Teaching Points

 Miller Fisher syndrome (MFS) is a variant of Guillain-Barre syndrome. It is characterized

by ophthalmoplegia, facial or bulbar weakness, ataxia, and areflexia. Other autoimmune
conditions should be taken into consideration including multiple sclerosis, sarcoidosis,
myasthenia gravis, and Lambert-Eaton myasthenic syndrome (LEMS), among other
autoimmune neurologic disorders. Although clinical symptoms strongly point to MFS,
further ancillary testing may be needed to rule out other possible diagnoses.

 The chest x-ray findings are nonsensitive and nonspecific for the diagnosis of MFS or
any alternative autoimmune diagnosis. This answer is only a distractor, although the
presence of hilar adenopathy could have pointed out sarcoidosis as an alternative
diagnosis to MFS.

 Although the history of acne and isotretinoin use is a risk factor for developing MFS, it
will not help one differentiate it from alternative diagnoses. Other drugs that increase the
risk of MFS included heroin, TNF-alpha inhibitors, epidural anesthesia, and
streptokinase.

 For MFS, CT and MRI scans of the spine may show thickening and enhancement of the
intrathecal spinal nerve roots and cauda equina, along with some spinal nerve root
enhancement. Other MRI descriptions that are rare but described in the literature include
hyperdensities in the spinal cord posterior columns, brain oculomotor, abducens, and
facial nerves. Also, electrodiagnostic studies may show reduced or absent sensory
responses without slowing of sensory conduction studies. However, fluid-attenuated
inversion recovery (FLAIR) sequence showing periventricular hyperdensities is a highly
sensitive finding for multiple sclerosis lesions and not MFS. Therefore, this is the correct
answer.

Teaching Points

 Herpes virus is not consistent with weakness in the lower extremities. It is more
associated with trigeminal neuralgia, a condition associated with severe, shooting or
jabbing pain that may feel like an electric shock. Spontaneous attacks of pain or attacks
triggered by touching the face, chewing, speaking or brushing teeth. This patient does not
exhibit these and therefore is not the correct answer.

 Although Epstein-Barr virus (EBV) has been implicated in the development of Guillain-
Barre syndrome (GBS) and Miller Fisher syndrome, it is uncommon and not the best
answer. EBV infection is mostly related to odynophagia, fatigue, fever, chills, malaise,
myalgias, sore throat, swollen lymph nodes, swollen tonsils, headache, and nausea. It is
mostly associated with mononucleosis infection. Although neurological symptoms such
as seizures, focal weakness, headaches and combative behavior are possible with chronic
EBV, it is rare, and mostly found in the pediatric population.
  The history of dizziness, loss of balance, arrhythmias, ophthalmoplegia, and distal
paresthesias is consistent with Miller Fisher syndrome (MFS). Supporting evidence
includes the electrodiagnostic finding of reduced sensory responses without slowing of
waves. A cross-reaction between peripheral nerve antigens and microbial/viral
components through molecular mimicry is thought to drive the inflammatory process of
this illness. Approximately two-thirds of cases are preceded by symptoms of upper
respiratory tract infection or diarrhea, and about 50% develop after following an
infection. In this patient, the presence of diarrhea in the present of travel history to Asia
should prompt one to be suspicious of food contamination as a source of GBS. Also, the
clinical symptoms are consistent with the MFS variant.

 Although syphilis may cause deficiencies in balance and sensation, the time course of this
patient is not suggestive of an infectious etiology. It would take years of untreated
syphilis to develop tabes dorsalis, a destruction of the posterior columns of the spinal
cord, which carry sensory information from the body to the brain. The time course of this
patient’s illness seems to be contrary to GBS or MFS. Usual time of onset for MFS in
97% of patients is about 12 hours to 28 days, with the average onset about 8 to 10 days
following the antecedent illness.

Teaching Points

 Anti-ganglioside antibodies are a specific finding for Miller Fisher syndrome (MFS),
brainstem encephalitis, or variants of Guillain-Barre syndrome (GBS). About 70% to
90% of patients will have positive anti-GQ1B through an enzyme-linked immunosorbent
assay (ELISA). Ten percent to 30% of patients will be seronegative, possibly related to
the requirement of calcium-dependent ligands to be present for a positive result. Anti-
myelin antibody is a serological finding that is associated with multiple sclerosis.
Antinuclear antibody is a highly sensitive marker for systemic autoimmune diseases such
as systemic lupus erythematosus, sarcoidosis, among others, but is not a specific finding
for MFS. Anti-cholinergic antibodies in the postsynaptic neuron is a specific serological
finding for myasthenia gravis.

 The pathophysiology of GBS and MFS is thought to be related to molecular mimicry

between peripheral nerve and viral or other microbial antigens. Humoral and cell-
mediated lymphocyte mobilization is thought to play a major role. Gangliosides are
important carbohydrate determinants for autoimmune activity, and antibodies are present
against it in MFS.

 When the classic triad of acute ophthalmoplegia, areflexia, and ataxia in the setting of
preceding viral upper respiratory tract infection or diarrhea is present, antibody and
serological testing may not be necessary, and the clinician can presume the diagnosis of
MFS. Treatment should not be delayed in severe presentation, as a delay can decrease
recovery time, morbidity, and mortality associated with GBS.
  The prognosis of MFS is excellent with a low case fatality rate in afflicted patients (less
than 5 %). The recovery time is good with ranging recovery times of 8 to 12 weeks.
Residual symptoms may be present in some patients, and recurrence has been reported.

Teaching Points

 This clinical presentation is suspicious for Miller Fisher syndrome (MFS), a rare variant
of Guillain Barre Syndrome (GBS). The classical triad of symptoms includes acute
ophthalmoplegia, areflexia, and ataxia. Distal lower extremity weakness, pain, and
paresthesias may be present. Other physical exam findings include diplopia, cranial nerve
palsies, and dampened corneal reflex. However, clinical symptoms by itself do not
predict prognosis on this condition.

 The presence of elevated cerebrospinal fluid (CSF) protein with normal findings in rest of
CSF studies should be suspicious for GBS. Anti-ganglioside antibody is a specific finding
for Miller Fisher syndrome, brainstem encephalitis, or other forms of GBS including a
pharyngeal-cervical-brachial weakness. In the setting of hyporeflexia and lack of
oropharyngeal dysphagia, Miller Fisher is the most likely diagnosis. However, serology is
not used as a predictor of mortality and morbidity, rather than a specific finding to
confirm the diagnosis of MFS.

 Multi-focal deficits in MFS has been reported in the literature, not surprising given the
pathophysiology of this condition including targeting of the myelin sheaths of the central
and peripheral nervous system. Although this phenomenon is known in many cases of
MFS, it is not a predictive factor of mortality or morbidity in patients.

 The most worrisome finding in a patient more than 50 years of age, regarding prognosis,
is the presence of hypoxemia on room air, as it is a risk factor for impending respiratory
failure in patients. Additionally, this finding is a major criterion for intensive care unit
admission in adults. Mechanical ventilation and ICU admission are recommended in
patients with at least one major criterion or 2 minor criteria. Major criteria include
hypercapnia with PaCO2 above 48 mm Hg, hypoxemia with PaO2 below 56 mm Hg
while the patient is breathing ambient air, vital capacity less than 15 mL/kg of body
weight, and negative inspiratory force less than -30 cm H2O. Minor criteria include an
inefficient cough, impaired swallowing, and atelectasis. Life-threatening complications
are more likely to occur in patients who meet criteria for intensive care unit admission.
These complications include sepsis, pneumonia, pulmonary embolism, autonomic
dysfunction and gastrointestinal bleeding. The risk of mortality or morbidity is higher in
these patients. Among severely affected patients, 20% to 33% may be unable to walk for
more than six months after symptom onset, especially if infected with Campylobacter
jejuni. Patients may also suffer from chronic psychiatric illness due to persistent pain and
disability, among other complications.

Teaching Points
 There is no known association between Miller Fisher syndrome and active smokers or
cocaine users. However, there is an association between heroin use and increased risk of
developing the disease.

 Although there has been a reported case of Norovirus causing miller fisher syndrome in a
nursing home in Japan, this is extremely rare, and although possible, not the best answer.

 The literature supports an association between certain drugs and the risk of developing
GBS and its variant Miller Fisher syndrome. These drugs include heroin, suramin,
streptokinase, and isotretinoin, use of TNF-alpha antagonist therapy, other concurrent
autoimmune diseases. This patient is on adalimumab; a TNF-alpha antagonist approved
for many autoimmune disorders, including rheumatoid arthritis.

 Although the mean age of onset for Miller Fisher syndrome is around 44 to 45 years old,
it is not a risk factor, more than an epidemiological finding. Also, men are affected more
than women on a 2:1 ratio.