Seronegative generalised myasthenia gravis: clinical features, antibodies, and their targets

doi:10.1016/S1474-4422(03)00306-5

The Lancet Neurology

Volume 2, Issue 2, February 2003, Pages 99-106

https://doi.org/10.1016/S1474-4422(03)00306-5 Get rights and content

Summary

Myasthenia gravis (MG) is a well-recognised disorder of neuromuscular transmission that can be diagnosed by the presence of antibodies to the acetylcholine receptor (AChR). However, some patients (about 15%) with generalised MG do not have detectable AChR antibodies. There is some evidence, however, that this “seronegative” MG is an antibody-mediated disorder. Plasma from patients with the disorder seems to contain various distinct humoral factors: IgG antibodies that reversibly inhibit AChR function; a non-IgG (possibly IgM) factor that indirectly inhibits AChR function; and an IgG antibody against the muscle-specific kinase (MuSK). The presence of antibodies against MuSK appears to define a subgroup of patients with seronegative MG who have predominantly localised, in many cases bulbar, muscle weaknesses (face, tongue, pharynx, etc) and reduced response to conventional immunosuppressive treatments. Moreover, muscle wasting may be present, which prevents complete response to these therapies.

Section snippets

Seropositive generalised MG

The clinical, pathophysiological, and therapeutic issues of seropositive MG have been reviewed elsewhere.1, 2 MG is the best-understood autoimmune disease of the nervous system, and one of the few conditions in which the effector mechanisms are thought to be entirely antibody-mediated. The antibodies are directed against AChR, which is exposed on the surface of the muscle membrane (figure 1), and lead to loss of AChRs, causing a defect in neuromuscular transmission with muscle weakness and

Seronegative MG

In the first comprehensive study of autoantibody status in patients with MG, Lindstrom and colleagues⁴ noted that AChR antibodies were not detectable in 13% of patients and suggested that they might have antibodies to another protein, or have a different form of the disease. seronegative MG is thus defined as generalised MG in which the diagnosis has been made on clinical, electrophysiological, and pharmacological grounds but in which AChR antibodies cannot be detected. The term Seronegative MG

Confirmation of a humoral factor

The response to plasma exchange in seronegative MG49, 50 and the transmission of the disorder from mother to child⁶⁴ clearly indicates that there is a circulating serum factor, probably IgG. The disease has been transferred to mice by injection of both plasma and immunoglobulin preparation from patients with seronegative MG. The mice did not show any obvious symptoms of MG, but electrophysiological tests in vitro revealed a defect in neuromuscular transmission in most animals.⁴⁹ One possible

Conclusions

There seem to be subtle differences between seronegative and seropositive MG, but these are difficult to quantify. The distinctions are based on studies in a few patients, in some of which there are concerns about diagnostic accuracy. Improvements in diagnostic accuracy in patients with seronegative MG is a high priority to facilitate clinical as well as experimental studies.

MG without AChR antibodies is proving to be heterogeneous. MuSK antibodies are found in about 40% of patients with

Search strategy and selection criteria

Data for this review were identified by searches of PubMed and Medline with the terms “seronegative myasthenia” and “myasthenia acetylcholine receptor negative” with or without “SFEMG”, “jitter”, or “tensilon/edrophonium”. We also referred to our own files for publications about myasthenia gravis. Abstracts were included only when they related directly to otherwise unpublished work by the authors. Only papers published in English were reviewed.

References (84)

VincentA et al.
Myasthenia gravis
Lancet
(2001)
EngelAG
The immunopathological basis of acetylcholine receptor deficiency in myasthenia gravis
Prog Brain Res
(1979)
RoseNR et al.
Defining criteria for autoimmune diseases (Witebsky's postulates revisited)
Immunol Today
(1993)
MittagTW et al.
Analysis of false negative results in the immunoassay for anti-acetylcholine receptor antibodies in myasthenia gravis
Clin Immunol Immunopathol
(1984)
WhitingPJ et al.
Acetylcholine receptor antibody characteristics in myasthenia gravis: fractionation of alpha-bungarotoxin binding site antibodies and their relationship to IgG subclass
J Neuroimmunol
(1983)
SonooM et al.
Single fiber EMG and repetitive nerve stimulation of the same extensor digitorum communis muscle in myasthenia gravis
Clin Neurophysiol
(2001)
KennettRP et al.
Repetitive nerve stimulation of anconeus in the assessment of neuromuscular transmission disorders
Electroencephalogr Clin Neurophysiol
(1993)
DurandMC et al.
Importance of neuromuscular “jitter” under stimulation in the diagnosis of myasthenia gravis
Neurophysiol Clin
(1997)
PaduaL et al.
SFEMG in ocular myasthenia gravis
Clin Neurophysiol
(2000)
FawcettPR et al.
Electrophysiological findings including single fibre EMG in a family with mitochondrial myopathy
J Neurol Sci
(1982)

YuYL et al.

A comparison of concentric needle electromyography, quantitative EMG and single fibre EMG in the diagnosis of neuromuscular diseases

Electroencephalogr Clin Neurophysiol

(1984)

IngEB et al.

The complication rate of edrophonium testing for suspected myasthenia gravis

Can J Ophthalmol

(2000)

BirmannsB et al.

Seronegative myasthenia gravis: clinical features, response to therapy and synthesis of acetylcholine receptor antibodies in vitro

J Neurol Sci

(1991)

EvoliA et al.

Clinical heterogeneity of seronegative myasthenia gravis

Neuromuscul Disord

(1996)

MossmanS et al.

Myasthenia gravis without acetylcholine-receptor antibody: a distinct disease entity

Lancet

(1986)

KuksJB et al.

Plasmapheresis in myasthenia gravis. a survey

Transfus Sci

(1998)

KuksJB et al.

Anti-acetylcholine receptor antibodies decrease after thymectomy in patients with myasthenia gravis: clinical correlations

J Autoimmun

(1991)

LuCZ et al.

Antibody-secreting cells to acetylcholine receptor and to presynaptic membrane receptor in seronegative myasthenia gravis

J Neuroimmunol

(1993)

LuCZ et al.

Antibody-secreting cells to acetylcholine receptor and to presynaptic membrane receptor in seronegative myasthenia gravis

J Neuroimmunol

(1993)

LiZ et al.

Modulation of acetylcholine receptor function in TE671 (rhabdomyosarcoma) cells by non-AChR ligands: possible relevance to seronegative myasthenia gravis

J Neuroimmunol

(1996)

BrooksEB et al.

A sensitive rosetting assay for detection of acetylcholine receptor antibodies using BC3H-1 cells: positive results in ‘antibody-negative’ myasthenia gravis

J Neuroimmunol

(1990)

ScuderiF et al.

Anti-p110 autoantibodies identify a subtype of “seronegative” myasthenia gravis with prominent oculobulbar involvement

Lab Invest

(2002)

KaminskiHJ

Myasthenia gravis and related disorders

(2003)

MacLennanC et al.

Acetylcholine receptor expression in human extraocular muscles and their susceptibility to myasthenia gravis

Ann Neurol

(1997)

LindstromJM et al.

Antibody to acetylcholine receptor in myasthenia gravis: prevalence, clinical correlates, and diagnostic value

Neurology

(1976)

Newsom-DavisJ et al.

Function of circulating antibody to acetylcholine receptor in myasthenia gravis: investigation by plasma exchange

Neurology

(1978)

ToykaKV et al.

Myasthenia gravis: passive transfer from man to mouse

Science

(1975)

PatrickJ et al.

Autoimmune response to acetylcholine receptor

Science

(1973)

LefvertAK et al.

Acetylcholine receptor antibody in myasthenia gravis: purification and characterization

Scand J Immunol

(1978)

TindallRS

Humoral immunity in myasthenia gravis: clinical correlations of anti-receptor antibody avidity and titer

Ann N Y Acad Sci

(1981)

SomnierFE

Clinical implementation of anti-acetylcholine receptor antibodies

J Neurol Neurosurg Psychiatry

(1993)

EvoliA et al.

Anti-AChR-negative myasthenia gravis: clinical and immunological features

Clin Invest Med

(1989)

VincentA et al.

Acetylcholine receptor antibody as a diagnostic test for myasthenia gravis: results in 153 validated cases and 2967 diagnostic assays

J Neurol Neurosurg Psychiatry

(1985)

SandersDB et al.

Seronegative myasthenia gravis

Neurology

(1997)

OgerJ et al.

Acetylcholine receptor antibodies in myasthenia gravis: use of a qualitative assay for diagnostic purposes

Can J Neurol Sci

(1987)

OhtaM et al.

Improved radioassay of anti-acetylcholine receptor antibody: application for the detection of extremely low antibody titers in sera from patients with myasthenia gravis

Clin Chem

(1990)

GottiC et al.

Detection of antibody classes and subpopulations in myasthenia gravis patients using a new nonradioactive enzyme immunoassay

Muscle Nerve

(1997)

BandiniF et al.

Ocular myasthenia mimicking a one-and-a-half syndrome

J Neuroophthalmol

(2001)

FrisbyJ et al.

Brainstem compression by a giant vertebrobasilar aneurysm mimicking seronegative myasthenia

J Neurol Neurosurg Psychiatry

(2001)

Kleiner-FismanG et al.

Myasthenia gravis mimicking stroke in elderly patients

Mayo Clinic Proc

(1998)

American Association of Electrodiagnostic Medicine Quality Assurance Committee

Literature review of the usefulness of repetitive nerve stimulation and single fiber EMG in the electrodiagnostic evaluation of patients with suspected myasthenia gravis or Lambert-Eaton myasthenic syndrome

Muscle Nerve

(2001)

KillianJM et al.

Decremental motor responses to repetitive nerve stimulation in ALS

Muscle Nerve

(1994)

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Median MGFA Class of II at baseline improved to an asymptomatic median classification at 12-months and last follow-up (p-values <.001) post-rituximab. Improvement in MGFA class was not significantly different between the groups. Twenty-one patients achieved clinical remission (12/17 AChR+, 9/16 MuSK+) with time to remission of 441.4 ± 336.6 days for AChR+ versus 230 ± 180.8 days for MuSK+ patients (p-value 0.049). The mean prednisone dosage requirement decreased significantly in both groups post-rituximab. AChR+ patients required more hospitalizations for exacerbation post-rituximab (p-value 0.046).
Rituximab treatment response is observed in both AChR+ and MuSK+ patients supporting the role of B cell depletion in the management of MG. While there was no significant difference between these groups in terms of clinical improvement, symptom-free state, and prednisone burden, MuSK+ MG patients may experience greater benefits, including earlier time to remission, fewer exacerbations and hospitalizations post-treatment.
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MG is often associated with pathological abnormalities of the thymus gland, including thymoma. It has been accepted that patients with thymoma-associated myasthenia gravis have antibodies against AChR [1]. Recently, there have been three cases of benign thymoma-associated seronegative myasthenia gravis reported in the literature [2,3].
Myasthenia gravis (MG) is generally caused by antibodies directed against the neuromuscular junction, including antibodies against the postsynaptic nicotinic acetylcholine receptor (AChR). Pathologic abnormalities of the thymus gland, including thymoma, are associated with MG. We report a 56-year-old woman who presented with double vision. Single fiber EMG confirmed myasthenia gravis. AChR, striational muscle and MuSK antibodies were absent in the serum. Chest CT demonstrated a malignant thymoma. We report the first case of seronegative myasthenia gravis associated with malignant thymoma. The case challenges the conventional wisdom that all patients with thymoma associated MG test positive for antibodies against AChR.
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ReviewSeronegative generalised myasthenia gravis: clinical features, antibodies, and their targets

Summary

Section snippets

Seropositive generalised MG

Seronegative MG

Confirmation of a humoral factor

Conclusions

Search strategy and selection criteria

Lancet

Prog Brain Res

Immunol Today

Clin Immunol Immunopathol

J Neuroimmunol

Clin Neurophysiol

Electroencephalogr Clin Neurophysiol

Neurophysiol Clin

Clin Neurophysiol

J Neurol Sci

Electroencephalogr Clin Neurophysiol

Can J Ophthalmol

J Neurol Sci

Neuromuscul Disord

Lancet

Transfus Sci

J Autoimmun

J Neuroimmunol

J Neuroimmunol

J Neuroimmunol

J Neuroimmunol

Lab Invest

Myasthenia gravis and related disorders

Acetylcholine receptor expression in human extraocular muscles and their susceptibility to myasthenia gravis

Ann Neurol

Antibody to acetylcholine receptor in myasthenia gravis: prevalence, clinical correlates, and diagnostic value

Neurology

Function of circulating antibody to acetylcholine receptor in myasthenia gravis: investigation by plasma exchange

Neurology

Myasthenia gravis: passive transfer from man to mouse

Science

Autoimmune response to acetylcholine receptor

Science

Acetylcholine receptor antibody in myasthenia gravis: purification and characterization

Scand J Immunol

Humoral immunity in myasthenia gravis: clinical correlations of anti-receptor antibody avidity and titer

Ann N Y Acad Sci

Clinical implementation of anti-acetylcholine receptor antibodies

J Neurol Neurosurg Psychiatry

Anti-AChR-negative myasthenia gravis: clinical and immunological features

Clin Invest Med

Acetylcholine receptor antibody as a diagnostic test for myasthenia gravis: results in 153 validated cases and 2967 diagnostic assays

J Neurol Neurosurg Psychiatry

Seronegative myasthenia gravis

Neurology

Acetylcholine receptor antibodies in myasthenia gravis: use of a qualitative assay for diagnostic purposes

Can J Neurol Sci

Improved radioassay of anti-acetylcholine receptor antibody: application for the detection of extremely low antibody titers in sera from patients with myasthenia gravis

Clin Chem

Detection of antibody classes and subpopulations in myasthenia gravis patients using a new nonradioactive enzyme immunoassay

Muscle Nerve

Ocular myasthenia mimicking a one-and-a-half syndrome

J Neuroophthalmol

Brainstem compression by a giant vertebrobasilar aneurysm mimicking seronegative myasthenia

J Neurol Neurosurg Psychiatry

Myasthenia gravis mimicking stroke in elderly patients

Mayo Clinic Proc

Literature review of the usefulness of repetitive nerve stimulation and single fiber EMG in the electrodiagnostic evaluation of patients with suspected myasthenia gravis or Lambert-Eaton myasthenic syndrome

Muscle Nerve

Decremental motor responses to repetitive nerve stimulation in ALS

Muscle Nerve

Review
Seronegative generalised myasthenia gravis: clinical features, antibodies, and their targets