Neurología. 2017 32(3) :137142 [626940]

Neurología. 2017; 32(3) :137—142
NEUROLOGÍA
www.elsevier.es/neurologia
ORIGINAL ARTICLE
Results of surgical treatment for juvenile myasthenia
gravis/H22845
F .J. Vázquez-Roquea,∗, M.O. Hernández-Oliverb, Y. Medrano Planaa,
A.
Castillo Vitllocha, L. Fuentes Herreraa, D. Rivero-Valerónb
aServicio de Cirugía Cardiovascular , Cardiocentro de Santa Clara, Santa Clara, Villa Clara, Cuba
bServicio de Neurología, Hospital Pediátrico Provincial, Santa Clara, Villa Clara, Cuba
Received 11 June 2015; accepted 2 September 2015
Available online 6 February 2017
KEYWORDS
Mediastinum;
Myasthenia;Thymoma;Thymectomy;Radical thymectomy;
ThymusAbstractIntroduction: Radical or extended thymectomy is an effective treatment for myasthenia gravis
in the adult population. There are few reports to demonstrate the effectiveness of this treat-
ment in patients with juvenile myasthenia gravis.
Objective: The main objective of this study was to show that extended transsternal thymec-
tomy is a valid option for treating this disease in paediatric patients.
Results: Twenty-three patients with juvenile myasthenia gravis underwent this surgical treat-
ment in the period between April 2003 and April 2014; mean age was 12.13 years and the sample
was predominantly female. The main indication for surgery, in 22 patients, was the generalised
form of the disease (Osserman stage II) together with no response to 6 months of medical treat-
ment. The histological diagnosis was thymic hyperplasia in 22 patients and thymoma in one
patient. There were no deaths and no major complications in the postoperative period. After
a mean follow-up period of 58.87 months, 22 patients are taking no medication or need less
medication to manage myasthenic symptoms.
Conclusions: Extended (radical) transsternal thymectomy is a safe and effective surgical treat-
ment for juvenile myasthenia gravis.
© 2015 Sociedad Espa˜nola de Neurolog ´ıa. Published by Elsevier Espa˜na, S.L.U. This is an open
access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/
4.0/).
/H22845Please cite this article as: Vázquez-Roque FJ, Hernández-Oliver MO, Medrano Plana Y, Castillo Vitlloch A, Fuentes Herrera L,
Rivero-Valerón D. Resultados del tratamiento quirúrgico en la miastenia gravis juvenil. Neurología. 2017;32:137—142.
∗Corresponding author.
E-mail address: [anonimizat] (F .J. Vázquez-Roque).
2173-5808/© 2015 Sociedad Espa˜nola de Neurolog ´ıa. Published by Elsevier Espa˜na, S.L.U. This is an open access article under the CC
BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/ ).

138 F .J. Vázquez-Roque et al.
PALABRAS CLAVE
Mediastino;
Miastenia;Timoma;Timectomía;Timectomía radical;
TimoResultados del tratamiento quirúrgico en la miastenia gravis juvenil
Resumen
Introducción:
La timectomía radical ampliada para el tratamiento de la miastenia gravis es
una opción efectiva en la población adulta. No ocurre lo mismo en el caso de la miastenia
gravis juvenil, ya que existen pocos reportes que demuestren su efectividad.
Objetivo: El principal objetivo de esta investigación fue el de demostrar que la timectomía
transesternal radical ampliada es una alternativa validada para el tratamiento de esta enfer-
medad en este grupo de pacientes.
Resultados: Con esta técnica fueron intervenidos 23 pacientes con miastenia gravis juvenil en
el periodo comprendido entre abril del 2003 y abril del 2014. La edad media fue de 12,13 a˜nos y
hubo un predominio en el sexo femenino. La principal indicación quirúrgica fue, en 22 pacientes,
la forma generalizada de la enfermedad (estadio ii de Osserman) sin respuesta al tratamiento
médico luego de 6 meses. El diagnóstico histológico fue de hiperplasia tímica en 22 pacientes y
timoma linfocítico tipo i en un paciente. No hubo fallecidos y no se presentaron complicaciones
mayores en el periodo postoperatorio. Con un seguimiento medio de 58,87 meses, 22 pacientes
se encuentran sin tratamiento o necesitando menor cantidad de medicamentos para el control
de los síntomas miasténicos.
Conclusiones: La timectomía transesternal ampliada es una opción segura y efectiva para el
tratamiento quirúrgico de la miastenia gravis juvenil.
© 2015 Sociedad Espa˜nola de Neurolog ´ıa. Publicado por Elsevier Espa˜na, S.L.U. Este es un
art´ıculo Open Access bajo la licencia CC BY-NC-ND (http://creativecommons.org/licenses/by-
nc-nd/4.0/ ).
Introduction
Juvenile myasthenia gravis (JMG) is an autoimmune disor-
der of unknown aetiology. In JMG, serum antibodies alter
neuromuscular transmission when they bind to acetylcholine
receptors located in the muscular membrane at the motor
end plate. This results in premature muscle fatigue progres-
sing to paralysis during muscle contraction. The incidence
of myasthenia gravis (MG) during the first 18 years of life
is 4 cases per 100 000 population. The most frequent forms
are juvenile MG (18%), transient neonatal MG (1.5%), and
congenital MG. JMG manifests with generalised myasthe-
nia (47%), ocular myasthenia (43%), and myasthenic crises
(10%). After 1 to 3 years, generalised myasthenia accounts
for 80% of all manifestations, whereas ocular myasthenia
drops to 20% and myasthenic crises, which only occur in the
context of generalised mysathenia, decrease to 5%.1—5The
thymus has been suggested as a possible site of origin given
that 75% of patients older than 20 have thymic abnormal-
ities, 85% display thymic hyperplasia with active germinal
centres, and 15% have thymomas. In addition, thymectomy
improves patients’ outcomes in most cases. Acetylcholine
receptors in thymic myoid cells may act as autoantigens
and trigger an immunological reaction at the level of the
thymus. Thymic CD4+T-cells stimulate serum B-cells, which
in turn will start producing antibodies against acetylcholine
receptors.6,7
JMG is pathophysiologically heterogeneous. In most
cases, it is associated with presence of acetylcholine recep-
tor antibodies. However , it has also been reported to
be associated with anti-MuSK antibodies and some cases
are considered ‘seronegative’ since no antibodies can be
detected using currently available techniques. Therefore,
diagnosis of the disease is not based solely on antibodydetection. The patient’s clinical profile and such neuro-
physiological studies as repetitive nerve stimulation and
especially jitter analysis play an important role in diagnosing
the disease. Pharmacological tests are also useful. Treat-
ment for JMG is symptomatic and aetiological. In patients
with generalised involvement and incomplete response
to treatment, a wide range of therapeutic measures
are applied to halt the autoimmune response, including
thymectomy, immunosuppresant agents, plasmapheresis,
and immunoglobulins.6,8—14Despite the controversy sur-
rounding treatment for MG, surgery has been shown to
be superior to medical treatment alone, even in cases of
JMG.12,13,15—22The main purpose of our study was to confirm
the validity of radical or extended transsternal thymectomy
for the treatment of JMG.
Patients and methods
Study characteristics
We conducted a prospective non-experimental study includ-
ing 23 patients diagnosed with JMG who underwent
extended thymectomy between April 2003 and April 2014.
The study was conducted in the cardiac surgery department
at Cardiocentro Ernesto Guevara and the Neurology Depart-
ment at Hospital Pediátrico Provincial, in Santa Clara, Cuba.
Procedure
We used the criteria by Cheng et al.21for diagnosing JMG,
indicating extended thymectomy, and assessing patients’
outcomes; the clinical criteria by Osserman and Genkins14

Results of surgical treatment for juvenile myasthenia gravis 139
Figure 1 (a) Complete resection of the thymus, mediastinal pleura, and fibrofatty connective tissue extending from the diaphragm
to the thyroid between the phrenic nerves. (b) Thymus, mediastinal pleura, and fibrofatty tissue.
for classifying MG; imaging criteria (chest radiography, CT)
to rule out thymoma; neurophysiological criteria (repetitive
nerve stimulation, single-fibre EMG); and pharmacological
criteria (Tensilon test).
Surgical treatment consisted of extended transsternal
thymectomy,20which involves resection of the thymus,
mediastinal pleura, and fibrofatty connective tissue extend-
ing from the diaphragm to the thyroid between the phrenic
nerves (Fig. 1a and b). Surgery was indicated based on the
following criteria21: resistance to pyridostigmine or immuno-
suppressant treatment, generalised myasthenia with no
signs of improvement after 6 months of medical treatment,
ocular myasthenia with partial response to pyridostigmine,
and lack of stable, complete remission for more than 2 years.
Before undergoing thymectomy, all patients started treat-
ment with intacglobin dosed at 400 mg/kg and administered
in 5 doses (3 before and 2 after surgery).
Variables
We recorded the following variables for each patient: age,
sex, Osserman stage, symptom onset, date of diagnosis,
date of surgery, time elapsed between symptom onset and
surgery (in months), time elapsed between diagnosis and
surgery (in months), preoperative treatment, postoperative
complications, length of stay in the intensive care unit, total
length of postoperative hospital stay, complications, his-
tological diagnosis, total postoperative follow-up time (in
months), and surgery outcomes (at 1, 3, and 5 years). Patient
were classified in 4 outcome groups21: taking no medica-
tion, taking less medication and displaying improvements,
taking less medication and displaying no improvements, and
experiencing exacerbation.We investigated the impact of time from symptom onset
to surgery on outcomes.
Statistical analysis
We used SPSS statistical software version 15 for Windows for
data processing and statistical analysis. Descriptive statis-
tics were used for all variables. Quantitative variables were
expressed as means ± SD and qualitative variables as abso-
lute values and percentages. The analysis was intended
to determine whether time between symptom onset and
surgery had an impact on surgical outcomes. Statistical sig-
nificance for this correlation was calculated using the Fisher
exact test. Qualitative variables were said to be correlated
for values of P ≤ .05.
Results
Table 1 summarises the studied quantitative variables. Mean
age of our sample was 12.13 years. The mean postoperative
follow-up time was 58.87 months. Mean time from symptom
onset to surgery was 20 months and mean time from
diagnosis to surgery was 10 months. The mean length of the
postoperative hospital stay was 8.3 days. Female patients
accounted for 6.9% of the sample; the most frequent
Osserman stage was stage II. Histology studies indicated
thymic hyperplasia in 22 patients and type 1 lymphocytic
thymoma in one; thymic remnants were found in 3 patients
(Table 2). In the patient with thymoma, JMG had manifested
with ocular myasthenia when she was 10; 2 years later , she
displayed generalised involvement and bulbar symptoms.
None of the patients died; they all were extubated within
T able 1 Distribution of patients according to the studied quantitative variables.
Quantitative variable Mean Min. Max. SD
Age (years) 12.13 6 18 3.87
Time from symptom onset to surgery 20.00 6 72 18.03
Time from diagnosis to surgery (months) 10.00 2 26 6.88
Length of postoperative stay (days) 8.13 6 14 1.89
Length of postoperative follow-up (months) 58.87 14 147 37.33
Source : Department of Statistics.

140 F .J. Vázquez-Roque et al.
T able 2 Patient distribution by sex and other qualitative
variables.
Variables n %
Sex
Male 9 39.1
Female 14 60.9
Total 23 100
Osserman
stage
I 1 4.3
IIa 13 56.5
IIb 9 39.2
Preoperative
treatment
Pyridostigmine 18 78.3
Prednisone 12 52.2
Azathioprine 3 13.1
Immunoglobulins 23 100
Histological
diagnosis
Thymic hyperplasia 22 95.7
Thymoma 1 4.3
Source : Department of Statistics.
the first 6 hours and stayed in the intensive care unit
for less than 48 hours. None of the patients experienced
myasthenic crises during the postoperative period. The
only postoperative complication was pleural effusion in one
patient; fluid was removed by pleural puncture. During the
postoperative period, the dose of parasympathomimetics
was reduced and the associated adverse effects were
monitored. All patients received medical treatment for
6 months after surgery; after that period, the doses and
number of drugs were reduced. We should point out that,
at one year of follow-up, 95.6% of the patients receivedeither no medication or lower doses to control symptoms;
at 3 years, this percentage had risen to 100% (Table 3).
Table 4 shows the influence of time between symptom onset
and surgery on surgery outcomes. Time from symptom
onset to surgery was less than one year in 12 patients and
more than one year in 11. Eleven of the former and only
one of the latter received no medication one year after
thymectomy. The Fisher exact test (P = .003) shows that
outcomes of extended thymectomy are significantly better
when time between symptom onset and surgery is less than
one year.
Discussion
JMG can be classified as prepubertal (symptoms appear
before puberty) or pubertal/postpubertal (symptoms mani-
fest during or after puberty). Both subtypes have distinctive
clinical characteristics. Prepubertal JMG is commonly linked
to ocular involvement and affects both sexes equally,
whereas pubertal and postpubertal JMG affects females
predominantly and its prognosis is better due to greater
likelihood of spontaneous remission. In adult MG, over 80%
of the cases of ocular myasthenia progress to generalised
myasthenia; in JMG, however , progression to generalised
myasthenia is less frequent, especially in the prepubertal
form.6,22,23,25—29In our sample, 7 patients (30.4%) had pre-
pubertal JMG and 16 (69.6%) postpubertal JMG; at time of
surgery they all had generalised myasthenia. Most patients
were female.
Remission may occur spontaneously or after a period
of medical treatment, especially in patients with pre-
pubertal JMG.23—26However , all patients diagnosed with
prepubertal JMG and followed up during the 1990s in
the neurology department at Hospital Pediátrico Provin-
cial continued to receive medication to control myasthenic
T able 3 Patient outcomes at different follow-up times.
Follow-up
1 year 3 years 5 years
n % n % n %
Total 23 100 16 69.5 7 30.4
No treatment 12 52.2 13 81.3 7 100
Improved with treatment 10 43.5 3 18.7
Did not improve with treatment 1 4.3
Source : Department of Statistics.
T able 4 Time from symptom onset to surgery: impact on patient outcomes.
Outcome at 1 year
Time from symptom onset to surgery No treatment Treatment Total
≤1 year 11 3 14
>1 year 1 8 9
Total
12 11 23
Fisher exact test, P = .003.
Source : Department of Statistics.

Results of surgical treatment for juvenile myasthenia gravis 141
symptoms upon reaching puberty. The likelihood of remis-
sion is also influenced by ethnicity.6,21—23The thymus is
known to play a major role in the aetiopathogenesis of JMG.
Thymectomy constitutes a valid treatment option since the
disappearance of thymic germinal centres halts antibody
production and diversification.30,31According to Gronseth
and Barohn,32patients with nonthymomatous autoimmune
MG have a greater probability of symptom remission or
improvement. More recent review articles including patients
with prepubertal JMG report increased remission rates after
thymectomy.33,34Special attention should be paid to young
children; the probability of remission is most frequent in
this population. The youngest patient in our series was
6. We should also mention purely ocular JMG: in these
cases, thymectomy has not been demonstrated to pre-
vent generalised progression and should therefore only be
used in patients refractory to medical treatment.21,27Only
one patient in our sample had ocular JMG at the time of
surgery. Surgery was indicated in this case since the patient
had experienced no improvements after a year of medi-
cal treatment and a CT scan revealed that the thymus had
doubled in size compared to a CT scan performed a year
previously. Another reason for considering thymectomy as a
treatment option for JMG is the actual possibility that myas-
thenic symptoms may be due to presence of a thymoma
even when CT images display a morphologically normal
thymus. This was the case of the patient who was histo-
logically diagnosed with type 1 lymphocytic thymoma after
thymectomy.
There are several routes of access for thymectomy.
Evidence shows that outcomes are independent of the
route of access if the thymus and fibrofatty tissue are
fully resected.16—22Bulkey et al.20and Masaoka et al.19
began conducting simple cervicomediastinal and transster-
nal thymectomies and subsequently performed extended
transsternal thymectomies that achieved higher remission
rates. According to the literature, surgery outcomes may
last up to 5 years after extended thymectomy and remis-
sion rates show a significant correlation with time from
symptom onset to surgery.16—22,33,34For this reason, we
decided to treat our patients with extended thymectomy
after a 6-month period of medical treatment failed to
achieve remission of myasthenic symptoms. Another factor
affecting outcome is the surgical technique used. Extended
thymectomy has been shown to be superior to conven-
tional thymectomy since it achieves complete resection
of tissues potentially containing thymic remnants, which
may be responsible for non-remission after surgery. Simi-
lar results have been published by Essa et al.22and Cheng
et al.21: after extended thymectomy, 90% and 91.1% of the
patients required either no treatment or lower doses to
control myasthenic symptoms. Despite published evidence
that video-assisted thoracoscopic thymectomy is effec-
tive, there is no consensus on the best route of access
for extended thymectomy.15,17Our results indicate that
extended transsternal thymectomy is a safe and effective
treatment option for JMG.
Conflicts of interest
The authors have no conflicts of interest to declare.References
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