Neuro-Ophthalmic Manifestations of Lambert-Eaton Myasthenic Syndrome

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Article initiated by:

Andrew Go Lee, MD, Andrew Thomson, MD, Peter W. Mortensen, MD, Subahari Raviskanthan, MBBS

All contributors:

Nagham Al-Zubidi, MD, Subahari Raviskanthan, MBBS, Sonali Singh MD

Assigned editor:

Sonali Singh MD

Review:

Assigned status Update Pending

 by Sonali Singh MD on May 5, 2023.

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Contributing Editors:	add

Lambert-Eaton Myasthenic Syndrome

DiseasesDB

4030

ICD-10

[1]73.1

ICD-9

358.3

OMIM

600003

MedlinePlus

000710

MeSH

D015624

Disease Entity

Disease

Lambert-Eaton myasthenic syndrome (LEMS) is a neuromuscular junction disorder characterized by presynaptic autoantibodies against voltage-gated calcium channels (VGCCs) and limb weakness that improves after repetitive voluntary muscle movement. LEMS typically presents with hyporeflexia, autonomic dysfunction, and extremity weakness that progresses caudal to cranial and proximal to distal. Ophthalmic manifestations of LEMS include ptosis and diplopia but unlike myasthenia gravis (MG), ocular and bulbar weakness presents late rather than early in the disease. However, cases of LEMS presenting as isolated ocular symptoms have been reported. Dry eyes and pupillary dysfunction may also result from autonomic dysfunction. Diagnosis may be clinical with electromyography and serology confirmatory testing. The diagnosis of LEMS warrants extensive oncological screening. Management includes investigation for and treatment of any underlying malignancy. Pharmacotherapy options include 3,4-diaminopyridine, pyridostigmine, and immunosuppression if needed.

Etiology

LEMS is an acquired autoimmune disease secondary to a paraneoplastic syndrome or associated with an underlying autoimmune disease risk.

Risk Factors

Around 60% of LEMS have an associated underlying tumor, and small cell lung cancer (SCLC) is the most common malignancy seen in LEMS. Smoking is a risk factor for LEMS, presumably because of the association with SCLC. Other malignancies with reported LEMS association include thymoma, carcinoid tumor, non-Hodgkin lymphoma, leukemia, prostate cancer, breast cancer, cervical cancer, malignant bone tumor, and transitional cell cancer of the bladder.

Pathophysiology

The autoantibodies formed in LEMS are directed against voltage-gated calcium channels present on presynaptic nerve terminals. The P/Q-type VGCCs, found on motor nerve terminals, are particularly affected, but antibodies to the N-type VGCCs, found on autonomic nerve terminals, may be seen. In response to an action potential, these transmembrane proteins allow the influx of calcium into the nerve terminal. Calcium is required for the fusion of acetylcholine-containing vesicles to the presynaptic membrane and subsequent release of acetylcholine into the synaptic cleft. At the neuromuscular junction, this leads to muscle contraction.

A proposed mechanism for autoantibody development is the cross-reactivity of antibodies against VGCCs expressed in high concentrations on SCLC tumor cells. VGCC antibodies may develop in the absence of cancer. This is known as non-tumor LEMS (NT-LEMS). NT-LEMS is associated with underlying autoimmune disease (e.g., thyroid disease), and the HLA-B8-DR 3 haplotype is seen in around 65% of patients.

Antibodies to the SOX1, a transcription factor expressed in SCLC cells, are present in 22-32% of patients with SCLC, 64-67% with SCLC-LEMS, and 0-5% with NT-LEMS, so they may assist in identifying SCLC-LEMS. Additionally, antibodies targeting other synapse-associated proteins are often present in LEMS patients. It is hypothesized that these autoantibodies form due to antigen exposure from immune-mediated destruction of motor endplates. The role in the disease process of these antibodies is not fully understood and have limited diagnostic value.

Diagnosis

The diagnosis may be made based on clinical features, and serologic and electrodiagnostic testing assists in diagnosis confirmation. LEMS often manifests before detecting malignant tumors, so the presence of LEMS warrants workup for underlying malignancy.

History

LEMS has a mean onset of around 60 years in SCLC-LEMS, but it can occur at almost any age. As for NT-LEMS, the mean age of onset has bimodal peaks at 35 and 60 years. Like MG, most NT-LEMS patients are female, while 65-75% of SCLC-LEMS patients are male. Determining history of smoking, autoimmune disease, and cancer may prove useful in the diagnosis.

Extremity weakness is the most common complaint and typically presents as symmetric extremity weakness that fluctuates during the day and worsens with warmth. Weakness in the legs is more common than in the arms and leads to difficulty rising from a seated position or climbing stairs. LEMS classically progresses over weeks to months from proximal to distal and caudal to cranial, eventually developing oculobulbar weakness. Cerebellar ataxia may be present as well. Uncommonly, patients complain of pain and stiffness accompanying this weakness. Respiratory failure is uncommon, but it may manifest with paralytic agent use or concurrent pulmonary disease.

Autonomic disturbances, especially anticholinergic, are seen in 80-96% of LEMS patients. In one study, dry mouth was the most frequent complaint found in 75% of patients. Other disturbances included erectile dysfunction, constipation, dry eyes, orthostatic hypotension, anhidrosis, and urinary retention.

Physical examination

A classic feature of LEMS is “Lambert’s sign,” where strength is improved with repeated voluntary muscle contraction (e.g., gradual increase in grip strength observed with sustained grip testing). However, as in myasthenia gravis, a continued effort will eventually lead to fatigue. Patients may present with extremity weakness and ocular/bulbar weakness, depending on disease progression. Deep tendon reflexes are often depressed or absent. Characteristic of LEMS, the reflexes may increase or appear after maximal voluntary contraction, but this finding has a low sensitivity. Despite weakness or prolonged disease, muscle atrophy is rarely observed.

Ophthalmic Manifestations

Ocular and bulbar symptoms are reported in 49-78% of LEMS and are usually seen late in the disease as it progresses craniocaudal. Compared to MG, the ocular and bulbar weakness seen in LEMS is typically milder and potentially under-appreciated. A Mayo Clinic retrospective review of 167 patients described the ophthalmic symptoms of LEMS including: ptosis (26%), diplopia (20.5%), decreased vision (14%), and dry eye (7%). Ocular signs included ptosis (26%), abnormal ocular motility (8.5%), strabismus (8%), pupillary dysfunction (7%), and dry eyes (2%). The dry eyes and pupillary dysfunction, usually seen as sluggish pupils, are likely intraocular manifestations of autonomic dysfunction. Although rare, LEMS presenting with isolated ocular symptoms has been reported as well.

Oncological Screening

LEMS may manifest before malignancy is detected, so extensive and repeated oncological screening should be considered after LEMS diagnosis. This may be accomplished with a PET scan or chest MRI every 3 to 6 months for at least 2 years. The DELTA-P score is a tool to help predict the presence of SCLC in LEMS and the need for additional screening. It may also assist in differentiating SCLC-LEMS and NT-LEMS. Each of the following, denoted by the acronym “DELTA-P,” constitutes one point in the score: bulbar signs (e.g., Dysarthria), Erectile dysfunction (not included for women), Loss of weight greater than ≥ 5% of body weight, Tobacco use at onset, Age ≥ 50-year-old, Karnofsky Performance less than 70. In the original 2011 publication by Titulaer et al., a score of 0 to 1 corresponds with a 0 to 2.6% chance of SCLC, while scores of 4, 5, and 6 correspond to 93.5%, 96.6%, and 100%, respectively.

Diagnostic Tests

Electrodiagnostic testing has high sensitivity and specificity in diagnosing LEMS and ruling out MG. On repeated nerve stimulation testing, the classic findings of a presynaptic neuromuscular transmission disorder may be observed as a low compound muscle action potential amplitude that increases over 60% with a high rate of stimulation or brief exercise.

Laboratory Tests

Detection of anti-voltage-gated calcium channel antibodies may be achieved with radioimmunoassay. In LEMS patients, anti-P/Q type VGCC antibodies are seen in 85-90% of patients. Anti-N type VGCCs antibodies are seen in 33% of patients. In the proper clinical context, the presence of VGCC antibodies may confirm the diagnosis. However, elevated anti-VGCC antibody titers have been found in other neurologic diseases, including those without autoimmune or inflammatory etiologies. Additionally, antibody titers do not correlate with disease severity, and the lack of anti-VGCC antibodies does not rule out LEMS. In seronegative patients, the anti-VGCC antibodies may be directed at an untested epitope or at levels below detection, especially in the presence of immunosuppressants. The incidence of SCLC is less common in seronegative (12%) vs. seropositive (60-70%) patients.

SOX antibodies have been used to differentiate LEMS with SCLC and NT-LEMS with 67% sensitivity and 95% specificity, but these antibodies have not been shown to impact the survival of SCLC patients.

Differential diagnosis

LEMS is often misdiagnosed, and MG is the most common incorrect attribution. This may be due to the rarity of LEMS. When compared with MG, LEMS has one-tenth to one-fourteenth the annual incidence and is 46 times less prevalent. LEMS and MG are not mutually exclusive and have been seen concomitantly in several case reports. Table 1 compiles differences between MG and LEMS.

Other diseases confused with LEMS include polymyositis, immune-mediated necrotizing myopathy, myotonic dystrophy type 2, Guillain-Barré syndrome, and amyotrophic lateral sclerosis. The lack of elevated creatine kinase, muscle pain, muscle fasciculation, or sensory symptoms may help in differentiating LEMS from other disorders.

Table 1: Comparing MG vs. LEMS
Finding	MG	LEMS
Antibodies	Postsynaptic Acetylcholine receptors	Presynaptic voltage-gated calcium channels
Most common associated tumor	Thymoma	Small cell lung cancer
Oculobulbar weakness	Common in early disease	Seen in later, severe disease
Disease progression	Craniocaudal	Caudocranial Proximal to distal
Weakness Post-exercise	Worsens	Improves
Deep Tendon Reflexes	Rarely diminished	Often depressed or absent with post-tetanic potentiation
Autonomic Dysfunction	Rare	Common
Response to pyridostigmine	Pronounced	Minimal

Management

If an associated tumor is present, management of the malignancy is a priority and has also been shown to improve LEMS symptoms. The immunosuppressive properties of chemotherapeutics may explain some of this improvement.

Medical therapy

3,4-diaminopyridine/amifampridine

Two formulations of 3,4-diaminopyrine (3,4-DAP), also called amifampridine, are FDA approved for the treatment of LEMS and are first-line therapy. One formulation is approved for patients 17-years and older and another for patients between 6 and 17-years-old. This drug blocks voltage-gated potassium channels on the presynaptic membrane, causing prolonged depolarization of the nerve terminal. A longer depolarization provides more time for VGCCs to stay open. Patients may complain of transient paresthesia and gastrointestinal symptoms. Some experience seizures, especially at high doses, so seizures are a contraindication.

Pyridostigmine

Pyridostigmine is an acetylcholine esterase inhibitor used to treat MG. It may also improve LEMS patients’ symptoms, but the response is to a lesser degree compared with MG.

Guanidine

Guanidine may be used in combination with pyridostigmine to treat LEMS symptoms. Adverse effects include some danger of renal failure and bone marrow suppression at higher doses.

Immunosuppression

For persistent symptoms, prednisolone, azathioprine, and rituximab have been used with some success. Plasmapheresis and IVIG have also been employed for severe or rapidly progressing disease.

Prognosis

The prognosis of LEMS is dependent on the presence of cancer versus autoimmune disease and the distribution of the weakness. SCLC is an aggressive disease and is often the cause of death in SCLC-LEMS patients.  However, the presence of LEMS in SCLC is associated with a longer overall survival independent of other prognostic variables. The prognosis of NT-LEMS varies depending on presentation and response to treatment. Unlike SCLC-LEMS, NT-LEMS does not seem to reduce lifespan.