Pediatric Neurology 50 (2014) 11e17

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Pediatric Neurology
journal homepage: www.elsevier.com/locate/pnu

Original Article

Lambert-Eaton Syndrome, an Unrecognized Treatable Pediatric

Neuromuscular Disorder: Three Patients and Literature Review
Mirna Hajjar MD b, *, Jennifer Markowitz MD a, Basil T. Darras MD a, John T. Kissel MD c,
Jayashri Srinivasan MD PhD b, H. Royden Jones MD a, b, y
a
Department of Neurology, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts
b
Department of Neurology, Lahey Clinic, Burlington, Massachusetts
c
Department of Neurology, Ohio State University School of Medicine, Ohio

abstract
BACKGROUND: Lambert-Eaton myasthenic syndrome, a presynaptic neuromuscular junction autoimmune disorder,
rarely occurs in children. Patients typically present with proximal lower extremity weakness with areflexia.
METHODS: We report three children presenting between ages 9 and 10 years diagnosed with Lambert-Eaton
myasthenic syndrome 2 years, 1 year, and 5 months later, respectively. Their clinical attributes are correlated
with nine other pediatric Lambert-Eaton myasthenic syndrome patients found in our literature review. RESULTS:
These patients were identified as having Lambert-Eaton myasthenic syndrome during their evaluation for prox-
imal weakness. Low-amplitude compound muscle action potentials classically facilitating >100% with voluntary
exercise and/or 50 Hz stimulation were essential to diagnosis. Three of the 12 children had associated malig-
nancies, two of them had lymphoproliferative disorders with onset of symptoms more rapid than the rest, and the
third had neuroblastoma. The nine nonparaneoplastic Lambert-Eaton myasthenic syndrome patients responded to
immunomodulatory therapy with close return to their baseline function. Complete remission no longer necessi-
tating medication was reported in two patients. Follow-up up to 17 years was available on two patients previously
reported. CONCLUSION: Lambert-Eaton myasthenic syndrome is a diagnosis that must be considered in children
presenting with unidentified proximal muscle weakness. In most children, Lambert-Eaton myasthenic syndrome is
a primary autoimmune disorder that is treatable. Nevertheless, a search for malignancy is recommended.
Keywords: Lambert-Eaton myasthenic syndrome (LEMS), neuromuscular transmission disorders, myasthenia, myopathy, pediatric
Pediatr Neurol 2014; 50: 11-17
Ó 2014 Elsevier Inc. All rights reserved.

Introduction Initially described in a paraneoplastic setting affecting

Lambert-Eaton myasthenic syndrome (LEMS) is a para-
neoplastic or primary autoimmune disorder of the presyn-
aptic neuromuscular junction, characterized by proximal
lower extremity weakness, areflexia, and dysautonomia.1
middle-aged adults with small-cell lung cancer, LEMS
occurs as a primary autoimmune disorder in younger adults
and rarely children. We present three pediatric LEMS
patients with literature review emphasizing this unusual,
potentially treatable disorder.

Methods
Initially presented as a poster at the 12th International Conference on Myas-
thenia Gravis and Related Disorders May 21-23, 2012, at The New York Academy of
Sciences. The clinical presentation and long-term course of our three patients
Article History: are reported. PubMed search using “pediatric,” “childhood,” or “chil-
Received April 29, 2013; Accepted in final form August 3, 2013 dren” with “Lambert-Eaton myasthenic syndrome” or “LEMS” was per-
* Communications should be addressed to: Dr. Hajjar; 33 Burleigh formed. Patients’ selection criteria included clinical presentation, nerve
Road, Apt. 14; Bangor, ME 04401. conduction studies demonstrating post-exercise or repetitive motor
E-mail address: mirnahajjar@gmail.com nerve stimulation facilitation response greater than 100%, and/or posi-
tive voltage-gated calcium channel antibodies. Including our three pa-
y
Deceased. tients, 12 children ages 3 to 19 years are reviewed (Table A and B). Our

0887-8994/$ - see front matter Ó 2014 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.pediatrneurol.2013.08.009
12 M. Hajjar et al. / Pediatric Neurology 50 (2014) 11e17

TABLE A.
Clinical summary of LEMS in children and adolescents

Author Age at Presenting Symptoms Clinical Findings NCS/EMG CK, AChR Ab,
(Year) Onset/ and VGCC Ab
Gender
Shapira 10/M Progressive weakness, Bilateral ptosis, ophthalmoparesis, - CMAP amplitude reduced NA
(1974) visual disturbance, right tongue deviation, Gower’s - 3 Hz: decrement
bone pain, cachexia sign, proximal > distal extremity - 25 Hz: 170% increment
for 1 month weakness and absent MSRs - MUAPs: small, polyphasic
Brown 19/F Progressive proximal Waddling gait, Gower’s sign, - CMAP amplitude reduced CK normal
(1974) weakness for 1 year, proximal lower > upper - 1 Hz: decrement of 68% from
calf/thigh muscle extremity weakness, the first CMAP amplitude
tenderness, and absent MSRs and later - 30 Hz: 500% increment
dry eyes reduced PFTs - 10 seconds’ exercise: 150%
increment
- MUAP: mildly myopathic
Chelmicka 9/F Progressive lower Mild muscle tenderness, weakness - CMAP amplitude reduced - CK normal
(1979) extremities of the neck flexion, proximal to 0.5 mV - AChR Ab: negative
weakness for lower > upper extremity - 10 seconds’ exercise: 300%
3 months and weakness, hip thrust, and increment
difficulty chewing circumduction when walking, - 20 Hz: increment
initially hypoactive then absent - 2 Hz: 50% decrement
MSRs, perioral skin tightness, - MUAP: variable
and respiratory
insufficiency
Streib 16/F Progressive lower Proximal lower > upper extremity - CMAP amplitude reduced AChR Ab: negative
(1981) extremities weakness weakness, waddling gait, and - 2 Hz: small decrement
for 6 months normal MSRs - 10 seconds’ exercise: 100%
increment
- 50 Hz: increment
Squier 15/M Progressive lower Ptosis, mild facial weakness, - CMAP amplitude reduced CK normal
(1991) extremities weakness moderate proximal weakness, - 3 Hz: 21% decrement
and fatigue followed 15 months - 15 seconds’ exercise: 1030%
Backache later by fatigable weakness and increment
initially hypoactive MSRs that - 10 Hz: decrement then
1 month later became absent increment
- MUAP: small polyphasic
units
Argov 7/M Bilateral ptosis, Ptosis, ophthalmoparesis, proximal - CMAP amplitude reduced AChR Ab: negative
(1995) ophthalmoparesis, extremity weakness, absent MSRs to 1 mV
and unsteady gait in the legs and trace in the arms - 3 Hz: 75% decrement
- 20 Hz: 250% increment
- MUAP: normal
Tsao (2002) 10/F Progressive lower Neck flexion/extension and - CMAP amplitude reduced - CK normal
Patient 1 extremities weakness proximal > distal extremity - 3 Hz: moderate decrement - VGCC Ab: elevated
for 5 months, weakness, Gower’s sign and - 50 Hz: >200% increment at 602 pmol/L
followed by hypoactive MSRs - MUAP: normal (normal <20)
dysphagia
Tsao (2002) 9/M Progressive lower Mild facial weakness, - CMAP amplitude reduced - AChR Ab negative
Patient 2 extremities weakness proximal > distal - 3 Hz: decrement - VGCC P/Q-Ab:
for 12 months and lower > upper - 10 seconds’ exercise: 62% elevated at 161
extremity worsening increment pmol/L (normal <28)
weakness, and hypoactive - 50 Hz: 124% increment
MSRs - MUAP: small
Hoffman 9/M Progressive lower NA - CMAP amplitude reduced VGCC Ab: elevated
(2003) extremities weakness - 15 seconds’ exercise: 1075%
and intermittent increment
dysarthria
Kostera 11/M Progressive lower Mild proximal weakness, - CMAP amplitude reduced - CK normal
(2009) extremities weakness, waddling gait, Gower’s - 3 Hz: 45% decrement - AChR Ab: negative
muscle fatigue, and sign, and absent MSRs - 30 seconds’ exercise: 82% - VGCC Ab: elevated
frequent falls for increment
6 months - MUAP: myopathic
 M. Hajjar et al. / Pediatric Neurology 50 (2014) 11e17 13

Table A (continued )

Author Age at Presenting Symptoms Clinical Findings NCS/EMG CK, AChR Ab,
(Year) Onset/ and VGCC Ab
Gender
Morgan- 3/M Proximal weakness, Quadriparesis, ptosis, - Low frequency stimulation: - VGCC Ab: positive
Followell ptosis, and and lower extremities 31% decrement
(2013) constipation areflexia - High-frequency stimulation:
278% increment
Hajjar et al 9/F Progressive proximal Worsening lower > upper - CMAP amplitude reduced - CK normal
(2012) weakness for 2 years extremity weakness, absent - 3 Hz ¼ 20% decrement - VGCC Ab:
requiring wheelchair MSRs, and intermittent - 10 seconds’ exercise: borderline
eventually and respiratory insufficiency 276% increment (i.e., 20 pmol/L)
intermittent - MUAP: myopathic (normal < 20)
dyspnea
Abbreviations:
AChR Ab ¼ Acetylcholine receptor antibody
CK ¼ Serum creatine kinase
CMAP ¼ Compound muscle action potential
EMG ¼ Electromyograph
LEMS ¼ Lambert-Eaton myasthenic syndrome
MSR ¼ Muscle stretch reflex
MUAP ¼ Motor unit action potential
NA ¼ Not available
NCS ¼ Nerve conduction studies
PFTs ¼ Pulmonary function tests
VGCC Ab ¼ Voltage-gated calcium channel antibody

second and third cases were previously reported during the initial part of
their disorder.2 We add a 17-year follow-up.
Patient 1
A 9-year-old girl developed slowly progressive weakness and fatigue
of the proximal legs manifesting initially with difficulty while playing
soccer (running inconsistently and repeatedly stopping). She progressed
to having difficulty climbing into the school bus and then trouble
walking up her entire driveway, which is 800 feet long. Her first evalu-
ation about a year after symptom onset revealed proximal leg weakness
and diminished muscle stretch reflexes. Serum creatine kinase was
normal. Acetylcholine receptor antibodies were absent. Compound
muscle action potential (CMAP) amplitudes were low; repetitive motor
nerve stimulation was not attempted. Electromyograph demonstrated
early recruitment of predominantly low-amplitude, short-duration
motor unit potentials. Quadriceps muscle biopsy demonstrated
increased sarcolemma nuclei, fiber size variation, and minimal fiber at-
rophy with type 2 fiber predominance, interpreted as an “indeterminate
myopathy.”
Two years after symptom onset, she was unable to walk more than
a 300-foot distance, at which point she got tired and has to stop; she
exhibited increased falling and difficulty arising from low postures. A
second evaluation was then undertaken at Boston Children’s Hospital.
Examination, using the Medical Research Council grading scale,
showed reduced strength in the following muscles: neck and knees
flexors 5, shoulder abductors 4þ; and hip flexors, knee extensors, and
hip adductors 3. Muscle stretch reflexes were absent. She had a
Trendelenburg gait. Electrodiagnostic tests showed very low CMAP
amplitudes. After 10 seconds of voluntary exercise, the median CMAP
facilitated 276% (Fig); 3 Hz stimulation produced a 20% decrement.
Electromyograph demonstrated small polyphasic motor unit potentials
with no abnormal spontaneous activity. Voltage-gated calcium channel
antibodies testing performed three times at Mayo Clinic was borderline
(0.02 with normal <0.02). No malignancy was found. Autoimmune
LEMS was diagnosed. Initial treatment with three courses of intrave-
nous immunoglobulin was not beneficial. Intercurrent upper respira-
tory tract infections exacerbated her weakness significantly and led to
respiratory function decline with forced vital capacity values reaching
66% of predicted. She improved significantly after treatment with a
combination of cyclosporine with a bridge of plasmapheresis for
immunosuppression and 3, 4-diaminopyridine (1 mg/kg/day in divided
aliquots every 4 hours) plus pyridostigmine (30 mg four times per day
with 135 mg at bedtime) for symptomatic therapy. Her improvement
continues without relapse. At age 14, she needs to awaken an hour
early to take her 3, 4-diaminopyridine and pyridostigmine to have
strength to complete her morning activities. Overall she does very well
walking 5 miles, but still has difficulty running. Examination demon-
strates a strength of 5 in previously weak muscles, areflexia, and
normalization of her pulmonary function tests (forced vital capacity is
116%).
Patient 2
A 10-year-old girl presented with progressive difficulty climbing
stairs, then walking shortly after a 24-hour diarrheal illness. The weak-
ness continued to progress to the point where she could not sit up. She
also developed dysphagia. Evaluation included initially normal nerve
conduction studies at another institution; however, repeat studies 5
months after symptom onset demonstrated low-amplitude CMAPs that
facilitated with exercise and moderate decrement at 3 Hz repetitive
motor nerve stimulation; 50 Hz repetitive motor nerve stimulation
demonstrated 200% facilitation. Serum voltage-gated calcium channel
antibody titers were 30 times’ normal. A malignancy workup was
negative. She was diagnosed with primary autoimmune LEMS. Intrave-
nous immunoglobulin combined with pyridostigmine led to minimal
nonsustained improvement of the upper extremities only. Pyridostig-
mine, plasmapheresis, and corticosteroids combined brought significant
improvement where she could walk independently and climb stairs; hip
flexor strength was at Medical Research Council grade 4. Prednisone was
discontinued subsequent to vertebral compression fracture; she was
effectively transitioned to cyclosporine. Subsequently, each time the
cyclosporine dose was weaned, proximal weakness and fatigue recurred.
When first seen at age 22 at Boston Children’s hospital, then Lahey clinic,
she was no longer taking cyclosporine. She had increasing weakness for
which 3, 4-diaminopyridine was initiated at 20 to 30 mg/day. This gave
her short-term but incomplete effect with persistence of mild proximal
weakness and fatigue. Thus cyclosporine (250 mg/day) was reinitiated
and pyridostigmine (180 mg/day) was added. At age 26 with this treat-
ment, she is able to carry out all her activities despite some mild
weakness.
Patient 3
A 10-year-old boy presented with a 1-year history of problems
arising from a squat and climbing stairs. His examination revealed
14 M. Hajjar et al. / Pediatric Neurology 50 (2014) 11e17

TABLE B.
Treatment and outcome in children/adolescents reported with LEMS

Author (Year) Age/Gender Associations Treatment Response Outcome

Shapira (1974) 10/M Leukemia - Neostigmine No improvement At 2-month follow-up:
died of underlying cancer
Brown (1974) 19/F No malignancy and - Pyridostigmine No significant improvement. At 8-year follow-up:
no autoimmune - Guanidine Prompt clinical improvement sustained improvement
background on guanidine
Chelmicka (1979) 9/F Positive ANA - Prednisone Improvement; relapse At 3-year follow-up:
and elevated - Pyridostigmine when sustained improvement
serum globulins - Guanidine weaned off nonsustained on guanidine
improvement, followed by
worsening of symptoms
Prompt sustained
improvement
Streib (1981) 16/F No associated “collagen - Pyridostigmine No improvement At 3-year follow-up:
vascular” disease - Prednisone Improvement; relapse sustained improvement
when weaned off on prednisone
Squier (1991) 15/M Family history of vitiligo - 3, 4 DAP, PLEX, Improvement NA
and thyrotoxicosis prednisone, and
azathioprine
Argov (1995) 7/M Burkitt’s lymphoma NA NA At 3-month follow-up:
died of underlying cancer
Tsao (2002) 10/F Occurred shortly after - Pyridostigmine and Nonsustained mild At 17-year follow-up:
Patient 1 a viral illness. IVIg improvement Improvement, sustained improvement
No malignancy - Pyridostigmine, but relapse and complication on cyclosporine,
intravenous from prednisone (vertebral 3,4 DAP and
methylprednisolone, compression) Marked pyridostigmine
and PLEX improvement, relapse
- Cyclosporine when weaned,
improvement
when resumed
Tsao (2002) 9/M No malignancy and - PLEX Improvement but developed At 2-year follow-up:
Patient 2 no autoimmune - Cyclosporine and complication (line infection) sustained improvement
background IVIg Improvement on cyclosporine
17-year follow-up;
patient is in complete
remission without
medication
Hoffman (2003) 9/M Multiple other NA NA NA
autoimmune
diseases
Kostera (2009) 11/M No malignancy and - Pyridostigmine and Improvement At 3.5-year follow-up:
no autoimmune prednisone Improvement sustained benefit on
background - Azathioprine azathioprine
Morgan-Followell 3/M Neuroblastoma - PLEX Improvement At 3-year follow-up,
(2013) - Tumor resection Improvement patient is in remission
Hajjar et al. 9/F No malignancy, or ther - IVIg No improvement At 6-year follow-up:
(2012) autoimmunity - PLEX No improvement sustained benefit on
- Cyclosporine, 3,4 Improvement cyclosporine,
DAP, and 3,4 DAP, and
pyridostigmine pyridostigmine
Abbreviations:
3, 4 DAP ¼ 3,4 diaminopyridine
ANA ¼ antinuclear antibody
IVIg ¼ Intravenous immunoglobulins
PLEX ¼ Plasma exchange

diffuse weakness with Medical Research Council grade 3 in the
neck flexors and hip abductors and 2 in the hip extensors, with all
other major groups grading 4. Within 3 months of presentation, his
strength deteriorated to where he was barely ambulatory. Evalua-
tion included 50 Hz repetitive motor nerve stimulation demon-
strating a 124% increment. Voltage-gated calcium channel antibodies
were markedly elevated. He was treated aggressively with plasma-
pheresis then cyclosporine followed by several courses of intrave-
nous immunoglobulin with gradual improvement of his strength
over the ensuing 2 years. He eventually improved reaching Medical
Research Council grade 4 at the hip flexors, hip abductors, and hip
extensors.
 M. Hajjar et al. / Pediatric Neurology 50 (2014) 11e17
FIGURE.
Patient 1: Left median motor nerve compound muscle action potentials
(CMAPs) recorded over the abductor pollicis brevis (APB) muscle. Top trace
shows baseline CMAP. Bottom trace shows 276% facilitation of the CMAP
10 seconds after maximal voluntary exercise.
He moved away from Ohio and was taking cyclosporine intermit-
tently. He remained significantly impaired in proximal strength (e.g., he
could not run) until age 19 when his strength began to improve on an
exercise regimen. He discontinued the cyclosporine at age 20, and has
been essentially symptom-free for the past 7 years. He participates in
running events and has no functional limitations.
Literature review
Clinical features
Progressive proximal lower extremity weakness was the presenting
symptom in 11 of the 12 children with LEMS (76%).2-10 Ptosis developed
at onset in the three children, with associated malignancies and during
the disease course in a teenager with nonparaneoplastic LEMS.11 Oph-
thalmoparesis followed ptosis in the two patients with lymphoprolifer-
ative malignancies. Difficultly chewing,7 dysphagia,2 and dysarthria8
each occurred singularly. Four patients had muscle fatigue,2,7,9,10 three
had muscle aching and stiffness,3,6,7 one had head drop,7 and three had
transient respiratory distress.6,7 Autonomic symptomatology in the form
of dry mouth and constipation accompanied initial complaints in two
patients.3,11 This was alluded to in two other children with “soreness and
grittiness of the eyes”6 and “tight perioral skin,”7 respectively.
Neurological examination
LEMS patients invariably demonstrate proximal leg weakness greater
than arm weakness. Neck flexor weakness occurred in three patients.2,7
Muscle stretch reflexes are classically absent or hypoactive early on.
However, two children had normal reflexes.2,4 Waddling gait,6,7,9 mildly
perceptible facial weakness,2,3,7 and quadriceps muscles atrophy2,6 also
occurred.
Temporal profile
Symptoms typically developed over weeks to months. The most rapid
onset occurred in the two children with lymphoproliferative disorders:
“1 day”5 during a relapse of Burkitt’s lymphoma and within 1 month in
the patient with leukemia.10
Associated conditions
One child had Graves’ disease, alopecia, psoriasis, vitiligo, immuno-
globulin A deficiency with chronic urticaria.8 Elevated serum antinuclear
15
antibody,7 onset immediately after a viral illness (patient 2),2 and family
history of vitiligo and thyrotoxicosis were reported in three LEMS chil-
dren, respectively. Three patients had malignancies: leukemia,10 Burkitt’s
lymphoma,5 and neuroblastoma.11
Three toddlers (at ages 1, 2, and 3 years) were reported to have LEMS
associated with an underlying neuroblastoma12,13; however, none ful-
filled standard diagnostic criteria for LEMS,14 including CMAP amplitude
facilitation or voltage-gated calcium channel antibody testing and
therefore were not included in this review.
Diagnostic studies
Voltage-gated calcium channel antibodies were elevated in five of
six (83%) children tested.2,8,9,11 Creatine kinase levels were normal.
Two of the three children with LEMS who underwent the edropho-
nium test had no response4,10; the third had a “weakly positive”
result.7
Motor nerve conduction studies classically demonstrate low-
amplitude CMAPs with normal conduction velocities and distal
latencies. Occasionally CMAP amplitudes initially are normal, as seen
in two children; however, within a few weeks these became
reduced.2,11
Repetitive motor nerve stimulation at low frequency (1-3 Hz) per-
formed in 11 children induced the typical decremental CMAP amplitude
response seen in LEMS.2-7,9-11 High-frequency repetitive motor nerve
stimulation (10-50 Hz) in eight children was abnormal in all, with
facilitation varying from 124 to 500%.2-7,10,11 Similarly, 10-30 seconds of
maximal voluntary effort produced facilitation in each of eight patients,
with responses varying from 62% to 1075%.2-4,6,7,10 Although post-
exercise facilitation in two patients did not exceed 100%,2,9 high-
frequency repetitive motor nerve stimulation in these two facilitated
CMAPs higher than 100%.
Electromyography typically demonstrates low amplitude, short
duration, and increased motor unit potential recruitment as seen in six of
10 (60%) children. Electromyography may be normal early on. No
abnormal spontaneous activity was observed.
Eight of 12 (67%) children with LEMS reviewed here underwent muscle
biopsy. Some were normal7-9; others had nonspecific findings.2,3,6,10
Treatment and follow-up
Guanidine hydrochloride increases the amount of acetylcholine
released by nerve terminals. Initially, this produced prompt, relatively
sustained clinical improvement in two pediatric patients with LEMS6,7,10;
however, bone marrow and renal toxicity led to withdrawal of guanidine
from formularies.
Using 3, 4-diaminopyridine by blocking voltage-gated potassium
channels leads to increased acetylcholine release. This medication was
helpful in the first two patients reported here.3
Acetylcholinesterase inhibitors (i.e. pyridostigmine) were ineffective
in children with LEMS when used as the primary therapy.4,6,7,10
Prednisone2-4,7 and plasmapheresis,2,3,11 alone or in combination,
have led to substantial improvement in some children. Inevitable com-
plications prevent long-term use of these agents. Intravenous immu-
noglobulin combined with pyridostigmine produced minimal
nonsustained as seen in patient 2 and marked improvement in patient
3 when combined with cyclosporine.2
Primary treatment with cyclosporine2 or azathioprine9 is useful.
Neuroblastoma resection after plasmapheresis led to complete
remission.11
Up to 17 years of follow-up was observed. Generally, children with
LEMS continued to rely on symptomatic and immunosuppressive
treatment to sustain a function very close to their baseline. Remission
was maintained without drugs in two patientsdone with autoimmune
LEMS and one with treated neuroblastoma. Fatal outcome was seen only
in the two patients with lymphoproliferative malignancies, where death
occurred within 3 months.
Discussion
LEMS is an autoimmune disorder rarely diagnosed in
children. Typically it presents in middle-aged adults most
16 M. Hajjar et al. / Pediatric Neurology 50 (2014) 11e17
commonly as a paraneoplastic syndrome mandating a
thorough search for an occult malignancy, primarily a
small-cell lung cancer. Younger adult LEMS patients usually
have a primary autoimmune disorder without a malignancy.
In children, immune-mediated nonparaneoplastic LEMS
was prevalent, because only three instances of 12 had an
associated malignancy. The youngest age of LEMS onset in this
review was 3 years of age; the majority presented after age 7.
The youngest age in which LEMS was described was in two
neonates, not included in this review, whose mothers had
nonparaneoplastic LEMS, and were born with hypotonia at
birth. Voltage-gated calcium channel antibodies tested in one
newborn were positive. Hypotonia resolved completely at age
2 to 3 weeks with no LEMS recurrence at short-term follow-
up.15,16
As in adults, proximal leg weakness is the major pre-
senting symptom of pediatric LEMS. Fifty percent devel-
oped either ophthalmic or lower bulbar symptoms.
Similarly, extraocular or bulbar symptoms occurred in
31/50 (62%) adult LEMS patients.1 Ptosis at onset was
prognostically a serious finding because all three children
with it were found to have a malignancy.5,10,11 As opposed to
adults with LEMS, autonomic symptoms in children are
uncommon.1 This may possibly be due to the fact that these
symptoms are difficult to excerpt from children’s history.
A myopathydcommonly leading to a muscle bio-
psydwas the usual initial diagnosis because LEMS children
invariably presented with progressive proximal limb
weakness. In retrospect, the normal creatine kinase level
was diagnostically important: when associated with low-
amplitude CMAPs, a possible LEMS diagnosis must be
considered before undergoing a muscle biopsy.
When additional symptoms of oculo-bulbar dysfunction
occur, myasthenia gravis needs to be considered. Although
these symptoms are less prominent in LEMS, their presence
does not exclude this diagnosis1,2,7,8dneither does wors-
ening weakness after prolonged exercise. However, in
LEMS, such fluctuations are very subtle or absent and lack
the typical diurnal variations of myasthenia gravis.
Electrodiagnostic testing is the best support for a LEMS
diagnosis. Low-amplitude CMAPs provide the initial clue if
there is no concomitant primary neurogenic or myopathic
process. This finding must always lead to investigation for a
defect in neuromuscular transmission. This is easily inves-
tigated by having the patient perform 10 seconds of
voluntary exercise. In LEMS, classically this will lead to more
than 100% CMAP facilitation, but early on, lower amplitude
facilitation may occur, as seen in one child (62%).2 A range of
25% to 100% facilitation is acceptable for a diagnosis of
LEMS.14 High frequency repetitive motor nerve stimulation
in LEMS patients always leads to significant facilitation.
Because high-frequency repetitive motor nerve stimulation
is uncomfortable, we recommend voluntary exercise to be
tried first because both techniques are diagnostically
equivalent. The one exception would be a child unable to
cooperate and voluntarily exercise for 10 seconds.
Both myasthenia gravis and LEMS have decremental re-
sponses (more than 10%) to low-frequency repetitive motor
nerve stimulation; however, myasthenic patients do not
have significant exercise-induced facilitation.14 Early on, the
diagnosis may initially be confused when CMAPs still have
normal amplitude.
If there is suspicion of LEMS, evaluating serum titers of
voltage-gated calcium channel or acetylcholine receptor
antibodies specific to LEMS and myasthenia gravis, respec-
tively, will help differentiate the two disorders. Although
our first patient’s voltage-gated calcium channel antibodies
were at the upper limits of normal, she had 276% post-
exercise CMAP facilitation. Very occasionally both LEMS and
myasthenia gravis coexist.17
Last, LEMS patients may initially be labeled as “psycho-
genic” based on their neurological examination wherein
slowed initiation of muscle contraction with subsequent
improvement because facilitation may be interpreted as a
“functional weakness.” Careful electromyograph and anti-
body testing will obviate this potential diagnostic error.
Whereas remission was possible in one patient with
nonparaneoplastic LEMS (patient 3), the remaining re-
ported children in this category depended on immuno-
suppression with or without symptomatic therapy to
sustain a near normal function.
Conclusion
In summary, LEMS always needs to be considered in the
differential diagnosis of proximal weakness in children
and adolescents, particularly with absent muscle stretch re-
flexes and normal serum creatine kinase values. Careful
clinical examination and electrodiagnostic testing, both
looking for evidence of posttetanic facilitation, may provide
important diagnostic clues. Contrary to adults, nonparaneo-
plastic LEMS prevailed in children. Nevertheless, a malig-
nancy workup is mandatory. Pediatric LEMS is a potentially
treatable disorder. Cyclosporine coupled with pyridostigmine
and 3, 4-diaminopyridine provided the best long-term
benefits.
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