Written by Dr D.Hilton-Jones, Consultant Neurologist, Oxford for the Muscular Dystrophy Campaign
It has been recognised for many years that some patients with muscle disease have particular problems with the muscles around the eyes, although other parts of the body can also be involved. Whilst research is continuing, it appears that most of these patients have either oculopharyngeal muscular dystrophy (OPMD) or mitochondrial chronic progressive external ophthalmoplegia (CPEO). The main features of these disorders are discussed below. Some of the symptoms and signs are common to both disorders.
Medical terms frequently used include: ptosis, external ophthalmoplegia, diplopia and dysphagia.
Ptosis – this describes drooping of the eyelids due to weakness of the muscle that normally lifts up the eyelid.
External ophthalmoplegia – this means weakness and restriction of muscle movement around the eye (external to the eye). It shows as slowness and incomplete range of movement of the eyes, and includes the eyelid muscle weakness that causes ptosis. These problems typically progress very slowly, hence the term ‘chronic progressive external ophthalmoplegia’.
Diplopia – this simply means double vision and occurs when the eye muscles on each side are not affected equally, so that the eyes point in slightly different directions.
Dysphagia – this means difficulty in swallowing. When mild, it may simply be a feeling of food sticking in the throat, but patients with severe dysphagia may not be able to swallow at all and can even choke on their own saliva.
Oculopharangeal muscular dystrophy (OPMD)
Muscular dystrophy is a term used to describe a number of conditions in which there is progressive muscle weakness, caused by the patient having a faulty gene. In OPMD the weakness mainly affects the ocular (eye) and pharyngeal (throat) muscles.
Symptoms and signs
Although the abnormal gene is present from birth, patients do not usually develop symptoms until the fifth or sixth decade of life. The first sign of the disorder is usually ptosis, but occasionally it is dysphagia. Very slowly, over many years, these problems progress. There is progressive restriction of eye movements and in rare cases this can lead to diplopia. The increasing ptosis may lead to the eyelid covering the pupil and impairing vision, and in an effort to compensate for this the forehead muscle becomes overactive, trying to help to lift up the eyelids, giving a frowning appearance, and the patient adopts a rather characteristic posture with the head tilted backwards.
Dysphagia, which is initially mainly for solid and dry foods, progresses slowly and eventually even swallowing fluids, including saliva, may become a problem. If dysphagia is severe, then there is a danger of aspiration, i.e. food and saliva.
After many years the patient may become aware of mild limb weakness, first around the shoulders and later around the hips, and of facial weakness, but marked weakness is uncommon. Life expectancy is little, if at all, altered.
There is no specific treatment for OPMD, but much that can be done to help the main symptoms of ptosis and dysphagia.
Glasses can be fitted with fine metal bars (ptosis props) that lift up the drooping eyelids. If these are unacceptable, and if the ptosis is severe, surgical elevation of the eyelids can be very successful.
Mild dysphagia can be helped by suitable attention to the consistency of the diet (with a dietician’s advice) and by exercises taught by a speech therapist. Occasionally drugs (e.g. cisapride) can be of value. In more severe cases, a relatively minor operation called cricopharyngeal myotomy, which cuts one of the throat muscles internally, can be valuable. If the dysphagia is preventing adequate nutrition or there is a risk of aspiration pneumonia, then alternative methods of feeding can be used. The most acceptable, in the long term, is gastrostomy. A minor operation is used to pass a tube through the front of the abdomen directly into the stomach. Patients and their relatives find this easy to manage at home.
Physiotherapy may be useful to help patients cope with limb weakness, although this is usually mild, and to reduce the risk of chest problems.
How is OPMD inherited?
In most cases the condition is inherited as an autosomal dominant disorder (see figure below), which means that each child of an affected individual has a 50% risk of inheriting the same condition. It is now possible, through a blood test, to determine whether somebody has inherited the abnormal gene but that is not always terribly helpful. Even if somebody has inherited the abnormal gene, it is impossible to predict when, if ever, they will develop symptoms. Such testing should only be performed after detailed discussion with a genetic counsellor.
The diagnosis can be confirmed by a blood test that identifies the underlying genetic abnormality. Electrical tests (EMG) and muscle biopsy are now rarely necessary.
Is there any research being conducted into OPMD?
The genetic fault that causes OPMD was identified in 1998. Although this was a very important discovery, which has given us a simple diagnostic test, it is likely to be some considerable time before the research allows us to identify a specific treatment for this condition. In the meantime, there is a great deal of research trying to identify how the genetic fault causes the physical problem.
Mitochondrial chronic external opthalmoplegia (CPEO)
Mitochondria are very small structures that are present within every cell in the body. They are vitally important for the chemical processes that generate the energy required to keep the cell alive and functioning normally. They contain many hundreds of proteins, most of which are generated as a result of the DNA (the genetic material) contained within the nucleus of the cell. However, mitochondria are unique in that they also have a small amount of their own DNA, which is responsible for producing some of the mitochondrial proteins.
Another unique feature is that this mitochondrial DNA is always inherited from the mother, not the father. Disorders of mitochondrial structure and function have been associated with a wide range of clinical problems, but one of the commonest features is chronic progressive external ophthalmoplegia (CPEO).
Symptoms and signs
The clinical features of the eye muscle involvement (the CPEO) are very similar to those described for oculopharyngeal muscular dystrophy (OPMD), and indeed in older patients it is not always easy to distinguish between the two conditions. Ptosis is the first feature, followed by progressive limitation of the range of eye movements. This is more severe than in OPMD and sometimes all eye movements are lost, with the eyes fixed in the mid-position so that the patient has to turn his/her head to see in different directions. Diplopia is uncommon. Overactivity of the forehead muscle occurs, as in OPMD.
Many other abnormalities have been described in patients with mitochondrial CPEO. Particularly common, but rarely causing symptoms, is a pigmentary retinopathy. At the back of the eye, over the outer edges of the retina, dark spots can be seen. Rarely, this can cause impairment of night vision or more troublesome visual problems.
Mild facial, neck and limb weakness may be apparent, and other common associated symptoms include mild dysphagia, deafness and short stature. Less commonly, there is clumsiness of limb movement (ataxia), epilepsy, mental subnormality, heart involvement and diabetes.
The pattern of symptoms varies with age of onset. In childhood, the combination of CPEO, pigmentary retinopathy and heart problems is referred to as the Kearns Sayre syndrome. In older patients heart involvement is uncommon and the main feature is the progressive external ophthalmoplegia. Virtually all possible combinations of the symptoms and signs mentioned above have been reported.
In children with Kearns Sayre syndrome, the main concern is the heart involvement, but this can be treated successfully with a pace-maker. In adults, the ophthalmoplegia progresses slowly and although limb weakness and tiring on exercise may develop, they are rarely major problems.
Although a number of drugs have been tried, none is of proven benefit. Management of the ophthalmoplegia and dysphagia is as described for OPMD, but dysphagia is less frequently a significant problem. Because of the occasional involvement of the heart, tests such as an electrocardiogram (ECG) and echocardiogram may be required. If the heart rhythm is disturbed a pace-maker may be needed.
How is CPEO inherited ?
In the majority of cases no other family members are affected and there is little risk of patients passing the condition on to their children. However, there are exceptions and genetic counselling is required. In some cases the condition can be passed from an affected mother to her children, but not from an affected father because of the maternal inheritance of mitochondrial DNA.
Most patients require a muscle biopsy. Under the microscope a rather typical pattern of adnormalities can be seen. In many patients it can be shown that there is a piece missing (a deletion) from the mitochondrial DNA extracted from the muscle biopsy specimen, which confirms the diagnosis. In other patients there is not a piece missing, but one of the 16,500 components (known as bases) of the DNA has been changed (mutated) to a different type.
Sometimes, more detailed tests are required, including exercising the patient and looking at chemical changes in the blood.