The diagnosis of acute Guillain-Barré Syndrome (GBS) is usually straightforward in typical cases, but unusual presentations broaden the differential diagnosis to many neuropathies and neuromuscular diseases. Variant forms of GBS, however, are encountered more frequently than most of the uncommon disorders that resemble GBS. In 1956, C. Miller Fisher described three patients with a syndrome of opthalmoplegia, ataxia, and areflexia and suggested it was a variant of GBS. Over 100 similar cases, in adults and children have appeared subsequently in the literature. The incidence of Fisher's syndrome in GBS is approximately 5%, though many cases begin with this variant before progressing to develop more generalized GBS. The initial symptom is usually double vision, which may be worse in particular directions of gaze. Unilateral or bilateral asymmetric abducens palsies are the initial findings, often progressing to ophthalmoplegia. Lid droop occurs in most patients with ophthalmoplegia, and the pupils may be asymmetrically dilated and un-reactive. In-coordination of the limbs with trouble walking and imbalance (one of Fisher's original patients likened his in-coordination to “walking like a drunken sailor”) usually develops within several days. The ataxia is often asymmetric typically involves all of the limbs, and has the qualities of a cerebellar tremor. Reflexes are usually absent in well developed cases after one week. Half have mild distal parenthesize and one-third have proximal limb weakness. Mild dizziness or light-headedness may occur, but vertigo, dysarthria and coma are not typical features of the Fisher syndrome and should suggest an alternative diagnosis, such as brainstem encephalitis or basilar artery disease. Although once considered a benign variant, approximately one-third of patients progress to ventilatory failure.

Fisher's syndrome follows the usual antecedent illnesses observed with typical GBS, including Epstein Barr virus, HIV and Campylobacter jejuna infection. Some cases have been associated with systemic illnesses, including systemic lupus erythematosus and lymphoma.

In the absence of the fully developed triad, Fisher's syndrome can be confused with acute viral, post-infectious or paraneoplastic encephalitis, brainstem infarction due to basilar artery thrombosis, or carcinomatous meningitis. Early in the disease course, when ophthalmoplegia is prominent and ataxia is minimal, other diagnosis considerations include myasthenia gratis and botulism.

The CSF protein concentration is elevated in most patients with Fisher's syndrome, though often less than in typical cases. Electrodiagnostic studies show a peripheral neuropathy in virtually all patients. Although characteristic electrophysiolopical features of demyelination have been reported in some cases most patients have minor motor conduction abnormalities with absent sensory potential more suggestive of an axonal neuropathy.

There has been controversy regarding the pathogenesis of the Fisher syndrome, and several investigators have proposed that cerebellar-like ataxia and eye movement abnormalities are the result of brainstem encephalitis. The lack of other central nervous system findings (coma, dysarthria, conjugate gaze abnormalities, Babinski signs), areflexia, normal brain MRI and brainstem evoked potentials, and absence of inflammatory cells in the spinal fluid in most cases provide compelling evidence against a brainstem disorder. Moreover, specific anti-nerve antibodies can be detected in virtually all patients with Fisher syndrome. These antibodies are directed against a ganglioside, GQ1b, that is found predominantly in ocular nerves. Lastly, pathology in a few well-studied cases demonstrated inflammation and demyelination of peripheral oculomotor nerves. There are several shared features of GBS and Fisher's syndrome that provide further evidence supporting a relationship between these disorders, including generalized areflexia, monophasic course, elevated CSF protein concentration, demyelinating features on EMG, response to immunotherapy and cases of Fisher's syndrome that crossover to typical GBS.

Patients with Fisher syndrome have been treated with plasma exchange or intravenous gamma globulin and many have apparently improved, but clinical trials demonstrating efficacy of these immunotherapies have not been performed. Physical and occupational therapy, eye patching and corneal care are beneficial to many patients. Although many patients with Fisher's syndrome evolve after several days or weeks into a more typical pattern of GBS with generalized weakness with respiratory failure as noted above, the majority of patients recover and the prognosis is excellent relapses have been reported but are rare.