Check Your Diagnosis — Patient 19

Mary Ellen Vanderlick, M.D.

Diagnosis

Miller Fisher Syndrome (MFS)

Clinical Summary

Patient #19 presented with external ophthalmoplegia, sluggishly reactive pupils, bilateral facial weakness, dysphagia, and areflexia following an upper respiratory illness during which she ate canned goods. She also complained of dizziness and headache and her symptoms had been ongoing for two to three days. She was not found to have orthostatic hypotension. As myasthenia gravis was a consideration, she underwent a tensilon test which was negative. She was then admitted to the ICU to monitor the respiratory status. As her pupils were dilated and sluggishly reactive, there was concern of autonomic involvement. Lumbar puncture performed was normal. Stool and serum were sent to the CDC for evidence of botulinum toxin and culture and she was treated with trivalent anti-toxin. She did not improve, but did remain stable. Initial EMG/NCV, performed by another service, was inconclusive. As the patient also had bilateral facial weakness, Lyme titers and an ACE level were obtained. An initial CT of the head in the ER was normal; however, to better evaluate the cranial nerves, an MRI was ordered and a repeat lumbar puncture was done.

Botulism versus a variant of Guillain-Barre syndrome (the Miller Fisher syndrome) were the primary considerations in this patient.

Botulism and Miller Fisher syndrome can present in a similar fashion with cranial nerve involvement and pupillary changes. If food-borne, botulism typically occurs as a descending paralysis. The patient is often sick prior to the onset of symptoms and tends to eat canned goods. Having a low vital capacity, pupillary changes, and a normal spinal fluid following symptoms that occurred 2-3 days before, botulism was a strong consideration. EMG can be useful for the differential and usually shows reduced CMAP amplitudes, normal nerve conductions, and post-tetanic facilitation. Stool or serum will be positive for botulinum toxin in adults; adults tend to ingest the preformed toxin while infants ingest the spores of Clostridium botulinum. Imaging studies and CSF should be normal. Adult botulinum poisoning is often fatal if untreated.

Other Considerations

Myasthenia gravis may present with rapid-onset of bulbar and respiratory weakness but without autonomic dysfunction. Patients often complain of diplopia, but rarely have complete ophthalmoplegia. There is usually limb weakness as well. Tensilon and EMG testing were not compatible with this diagnosis.

Carcinomatous meningitis may present with multiple cranial nerve involvement. As this patient had no lymphadenopathy, no white blood cells, and a normal protein in the initial spinal fluid, this diagnosis was unlikely.

Sarcoidosis can cause bilateral facial weakness. With the rapid onset of the cranial nerves involved, CXR not showing lymphadenopathy, a normal spinal fluid, and normal ACE level, this was unlikely.

Lyme disease also can cause bilateral facial weakness. She had not been in an endemic area, had an initial normal spinal fluid, and negative Lyme titers. This diagnosis was unlikely.

Brainstem pathology, especially ischemia, may present with multiple cranial nerve involvement; however, one would expect some alteration in consciousness. Initial imaging study (CT) was normal.

Thyroid disease can cause ophthalmoparesis due to chronic lymphocytic infiltration of the extraocular muscles; however, this would not account for her other symptoms.

Acute intermittent porphyria can be confused with Guillain-Barre syndrome as it tends to cause a motor neuropathy. Patients often have abdominal pain, neuropsychiatric symptoms, and a family history. As she did not have these findings, this diagnosis was unlikely. Urine screen for porphobilinogens was negative.

The MRI with and without contrast showed enhancement on T1 for cranial nerves III, IV, V, and VI. Repeat lumbar puncture showed an elevated protein. There was no evidence of botulinum toxin in serum or stool, and the culture was also negative. Repeat EMG/NCV showed normal repetitive stimulation, slowing of the mid portion of the facial nerve, and nonconductible upper and lower portions as well as absent H-reflexes. As the diagnosis in this patient was considered to be Miller Fisher syndrome, the patient was treated with intravenous immunoglobulin. GQ1B antibody titers are still pending.

Discussion

There are several variants of GBS that do not have the characteristic generalized weakness; the most recognized variant being the Miller Fisher syndrome. The core syndrome consists of areflexia, ophthalmoplegia, and ataxia. The ratio of men to women is 2:1 and the average age of onset is 43.6 years. A viral infection often precedes the neurological symptoms in the majority of cases with an average symptom free interval of ten days. Campylobacter jejuni has been implicated as well.

Clinical Features

About two-thirds of patients present with diplopia, with the remainder presenting with only ataxia or with both symptoms simultaneously. Patients tend to complain of dizziness, but not of vertigo. The disease progresses over five to ten days, sometimes up to three weeks. External ophthalmoplegia begins relatively symmetrically and most patients progress to have complete immobilization of the globes. Less than half develop pupillary sphincter paralysis and more than half have bilateral but often asymmetric ptosis. Almost half of the cases are not the pure syndrome of areflexia, ataxia, and ophthalmoplegia but have additional features consistent with a peripheral neuropathy (including paraesthesias of the distal limbs, oropharyngeal weakness, or bi-facial weakness). Approximately ten percent of cases initially have mild proximal weakness, some of which will progress to generalized GBS. Bladder dysfunction or more widespread dysautonomia is occasionally seen.

Diagnosis

Diagnosis is based on the clinical findings, an elevated CSF protein, and by EMG. EMG/NCV studies vary from patient to patient. Findings include normal motor and sensory conduction velocities with absent H reflexes, slowed nerve conduction velocities, reduced sensory nerve action potential amplitudes, or normal studies. Motor studies can become abnormal late in the course, even as they are recovering. Imaging studies are often normal although cranial nerve enhancement has been described.

Pathology

The pathology of Miller Fisher syndrome has long been disputed. Peripheral, brainstem encephalitis, or a combination has been proposed. The current belief is that the pathology is peripheral.

Antibodies to the ganglioside GQ1b is associated with Miller Fisher syndrome. Titers of 1:40 by ELISA are significant. GQ1b is found at paranodal segments and in highest concentrations in the oculomotor, trochlear, and abducens nerves.

Treatment

Treatment is with either plasmapheresis or intravenous immunoglobulin. No double-blind, controlled trials have been reported.

Prognosis

Prognosis is good with recovery after a mean of 10 weeks. Most patients show a complete remission without any residual symptoms. Several cases of relapsing disease have been reported.

References

  1. Arakawa Y, Yoshimura M, Kobayashi S, et al. The use of intravenous immunoglobulin in Miller Fisher syndrome. Brain Dev. 1993;15:231-3.
  2. Bradley WG, Daroff RB, Fenichel GM, Marsden CD. editors. Neurology in clinical practice. 2nd ed. 1996.
  3. Berlit P, Rakicky J. The Miller Fisher syndrome. J Clin Neuroophthalmol. 1992;12:57-63.
  4. Chiba A, Kusunoki S, Obata H, et al. Serum anti-GQ1b IgG antibody is associated with ophthalmoplegia in Miller Fisher syndrome and Guillain-Barre syndrome: Clinical and immunohistochemical studies. Neurology. 1993;43:1911-7.
  5. Fulbright R, Erdum E, Sze G, Byrne T. Cranial nerve enhancement in the Guillain-Barre syndrome. AJNR Am J Neuroradiol. 1995;16(4 suppl):923-5.
  6. Ropper AH. Miller Fisher syndrome and other acute variants of Guillain-Barre syndrome. Baillieres Clin Neurol. 1994;3(1):95-106.
  7. Shapiro BE, Soto O, Shafquat S, Blumenfeld H. Adult botulism. Muscle Nerve. 1997;20:100-2.
  8. Shuaib A, Becker WJ. Variants of Guillain-Barre syndrome: Miller Fisher syndrome, facial diplegia and multiple cranial nerve palsies. Can J Neurol Sci. 1987;14(4):611-6.

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