Opsoclonus-myoclonus syndrome (OMS) is a rare
neurological disorder characterized by progressive opsoclonus
(irregular, rapid, horizontal and vertical eye movements), myoclonus,
cerebellar dysfunction and severe hypotonia. Evidence for an autoimmune
mechanism includes the presence of serum autoantibodies to several
neural antigens and improvement of symptoms with immunosuppressive
therapy.
Plasmapheresis has been described as a modality of
treatment in idiopathic OMS(1). We report the beneficial effects of
plasma-pheresis in, to the best of our knowledge, in the youngest
patient of OMS in the world literature. We also found the presence of
antineuronal antibodies in 2 subjects with OMS, which indicate its
autoimmune etiology.
Case Report
An 18-month-old male boy born of non consanguineous
marriage was brought with complaints of instability of gait, chaotic eye
movements and severe irritability, since one year of age, following an
attack of fever. He was asymptomatic till then, with normal
developmental milestones. There was no significant prenatal, natal, or
postnatal insult. There was no family history of similar illness.
He was diagnosed as having post-viral cerebellar
ataxia in the local hospital, and was treated with dexamethasone and
clonazepam. The ataxia improved initially, but relapsed when
corticosteroids were tapered. Brain MRI, EEG, 24 hr urinary
catecholamines, abdominal ultrasound, and peripheral smear were normal.
On examination he was highly irritable, and had chaotic eye movements,
titubation, severe truncal ataxia and bilateral intention tremor. The
sleep was interrupted due to frequent myoclonic jerks of the limbs, and
there was loss of ability to communicate even non-verbally. A
provisional diagnosis of idiopathic opsoclonus myoclonus syndrome was
made, and he was investigated to rule out an occult neuroblastoma. Chest
X-ray, CT scan of the chest and abdomen, bone marrow study and
urinary catecholamine level were normal. He was started on ACTH
injections at a dose of 20 U daily subcutaneously with gradual increase
to 40 U daily. There was significant improvement within 10 days, and
ACTH was slowly tapered off over a period of 1 month. At this time the
child was able to walk with support but still had severe bilateral
intention tremor of the hands. Therapy with intravenous immunoglobulin (IVIG)
was not possible due to the cost involved. The medical team, in
consultation with the family, decided to initiate a trial of
plasmapheresis with concomitant immunosuppression.
A plasmafilter (GAMBRO) was utilized with 40
ml/kg/day of plasma exchange with fresh frozen plasma as replacement
fluid. Plasmapheresis was performed on days 1, 3, 5, and then twice
weekly for two more weeks. He developed severe anemia with hemolysis
after the last plasmapheresis, and received a fresh blood transfusion.
Within 2 weeks after initiation of pheresis he showed signs of
improvement. By two months he made a near-total recovery. The patient
also received concomitant treatment with prednisolone and azathioprine.
Prednisolone was given for 6 months at a dose of 1 mg/kg/day, and then
tapered gradually to 0.5 mg/kg as a single dose on alternate days for
two years. Azathioprine (1 mg/kg/day) was given orally for a year.
Serum samples showed weak reactivity against 40 KD
autoantibodies probably due to prior ACTH therapy and plasmapheresis.
The subject is now 5-year-old and off all medications
since 12 months. His gross motor ability is normal for age, but his fine
motor ability is below average though his handwriting is legible. The
expressive and receptive language skills by Washington’s scale are found
to be appropriate for 4 years. He has normal social skills.
Another 2½-year-old girl child presented with
cerebellar ataxia and opsoclonus of one yr duration, and on evaluation
had a 1.8 × 2 cm tumor in the left adrenal gland. The serum, tested
before removal of the tumour, showed reactivity against 150 KD, 54 KD
and 62 KD autoantigens. Immunohistochemistry identi-fied the tumor as a
ganglioneuroma and hence no chemotherapy or plasmapheresis was given.
The child gradually recovered and is asymptomatic since the last one
year.
Discussion
Opsomyoclonus, myoclonic encephalo-pathy of
Kinsbourne or "dancing eyes-dancing feet" syndrome is a devastating and
debilitating disease with an unfavourable outcome.The pathophysiology of
OMS has been speculated to involve IgG and IgM autoantibodies directed
against neural antigens in cerebellar Purkinje cells, cerebral cortical
neurons and axons. The auto-antibodies in OMS are distinct and therefore
suggest a causal relationship(1). The immune mechanism may be a Type II
or IV hyper-sensitivity. However, it is not commercially viable to do
routine autoantibody testing in OMS, due to the large variety of
potential autoantibodies that may be found in OMS with Neuroblastoma(2).
The overall incidence of OMS in children with
neuroblastoma is approximately 3%. Approximately 90% patients with
neuro-blastoma and OMS show long term survival, whereas only 55% of all
children with NB survive their disease. The tumor of children with OMS
are almost exclusively neuro-blastoma, ganglioneuromas or rarely
hepato-blastoma. The neuroblastoma associated with OMS is a small, well
differentiated tumor with favourable histological subtype expressing low
number of n-myc copies. Amplification of n-myc in
neuroblastoma is known to correlate with advanced stage or rapid
progression of disease. N-myc is never found in benign
ganglioneuromas. The other agents known to cause symptoms of OMS include
poisoning due to thallium, strychnine, organophos-phates, toluene and
drugs like amytriptyline, lithium, phenytoin.
Viruses such as Epstein-Barr virus, St. Louis
encephalitis, Coxsackie B3 and mumps have been identified with postviral
OMS. Post viral OMS is considered to be secondatry to "molecular
mimicry" wherein immune cells primed against the viral peptides attack
neural cells expressing similar antigens(3). Anti-neurofilament
antibodies of 210 KD (IgG) were found in sera from children with OMS and
the disappearance of the antibody during ACTH treatment suggests
clinical relevance(3-5). The mechanism of brain injury in OMS may be by
direct attack by antigen specific T cells, non-specific lymphocytes such
as natural killer cells or cytokines released by activated cells or
autoantibodies.
Currently, there is no well accepted treatment for
OMS. Generally treatment has consisted of immunosuppression to reduce
the formation of antibodies and towards removal of antibodies. ACTH and
corticosteroids both lead to rapid improvement of the neurological
symptoms, but most patients have frequent relapses following tapering or
withdrawal of the drug(6). ACTH seems to act as a direct
immunosuppressive and appears to inhibit the antibody response to T-cell
dependent antigens. Corticosteroids decrease lympho-cyte differentiation
and proliferation, inhibit phagocytosis, and suppress production of
interleukins(7). There are small case reports of treatment with IVIG,
plasmapheresis and immunoadsorption in OMS patients(3,8,9). IVIG has
shown promising results but needs to be administered in high dose for
prolonged periods. IVIG downregulates interleukin 2 production by
T-cells. Tumors, if associated, should be removed.
There is only a single case report in the world
literature of therapeutic plasmapheresis for idiopathic OMS in a
6-year-old child(1). There is anecdotal evidence of cases in adults, but
our patient was the youngest child ever to have undergone plasmapheresis
for OMS.
Immunoadsorption offers the advantage of avoidance of
colloid infusion following plasmapheresis. However the protein A column
that are available bind only to IgG. Pheresis is more immunosuppressive
by non-selectively removing other plasma proteins, which is an advantage
in OMS where both IgG and IgM antibodies are incriminated.
The justification for concomitant use of oral
immunosuppressive medications was based on prior evidence that the
suppression of antibody production and prevention of antibody rebound
effect were helpful in the outcome of this disease(10,11).Our patient
tolerated these medications well and had no adverse effects other than
transient cushingoid features. The dramatic clinical improvement in our
patient within 2 weeks of initiation of plasmapheresis strongly supports
the notion that it was the pheresis that was of benefit. He was able to
walk without support following pheresis, which he had never been able to
do with ACTH or corticosteroids. Earlier he relapsed whenever the
steroid dosage was tapered, but this time the improvement was maintained
even after discontinuing pheresis and after tapering the dose of
corticosteroids. He has not had any relapse of OMS since 3 years post-pheresis.
We propose that plasmapheresis with concomitant oral
immunosuppression should be considered as a potentially effective
treatment for idiopathic OMS in a child who is refractory to
conventional treatment with ACTH, corticosteroids and IVIG, because
delay in treatment might lead to continued brain damage.
Acknowledgement
The authors are indebted to Dr. Franz Blaes,
Department of Neurology, Justus-Liebig University, Giessen, Germany for
doing the autoantibody testing.
Contributors: SSR diagnosed and managed the
patient and will act as the guarantor. PJM did the plasmapheresis.
Funding: None.
Competing interests: None stated.
