Oculobulbar involvement is typical with Lambert-Eaton myasthenic syndrome

Oculobulbar symptoms and/or signs were present in 18 of 23 (78%) of Lambert-Eaton myasthenic syndrome (LEMS) patients evaluated at the Lahey Clinic (Table). Sixty-five percent (15 of 23) of our patients had ptosis and/or diplopia, each present in 11 individuals. Bulbar signs and symptoms, including dysarthria in 10 and dysphagia in 8 patients, also were observed among our LEMS population. More than one prereferral oculobulbar feature occurred in 13 of our LEMS patients. Prereferral diagnostic considerations included myasthenia gravis, myopathies, and psychiatric disorders. These findings suggest that these atypical characteristics served to dissuade some colleagues from a diagnosis of LEMS. Thus, the presence of oculobulbar symptoms and signs cannot be used to exclude LEMS from the differential diagnosis.     

Ocular myasthenia gravis: response to long-term immunosuppressive treatment.

OBJECTIVE: Ocular myasthenia gravis is a subtype of myasthenia gravis that causes relatively mild disability, but may convert into severe generalised muscle weakness. A universal management plan for ocular myasthenia gravis has not been established. This study was performed to determine the outcome of ocular myasthenia gravis with the currently available therapeutic options. METHODS: Retrospective analysis of 78 patients with ocular myasthenia gravis with a mean disease duration of 8.3 (range 0.5-58.3) years. RESULTS: In 54 patients (69%) symptoms and signs remained confined to the extraocular muscles during the observation period. The remaining 24 patients (31%) developed symptoms of generalised myasthenia gravis; 50% of them within two years, 75% within four years after onset. A somewhat reduced risk of generalisation was found in those with mild symptoms, normal repetitive nerve stimulation test, and low or absent antiacetylcholine receptor (AChR) antibodies at the time of diagnosis. Patients receiving immunosuppressive treatment (corticosteroids and/or azathioprine) rarely developed generalised myasthenia gravis (six of 50, 12%). Those without such treatment, usually due to uncertain diagnosis and late referral, converted into generalised myasthenia gravis significantly more often (18 of 28, 64%). CONCLUSIONS: The prognosis of ocular myasthenia gravis is good. A conventional scheme with short-term corticosteroids and long-term azathioprine seems adequate to achieve remission in most patients. The proportion of patients developing generalised myasthenia gravis was smaller in this population compared with previously published groups (usually 50%-70%). Early immunosuppressive treatment is at least partially responsible for this finding. Thymectomy (performed here in 12 patients with an abnormal chest CT) also correlated with a good outcome, but had no apparent advantage over medical treatment alone.     

Anti-MuSK myasthenia gravis presenting with purely ocular findings

BACKGROUND: Antibodies to a muscle-specific receptor tyrosine kinase (MuSK) have been found in approximately 40% of patients with generalized myasthenia gravis who are seronegative for the antiacetylcholine receptor antibody. Many of the patients with anti-MuSK antibodies have prominent oculobulbar symptoms or weakness of the neck and respiratory muscles, but patients with ocular myasthenia have not been described. OBJECTIVE: To report a case of ocular myasthenia due to anti-MuSK antibodies. PATIENT: A young woman with ocular myasthenia and antibodies to MuSK. RESULTS: Anti-MuSK antibody was detected by radioimmunoassay using highly purified MuSK recombinant antigen. CONCLUSION: Ocular myasthenia gravis is a presentation of the anti-MuSK antibody syndrome.     

A review of the histopathological findings in myasthenia gravis: Clues to the pathogenesis of treatment-resistance in extraocular muscles

In myasthenia gravis autoantibodies target components of the neuromuscular junction causing variable degrees of weakness. In most cases, autoantibodies trigger complement-mediated endplate damage and extraocular muscles may be most susceptible. A proportion of MG cases develop treatment-resistant ophthalmoplegia. We reviewed publications spanning 65 years reporting the histopathological findings in the muscles and extraocular muscles of myasthenic patients to determine whether pathological changes in extraocular muscles differ from non-ocular muscles. As extraocular muscles represent a unique muscle allotype we also compared their histopathology in myasthenia to those in strabismus. We found that in myasthenia gravis, the non-ocular muscles frequently demonstrate neurogenic changes regardless of myasthenic serotype. Mitochondrial stress/damage was also frequent in myasthenic muscles and possibly more evident in muscle-specific kinase antibody-positive MG. Although myasthenia-associated paralysed extraocular muscles demonstrated prominent fibro-fatty replacement and mitochondrial alterations, these features appeared commonly in paralysed extraocular muscles of any cause. We postulate that extraocular muscles may be more susceptible than limb muscles to poor contractility as a consequence of myasthenia, resulting in a cascade of atrophy signaling pathways and altered mitochondrial homeostasis which contribute to the tipping point in developing treatment-resistant myasthenic ophthalmoplegia. Early strategies to improve force generation in extraocular muscles are critical.     

Maximal bite force and surface EMG in patients with myasthenia gravis

Masticatory muscle strength was quantified in patients with bulbar myasthenia gravis and compared with that of patients with ocular myasthenia gravis, patients in clinical remission (whether or not pharmacological) who previously suffered from bulbar myasthenia gravis, and healthy subjects. Maximal bite force and maximal activity of the masseter and temporalis muscles and of the submental muscle complex were measured. Bite force was decreased in the patients with bulbar myasthenia gravis, but was normal in the patients in the clinical remission group and in the ocular group. These findings were consistent with the results of electromyographic data. Although subjective reports of masticatory muscle weakness provide valuable information, quantitative measurements provide more information about the degree of muscle weakness of individual muscles. This is especially important for longitudinal evaluation of therapy in individual patients and for pharmacotherapeutic research.     

Myasthenia gravis Lambert‐Eaton overlap syndrome

Introduction: To assess whether a myasthenia gravis (MG) Lambert‐Eaton overlap syndrome (MLOS) exists. Methods: Case reports that met the universally accepted diagnostic criteria for MG and Lambert‐Eaton myasthenic syndrome (LEMS) were sought through a PubMed search. Fifty‐five possible cases of MLOS were identified. Results: Thirty‐nine cases met the diagnostic criteria for MG and LEMS. Analysis of clinical features showed that these patients have common MG and LEMS symptoms: oculo‐bulbar paresis and good response to anti‐cholinesterase for MG and limb weakness and decreased or absent reflexes for LEMS. All had the classical LEMS pattern in the repetitive nerve stimulation test: low compound muscle action potential amplitude and incremental response > 60% with brief exercise or at high rate of stimulation. Eight patients had combined positive acetylcholine receptor antibody (AChR‐ab) or muscle‐specific kinase‐ab and voltage‐gated calcium channel‐ ab tests. Conclusions: A myasthenia gravis Lambert‐Eaton overlap syndrome (MLOS) does exist. Muscle Nerve 53 : 20–26, 2016     

Extraocular muscle responses to high dose intravenous methylprednisolone in myasthenia gravis

Three patients with generalised myasthenia gravis and three with ocular myasthenia gravis received two to five courses of high dose intravenous methylprednisolone because of the failure of standard immunomodulating therapies. Changes in myasthenic signs were assessed using a four step system for grading muscle weakness and fatiguability in 10 test items. Although a brief and modest amelioration was found from day 1 to day 2 after the initial infusion in two patients with generalised myasthenia gravis, all three experienced a prolonged phase of worsening followed by improvement before the next course. Conversely, for two of the patients with ocular myasthenia gravis, a transient but dramatic improvement of ptosis and ocular immobility was noted from 90 minutes to 5 hours after initiating the first infusion, followed by mild or no exacerbation. This 3 hour improvement may be related not only to possible differences in the neuromuscular junction, but also to corticosteroids unmasking the central adaptation for the peripheral ocular muscle weakness by increasing the acetylcholine release.     

Seronegative myasthenia gravis

Six to 20 p.cent of patients with generalized myasthenia gravis and 30 to 50 p.cent of those with ocular myasthenia gravis do not have anti AchR antibodies. Strict clinical, pharmacological and electrophysiological criteria are needed for the diagnosis of sero-negative myasthenia gravis. Sero-negative myasthenia gravis is an autoimmune disorder. But thymic hyperplasia is generally absent. Antibodies directed against the muscle receptor of tyrosine kinase (anti MuSK antibodies) were recently demonstrated in 40 to 70 p.cent of patients with sero-negative myasthenia gravis. Sero-negative and sero-positive myasthenia gravis may be clinically very similar. But sero-negative myasthenia gravis may express predominantly severe oculobulbar weakness or mainly neck, shoulder and respiratory muscle weakness. Sero-negative myasthenia gravis is never associated with thymoma. Sero-negative myasthenia gravis responds to immunodulation but perhaps less well than sero-positive myasthenia gravis.     

Diagnostic difficulties in myasthenia gravis

Four patients with myasthenia gravis presented with severe, largely isolated, bulbar and respiratory muscles weakness. Tensilon tests were positive and antiacetylcholine receptor (anti-AChR) antibody titers were negative in all patients. Only 1 patient had a greater than 10% decremental response during the period of respiratory failure. Although routine nerve conduction studies were normal, all had very low-amplitude diaphragmatic compound muscle action potentials. Three patients had abundant fibrillation potentials and positive sharp waves largely restricted to respiratory muscles. Clinical and electrophysiological findings improved with corticosteroids, and surprisingly, decremental responses became positive in all patients. The assessment of patients with largely isolated bulbar and respiratory muscle weakness due to myasthenia gravis may be difficult and misleading, as anti-AChR antibody titers may be negative, decremental responses may be absent, and electrophysiological assessment atypical. Due consideration of clinical symptomatology, a Tensilon test, and a trial of immunosuppression may be necessary to establish the diagnosis. © 1998 John Wiley & Sons, Inc. Muscle Nerve 21:577–583, 1998.     

Clinical aspects of neuromuscular transmission disorders

Autoimmune disorders of neuromuscular transmission are caused by antibodies (abs) directed against membrane proteins at the motor end-plate. Myasthenia gravis (MG) is due, in most cases, to abs against the nicotinic acetylcholine receptor (AChR). Anti-AChR-positive MG actually includes different disease entities: weakness can be confined to extrinsic ocular muscles or can be generalized; patients with generalized MG (G-MG) can be subdivided on the basis of age of onset, HLA association and thymic pathology. About 15% of G-MG patients are anti-AChR-negative; in a proportion of these cases serum abs against the muscle- specific kinase (MuSK) are found. Anti-MuSK-positive MG is characterized by predominant involvement of bulbar muscles and very low frequency of thymic pathology. The Lambert-Eaton myasthenic syndrome (LEMS) is caused by abs against voltage-gated calcium channels at nerve terminal. LEMS is characterized by muscle weakness and autonomic disturbances and it is paraneoplastic in over 50% of the cases. In neuromyotonia and cramp-fasciculation syndrome, that are thought to be due to anti-voltage-gated potassium channel abs, signs of peripheral nerve hyperexcitability can be associated with CNS features.     

Ocular aspects of myasthenia gravis

Ocular myasthenia gravis is a not uncommon autoimmune disorder causing diplopia, ptosis, and weakness of lid closure. The predilection of myasthenia for the ocular muscles may be related to differences between limb and extraocular muscles in either physiological function or antigenicity. Clinically, ocular myasthenia can mimic any form of pupil-sparing ocular motility disorder. Dynamic abnormalities of myasthenic eye movements may reflect the primary hallmarks of the disease, which are fatigability and variability in strength, or secondary adaptive effects by the central nervous system. Tests to confirm the diagnosis include edrophonium challenge, repetitive nerve stimulation, single-fiber electromyography (EMG) of the frontalis, and assays for antibody directed against the acetylcholine receptor: all are less sensitive for ocular myasthenia than for generalized myasthenia. There is a higher incidence of other autoimmune conditions in myasthenia, notably thymoma and thyroid dysfunction. The differential diagnosis includes other diseases of the neuromuscular junction, such as Lambert-Eaton syndrome and botulism. Treatment consists of symptomatic use of acetylcholinesterase inhibitors and immunosuppression with steroids or azathioprine. Between 50 and 70% of patients with ocular myasthenia will eventually develop generalized disease: there is some retrospective data that steroids or azathioprine may reduce this by about 75%. The role of thymectomy in ocular myasthenia remains unclear.     

What's in a smile?: Quantification of the vertical smile of patients with myasthenia gravis

Many patients with myasthenia gravis who experience bulbar symptoms show a vertical smile, which may have a considerable, and often underestimated, impact on social life. Peri-oral muscle function can be quantified by calculating lip-length and snout indices, which indicate the degree to which a person is capable of smiling and of pursing the lips, respectively. In the present study patients with bulbar myasthenia gravis were compared to patients with ocular myasthenia gravis, patients now in remission (but previously suffering from bulbar myasthenia gravis), and healthy subjects. The lip-length and snout indices of patients with bulbar myasthenia gravis were significantly lower than those of the other groups. The facial impairments were no longer detectable in patients with bulbar myasthenia gravis in remission and no subclinical impairments in lip-length and snout indices were found in the ocular myasthenia gravis group. These findings were consistent with the patients' reports of impairment of smiling and other oral functions. The patients suffering from a vertical smile or other oral impairments were well aware of their condition, most probably because of the social consequences of being unable to smile. The indices could be of importance in the longitudinal evaluation of therapy in individual patients and in pharmacotherapeutical research. We found a low correlation between the lip-length and snout indices, which reflects the capricious pattern of involvement of separate muscles in myasthenia gravis. Therefore both indices deserve special attention if they are used for monitoring myasthenic symptoms.     

Neuromuscular disorders and thymoma

We describe a patient who had asymmetrical atrophy of limb muscles and myasthenic weakness of neck, facial, and bulbar muscles. Electrophysiological tests indicated myasthenia gravis of facial muscles and changes consistent with an asymmetrical motor neuropathy as a cause of the muscle atrophy. Both conditions occurred as complications of a locally invasive thymoma, and both failed to improve after surgery and radiation but substantially improved with subsequent treatment by corticosteroids, azathioprine, and plasmapheresis. Review of the literature disclosed that several neuromuscular conditions may be associated with thymoma, the commonest being myasthenia gravis. Muscle atrophy may occur in 10% of patients who have myasthenia gravis, whether associated with or without thymoma. Its mechanism is debated, and further studies are needed, but observations in our patient suggest the atrophy is due to a motor neuropathy. Primary treatment of the thymoma by surgery, irradiation if the tumor is invasive, and immunosuppressive therapy for neuromuscular complications offers a relatively good prognosis for this group of patients.     

Heterogeneity and shifts in distribution of muscle weakness in myasthenia gravis

The distribution of muscle weakness in myasthenia gravis (MG) patients with acetylcholine receptor (AChR) antibodies is highly variable. As muscle groups respond differently to therapeutic interventions, it is important to acknowledge this variability. We analysed the distribution of muscle weakness in 225 AChR MG patients over time. On the basis of combinations of muscle weakness, seven phenotypes were defined: ‘ocular’ (O), ‘bulbar’ (B), ‘neck/limbs/respiratory’ (NLR), or a combination (O+B, O+NLR, B+NLR and O+B+NLR). MG remained restricted to ocular weakness in 5%, whereas 7% never had ocular weakness. At last follow-up, ocular or bulbar weakness had resolved more frequently than NLR weakness (40%, 38% and 25%; p = 0.003, respectively). Patients with O, B or OB phenotype at baseline had a higher age at onset and were more frequently male than patients with NLR, ONLR, BNLR or OBNLR phenotype (52.7 ± 17.5 vs. 44.0 ± 18.9; p = 0.007 and 64% vs. 37%; p = 0.002, respectively). MG patients have heterogeneous distributions of muscle weakness and frequently shift between phenotypes. The phenotypic variations found in AChR MG suggest that also other factors aside from the AChR antibody mediated immune response are of importance in determining the disease expression in MG.     

HTLV‐1–associated myelopathy/tropical spastic paraparesis and peripheral neuropathy following live‐donor renal transplantation

Introduction: Our aim in this study was to provide an updated literature review of electrodiagnostic testing in myasthenia gravis and Lambert–Eaton myasthenic syndrome. Methods: A systematic review of the recent literature was performed using the following key words: myasthenia gravis (MG); Lambert–Eaton myasthenic syndrome (LEMS); electromyography (EMG); repetitive nerve stimulation (RNS); single‐fiber electromyography (SFEMG); nerve conduction study; and normative values. Results: Several articles supported testing of facial, bulbar, and respiratory muscles in the diagnosis of neuromuscular junction (NMJ) disorders, including muscle‐specific kinase antibody (MuSK)‐seropositive MG. Several articles supported use of concentric needle EMG as an alternative to SFEMG jitter in disorders of neuromuscular transmission. A limited number of articles addressed measurement of area (vs. amplitude) decrement in RNS and decreasing the threshold of post‐exercise facilitation. Conclusions: Electrodiagnostic testing continues to be useful for diagnosis of MG and LEMS, although the quality of the evidence is not great. This literature review summarizes RNS and jitter measurement of facial and respiratory muscles and use of concentric needle EMG for SFEMG. Muscle Nerve 52:455–462, 2015     

Limb-girdle myasthenia gravis in a 10-year-old girl: a case report

A 10-year-old girl presented with progressive proximal limb muscle weakness without facial, ocular, or bulbar muscle involvement. There was no fatigability or diurnal fluctuation in symptoms. Her weakness worsened with febrile illnesses and recovered with accruing disabilities over a few weeks. Serum creatine kinase levels and muscle biopsy were normal. A significant decrement on repetitive nerve stimulation test and positive response to therapeutic neostigmine challenge test confirmed the diagnosis of limb-girdle myasthenia. She responded well to corticosteroids and thymectomy, demonstrating a likely autoimmune etiology. This case highlights the long-term fluctuations in a case of myasthenia gravis and the need for a high index of suspicion for myasthenia in children presenting with unexplained muscle weakness, even in the absence of typical features such as fatigability, diurnal fluctuation, and oculobulbar weakness.     

Ocular myasthenia: evaluation of Tensilon tonography and electronystagmography as diagnostic tests

The value of electronystagmography (ENG) and of tonography in monitoring the beneficial effect of edrophonium chloride (Tensilon) on the extraocular muscles in myasthenia gravis has been assessed. Studies were performed on 17 patients with myasthenia gravis and on 18 control subjects, of whom nine had extraocular muscle weakness due to myopathic or neurogenic lesions.     

Paradoxical lid elevation with sustained upgaze: a sign of Lambert-Eaton syndrome

Myasthenia gravis and Lambert-Eaton myasthenic syndrome are causes of acquired extraocular muscle weakness and ptosis. Exacerbation of ptosis after sustained upgaze is a clinically useful sign in the diagnosis of myasthenia gravis. A 54-year-old woman with established Lambert-Eaton myasthenic syndrome exhibited transient improvement of her ptosis after sustained upgaze. We suggest that paradoxical lid elevation after sustained upgaze may be a clinically useful sign in distinguishing Lambert-Eaton myasthenic syndrome from myasthenia gravis.     

Ice pack test for myasthenia gravis

A common symptom of myasthenia gravis is eyelid ptosis. Often, the edrophonium test is negative, particularly in ocular myasthenia gravis. Myasthenic weakness is often improved by cold. We applied ice packs to the eye in 10 myasthenic patients and 7 disease controls. Eight of 10 patients with myasthenia gravis improved, whereas none of the controls improved. The ice pack test is useful in the diagnosis of myasthenia gravis.     

Edrophonium infrared optokinetic nystagmography in the diagnosis of myasthenia gravis.

Horizontal optokinetic nystagmus was measured by an infrared eye movement recording technique before and after the administration of intravenous edrophonium chloride in 16 patients wtih proved myasthenia gravis. All the patients, even those without clinically apparent ophthalmoparesis, demonstrated an increased amplitude of optokinetic nystagmus after administration of the drug. None of 12 control patients, many with ophthalmoparesis, showed increased optokinetic nystagmographic amplitude. The superiority of infrared recording techniques to electro-ocuography was discussed. Edrophonium infrared optokinetic nystagmography proved to be a sensitive and specific test of myasthenic weakness in extraocular muscles.