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Grebenciucova et al. Etanercept-associated Miller-Fischer syndrome

CASE REPORT with intravenous immunoglobulins or plasmaphoresis,
although according to the Cochrane review, patients
A 54-year-old male with history of psoriatic arthritis who were not treated with either therapy had similar
presented for an evaluation of the acute onset of outcomes at 6 months. However, the data are
[4]
ocular pain and double vision. He had recently started difficult to interpret due to the low incidence of the
Etanercept, an anti-TNFα antibody. Five days after disease and consequent lack of randomized placebo-
the 1st infusion, he developed rhinitis and a cough, controlled trials. In most cases, the course of the
which resolved in several days. He proceeded with disease is self-limiting and the outcomes are favorable.
his weekly 2nd and 3rd infusions, but 2 days after the In our patient, the onset of MFS was preceded by a
3rd infusion he developed blurred vision in the right viral prodrome, but also occurred in the context of an
eye and pain with eye movement. Two days later, anti-TNFα agent.
he developed double vision and ocular pain when
attempting upgaze, followed by headache and pain The use of anti TNFα agents in the treatment
with eye movement in all directions. of various rheumatological disorders such as
sarcoidosis, rheumatoid arthritis, and psoriasis has
Three days after the onset of his symptoms, he was been increasingly recognized as causal to cases of
evaluated by an ophthalmologist who noted incomplete demyelination, some of which remain monophasic,
adduction of the left eye on far right gaze. Five days with a minority transitioning into multiple sclerosis.
later, a neuro-ophthalmologic examination showed Due to their anti-inflammatory activity, anti-TNFα
bilateral eye adduction weakness with an upgaze agents have been previously investigated in multiple
palsy, along with a mild left eye ptosis and miosis. sclerosis, however a randomized placebo-controlled
Direct and consensual reaction of pupils was intact. trial of anti-TNFα agent in multiple sclerosis showed
There was no afferent pupillary defect or disc edema. worsening of the disease activity in the anti-TNFα
group. [5]
The rest of the neurological examination was significant
for areflexia, while cerebellar exam was normal. TNFα is a cytokine that binds to TNF receptor 1
(TNFR1) or 2 (TNFR2). TNFR1 binding results in the
A contrast-enhanced magnetic resonance imaging inflammatory effects of TNF, while TNFR2 binding
(MRI) of the brain was performed 3 days after onset contributes to the maintenance of immune tolerance.
of symptoms, and no midbrain or pontine lesions were TNFα binding to TNFR2 in conjunction with IL-2
noted. There was no optic nerve enhancement noted result in T regulatory cells proliferation, increase
on orbital imaging. Acetyl-choline receptor and muscle in forkhead box P3 expression and an increased
specific kinase antibodies were both negative. immunosuppressive activity. Thus, inhibiting TNF
[6]
can alter the balance between the effector and
He underwent another MRI two weeks after the onset regulatory T cells, potentially leading to dysregulation
of symptoms, and both MRI of the brain and orbits of immune tolerance and allowing an increased activity
with and without contrast were again unremarkable. of autoreactive T cells. As a result of this imbalance,
At this point, MFS was considered, and a GQ1b humoral immunity can be further activated resulting in
antibody was tested, which was positive with a titer of the auto-reactive antibody generation. It is possible
[7]
1:12,800. One month after the onset of his symptoms, that in the immunogenetically susceptible people, the
he was essentially asymptomatic, and his neurologic use of anti-TNFα agents may result in an episode of
examination normalized, other than residual areflexia. demyelination or unmask the predilection for multiple
sclerosis. The detailed pathophysiological mechanism
DISCUSSION has not been fully elucidated.

MFS is a rare self-limiting demyelinating syndrome Cases of GBS have also been associated with the use
that is considered to be a variant of GBS. Annual of anti-TNFα agents.
incidence is estimated to be one case per million. A
[3]
clinical triad of ophthalmoplegia, arreflexia, and ataxia Besides our case, a review of the literature uncovered
is the classic presentation. three prior cases of MFS in association with the use
of anti-TNFα blockers [Table 1]. [8-10] The underlying
An antibody to the neuronal GQ1b (or in some cases mechanism of MFS in association with anti-TNFα
GT1a) is highly sensitive and specific for the diagnosis blockers is likewise unclear. In our case, given
of MFS. About 60% of cases are preceded by a viral a preceding viral illness, it becomes of interest
or in some cases bacterial illness. The disease occurs whether the anti-TNFα agent further contributed
more commonly in males than females and is treated to the development of the syndrome or if it had any
94 Neuroimmunology and Neuroinflammation ¦ Volume 4 ¦ May 23, 2017