muscle & Nerve, Dec 5, 2020

IntroductionThe Duke Myasthenia Gravis (MG) Clinic Registry is a disease‐specific database contai... more IntroductionThe Duke Myasthenia Gravis (MG) Clinic Registry is a disease‐specific database containing physician‐derived data from patients seen in the Duke MG Clinic since 1980.MethodsData from 1060 MG patients initially seen between 1980 and 2008 were reviewed.ResultsFifty‐four percent were male. Symptoms began after age 50 in 66% of males and 42% of females. Peak onset age in males was in their 60's; females had no predominant onset age. Onset age for both sexes increased from 1980 to 2008. Thymoma was present in 8.5%. Weakness was limited to ocular muscles for at least 2 y in 22% and became generalized later in 8.3% of these. Acetylcholine receptor antibodies were present in 78% overall, 82% with generalized MG and 52% with ocular MG (OMG). The distribution of MG disease class was similar in males and females, except that a greater proportion of women experienced myasthenic crisis and men were more likely to have OMG.DiscussionData in the Registry permit comprehensive and longitudinal analysis of a validated MG population. Analysis of Registry data shows that the frequency of AChR antibody negative MG, ocular MG, and thymoma are similar to other reports, but the onset age and proportion of males have progressively increased compared to studies published more than 20 y ago. These observations demonstrate the value of collecting comprehensive clinical information and comparing historic and contemporary populations. Other potential uses of Registry data include comparison of outcome measures in different disease subgroups and the response to specific treatments.

Annals of clinical and translational neurology, Sep 27, 2019

Our objective is to report longitudinal results of the MG-ADL, MG-Composite, MG-MMT, and MG-QoL15... more Our objective is to report longitudinal results of the MG-ADL, MG-Composite, MG-MMT, and MG-QoL15 in an open-label trial of therapeutic plasma exchange in myasthenia gravis. Ten MG patients experiencing exacerbation had assessments prior to, immediately following, and at selected time points post-TPE. Changes from baseline to 2 weeks post-TPE were: MG-ADL median À5.0, P < 0.0033, MG-QoL15 median À13.0, P < 0.001, MG-MMT median À10.0, P < 0.0001, and MG-Composite median À10.0, P < 0.005. TPE produced a rapid, clinically significant change in all instruments, indicating these outcome measures are robust endpoints for clinical trials of rapidly efficacious MG therapies.

Journal of Autoimmunity, Aug 1, 2014

Muscle specific tyrosine kinase myasthenia gravis (MuSK MG) is a form of autoimmune MG that predo... more Muscle specific tyrosine kinase myasthenia gravis (MuSK MG) is a form of autoimmune MG that predominantly affects women and has unique clinical features, including prominent bulbar weakness, muscle atrophy, and excellent response to therapeutic plasma exchange. Patients with MuSK MG have predominantly IgG4 autoantibodies directed against MuSK on the postsynaptic muscle membrane. Lymphocyte functionality has not been reported in this condition. The goal of this study was to characterize T cell responses in patients with MuSK MG. Intracellular production of IFN-gamma, TNF-alpha, IL-2, IL-17, and IL-21 by CD4þ and CD8þ T cells was measured by polychromatic flow cytometry in peripheral blood samples from 11 Musk MG patients and 10 healthy controls. Only one MuSK MG patient was not receiving immunosuppressive therapy. Regulatory T cells (Treg) were also included in our analysis to determine if changes in T cell function were due to altered Treg frequencies. CD8þ T cells from MuSK MG patients had higher frequencies of polyfunctional responses than controls, and CD4þ T cells had higher IL-2, TNF-alpha, and IL-17. MuSK MG patients had a higher percentage of CD4þ T cells producing combinations of IFN-gamma/IL-2/TNF-gamma, TNF-alpha/IL-2, and IFN-gamma/TNF-alpha. Interestingly, Treg numbers and CD39 expression were not different from control values. MuSK MG patients had increased frequencies of Th1 and Th17 cytokines and were primed for polyfunctional proinflammatory responses that cannot be explained by a defect in CD39 expression or Treg number.

Clinical Neurophysiology, Jun 1, 2008

Objective: Peripheral nerve ultrasound is an emerging tool in the diagnosis of carpal tunnel synd... more Objective: Peripheral nerve ultrasound is an emerging tool in the diagnosis of carpal tunnel syndrome (CTS). Although numerous publications have cited an increased median nerve area at the wrist to be the diagnostic of CTS, there has been considerable variability in the published normal values for this measurement. Our objective is to collect data on the wrist-to-forearm ratio (WFR) of median nerve area in patients with CTS and healthy controls. Methods: Patients with electrodiagnostically proven CTS underwent ultrasonography of the median nerve at the wrist and forearm. The median nerve area was measured at these points and compared to values from asymptomatic volunteers. Results: The WFR of median nerve area in asymptomatic volunteers was 1.0 ± 0.1. The WFR in patients presenting with CTS was 2.1 ± 0.5. Conclusions: The WFR in patients with CTS is elevated as compared to asymptomatic controls. A WFR of P1.4 gave 100% sensitivity for detecting patients with CTS while using only median nerve area at the wrist resulted in a sensitivity of 45-93%, depending on the cutoff value used. Significance: The WFR of median nerve area promises to be a valid means of diagnosing CTS, and may be superior to measuring median nerve area at the wrist alone.

Journal of Neuroimmunology, Aug 1, 2020

A detailed understanding of the role of Tfh cells in MuSK-antibody positive myasthenia gravis (Mu... more A detailed understanding of the role of Tfh cells in MuSK-antibody positive myasthenia gravis (MuSK-MG) is lacking. We characterized phenotype and function of Tfh cells in MuSK-MG patients and controls. We found similar overall Tfh and follicular regulatory (Tfr) T cell frequencies in MuSK-MG and healthy controls, but MuSK-MG patients exhibited higher frequencies of Tfh17 cells and a higher ratio of Tfh:Tfr cells. These results suggest imbalanced Tfh cell regulation, further supported by increased frequencies of CD4 T cells co-producing IL-21/IL-17 and IL-17/IFN-γ, and increased Tfh-supported IgG production. These results support a role for Tfh cell dysregulation in MuSK-MG immunopathology.