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Acute respiratory failure in a middle aged woman

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Q1: What is the differential diagnosis for this clinical presentation?

The differential diagnosis would include myasthenia gravis, Guillain-Barré syndrome, myotonic dystrophy, and mitochondrial myopathy.

The combination of peripheral and ocular muscle weakness together with the patient's history of other autoimmune conditions would be suggestive of myasthenia gravis as the underlying pathology. Although the condition has a peak age of onset at approximately 30 years, it is also associated with a later peak in more elderly age groups, often related to an underlying thymoma.

Guillain-Barré syndrome must be included because of the generalised muscle weakness and areflexia. The absence of sensory signs is also not atypical, although most cases are associated with a preceding viral illness. The Miller-Fisher variant should be considered but ataxia typically occurs in association with the ocular palsy.

Ptosis, muscle weakness, and a positive family history would prompt one to consider myotonic dystrophy as a possible diagnosis. Although 61 years would be considered old for a first presentation of previously unrecognised adult onset myotonic dystrophy, a milder condition can present after the age of 50.1 Ocular palsies, while previously described, are uncommon.2

Finally, mitochondrial diseases can be included because of their association with myopathies and neuropathies in a patient with a positive family history. Importantly, however, they are of maternal, not paternal, inheritance, as would be suggested in this case.

Q2: What does the electrocardiogram (fig 1 in questions; see p 664) show and what is the significance of this?

There is a prolonged P-R interval of 0.24 mm/s, first degree heart block. This is of significance because first degree heart block is a common cardiac conduction defect identified in patients with myotonic dystrophy,3 its prevalence in the condition increasing with advancing age of the patient. As in this case, conduction defects are usually asymptomatic in myotonic dystrophy and should be screened for with an electrocardiogram.

Figure 1

Haematoxylin and eosin staining of quadriceps muscle biopsy (magnification × 40).

Cardiac abnormalities are also features of both Guillain-Barré syndrome and myasthenia gravis. Guillain-Barré syndrome is associated with minor T wave changes in around 10% of cases and in myasthenia gravis, a prolonged Q-T interval and sinus arrhythmias are more typical. Cardiac features of mitochondrial diseases include cardiomyopathy and congestive cardiac failure.

Q3: What other clinical findings would be useful to elicit?

Other clinical signs which would be useful in obtaining a diagnosis include a slowly relaxing grip when the patient shakes hands, the classical sign of myotonia. Percussion myotonia can be demonstrated by tapping over the patient's thenar eminence, which induces contraction and slow relaxation of the abductor pollicis brevis muscle. Tongue myotonia may be demonstrated by tapping a spatula placed on the patient's tongue. Both grip myotonia and percussion myotonia were displayed in this case.

In a suspected case of myotonic dystrophy the examination should also include eye examination for cataracts and subcapsular deposits. Atrophy and weakness of the neck flexors should be assessed. Urinalysis and blood sugar testing should be performed to identify coexistent diabetes mellitus and in a male patient gynaecomastia and testicular atrophy should be examined for.

Where myasthenia gravis is suspected the demonstration of fatiguability is important.

Q4: What further investigations would you like to perform?

Useful tests to help differentiate between the conditions previously discussed are listed in box 1.

Box 1: Investigations of use in making a final diagnosis

  • Tensilon test.

  • Repetitive stimulation electromyography.

  • Nerve conduction studies.

  • Autoantibody screen —including antiacetylcholine and antistriated muscle antibodies.

  • Muscle biopsy.

  • Genetic analysis.

The administration of edrophonium, a tensilon test, would be useful in helping to confirm myasthenia gravis. A significant improvement in the function of at least two muscle groups, as assessed by an independent observer would suggest the diagnosis.

Repetitive stimulation electromyography would be expected to show myotonic discharges and a reduction in the number of active motor units in a case of myotonic dystrophy. An electromyogram in this case was not useful in assisting with the diagnosis. Nerve conduction studies were within normal limits, suggesting that Guillain-Barré syndrome was unlikely in this case.

An autoantibody screen, including antiacetylcholine receptor antibody and antistriated muscle antibodies would also be necessary. In this patient neither antibody was positive.

A muscle biopsy would be helpful in distinguishing between myotonic dystrophy and mitochondrial disease. In our patient the muscle biopsy showed marked variation in fibre shape and size with focal fibre atrophy and hypertrophic fibres. There was an increased number of fibres with internal nuclei, many showed whorling (fig 1). ATPase staining showed type 1 fibre deficiency (fig 2). The overall appearances were felt to be consistent with a diagnosis of myotonic dystrophy.

Figure 2

ATPase staining of muscle biopsy (magnification × 40).

Once a histological diagnosis is made it should be confirmed with the help of genetic testing. The classical genetic defect responsible for myotonic dystrophy is an expanded cystosine-thymine-guanine (CTG) repeat in the 3′ untranslated region of chromosome 19q13.3.4 In this patient genetic testing revealed the above abnormality confirming the final diagnosis to be myotonic dystrophy.

Discussion

This case illustrates an unusual cause of a common clinical presentation. Myotonic dystrophy is an autosomal dominant condition with multisystem involvement. It is the most common adult form of muscular dystrophy with an incidence of 13 per 100 000 people.5 Many cases remain unrecognised so the true incidence is likely to be higher.

Myotonic dystrophy is caused by an expanded CTG trinucleotide repeat in the 3′ untranslated region of chromosome 19q13.3, the myotonic dystrophy protein kinase gene (DMPK). Normal individuals have between five and 37 repeats of the CTG sequence whereas individuals with myotonic dystrophy typically have greater than 100 such repeats.6 The length of the repeat correlates with both the age of onset and the severity of the condition.1 A proximal form of myotonic dystrophy has been described in which sufferers do not exhibit the CTG trinucleotide repeat in the DMPK gene but instead have an abnormality on chromosome 3q.7

Adult myotonic dystrophy has a mean age of onset of 20–25 years of age.5 Clinically, it can present in a variety of ways to various specialties reflecting its multisystem involvement. Ultimately, as previously described, a combination of muscle weakness and myotonia allows the diagnosis to be made.

Muscle weakness can affect both striated and smooth muscles. Facial weakness and ptosis are often the earliest detectable features of the condition. Mild abnormalities may become apparent only by examining old photographs of the patient. Extraocular and jaw muscles can also become involved leading to the development of the classical myopathic facies. With advancing disease pharyngeal muscle involvement may lead to swallowing difficulties and an indistinct, nasal voice.

Muscle weakness in the limbs often begins distally, moving proximally with progression of the condition. Smooth muscle involvement produces many of the associated problems including dilatation and reduced motility in the oesophagus leading to aspiration, slowing of colonic movement resulting in constipation and megacolon and delayed emptying of the gallbladder predisposing to gallstone formation.5

Selective degeneration of muscle fibres within the cardiac conducting system appear to be responsible for the arrhythmias and conduction defects which occur in myotonic dystrophy. Another documented feature of the condition is the development of premature senile cataracts. Myotonia should be sought in any young patient presenting to an ophthalmology clinic with cataracts in whom no obvious cause can be identified.

Myotonic dystrophy can generally be diagnosed on the basis of a clear history and thorough examination. In difficult cases such as the one discussed, a muscle biopsy will frequently be diagnostic. Histologically muscle fibres will classically show marked variation in size and shape. Type 2 fibres become hypertrophic and develop a “moth eaten” appearance while type 1 fibres become atrophic. An early change is the identification of an increased number of centrally placed nuclei in muscle fibres. Other typical changes include ringed fibres and homogenous areas of sacroplasm adjacent to them.5 Many of these changes are evident in the muscle biopsy of this patient (figs1 and 2).

Prognostically, patients with adult onset myotonic dystrophy have a life expectancy of approximately 54 years.1 Myotonic dystrophy follows a progressive course with up to 14% of sufferers requiring a wheelchair due to motor disability before death.1 Pneumonia is the most frequent complication resulting in death. This is due to a combination of factors including poor pharyngeal muscle function, delayed gastric and oesophageal emptying, weakness of respiratory and diaphragmatic musculature, and eventually decreased central respiratory drive. Treatment is directed at prevention of aspiration, aggressive antibiotic regimens, and ventilatory support if necessary.

Cardiac arrhythmias also account for a large proportion of deaths. Sudden death from cardiac problems in myotonic dystrophy appear to be independent from the severity of the condition. Frequent electrocardiograms are advised to detect conduction problems early. Elective cardiac pacing is of some benefit but sudden death can still occur in patients with permanent cardiac pacemakers in situ.1 Other important causes of death include fractures resulting from falls and postoperative complications.

At present no proven effective treatment is available for the underlying muscular problems in myotonic dystrophy, although drugs such as phenytoin and mexiletine have been used with limited benefit to improve myotonia. A recent pilot study on the use of intravenous dehydroepiandrosterone sulfate reported a benefit in improving muscle strength, decreasing myotonia, and improving cardiac conduction. Further controlled trials would be necessary before this becomes accepted treatment.8

Medical management is aimed at the detection and treatment of serious complications. Myotonic dystrophy remains an under diagnosed condition. We postulate that in this case the patient's father had myotonic dystrophy and died from a respiratory complication. Making the diagnosis early allows other family members to be offered the chance of genetic screening. Underlying neuromuscular disease in general and myotonic dystrophy in particular should always be considered in patients presenting with acute respiratory failure.

Final diagnosis

Myotonic dystrophy.

Box 2: Learning points

  • Myotonic dystrophy is the commonest muscle disease in adults.

  • Inheritance is autosomal dominant and the genetic defect is a trinucleotide repeat expansion on chromosome 19q13.

  • The size of the repeat expansion correlates with the age of onset an severity of the clinical course.

  • Ocular palsies, although uncommon, are described.

  • Grip and percussion myotonia are clinical hallmarks.

  • Electromyography and muscle biopsy demonstrate characteristic changes and are useful tools in diagnosis.

  • Cardiac conduction defects are common and cardiopulmonary complications are the commonest mode of death

  • The availability of genetic screening and counselling for relatives is essential.

References

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