Total External Ophthalmoplegia:
Wray, Shirley H.
Shirley H. Wray, MD, PhD, FRCP, Professor of Neurology, Harvard Medical School; Director, Unit for Neurovisual Disorders, Massachusetts General Hospital
Total External Ophthalmoplegia;
Acute Inflammatory Demyelinating Neuropathy;
Guillian Barre Syndrome – Miller Fisher Syndrome;
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The patient is a 74 year old woman who one month prior to admission suffered from a non-productive cough, right ear pain, and pharyngitis treated with amoxicillin.
On the day prior to admission she awoke with blurred vision and horizontal and vertical diplopia that persisted all day.
The next morning she was worse with ptosis of the right eyelid and difficulty “navigating” around her home.
She consulted her ophthalmologist and was referred to the Massachusetts Eye and Ear Infirmary and then referred to the Massachusetts General Hospital Emergency Room.
Bilateral ptosis with palpebral fissures of 1.5 mm OU
Upgaze severely limited to 35° OS and 15° OD
Downgaze limited 45° OS and 15° OD
Horizontal eye movements, bilateral weakness of adduction with no nystagmus of the abducting eye
Absent deviation of the eyes up under closed lids (Bell’s phenomenon)
Anisocoria, left pupil slightly larger than the right, both reacted briskly to light and near.
Motor and sensory system normal
Reflexes 2+ throughout and symmetrical
Flexor plantar responses
Coordination: Mild gait ataxia, no limb ataxia
The most important investigations in suspected cases of the Guillian Barré syndrome (GBS) or the variant, the Miller Fisher syndrome (MFS) are:
1. Electrodiagnostic studies and
2. Examination of the cerebrospinal fluid (CSF)
The most frequent early electrodiagnostic findings in GBS and MFS are:
1. A reduction in the amplitude of muscle action potentials
2. Slow nerve conduction velocity
3. Conduction block in motor nerves singly or in combination
4. Prolonged distal latencies (reflecting distal conduction block)
5. Prolonged or absent F-responses (indicating involvement of proximal parts of nerves and roots) and reflecting focal demyelination.
6. Delayed or absent H-reflex (which really just confirms the loss of ankle jerks).
A limited electrodiagnostic examination may be normal early in the illness as in this case. A more thorough study, which includes measurement of late responses, almost invariably shows disordered conduction in an affected limb within days of the first symptom.
In this patient electrodiagnostic studies were done on day 14 when the deep tendon reflexes were present and showed no abnormality.
Cerebrospinal fluid protein 54 mg/dl
No white blood cells
Usually, the CSF protein is normal in the first few days of the illness. Then the protein level begins to rise reaching a peak in 4 to 6 weeks and persisting elevated for several weeks.
In Dr. Ropper’s experience patients with MFS have a higher incidence of normal or only slightly elevated CSF protein during the course of their illness.
No stool cultures were obtained.
Miller Fisher Syndrome (MFS)
Over the next several days, the patient’s signs progressed to complete bilateral ptosis and significant weakness of abduction and adduction of both eyes. Vertical ophthalmoplegia became complete.
At this time, the patient became areflexic.
Intravenous immunoglobulin (0.4 g/kg per day for five consecutive days)
The patient was hospitalized for 21 days. At the time of discharge there was a 50% improvement in bilateral ptosis, and in abduction of both eyes. Vertical gaze remained paretic.
She was discharged to the care of her sister and returned to the neuromedical clinic four weeks later. She had considerable improvement in her ptosis and ophthalmoplegia.
Two months later she had made a full recovery.
This patient with the Miller Fisher Syndrome (MFS) a variant of the Gullian Barre Syndrome (GBS) had the following signs:
On hospital day 5 she had:
Mild bilateral asymmetrical ptosis
Overaction of the frontalis muscle
Gaze right, adduction weakness of the left eye
No nystagmus of the abducting right eye
Gaze left, adduction weakness of the right eye
No nystagmus of the abducting left eye
Vertical gaze absent
Absent Bell’s phenomenon
Recovering facial diplegia with
Mild bilateral facial weakness
In 1956 Miller Fisher published a paper in the New England Journal of Medicine describing an unusual acute idiopathic polyneuritis characterized by:
1. Total external ophthalmoplegia
2. Severe ataxia and
3. Loss of the deep tendon reflexes
The nature of the illness was not recognized until he saw the third case, when, in association with a mild peripheral neuropathy, the cerebrospinal fluid showed an albuminocytologic dissociation with a total protein of 348 mg/100 ml. and no cells.
The syndrome Miller Fisher described proved to be a variant of acute idiopathic polyneuritis (GBS) in which limb involvement was minimal or absent.
In two of Miller Fisher’s cases, (case 1 and 2) external ophthalmoplegia was complete and the eyes fixed in primary gaze. Case 3 had bilateral sixth nerve paralysis and slight rotary nystagmus on attempted lateral gaze. Bilateral ptosis was added to the picture two days later.
GBS is now viewed as a group of distinct disorders which include the following variants, tabulated by Ropper and Brown (Table 46-3 (18)).
Fisher syndrome of ophthalmoplegia, ataxia and areflexia
Cervico-brachial-pharyngeal, often with ptosis
Bilateral facial or abducens weakness with distal paresthesias
Ophthalmoplegia with GQ1b autoantibodies
Generalized ataxia without dysarthria or nystagmus
The degree of ophthalmoparesis is variable but certain patterns suggest involvement of either the peripheral or central nervous system.
The ophthalmoplegia may resemble:
Horizontal or vertical gaze palsy
Internuclear ophthalmoplegia, and
Ptosis is often absent even in the presence of significant ophthalmoparesis.
Bell’s phenomenon is often preserved even when vertical eye movements are absent.
Signs pointing to cerebellar dysfunction are:
Impairment of smooth pursuit
Suppression of the vestibular ocular reflex
Dr. Fisher was himself impressed by the presence of ataxia unaccompanied by sensory loss, and “reluctantly interpreted” the clinical signs as “manifestations of an unusual and unique disturbance of peripheral neurons”.
No imaging studies are available in this patient.
The MRI findings in another patient with MFS have been reported.
The patient was a 25 year old woman with complete external ophthalmoplegia, ptosis, limb ataxia and areflexia.
T1-weighted images with Gd-DTPA on day 15 of her illness, demonstrated enhancement of the posterior nerve roots of the cauda equina.
MRI on day 32 revealed swelling and enhancement of the bilateral ocular motor nerves, as well as the facial nerves and the abducen nerves.
The patient received high-dose intravenous immunoglobulin therapy and had marked improvement in her ophthalmoplegia.
Repeat MRI with gadolinium, after recovery, showed no enhancement of the cauda equina nor of the cranial nerves.
In this patient IgG anti-GQ1b and GD1b antibodies were detected.
In 1993, Chiba et al reported the presence of serum IgG antibody against ganglioside GQ1b in patients in the acute phase of the Miller Fisher syndrome and pointed out that this immunologic feature was common to both MFS and GBS.
To check for Anti-GQ1b antibody, I sent the serum of this patient and the serum from a second case of MFS, a young man presenting with bilateral sixth nerve palsy, (ID944-5) to Professor Newsom-Davis in Oxford to study. Both these patients were found to have the Anti-GQ1b IgG antibody.
Both GBS and the MFS are cell mediated immunological diseases directed at peripheral nerve resulting in acute idiopathic polyneuritis.
Autoantibodies: A number of autoantibodies directed at components of nerve ganglioside are detected inconsistently in patients with GBS. Anti-GQ1b IgG is the most important and is the autoantibody found in almost all patients with ophthalmoplegia.
Antibodies against the ganglioside GQ1b have also been detected in patients with Bickerstaff’s brainstem encephalitis. Bickerstaff’s encephalitis is characterized by ophthalmoplegia and ataxia but is also accompanied by pyramidal and sensory tract findings and cerebrospinal fluid pleocytosis.
GM1 autoantibody may be found in approximately one-third of patients with GBS early in their course, corresponding in most instances to a predominantly motor presentation and to axonal damage.
The highest titres of anti-GM1 antibody are usually associated with cases that follow Campylobacter infections.
Autoantibodies directed against GD1a or GT1b have been associated in some cases with the pharyngeal-brachial-cervical variant.
Pathology: Pathological studies in cases of GBS have failed to demonstrate any changes within the neuroaxis, and there is thus no morbid anatomic basis for attributing the clinical picture to a disturbance within the brainstem.
Virtually all cases have shown perivascular (mainly perivenous) lymphocytic infiltrates scattered throughout the cranial nerves, ventral and dorsal nerve roots and dorsal root ganglia and along the entire length of the peripheral nerves. Swelling of nerve roots at the site of their dural exit has been emphasized by some authors and theorized to cause root damage.
In patient’s whose electrophysiologic tests display severe axonal damage early in the illness, the pathologic findings corroborate the predominately axonal nature of the disease with secondary myelin damage and little inflammatory response.
Campylobacter jejuni may be the responsible trigger in GBS and MFS since Anti-GQ1b antibodies bind to surface epitopes on this organism, and its lipopolysaccharide fraction may molecularly mimic the ganglioside.
Miller Fisher Syndrome; Acute inflammatory demyelinating neuropathy;
Specific treatment of the presumed immune disorder that underlies GBS and the Miller Fisher Syndrome include plasma exchange and intravenous immunoglobulin IVIG (0.4 g/kg per day for five consecutive days).
IVIG stops Anti-GQ1b antibodies from binding to GQ1b ganglioside receptors and thereby prevents the electrophysiological effects.
Approximately 3 to 5% of patients do not survive an attack of GBS.78.
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