Miller Fisher syndrome

Miller Fisher syndrome also called Fisher’s syndrome, is a rare acquired nerve disease considered to be a rare variant of of Guillain-Barré syndrome ¹. Miller Fisher syndrome main features are lack of muscle coordination (ataxia), eye muscle weakness resulting in the inability to move the eyes in several directions (ophthalmoplegia), and the absence of tendon reflexes (areflexia). Miller Fisher syndrome is observed in only about 1% to 5% of all cases of Guillain-Barré syndrome worldwide ². Guillain-Barré syndrome is a serious and possibly fatal acute immune-mediated polyneuropathy that typically presents with ascending muscle paralysis and can progress to respiratory failure and death. Miller Fisher Syndrome was named after neurologist Dr. C. Miller Fisher who first described it in 1956 as a limited variant of ascending paralysis, Guillain-Barré syndrome ².

Miller Fisher syndrome symptoms often start several days after a viral illness ³. Miller Fisher syndrome begins with the rapid development, over days, of weak eye muscles, with double or blurred vision, and often drooping eyelids with facial weakness; poor balance and coordination with sloppy or clumsy walking; and loss of deep tendon reflexes – the triad of ophthalmoplegia, ataxia, and areflexia. Other symptoms include generalized muscle weakness and respiratory failure.

The cause of Miller Fisher syndrome is not known, but it is thought to be an autoimmune disease in which there are autoantibodies that attack the nerves. In most people with Miller Fisher syndrome an antibody (anti-GQ1b) is identified. The presence of these autoantibodies helps confirm the diagnosis of Miller Fisher syndrome ¹.

Miller Fisher syndrome treatment includes intravenous immunoglobulin (IVIG), plasmapheresis (a plasma exchange procedure in which the antibodies are removed from the blood) and supportive care. The prognosis is usually good, and in most cases, there is almost complete recovery within 6 months ⁴. In rare cases, Miller Fisher syndrome may progress and permanent neurological deficits may be present ⁵.

The annual incidence of Miller Fisher syndrome is about 0.1 per 100,000 population in the UK ⁶. According to the World Health Organization (WHO), there are about 20,000 neurologists in Western Europe, the USA and Canada.

In 1932, Collier first described the triad of ataxia, areflexia and ophthalmoplegia as a variant of the Guillain-Barre syndrome ⁷. In 1956, Charles Miller Fisher, a Canadian stroke specialist, described 3 patients with acute
external ophthalmoplegia, sluggish pupillary reflexes, ataxia and areflexia ⁸. Two patients had no weakness, and the other had a facial palsy and possible weakness. All 3 patients recovered spontaneously. Because some Guillain-Barré syndrome patients had ophthalmoplegia and other similarities, Fisher concluded that these patients had suffered a disorder akin to Guillain-Barré syndrome. The syndrome was later called Miller Fisher syndrome. Many studies showed the similarities in the pathogenesis of Miller Fisher syndrome and Guillain-Barré syndrome. Miller Fisher syndrome shows a higher level of sensory and central nervous system involvement. The ataxia in Miller Fisher syndrome is due to peripheral mismatch between proprioceptive input from muscle
spindles and kinesthetic information for joint receptors.

Berlit et al ⁹ viewed 223 cases of Miller Fisher syndrome. The first symptom was diplopia (38.6%) or ataxia (20.6%). Areflexia was present in 81.6% of cases. The cranial nerves other than III were involved in 127 cases (56 .9%): cranial nerves VII (45.7%), IX and X (39.9%), and XII (13%) were involved. In 53 cases, tetraparesis occurred. Elevated cerebrospinal fluid (CSF) protein was present in 134 patients (64.4%). CSF findings were normal in 56 patients, and 18 patients had mild pleocytosis. The prognosis of Miller Fisher syndrome was good. Recovery occurred after a mean time period of 10.1 weeks. Residual symptoms were present in 74 cases (33.2%), recurrence of Miller Fisher syndrome was reported in 7 patients, and 8 patients died.

Fross et al ¹⁰ reported in 10 patients with typical Miller Fisher syndrome electrophysiological abnormalities characteristic of axonal neuropathy or neuronopathy with predominant sensory nerve changes in the limbs and motor damage in the cranial nerves.

Uncini et al ¹¹ reported an Miller Fisher syndrome patient with antibodies to GQ1b who developed limb weakness. Serial motor conduction velocities showed a marked reduction in the amplitudes of distal compound muscle action potentia, reaching low at 2 to 3 weeks, followed by a dramatic improvement in the 5th week. Motor conduction velocities were in the normal range, with the distal motor latencies changing only slightly without the conduction block between the root and the distal nerves. These data might suggest an axonal neuropathy or a distal demyelinating conduction block.

Miller Fisher syndrome variant

Different variants of Miller Fisher syndrome are present with a common tie of the GQ1b antibody. Some cases have only one or two symptoms out of the triad. Some patients have combined features of Guillain-Barre syndrome and Miller Fisher syndrome, in which the oculomotor disturbance and limb weakness occur within a few days of one another (Guillain-Barre syndrome overlap variant: ophthalmoplegia, weakness, areflexia and ataxia) ⁷. Recurrent Miller Fisher syndrome is also reported rarely ¹². There are also lower cranial nerve variants of Guillain-Barre syndrome and atypical Miller Fisher syndrome. It was reported that the oculomotor nerves were involved early in 7 cases of the ophthalmoplegic variants of Guillain-Barre syndrome, and the cranial nerves IX, X and XI were involved early in 9 cases of a lower cranial nerve variant of Guillain-Barre syndrome ¹³.

Ataxic neuropathies

Kusunoki et al ¹⁴ found 5 patients with a variant form characterized by ataxia but no ophthalmoplegia in 149 patients who had the IgG anti-GQ1b antibody without profound weakness. These cases could fit with autoimmune ataxic neuropathy, having pathological lesions mainly in the dorsal root ganglion. GD1b antibody plays the key pathogenic role in autoimmune ataxic neuropathies. Because of the existence of crossreactivity between GQ1b and GD1b, it is thought that the pathogenesis of this form is similar to that of Miller Fisher syndrome ⁷.

Miller Fisher syndrome causes

The cause(s) of Miller Fisher Syndrome is not completely understood. Miller Fisher syndrome is thought to be an autoimmune process in which a preceding infection stimulates production of an antibody that reacts to a glycolipid found on neuronal membranes, causing demyelination and loss of function of the peripheral nerves ². The waddling, duck-like gait is likely due to the loss of a fat rich insulating material called myelin around nerves, designated as 1A, that innervate the major sensory organ of muscle called the muscle spindle. These fibers send information to the spinal cord about the speed and extent of muscle stretch without which skeletal muscles can not properly function. As the clinical course progresses, other sensory fibers can be involved as well as motor and autonomic fibers that respectively innervate muscles that move the eyes and face and control function of the eye, pupil and the bladder. Multiple lines of evidence support an auto-immune mechanism in which the preceding/triggering infection stimulates production of an antibody that reacts to a sugar found on both the surface of infectious organism and the peripheral nerve causing demyelination and loss of function of the nerve. In most people with Miller Fisher Syndrome (96%) an antibody called anti-GQ1b is identified, a ganglioside that has
been isolated in the paranodal regions of third, fourth and sixth cranial nerves in humans ¹⁵. This is especially important as the GQ1b antigen is located on the Schwann cells of the ocular cranial nerves. The presence of these autoantibodies confirms the diagnosis of Miller Fisher syndrome.

The presence of GT-1 GD-2 and GD1-b antibodies are much less frequently ¹⁶. Autoantibodies, identified in about 95% of cases, would induce neuro-muscular blockade responsible of a significant part of symptomatology ¹⁷.

Miller Fisher syndrome symptoms

Miller Fisher Syndrome usually begins with the rapid development, over days, of 3 problems:

• weak eye muscles, with double or blurred vision, and often drooping eyelids with facial weakness;
• poor balance and coordination with sloppy or clumsy walking; and
• on physical examination, loss of deep tendon reflexes, such as the knee and ankle jerk.

Patients typically seek medical attention because of rapid decrease in vision over days and/or difficulty walking. These changes are frequently preceded by a viral or diarrheal illness 1 to 4 weeks earlier. Slurred speech, difficulty swallowing and abnormal facial expression with inability to smile or whistle may also occur.

Miller Fisher syndrome diagnosis

Examination shows poor balance and coordination of the hands as well as loss of deep tendon reflexes and eye muscle weakness. Facial weakness, enlarged or dilated pupils and a decreased gag reflex on stimulation of the throat can be present in some patients. Tests of nerve conduction may show diminished activity of nerves that carry sensory information to the spinal cord and brain.

Magnetic resonance (MRI) or other imaging of the brain and/or spinal cord are usually normal. Spinal fluid protein is often elevated.

Pure Miller Fisher Syndrome is uncommon, with many patients going on to develop the prominent widespread weakness of Guillain-Barré syndrome.

In most people with Miller Fisher Syndrome (96%) an antibody called anti-GQ1b is identified. This is especially important as the GQ1b antigen is located on the Schwann cells of the ocular cranial nerves. The presence of these autoantibodies confirms the diagnosis of Miller Fisher syndrome.

Miller Fisher syndrome treatment

Fortunately, Miller Fisher syndrome is often short lived, progressing for only a few weeks and then improving. Miller Fisher syndrome symptoms can signal the beginning of Guillain-Barré syndrome, with breathing difficulties, so patients are often hospitalized for observation. Miller Fisher syndrome treatment, just as typical Guillain-Barré syndrome, consists of intravenous immunoglobulin (IVIG) or plasmapharesis and supportive care. IVIG results in an influx of new antibodies which competitively bind to the antigen site, thereby reducing the ability of harmful autoantibodies to bind; whereas, plasmapheresis removes the antibodies from the blood entirely.

In pure Miller Fisher syndrome, a near full recovery typically occurs within 2-3 months.

Miller Fisher syndrome recovery time

The prognosis for most individuals with Miller Fisher syndrome is good. In most cases, recovery begins within 2 to 4 weeks of the onset of symptoms, and may be almost complete within 6 months ⁴. In rare cases, Miller Fisher syndrome may progress and permanent neurological deficits may be present ⁵. Relapses may occur rarely in less than 3 percent of cases ³.

Mori et al ¹⁸ reviewed the clinical features and outcome of Miller Fisher syndrome for 50 consecutive patients including 28 patients who received no immunotherapy. Besides the characteristic clinical triad (ophthalmoplegia, ataxia, and areflexia), pupillary abnormalities, blepharoptosis, and facial palsy are frequent in Miller Fisher syndrome, whereas sensory loss is unusual despite the presence of profound ataxia. Patients with Miller Fisher syndrome usually had good recovery and no residual deficits.

References

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