Grand Rounds at the New England Eye Center

Middle-aged man presents with acute bilateral ophthalmoplegia, right-sided ptosis

He also displayed an ataxic gait and reduced reflexes.

A 47-year-old man presented to the emergency department at the University of New Mexico with 4 days of diplopia and bilateral retro-orbital pain. He had been feeling well until 2 weeks earlier when he developed a flu-like illness with fever, chills, myalgias, nausea and vomiting. These symptoms resolved without treatment. Subsequently, the patient developed double vision and ocular pain. On review of symptoms, he also reported new unsteadiness with walking as well as right-sided facial and eyelid drooping.

Alison J. Lauter
Alison J. Lauter
Sarah E. Thornton
Sarah E. Thornton

The patient’s medical history was remarkable for two episodes of bilateral Bell’s palsy occurring more than 10 years earlier. He also reported hypertension and diabetes. The patient’s home medications included lisinopril. He denied any medication allergies. He was a current smoker and consumed approximately four alcoholic beverages per day.

Examination

On initial examination, the patient’s visual acuity measured 20/25 at near in each eye. The right pupil was 1.5 mm in diameter and reacted minimally to light, and the left pupil was 3 mm in diameter and reacted minimally to light. There was no relative afferent pupillary defect. Color vision and confrontation visual field testing were normal in each eye. Extraocular movements were significantly restricted bilaterally in all gaze directions (Figure 1).

Motility examination
Figure 1. Motility examination reveals significant restriction bilaterally in all gaze directions.
Source: Sarah Adelson, MD, and Kevin Sitko, MD

On external examination, there was marked ptosis of the right upper eyelid with a margin reflex distance of –3 mm (Figure 2). There was no proptosis. Slit lamp and dilated fundus examinations were unremarkable.

External photograph
Figure 2. External photograph demonstrates marked ptosis of the right upper eyelid.

On neurologic examination, the patient displayed an ataxic gait. Reflexes were reduced in the biceps, triceps and brachioradialis. The neurologic exam was otherwise normal.

What is your diagnosis?

See answer on next page.

Bilateral ophthalmoplegia

The precipitous onset of symptoms including bilateral ophthalmoplegia, unilateral ptosis, gait change and diminished deep tendon reflexes warrants expeditious workup and management. The presence of a brainstem stroke, cavernous sinus thrombosis, paranasal sinus disease with orbital extension (such as Mucor infection) or pituitary apoplexy must be ruled out. Other differential considerations include Miller Fisher variant of Guillain-Barré syndrome (GBS), neuromuscular diseases such as myasthenia gravis or botulism, Wernicke’s encephalopathy, or infectious or inflammatory vasculitis.

Given the patient’s clinical findings in the setting of a recent flu-like illness with gastrointestinal symptoms, the diagnosis of a demyelinating polyradiculopathy such as GBS was considered highly likely. The Miller Fisher syndrome (MFS) variant of GBS can cause abnormal eyelid function and varying levels of external ophthalmoplegia in addition to pupillary abnormalities from involvement of the pupillary sphincter and ciliary muscles.

Bulbar myasthenia gravis (MG) commonly presents with diplopia and external ophthalmoplegia, but the pupillary examination is typically normal. Botulism can also cause bilateral cranial neuropathies, ptosis and descending motor weakness but was considered less likely in this case based on lack of exposure to poorly preserved foods. Peripheral demyelinating polyradiculopathy from infectious causes such as Lyme disease, herpes simplex virus, varicella-zoster virus and syphilis, or from inflammatory/neoplastic conditions such as lymphoma, would be likely to have significant findings on neuroimaging and could be confirmed with lumbar puncture and cerebrospinal fluid (CSF) studies. Cerebral vasculitis can present variably depending on the size of affected blood vessels and the region of central nervous system involvement but can cause cranial nerve palsies and optic neuropathies. Wernicke encephalopathy from thiamine deficiency was also considered in this case, but it typically presents with altered mental status and nystagmus, neither of which was present in our patient.

Workup and management

The patient was sent for a CT head and CT venogram head to rule out acute brainstem stroke or hemorrhage and sinus thrombosis. The studies showed moderate sinusitis without orbital extension. There was no evidence of thrombosis or other intracranial abnormality. The patient then obtained a brain MRI, which showed no cranial nerve enhancement and no intracranial findings.

Laboratory testing was obtained for HIV, syphilis, Lyme serologies, Quanti­FERON-TB Gold, ANA, ACE, TSH, thiamine, ESR/CRP, antiganglioside GM1/2 IgG/IgM antibodies for GBS, serum antiganglioside GQ1b IgG antibody for Miller Fisher, and serum anti-acetylcholine receptor and anti-muscle-specific kinase antibodies for myasthenia gravis. Lumbar puncture was performed.

The patient was admitted for further evaluation and close monitoring. He was started on cefepime, vancomycin and metronidazole for sinusitis while awaiting the results of laboratory and CSF testing. As the laboratory testing gradually returned with antibody testing still pending, Miller Fisher syndrome remained the most likely diagnosis. Intravenous immunoglobulin (IVIG) was started 4 days into the patient’s admission, and he received three total cycles before discharge.

Discussion

Miller Fisher syndrome is a variant of GBS characterized by typical findings of ataxia, ophthalmoplegia and areflexia. Males are twice as likely to get MFS and the mean age of onset is 43.6 years. The location of pathology is hypothesized to be in the peripheral cranial nerves, specifically at the nodes of Ranvier, although the ataxia has cerebellar features that would suggest pathology in the central nervous system.

Most patients with MFS report a history of illness 1 to 3 weeks before the development of ophthalmoplegia or ataxia, associated with Campylobacter jejuni infection in 20% of cases and Haemophilus influenzae infection in 8% of cases. This suggests an infection-induced autoimmune etiology in the pathogenesis of this disease. Up to 80% of patients have autoantibodies to ganglioside GQ1b, a glycolipid found in neurons.

In MFS, the presenting complaint is diplopia in 65% of cases. Ophthalmoplegia, which may be bilateral, is seen in about 50% of patients. Approximately one-quarter of patients will develop extremity weakness, linking this disorder to GBS. Ataxia, which occurs in 32% of cases, is considered to be cerebellar in origin. Areflexia is present in 80% of patients. Detailed clinical examination, neuroimaging and laboratory testing can help reach the diagnosis and rule out other conditions. Lumbar puncture can be helpful, as elevated protein suggests a diagnosis of MFS.

Given the presumed pathogenesis, treatment strategies have focused on eliminating the offending antibodies from the bloodstream with either IVIG or plasmapheresis. Plasmapheresis, which removes complement and antibodies in a nonspecific way, appears to be most effective when started within 2 weeks of symptom onset in patients who cannot walk independently. Importantly, the combination of plasmapheresis and IVIG is not significantly better than plasma exchange or IVIG alone. Recovery almost always occurs without treatment, but treatment can expedite the process. The recovery period for ataxia in MFS is approximately 1 month, and the ophthalmoplegia typically resolves over 3 months.

Clinical course

The patient showed gradual improvement in his neurologic status after each round of IVIG. By the time of discharge, his diplopia and ptosis had improved significantly. After discharge, his serum anti-GQ1b IgG antibody was found to be elevated, which confirmed the diagnosis of Miller Fisher syndrome.

A 47-year-old man presented to the emergency department at the University of New Mexico with 4 days of diplopia and bilateral retro-orbital pain. He had been feeling well until 2 weeks earlier when he developed a flu-like illness with fever, chills, myalgias, nausea and vomiting. These symptoms resolved without treatment. Subsequently, the patient developed double vision and ocular pain. On review of symptoms, he also reported new unsteadiness with walking as well as right-sided facial and eyelid drooping.

Alison J. Lauter
Alison J. Lauter
Sarah E. Thornton
Sarah E. Thornton

The patient’s medical history was remarkable for two episodes of bilateral Bell’s palsy occurring more than 10 years earlier. He also reported hypertension and diabetes. The patient’s home medications included lisinopril. He denied any medication allergies. He was a current smoker and consumed approximately four alcoholic beverages per day.

Examination

On initial examination, the patient’s visual acuity measured 20/25 at near in each eye. The right pupil was 1.5 mm in diameter and reacted minimally to light, and the left pupil was 3 mm in diameter and reacted minimally to light. There was no relative afferent pupillary defect. Color vision and confrontation visual field testing were normal in each eye. Extraocular movements were significantly restricted bilaterally in all gaze directions (Figure 1).

Motility examination
Figure 1. Motility examination reveals significant restriction bilaterally in all gaze directions.
Source: Sarah Adelson, MD, and Kevin Sitko, MD

On external examination, there was marked ptosis of the right upper eyelid with a margin reflex distance of –3 mm (Figure 2). There was no proptosis. Slit lamp and dilated fundus examinations were unremarkable.

External photograph
Figure 2. External photograph demonstrates marked ptosis of the right upper eyelid.

On neurologic examination, the patient displayed an ataxic gait. Reflexes were reduced in the biceps, triceps and brachioradialis. The neurologic exam was otherwise normal.

What is your diagnosis?

See answer on next page.

PAGE BREAK

Bilateral ophthalmoplegia

The precipitous onset of symptoms including bilateral ophthalmoplegia, unilateral ptosis, gait change and diminished deep tendon reflexes warrants expeditious workup and management. The presence of a brainstem stroke, cavernous sinus thrombosis, paranasal sinus disease with orbital extension (such as Mucor infection) or pituitary apoplexy must be ruled out. Other differential considerations include Miller Fisher variant of Guillain-Barré syndrome (GBS), neuromuscular diseases such as myasthenia gravis or botulism, Wernicke’s encephalopathy, or infectious or inflammatory vasculitis.

Given the patient’s clinical findings in the setting of a recent flu-like illness with gastrointestinal symptoms, the diagnosis of a demyelinating polyradiculopathy such as GBS was considered highly likely. The Miller Fisher syndrome (MFS) variant of GBS can cause abnormal eyelid function and varying levels of external ophthalmoplegia in addition to pupillary abnormalities from involvement of the pupillary sphincter and ciliary muscles.

Bulbar myasthenia gravis (MG) commonly presents with diplopia and external ophthalmoplegia, but the pupillary examination is typically normal. Botulism can also cause bilateral cranial neuropathies, ptosis and descending motor weakness but was considered less likely in this case based on lack of exposure to poorly preserved foods. Peripheral demyelinating polyradiculopathy from infectious causes such as Lyme disease, herpes simplex virus, varicella-zoster virus and syphilis, or from inflammatory/neoplastic conditions such as lymphoma, would be likely to have significant findings on neuroimaging and could be confirmed with lumbar puncture and cerebrospinal fluid (CSF) studies. Cerebral vasculitis can present variably depending on the size of affected blood vessels and the region of central nervous system involvement but can cause cranial nerve palsies and optic neuropathies. Wernicke encephalopathy from thiamine deficiency was also considered in this case, but it typically presents with altered mental status and nystagmus, neither of which was present in our patient.

Workup and management

The patient was sent for a CT head and CT venogram head to rule out acute brainstem stroke or hemorrhage and sinus thrombosis. The studies showed moderate sinusitis without orbital extension. There was no evidence of thrombosis or other intracranial abnormality. The patient then obtained a brain MRI, which showed no cranial nerve enhancement and no intracranial findings.

Laboratory testing was obtained for HIV, syphilis, Lyme serologies, Quanti­FERON-TB Gold, ANA, ACE, TSH, thiamine, ESR/CRP, antiganglioside GM1/2 IgG/IgM antibodies for GBS, serum antiganglioside GQ1b IgG antibody for Miller Fisher, and serum anti-acetylcholine receptor and anti-muscle-specific kinase antibodies for myasthenia gravis. Lumbar puncture was performed.

The patient was admitted for further evaluation and close monitoring. He was started on cefepime, vancomycin and metronidazole for sinusitis while awaiting the results of laboratory and CSF testing. As the laboratory testing gradually returned with antibody testing still pending, Miller Fisher syndrome remained the most likely diagnosis. Intravenous immunoglobulin (IVIG) was started 4 days into the patient’s admission, and he received three total cycles before discharge.

Discussion

Miller Fisher syndrome is a variant of GBS characterized by typical findings of ataxia, ophthalmoplegia and areflexia. Males are twice as likely to get MFS and the mean age of onset is 43.6 years. The location of pathology is hypothesized to be in the peripheral cranial nerves, specifically at the nodes of Ranvier, although the ataxia has cerebellar features that would suggest pathology in the central nervous system.

PAGE BREAK

Most patients with MFS report a history of illness 1 to 3 weeks before the development of ophthalmoplegia or ataxia, associated with Campylobacter jejuni infection in 20% of cases and Haemophilus influenzae infection in 8% of cases. This suggests an infection-induced autoimmune etiology in the pathogenesis of this disease. Up to 80% of patients have autoantibodies to ganglioside GQ1b, a glycolipid found in neurons.

In MFS, the presenting complaint is diplopia in 65% of cases. Ophthalmoplegia, which may be bilateral, is seen in about 50% of patients. Approximately one-quarter of patients will develop extremity weakness, linking this disorder to GBS. Ataxia, which occurs in 32% of cases, is considered to be cerebellar in origin. Areflexia is present in 80% of patients. Detailed clinical examination, neuroimaging and laboratory testing can help reach the diagnosis and rule out other conditions. Lumbar puncture can be helpful, as elevated protein suggests a diagnosis of MFS.

Given the presumed pathogenesis, treatment strategies have focused on eliminating the offending antibodies from the bloodstream with either IVIG or plasmapheresis. Plasmapheresis, which removes complement and antibodies in a nonspecific way, appears to be most effective when started within 2 weeks of symptom onset in patients who cannot walk independently. Importantly, the combination of plasmapheresis and IVIG is not significantly better than plasma exchange or IVIG alone. Recovery almost always occurs without treatment, but treatment can expedite the process. The recovery period for ataxia in MFS is approximately 1 month, and the ophthalmoplegia typically resolves over 3 months.

Clinical course

The patient showed gradual improvement in his neurologic status after each round of IVIG. By the time of discharge, his diplopia and ptosis had improved significantly. After discharge, his serum anti-GQ1b IgG antibody was found to be elevated, which confirmed the diagnosis of Miller Fisher syndrome.