The Journal of the Arkansas Medical Society Issue 5 Volume 115 | Page 20

biologic agent. The symptoms improved, and he did
not have any headache, but he still complained of
diplopia and fatigue two months after the hospital
course. Neurological examination including cranial
nerve examination was normal two months follow-
ing discharge. Behavioral evaluation at this time re-
vealed normal mood and affect, language, thought
and cognition.
During the hospital stay, notable labs included:
(i) an elevated total bilirubin (1.08 U/L) and liver
enzymes ( AST 51 U/L, ALT 169 U/L); (ii) a low HDL
cholesterol (13.5 mg/dl); other lipid parameters
within normal limits (LDLc 83.7 mg/dl, cholesterol
114 mg/dl, triglyceride 77, cholesterol/HDL ratio
5.6); (iii) C reactive protein (CRP) was non-elevated
at 0.29 mg/L; (iv) WBC count was 12.1 k/UL on day
of admission (Neutrophils 87% and lymphocyte 6%);
(v) D-dimer was unelevated at 0.26 ug/ml; (vi) the
sedimentation rate was 0 ml/hr; (vii) negative ANA
titer; (viii) Notable parameters in comprehensive
metabolic panel (CMP) revealed glucose 138 mg/dl,
HbA1C 5%, Calcium 9.8 mg/dl, Magnesium 2.2 mg/
dl, TSH 0.66 UIU/ml.
Clear CSF was obtained by lumbar puncture (LP)
performed by aseptic procedures under anesthesia.
Notable finding during CSF examination was slightly
elevated protein (50) and glucose (81). No oligoclo-
nal band was detected by isoelectric focusing (IEF).
Oligoclonal bands are usually present in the CSF in
greater than 85% patients with the demyelinating
disease multiple sclerosis. It may also be detected
in brain tumor, infarction, CNS lupus, inflammatory
polyneuropathy, and sub-acute sclerosing panen-
cephalitis. CSF cultures were normal.
HIV1 and 2 IgG antibodies were undetected.
RPR was non-reactive. Lyme antibody was detect-
ed (1.84; >1.10 is considered as positive). Further
Lyme-specific antibodies were evaluated by western
blotting. 41 kDa and 66 kDa IgG bands were detect-
ed; all other bands for IgM and IgG were negative.
Myelin basic protein was less than 2 mg/L. CSF
IgG was 2.3 mg/dl, albumin CSF 23.8 mg/dl, IgG se-
rum 773 and albumin serum 3.5 g/l, leading to IgG
index of 0.44 (normal 0.66).
Routine MRI of brain without contrast and with
Magnevist did not reveal any acute intracranial ab-
normality or abnormal enhancement. A few tiny foci
of increased T2 and FLAIR signals was seen scat-
tered throughout the cerebral hemisphere, which is
a nonspecific finding seen in chronic migraine head-
aches. However, these findings may also be indica-
tive of demyelination. There was no restricted diffu-
sion to suggest infarction, no extra-axial collection,
and normal vascular flow voids of the skull base.
3D time-of-flight magnetic resonance angiography
(MRA) of the intracranial arterial vessels showed
normal patterns of the vascularity of the circle of
Willis, with a normal variation of the right postero-
inferior cerebellar artery (PICA). Vertebral and basilar
arteries showed normal dimension bilaterally with-
out aneurysm.
The remainder of the hospital course involved
insertion of a PICC for administration of ceftriaxone
for suspected Lyme disease, though this consid-
eration was low on the differential. USG abdomen
revealed distended gall bladder with several gall
stones. Blood culture during the hospital course had
shown no growth.
The gentleman in discussion is a fitness in-
structor, lives at home with his wife, and has a pet
dog. He denied any history of drug or tobacco use.
Though numerous joint involvement due to rheu-
matoid arthritis, our patient is a lifestyle coach and
actively participates in gym activities and golf. Im-
portant past medical history includes herpes zoster
involving the face about five years ago. The patient
did not remember the sidedness, although his wife
reported that it might have been on the right side.
Discussion
The current report presents an associative
condition of use of the biologic agent anti-TNF an-
tagonist etanercept and development of diplopia
and other neurologic symptoms resembling the
heterogeneous presentation of multiple sclerosis.
These could have resulted from the effects of etan-
ercept. The only correlative evidence we can offer
in support of this association is that the patient’s
symptoms considerably improved after cessation
of the medication.
The role of cytokines in maintenance of my-
elination is being increasingly appreciated. Thus,
cytokine antagonists may cause demyelination,
involving both cranial and peripheral nerves. 1,2 We
ruled out preliminary demyelinating disorders like
multiple sclerosis by negative oligoclonal bands as
well as normal CSF IgG index. The third, fourth and
sixth cranial nerves traversing through the cavern-
ous sinus derives its blood supply from adjacent
vessels. 3 MR angiography revealed intact basilar
vasculature, as well as the internal carotids and
normal cavernous sinuses. The lipid parameters for
our patient was also normal. The likelihood that an
acute or acute-on-chronic vascular disorder result-
ing from metabolic dysfunction affecting the nerve
116 • THE JOURNAL OF THE ARKANSAS MEDICAL SOCIETY
supply of the cranial nerves supplying the extra-
ocular muscles, leading to the visual disturbances,
was likely low. Two months after the episode, clinical
evaluation demonstrated normal function of cranial
nerves, though the left pupillary reaction to light was
somewhat sluggish.
Whether etanercept contributed to cognitive
deficits cannot be predicted by the information ob-
tained from our patient. The patient had no evidence
of any cognitive deficit two months after the initial
episode. The significance of the periventricular T2/
FLAIR signals also remains unknown.
Earlier, a single report has identified extraocular
myopathy leading to painful diplopia after the use of
etanercept. Our report delineates a similar associa-
tive condition, though we remain unsure of whether
demyelinating nerve disease involving the cranial
nerves supplying the extra-ocular muscles or a my-
opathy per se was the cause of the development of
the visual disturbances. The patient had other neu-
rologic features, including headache and transient
cognitive decline, without any frank neurovascular
abnormality detected by imaging and routine neuro-
logic evaluation. It is prudent to be aware about such
situations, which may help in continued clinical care.
MRI did not reveal any frank demyelination.
Though precision medicine has ushered in
newer agents for pharmacotherapy catering to
novel treatments for a wide variety of diseases, use
of these agents should always be with caution. The
present case highlights this issue. Complete infor-
mation from package insert and other literature
should be obtained prior to using these medications.
Anti-TNF alpha based medications is now common
pharmacologic drugs used for many autoimmune
and inflammatory conditions, including arthritides of
diverse etiologies. Anti TNF– α drugs have been as-
sociated with multiple sclerosis, optic neuritis, acute
transverse myelitis, progressive multifocal leucoen-
cephalopathy, and acute and chronic inflammatory
demyelinating polyneuropathy. 1-2, 4-11 Precise neu-
roimmune interactions are not known. Despite high
TNF– α levels in multiple sclerosis plaques and the
cerebrospinal fluid, anti-TNF– α drugs seem to trig-
ger MS and worsen its course. 10-12
The development of neurological disorders in
patients on anti-TNFalpha medications is stochas-
tic in nature. 13-15 A recent study has shown that a
certain type of single nucleotide polymorphism
(SNP) on the TNF receptor increases susceptibility
to demyelinating disorders, the mutated receptor
itself acting in aberrant signaling leading to de-
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