Grand Rounds at the New England Eye Center

Middle-aged woman presents with rapidly progressive bilateral ptosis and diplopia

Exam findings also include generalized weakness, areflexia, dysarthria and dysphagia.

A 56-year-old woman presented to Tufts Medical Center with a 2-day history of rapid-onset binocular horizontal diplopia and an inability to open her eyes. Her double vision was initially present in left gaze only but soon involved all directions of gaze. She noted the inability to open her left upper eyelid 2 days before presentation, which was soon followed by involvement of the right upper eyelid 1 day later. Her vision was otherwise stable. She denied any eye pain or other ophthalmic complaints.

Along with her ocular symptoms, she had also developed generalized weakness, tingling of hands and feet bilaterally, and difficulty speaking and swallowing. Before the onset of these constellation of symptoms, she had been completely asymptomatic. The patient presented to an outside emergency department the previous day and was discharged home after a head CT was unremarkable.

Her medical history included hepatitis B infection treated 10 years prior and a pilonidal cyst removed at age 17 years. Review of systems revealed that 2 weeks before presentation, she had experienced an upper respiratory infection, primarily symptomatic with rhinorrhea and phlegmatic cough. Her primary care physician had prescribed oral doxycycline, which she had to stop taking when she developed a generalized pruritic rash. She had known allergies to iodine and shellfish. She was not taking any medications at presentation. She worked as an office secretary and denied any sexual risk factors, recreational drug use or alcohol intake. She smoked half a pack of cigarettes a day, leading to a 44 pack-year history. Family history was only pertinent for vitamin B12 deficiency in her sister.

Examination

Figure 1. Bedside photograph showing bilateral complete ptosis of the upper eyelids.

Source: Melina I. Morkin, MD, Laurel N. Vuong, MD, and Thomas R. Hedges III, MD

Figure 2. Bedside motility examination showed an esotropia in primary gaze (a). The patient’s esotropia worsened in right gaze, with an approximately 50% abduction deficit of the right eye (b). Upgaze appeared intact (c). Her esotropia also worsened in left gaze, with an approximately 90% to 95% abduction deficit of the left eye (d). Downgaze appeared intact (e).

The patient was initially evaluated at bedside. Near vision with correction was 20/30 bilaterally. Color vision and confrontation visual fields were full in both eyes. Pupils were symmetric, reacted briskly to light and showed no evidence of a relative afferent pupillary defect. IOPs were within normal limits bilaterally. She was unable to voluntarily open her eyes (Figure 1). There was also abduction limitation bilaterally, worse in the left eye than the right (Figures 2a to 2e). In primary gaze, there was a 30 D esotropia, which increased to more than 45 D in right and left gaze. The rest of the ocular examination was unremarkable.

Neurological examination revealed dysarthria and nasal phonation leading to diminished intelligibility. She had bilateral upper and lower facial weakness. Muscle strength was moderately decreased in the left arm and right leg. Sensation was reduced in her fingers and toes. Deep tendon reflexes were diffusely suppressed. Cerebellar function examination demonstrated a mild left dysmetria on finger-to-nose test. Gait was stable with normal initiation, but there was decreased stride length and arm swing. Respiratory mechanics were poor, leading to difficulty breathing.

What is your diagnosis?

See answer on next page.

Precipitous onset of symptoms

The precipitous onset of symptoms, including ptosis, cranial nerve palsies, dysarthria, muscle weakness and sensory changes, warrants expeditious diagnosis and management. The presence of a brainstem stroke should be first ruled out. Imaging did not support that diagnosis.

The history of a recent upper respiratory infection along with systemic neurological symptoms makes the diagnosis of a demyelinating polyradiculopathy, such as Guillain-Barré syndrome (GBS), most likely. The Miller Fisher syndrome (MFS) variant would explain the progressive bulbar palsy (lower motor neuron paralysis affecting swallowing, speech and chewing), profound bilateral ptosis, bilateral sixth cranial nerve palsies, facial weakness, paresthesia and diminished reflexes.

Bulbar myasthenia gravis (MG) could be consistent with the exam findings, but the lack of daily variation of symptoms, complete absence of other neurological complaints before the acute episode, and presence of generalized decreased reflexes make MG unlikely. Botulism can also cause bulbar palsy with bilateral cranial neuropathies, ptosis, facial and typically symmetric descending weakness, and respiratory difficulties with preserved consciousness. A history of consuming poorly preserved food should be investigated. Diagnostic confirmation is achieved by identifying the botulinum toxin from a stool or intestinal specimen or isolating Clostridium botulinum from a wound site. Additionally, electromyography (EMG) testing with repetitive nerve stimulation helps differentiate MFS from a neuromuscular junction disorder; in both MG and botulism, sensory involvement is absent.

A lumbar puncture is usually performed for suspected peripheral demyelinating polyradiculopathy to rule out infectious diseases, such as Lyme disease, or malignant conditions, such as lymphoma. Rarely, elevated protein can cause increased intracranial pressure in GBS. The differential diagnosis also includes Wernicke encephalopathy and brainstem encephalitis, but these typically present with altered mental status. Patients with Wernicke encephalopathy usually develop nystagmus, which is not associated with MFS.

Clinical manifestations of cerebral vasculitis vary widely depending on the affected blood vessels (small- vs. medium-sized vessels) as well as the region of the central nervous system involved. Diffuse involvement can lead to the development of headaches, seizures and confusion. Focal involvement, such as in polyarteritis nodosa, granulomatosis with polyangiitis, giant cell arteritis and systemic lupus erythematosus, can manifest with cerebrovascular accidents, cranial nerve palsies and optic neuropathies. Ancillary laboratory testing and neuroimaging studies help reach the diagnosis of vasculitis.

Workup and management

The patient was admitted for close monitoring and further evaluation. Lyme serology, angiotensin converting enzyme, vitamin B12, thyroid-stimulating hormone, antinuclear antibodies, rheumatoid factor, antineutrophil cytoplasmic antibodies, C-reactive protein, erythrocyte sedimentation rate, and complement C3 and C4 levels were within normal limits. Serum anti-acetylcholine receptor and anti-muscle specific kinase antibodies were obtained and eventually found to be negative. Serum antiganglioside GQ1b IgG antibody was also ordered to evaluate for Miller Fischer variant. Brain MRI showed subtle enhancement along the cisternal segment of the facial nerves, fifth cranial nerves and left sixth cranial nerve on post-contrast fluid-attenuated inversion recovery and T1 sequences. On lumbar puncture, clear, colorless cerebrospinal fluid (CSF) was obtained, with an opening pressure of 11 cm H2O and a normal profile. Placement of an ice pack over her eyelids did not improve the ptosis. Repetitive nerve stimulation EMG performed 1 day after presentation was not consistent with a neuromuscular junction pathology, such as myasthenia gravis.

During the patient’s first days of hospitalization, abduction in the right eye worsened (from a 50% deficit to a 75% deficit), and abduction in the left eye remained fully impaired. Her dysarthria and dysphagia also worsened. Given the risks of aspiration, oral intake was contraindicated. She did not require intubation. Her peripheral weakness also worsened, especially in her upper extremities, and she continued to be completely areflexic.

Miller Fisher variant was the leading diagnosis given her symptoms and otherwise negative workup. Plasmapheresis was started 2 days after presentation, aiming for a total of five cycles. Complete blood count, metabolic and coagulation panels, and fibrinogen levels were monitored during the treatment period.

Repeat EMG and nerve conduction study 4 days after presentation indicated the presence of a generalized, multifocal dysfunction of conduction affecting sensory nerves. There was no evidence of demyelinating pathology beyond that attributable to a probable left median nerve entrapment at the wrist.

The patient showed gradual improvement in her neurologic status after five rounds of plasmapheresis. Her speech, swallowing and respiratory mechanics improved. No new peripheral symptoms were discovered. Her diet was progressively advanced as tolerated. By the end of the first week, she had fully recovered strength in all extremities and was able to eat solid food. Her facial weakness and bilateral ptosis remained. After 10 days of hospitalization, she was discharged to an acute rehabilitation facility. After discharge, her serum anti-GQ1b IgG antibody was found to be elevated and confirmed the diagnosis of MFS.

At her 2-month follow-up, her ptosis was resolved and the bilateral sixth nerve palsies were improved. Prisms were not recommended given that her diplopia would change with time. Instead, the left lens of her glasses was fogged. On her last follow-up appointment, 5 months after presentation, diplopia was present only with extreme lateral gaze. The range of abduction had recuperated to approximately 90% in both eyes.

Discussion

Miller Fisher syndrome is characterized by a triad of ataxia, ophthalmoplegia and areflexia, and is classically described as a variant of GBS. It occurs in 5% of GBS cases in the U.S. and in 25% of GBS patients in Japan. The male-to-female ratio is 2:1, with a mean age of 43.6 years at onset. Most patients with MFS have evidence of infection 1 to 3 weeks before the development of ophthalmoplegia or ataxia, associated with Campylobacter jejuni infection in 20% of patients and Haemophilus influenzae infection in 8% of cases. Autoantibodies are thought to bind to myelin antigens and activate an acute demyelinating inflammatory cascade. In GBS, the classic pathological features include inflammatory infiltrates and areas of segmental demyelination in motor and sensory nerves and spinal roots. The pathological findings of the “pure” MFS remain uncertain because almost all patients eventually experience a complete recovery and fatalities are extremely infrequent.

The initial presenting complaint is commonly diplopia (39% of cases). Ophthalmoplegia, which may be bilateral, is seen in about 50% of patients. Approximately one-quarter of cases will develop extremity weakness, linking this disorder to GBS. Ataxia, which occurs in one-fifth of cases, is usually cerebellar in origin. Areflexia is present in 80% of patients. Considering these percentages, the classic triad may not always be present. Incomplete forms include acute ophthalmoplegia without ataxia and acute ataxic neuropathy without ophthalmoplegia.

Detailed clinical examination, brain imaging and EMG testing can help reach the diagnosis and rule out other conditions, such as brainstem stroke, Wernicke’s encephalopathy, myasthenia gravis and botulism. Brain MRI may show enhancement of the affected cranial nerves. Spinal MRI can even demonstrate enhancement and thickening of the spinal nerve roots. Both EMG studies, which uncover reduced or absent sensory responses without slowing of sensory conduction velocities, and CSF testing, which shows elevated CSF protein, suggest the diagnosis of MFS. Additionally, antibodies against GQ1b, a ganglioside nerve component, are present in 85% to 90% of patients with MFS. Positive anti-GQ1b antibodies may also be seen in GBS with ophthalmoparesis, Bickerstaff encephalitis (characterized by encephalopathy and hyperreflexia with features of MFS, such as ophthalmoplegia and ataxia), and the pharyngeal-cervical brachial GBS variant, but not in disorders other than GBS.

Plasma exchange, which nonspecifically removes antibodies and complement and reduces nerve damage, appears to be most effective when started within the first 2 weeks after disease onset in patients who cannot walk independently. The usual treatment regimen consists of five plasma exchanges over a period of 2 weeks. Treatment with intravenous immunoglobulin (IVIG) is reported to be similarly effective. Importantly, the combination of plasma exchange and IVIG is not significantly better than plasma exchange or IVIG alone.

Early swallowing assessment will identify cases at risk for aspiration. For patients who are not ambulatory, prophylaxis against deep vein thrombosis should be started. Evaluation of respiratory function is crucial, including careful observation for dyspnea and use of accessory muscles.

The prognosis of MFS is good. The disease typically peaks at 1 week, and improvement often starts at 2 weeks. Recovery from ataxia and ophthalmoplegia takes an average of 1 month and 3 months, respectively. By 6 months after the onset of neurological symptoms, most patients have recovered from both. Although MFS is usually monophasic, it can occasionally recur. Secondary infections, such as pneumonia or sepsis, are infrequent causes of morbidity and mortality.

A 56-year-old woman presented to Tufts Medical Center with a 2-day history of rapid-onset binocular horizontal diplopia and an inability to open her eyes. Her double vision was initially present in left gaze only but soon involved all directions of gaze. She noted the inability to open her left upper eyelid 2 days before presentation, which was soon followed by involvement of the right upper eyelid 1 day later. Her vision was otherwise stable. She denied any eye pain or other ophthalmic complaints.

Along with her ocular symptoms, she had also developed generalized weakness, tingling of hands and feet bilaterally, and difficulty speaking and swallowing. Before the onset of these constellation of symptoms, she had been completely asymptomatic. The patient presented to an outside emergency department the previous day and was discharged home after a head CT was unremarkable.

Her medical history included hepatitis B infection treated 10 years prior and a pilonidal cyst removed at age 17 years. Review of systems revealed that 2 weeks before presentation, she had experienced an upper respiratory infection, primarily symptomatic with rhinorrhea and phlegmatic cough. Her primary care physician had prescribed oral doxycycline, which she had to stop taking when she developed a generalized pruritic rash. She had known allergies to iodine and shellfish. She was not taking any medications at presentation. She worked as an office secretary and denied any sexual risk factors, recreational drug use or alcohol intake. She smoked half a pack of cigarettes a day, leading to a 44 pack-year history. Family history was only pertinent for vitamin B12 deficiency in her sister.

Examination

Figure 1. Bedside photograph showing bilateral complete ptosis of the upper eyelids.

Source: Melina I. Morkin, MD, Laurel N. Vuong, MD, and Thomas R. Hedges III, MD

Figure 2. Bedside motility examination showed an esotropia in primary gaze (a). The patient’s esotropia worsened in right gaze, with an approximately 50% abduction deficit of the right eye (b). Upgaze appeared intact (c). Her esotropia also worsened in left gaze, with an approximately 90% to 95% abduction deficit of the left eye (d). Downgaze appeared intact (e).

The patient was initially evaluated at bedside. Near vision with correction was 20/30 bilaterally. Color vision and confrontation visual fields were full in both eyes. Pupils were symmetric, reacted briskly to light and showed no evidence of a relative afferent pupillary defect. IOPs were within normal limits bilaterally. She was unable to voluntarily open her eyes (Figure 1). There was also abduction limitation bilaterally, worse in the left eye than the right (Figures 2a to 2e). In primary gaze, there was a 30 D esotropia, which increased to more than 45 D in right and left gaze. The rest of the ocular examination was unremarkable.

Neurological examination revealed dysarthria and nasal phonation leading to diminished intelligibility. She had bilateral upper and lower facial weakness. Muscle strength was moderately decreased in the left arm and right leg. Sensation was reduced in her fingers and toes. Deep tendon reflexes were diffusely suppressed. Cerebellar function examination demonstrated a mild left dysmetria on finger-to-nose test. Gait was stable with normal initiation, but there was decreased stride length and arm swing. Respiratory mechanics were poor, leading to difficulty breathing.

What is your diagnosis?

See answer on next page.

PAGE BREAK

Precipitous onset of symptoms

The precipitous onset of symptoms, including ptosis, cranial nerve palsies, dysarthria, muscle weakness and sensory changes, warrants expeditious diagnosis and management. The presence of a brainstem stroke should be first ruled out. Imaging did not support that diagnosis.

The history of a recent upper respiratory infection along with systemic neurological symptoms makes the diagnosis of a demyelinating polyradiculopathy, such as Guillain-Barré syndrome (GBS), most likely. The Miller Fisher syndrome (MFS) variant would explain the progressive bulbar palsy (lower motor neuron paralysis affecting swallowing, speech and chewing), profound bilateral ptosis, bilateral sixth cranial nerve palsies, facial weakness, paresthesia and diminished reflexes.

Bulbar myasthenia gravis (MG) could be consistent with the exam findings, but the lack of daily variation of symptoms, complete absence of other neurological complaints before the acute episode, and presence of generalized decreased reflexes make MG unlikely. Botulism can also cause bulbar palsy with bilateral cranial neuropathies, ptosis, facial and typically symmetric descending weakness, and respiratory difficulties with preserved consciousness. A history of consuming poorly preserved food should be investigated. Diagnostic confirmation is achieved by identifying the botulinum toxin from a stool or intestinal specimen or isolating Clostridium botulinum from a wound site. Additionally, electromyography (EMG) testing with repetitive nerve stimulation helps differentiate MFS from a neuromuscular junction disorder; in both MG and botulism, sensory involvement is absent.

A lumbar puncture is usually performed for suspected peripheral demyelinating polyradiculopathy to rule out infectious diseases, such as Lyme disease, or malignant conditions, such as lymphoma. Rarely, elevated protein can cause increased intracranial pressure in GBS. The differential diagnosis also includes Wernicke encephalopathy and brainstem encephalitis, but these typically present with altered mental status. Patients with Wernicke encephalopathy usually develop nystagmus, which is not associated with MFS.

Clinical manifestations of cerebral vasculitis vary widely depending on the affected blood vessels (small- vs. medium-sized vessels) as well as the region of the central nervous system involved. Diffuse involvement can lead to the development of headaches, seizures and confusion. Focal involvement, such as in polyarteritis nodosa, granulomatosis with polyangiitis, giant cell arteritis and systemic lupus erythematosus, can manifest with cerebrovascular accidents, cranial nerve palsies and optic neuropathies. Ancillary laboratory testing and neuroimaging studies help reach the diagnosis of vasculitis.

PAGE BREAK

Workup and management

The patient was admitted for close monitoring and further evaluation. Lyme serology, angiotensin converting enzyme, vitamin B12, thyroid-stimulating hormone, antinuclear antibodies, rheumatoid factor, antineutrophil cytoplasmic antibodies, C-reactive protein, erythrocyte sedimentation rate, and complement C3 and C4 levels were within normal limits. Serum anti-acetylcholine receptor and anti-muscle specific kinase antibodies were obtained and eventually found to be negative. Serum antiganglioside GQ1b IgG antibody was also ordered to evaluate for Miller Fischer variant. Brain MRI showed subtle enhancement along the cisternal segment of the facial nerves, fifth cranial nerves and left sixth cranial nerve on post-contrast fluid-attenuated inversion recovery and T1 sequences. On lumbar puncture, clear, colorless cerebrospinal fluid (CSF) was obtained, with an opening pressure of 11 cm H2O and a normal profile. Placement of an ice pack over her eyelids did not improve the ptosis. Repetitive nerve stimulation EMG performed 1 day after presentation was not consistent with a neuromuscular junction pathology, such as myasthenia gravis.

During the patient’s first days of hospitalization, abduction in the right eye worsened (from a 50% deficit to a 75% deficit), and abduction in the left eye remained fully impaired. Her dysarthria and dysphagia also worsened. Given the risks of aspiration, oral intake was contraindicated. She did not require intubation. Her peripheral weakness also worsened, especially in her upper extremities, and she continued to be completely areflexic.

Miller Fisher variant was the leading diagnosis given her symptoms and otherwise negative workup. Plasmapheresis was started 2 days after presentation, aiming for a total of five cycles. Complete blood count, metabolic and coagulation panels, and fibrinogen levels were monitored during the treatment period.

Repeat EMG and nerve conduction study 4 days after presentation indicated the presence of a generalized, multifocal dysfunction of conduction affecting sensory nerves. There was no evidence of demyelinating pathology beyond that attributable to a probable left median nerve entrapment at the wrist.

The patient showed gradual improvement in her neurologic status after five rounds of plasmapheresis. Her speech, swallowing and respiratory mechanics improved. No new peripheral symptoms were discovered. Her diet was progressively advanced as tolerated. By the end of the first week, she had fully recovered strength in all extremities and was able to eat solid food. Her facial weakness and bilateral ptosis remained. After 10 days of hospitalization, she was discharged to an acute rehabilitation facility. After discharge, her serum anti-GQ1b IgG antibody was found to be elevated and confirmed the diagnosis of MFS.

PAGE BREAK

At her 2-month follow-up, her ptosis was resolved and the bilateral sixth nerve palsies were improved. Prisms were not recommended given that her diplopia would change with time. Instead, the left lens of her glasses was fogged. On her last follow-up appointment, 5 months after presentation, diplopia was present only with extreme lateral gaze. The range of abduction had recuperated to approximately 90% in both eyes.

Discussion

Miller Fisher syndrome is characterized by a triad of ataxia, ophthalmoplegia and areflexia, and is classically described as a variant of GBS. It occurs in 5% of GBS cases in the U.S. and in 25% of GBS patients in Japan. The male-to-female ratio is 2:1, with a mean age of 43.6 years at onset. Most patients with MFS have evidence of infection 1 to 3 weeks before the development of ophthalmoplegia or ataxia, associated with Campylobacter jejuni infection in 20% of patients and Haemophilus influenzae infection in 8% of cases. Autoantibodies are thought to bind to myelin antigens and activate an acute demyelinating inflammatory cascade. In GBS, the classic pathological features include inflammatory infiltrates and areas of segmental demyelination in motor and sensory nerves and spinal roots. The pathological findings of the “pure” MFS remain uncertain because almost all patients eventually experience a complete recovery and fatalities are extremely infrequent.

The initial presenting complaint is commonly diplopia (39% of cases). Ophthalmoplegia, which may be bilateral, is seen in about 50% of patients. Approximately one-quarter of cases will develop extremity weakness, linking this disorder to GBS. Ataxia, which occurs in one-fifth of cases, is usually cerebellar in origin. Areflexia is present in 80% of patients. Considering these percentages, the classic triad may not always be present. Incomplete forms include acute ophthalmoplegia without ataxia and acute ataxic neuropathy without ophthalmoplegia.

Detailed clinical examination, brain imaging and EMG testing can help reach the diagnosis and rule out other conditions, such as brainstem stroke, Wernicke’s encephalopathy, myasthenia gravis and botulism. Brain MRI may show enhancement of the affected cranial nerves. Spinal MRI can even demonstrate enhancement and thickening of the spinal nerve roots. Both EMG studies, which uncover reduced or absent sensory responses without slowing of sensory conduction velocities, and CSF testing, which shows elevated CSF protein, suggest the diagnosis of MFS. Additionally, antibodies against GQ1b, a ganglioside nerve component, are present in 85% to 90% of patients with MFS. Positive anti-GQ1b antibodies may also be seen in GBS with ophthalmoparesis, Bickerstaff encephalitis (characterized by encephalopathy and hyperreflexia with features of MFS, such as ophthalmoplegia and ataxia), and the pharyngeal-cervical brachial GBS variant, but not in disorders other than GBS.

PAGE BREAK

Plasma exchange, which nonspecifically removes antibodies and complement and reduces nerve damage, appears to be most effective when started within the first 2 weeks after disease onset in patients who cannot walk independently. The usual treatment regimen consists of five plasma exchanges over a period of 2 weeks. Treatment with intravenous immunoglobulin (IVIG) is reported to be similarly effective. Importantly, the combination of plasma exchange and IVIG is not significantly better than plasma exchange or IVIG alone.

Early swallowing assessment will identify cases at risk for aspiration. For patients who are not ambulatory, prophylaxis against deep vein thrombosis should be started. Evaluation of respiratory function is crucial, including careful observation for dyspnea and use of accessory muscles.

The prognosis of MFS is good. The disease typically peaks at 1 week, and improvement often starts at 2 weeks. Recovery from ataxia and ophthalmoplegia takes an average of 1 month and 3 months, respectively. By 6 months after the onset of neurological symptoms, most patients have recovered from both. Although MFS is usually monophasic, it can occasionally recur. Secondary infections, such as pneumonia or sepsis, are infrequent causes of morbidity and mortality.