Patients attend practice complaining of having had double vision which cannot be borne out during the assessment of binocular vision. This may be due to a diurnal variation where an anomaly emerges at the end of the day but, with overnight rest, is no longer found the next morning. It is important to be aware of such an anomaly. It is, however, possible to time how long it takes for the diplopia (and/or a ptosis) to appear after working the muscles in different directions of gaze. This is helpful when assessing patients with either Parkinson’s or myasthenia gravis.
Case 1
A 76-year-old female patient came in for an eye examination complaining of having a ‘drooping right eyelid’ for the past two weeks. She was also experiencing some dull headaches and a more general ‘heavy lid feeling’.
Ocular examination
• No change in her myopic prescription, with visual acuity of 6/9 each eye and N5 unaided.
• Ocular muscle balance showed no signs of phoria or tropia and no double vision.
• Hess plot showed no signs of incomitancy.
• Pupils were symmetrical and reflexes were normal.
• Fundus revealed no abnormalities.
• Grade 2 right eyelid ptosis, but with no anhydrosis or lack of sweating seen.
• Right eyelid ptosis increased on looking up for a period of twenty seconds (figure 1).
Figure 1
Management
Firstly, Horner’s syndrome was ruled out on the basis there was no signs of miotic pupil or anhidrosis. Age-related ptosis was discounted on the basis of recency of onset.
The patient was referred to her general practitioner with a provisional diagnosis of myasthenia gravis. This was on the basis of eyelid muscle weakness and increasing ptosis on up gaze after 20 seconds. It was further suggested that the patient be referred to a neurologist to confirm myasthenia gravis.
Neurologist assessment
The neurologist undertook the following tests:
• MRI scan – this revealed multiple, scattered, deep white matter lesions, a high T2 FLAIR signal intensities and periventricular high T2 FLAIR signal consistent with small vessel disease. No signs of a stroke.
• Throat and face muscle assessment – slight swallowing issues were discovered and thought to be due to dryness of the mouth. There were no facial muscle droop or chewing problems. Breathing showed slight shortness of breath.
• Neck and limb muscle assessment – no weakness of the neck, arm and leg muscles.
• Eye muscles – right eyelid ptosis which increased on upward gaze after a short period of 20 seconds. The timing test shows muscle fatigue with repetitive use.
• Chest X-ray – no signs of thymoma (thymus tumour) and no signs of thymic hyperplasia (enlarged thymus due to influx of B-cells).
• Blood radio immunoassay tests – slightly raised B-cell antibodies indicating slightly raised acetylcholine receptor antibodies. Muscle specific kinase antibodies (MUSK) were not raised. Radio immunoassay is a technique devised by Noble prize winners Berson and Yalow in 1966. It is a very sensitive test that measures the concentration of a specific antibody (acetylcholine receptor or MUSK antibody) in the blood serum against a radioactive labelled antigen.
• Single breath count – single breath count was below normal at 30. This is done by asking the patient to count out loud after maximal intake of breath. Reaching 50 indicates normal single breath count and below 15 indicates a dangerously low forced vital capacity.
• Single fibre electromyography (EMG) – single fibre EMG of the orbicularis oculi and the right frontalis muscles registered borderline myasthenia gravis. Single fibre EMG is the most sensitive test in detecting neuro-muscular transmission defects such as myasthenia gravis (MG) and motor neurone disorders, but it is not a definite test for MG. It depends on using a single fibre needle electrode to an record action potential from individual muscle fibres from the same motor unit. Normal action potentials should be 200 microvolts in amplitude in less than 300 microseconds.
The neurologist confirmed ocular myasthenia gravis mainly on the basis of increased eyelid muscle weakness on repeated movement and EMG recording. Physostigmine 60mg (three times a day) was prescribed and the patient showed marked improvement in her ptosis.
Case 2
An 84-year-old male patient made an emergency appointment having experienced vertical double vision. Motility and Hess Screen tests implied a possible partial 3rd nerve palsy. The Hess plot showed down and out movement, but no pupil involvement and no eyelid ptosis were seen.
Figure 2
The patient was referred to the eye specialist with a provisional diagnosis of partial 3rd nerve palsy. The patient was already on warfarin and anti-cholesterol medication, so it was assumed that this was a small vessel abnormality and that it would recover. After three weeks the double vision indeed recovered. However, a second and then third episode of double vision happened a year later. Once again, each episode lasted three weeks before
resolving.
At the next attendance to our practice, the patient reported vertical double vision once again, and this time with intermittent ptosis of the left eyelid. This time he was referred to a neuro-ophthalmologist whose diagnosis was myasthenia gravis based on the clinical picture; namely, several episodes of diplopia and spontaneous resolution as well as intermittent ptosis.
Neuro-ophthalmologist assessment
• Single breath count – his single breath count appeared normal at 43. Forced vital capacity (FVC) was normal; 3.71 while standing and 3.34 while supine.
• Ocular muscle tests – diplopia on sustained upgaze for 20 seconds, on left gaze after 15 seconds and on sustained right gaze after just five seconds. The left lid was held at all times for this diplopia test. The deviation varied from 1.5 Δ to 4 Δ base up in the left eye (figure 3).
• Orbicularis oculi muscle – ptosis of the left lid which dropped after 10 seconds on prolonged upgaze. Normal strength of the orbicularis oculi muscle. Our test revealed the ptosis as seen in figure 3.
Figure 3
• Neck and limb muscle assessment – no weakness of neck, arms or leg muscles. No fatigue in shoulder abduction. Neck flexion and extension strong (5/5 score).
• Throat and face muscle assessment – no face drop, no problems with chewing, swallowing or dryness of the mouth.
• Blood tests – awaiting these results at time of writing.
• EMG – awaiting these results at time of writing.
• Thymic imaging – awaiting these results at time of writing.
It was initially decided to prescribe physostigmine (60mg three times a day). The patient had asthma and used inhalers and so it was subsequently decided to stop the physostigmine whose side-effects include wheezing and shortness of breath.
The ptosis was increasing, so to relieve his symptoms a course of corticosteroid (prednisolone) was considered. However, it was decided not to proceed with steroids as they would cause more harm than good and because there were no systemic features of myasthenia gravis. The final decision was to fog one lens of his spectacles which the patient was happy to accept.
Myasthenia Gravis
Myasthenia gravis was first described by Samuel Wilks in 1877 and given a Latin named derived from ‘myo’ (muscle), ‘asthenia’ (abnormal physical weakness or lack of energy) and ‘gravis’ (weakness). Myasthenia gravis is an autoimmune disease whereby the immune system that normally defends the body instead releases antibodies that attack the body. Myasthenia gravis is characterised by weakness and rapid fatigue of any of the muscles under your voluntary control.
The cause is thought to be a breakdown in communication between the nerves and the muscles. The condition is common in women under the age of 40 and in men over the age of 60, but can occur at any age.
Symptoms improve with rest, so muscle weakness can come and go. However, MG symptoms tend to progress over time, usually reaching their worst within a few years after the onset of the disease.
Approximately 15 to 20% of MG patients may experience myasthenia crisis, a life-threatening condition that occurs when the muscles that control breathing become too weak to aid breathing.
Figure 4
The disease is due to problems at the neuromuscular junction or synapse (figure 4). In nerve cells, mitochondria, choline and acetyl CoA combine to form the neurotransmitter acetylcholine (ACH). A synaptic vesicle containing ACH is released into the synaptic cleft, and ACH attaches to the acetylcholine receptor on the surface of the muscle cell allowing an inward influx of electric current and triggering muscle contraction. This could be hand or leg movement or eyelid movement.
An enzyme (anticholinesterase) then breaks down the acetylcholine in the synaptic cleft to acetyl and choline. The choline is then transported back into the axon terminal to make more ACH.
There are four causes of MG; MG-Acetylcholine receptor antibody positive, MG- MUSK positive, and two related to the thymus gland, namely thymoma and thymic hyperplasia. The thymus gland is located in the chest just below the throat and this gland plays a pivotal role in the development of the immune system. Up to childhood the gland teaches the immune cells, called T-cells, to recognise self from foreign.
MG-acetylcholine receptor antibody positive – 85% of people with MG have lots of B-cell antibodies in the blood (and said to be seropositive). These antibodies target and destroy many of the acetylcholine receptors on the muscle. The muscles response to repeated nerve cell signals declines with time and the muscle becomes weak and tired, as seen in the progressive ptosis.
Figure 5
MG-MUSK-positive – 15% of people with MG show hardly any antibodies for acetylcholine receptors in the blood serum (so are seronegative). It is thought that these people have antibodies to a muscle specific kinase protein (MUSK protein). MUSK is a receptor tyrosine kinase that helps organise ACH receptors on the muscle cell surface and helps in the formation and maintenance of the neuromuscular junction. A nerve-derived proteoglycan called agrin triggers MUSK. In MUSK MG, the protein agrin is blocked leading to lack of acetylcholine receptors on the muscle surface (figure 6).
Figure 6
Thymus-related – about 15% of MG patients have a non-malignant thymic tumour called a thymoma, while another 15% have overactive thymic cells, a condition called thymic hyperplasia. In thymic hyperplasia, there is an influx of reactive B-cells in an otherwise normal thymus leading to an increase in size of the thymus gland. Dysfunction of the thymus gland obscures the T-cells ability to distinguish self from foreign and makes them susceptible to attack the body’s own cells.
Myasthenia gravis can affect any of the voluntary muscles, although certain muscle groups are more commonly affected than others. Muscle groups affected include:
• Eye muscles – 50% of patients experience either eyelid ptosis or diplopia. Diplopia could be horizontal or vertical.
• Face and throat muscles – 15% of patients may experience difficulty chewing, altered speaking, difficulty swallowing, difficulty breathing and limited facial expression (loss of smile).
• Neck and limb muscles – usually happens alongside eye, facial and throat muscle weakness. The patient exhibits weakness in the neck, arms and limbs.
In summary, MG patients may have difficulty seeing, closing eyes, breathing, swallowing, chewing, walking, using arms and legs and holding their neck up.
Factors that can exacerbate the effects of MG include:
• Fatigue
• Exercise
• Illness
• Stress
• Medication – such as β-blockers, quinine, phenytoin and certain anaesthetics or antibiotics.
Treatment of MG is initially with pyridostygmine (10 to 60mg every four to eight hours). MUSK-MG patients do not respond to acetylcholinesterase inhibitors (ACEIs) such a pyridostigmine.
Patients with significant side effects from ACEI drugs often benefit from corticosteroid treatment. Prescribing is initially 30mg a day of prednisolone followed by a gradual and slow tapering to the minimum effective dose of drug. Combined therapy (with immunosuppressive agent such as azathioprine) is also effective. Thymectomy is considered in cases of thymoma or hyperplastic thymus.
Kirit Patel is an optometrist in independent practice in Radlett, Hertfordshire.
