Myalgic Encep ha lo myel itis

For a number of years there has been controversy over the identity of myalgic encephalomyelitis. Are the symptoms after a possible virus infection organic in nature, or are they of psychogenic origin? They may well be due to both factors, but the firm belief that one or other is paramount will have a significant effect on management. The condition has been described under a number of labels: Royal Free disease, Akureyi or Iceland disease, epidemic vegetative neuritis, epidemic neuromyasthenia, and the post-viral fatigue syndrome.

Symptoms and signs The condition most frequently affects young adults, and females more than males. It usually starts with a mild sore throat or with transient abdominal pain, anorexia, nausea, vomiting and diarrhoea and a low-grade fever with malaise and headache; symptoms suggestive of a viral infection.

Other symptoms are many and varied and include vertigo, tinnitus and pains in all parts of the body. Signs of involve- ment of the cranial nerves can occur as the weeks pass, such as abnormal pupillary reactions, weakness of external ocular muscles, nystagmus, and palatal and facial weakness. There may be variable motor weakness, with no wasting', loss of muscle tone, severe and painful muscle spasms, muscle tenderness, twitching and fasciculation of the muscles and difficulty in initiating voluntary movement. Paraes- thesia and hyperaesthesia are reported, and sometimes sensory loss over the distal parts of the limbs or over one half of the body, sparing the face. One of the difficulties in diagnosis is the variation in symptomatology, with reports of consti- pation, frequency, retention, disturbances of the autonomic nervous system such as orthostatic tachycardia, episodes of sweating and coldness of the limbs; and symptoms of cerebral dysfunction, in- cluding impairment of memory and concentration, drowsiness, hyperacusis

(sometimes alternating with deafness), 9 hallucinations and vivid dreams. x

The most characteristic and essential G symptom is muscle fatiguability, so that s? those affected become very limited in what they can do, but DAVID et aL2 have

6 emphasised how important it is to define fatigue. Does this mean muscle weakness, or lassitude as in prolonged illnesses, or E weariness as in neurasthenia? The 2 diagnosis of myalgic encephalomyelitis 2 probably should not be made if this 8 symptom is absent. Over a number of p months other symptoms such as 9,

.P depression, emotional lability, irritability, g 3 panic states and behaviour, personality

and mood changes can become more 1.

9 3 obvious3. % with injection of the pharynx, transient 2

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Reported signs can be equally varied

rashes4, neck rigidity, palpable liver and spleen, enlargement of the glands in various parts of the body, with abnormal lymphocytes in the peripheral blood, abnormal tendon jerks and extensor plantar responses, and ataxia. It has been suggested that preservation of the tendon reflexes may indicate a mid-brain lesion5.

Abormal investigations The EMG has shown involvement of motor units at the level of the spinal cord, with a reduction in the number of motor- unit potentials, even to discrete motor- unit activity, individual potentials often being polyphasic; and by grouping of motor-unit potentials6. Abnormal visual evoked responses have been reported, as have non-specific EEG changes, with asymmetries and an excess of slow and sharp waves', especially in those with behavioural changes. Nerve conduction studies have been normal. Serum lactic dehydrogenase concentrations, myoglobin and glutamic oxaloacetic transaminase levels can be raised, but not phospho- creatine kinase. The serum pyruvate can be reduced, and hypoglycaemia, abnormal glucose tolerance curves and increased creatinuria and creatine/creatinine ratios have been reported. The CSF is almost always found to be normal4.

There have been a number of other findings, but most of them have not been conclusive as far as diagnosis is concerned. They include a high incidence 677

of anti-complementary activity8, prolifer- ation of lymphocytes in vitro, suggesting circulating immune complexes, and positive Paul-Bunnell screening tests in a number of patients during the Great Ormond Street Hospital epidemic*; elevated neutralising antibody titres to Cocksackie B virus3; and involvement of an enteric bacteria in the Washington D.C. epidemic'. In the Adelaide epidemic, an agent was transmitted to monkeys, and infiltration of nerve roots with lympho- cytes and monocytes and occasional patchy damage in the myelin sheaths was found9. Abnormalities have been noted in the shape of red blood-cells from patients with myalgic encephalomyelitis, which may affect their passage through the capillaries and the exchange of oxygen, lactate and potassiumlO.

Research has shown other abnormal immunological results, such as increased IgM, decreased or deficient IgA and reduced complementary factor ~ 4 ~ . In an analysis of 50 patients, BEHAN et al.'], apart from stressing that all had gross fatigue, made worse by exercise, found among them a reduction in the number of suppressor/cytotoxic T lymphocytes in the acute syndrome and of helperhducer T lymphocytes when it was chronic; and up to 70 per cent had impaired T-cell function as estimated by lymphocyte protein synthesis. There were also high titres of antibodies to smooth muscle, thyroglobulin, nuclear constituents and gastric parietal cells in some cases. Muscle biopsies showed scattered necrotic muscle fibres and a moderate increase in size and number of type I1 fibres; and on electron- microscopy occasional tubular inclusions and mitochondria increased at the periphery of the fibres.

Nuclear magnetic resonance studies are inconclusive, but evidence of an increased production of lactic acid in the muscle has been demonstrated by this technique, which may indicate a disorder of metabolic regulation3.

Possible causes As already stated, there have been suggestions of infection with Coxsackie viruses, and also with Echo viruses12, and it is known that prolonged illness can occur after glandular fever and infection

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with the Epstein-Barr virus. BORYSIEWICZ et a1.13 found that normal recovery was associated with the development of EBV- specific antibodies and memory cytotoxic T-cells, but three patients with symptoms lasting up to two years had reduced or absent antibodies to EBV nuclear antigen. These, and one other similar patient, had reduced Esv-specific cytotoxic T-cell activity and the defect was thought to be Esv-specific, as all reactive cytotoxic T- cell responses were normal. It is con- sidered that prolonged symptoms may be associated with a defect in Esv-specific immunity.

In the most recent study, YOUSEF et aI.l4 examined 70 patients with the post- viral fatigue syndrome and 30 controls. Positive viral cultures were obtained from 22 per cent of the patients and 7 per cent of the controls. An enterovirus group- specific monoclonal antibody 5-D8/1, directed against the vP1 polypeptide, was used to detect enteroviral antigen in the circulation, either free or complexed with antibody. vpl antigen was detected in the serum of 51 per cent of a further group of 87 patients. The number of patients positive for vp1 antigen was greater (42144) when IgM complexes were detect- able than when not (2/23). One year later 17 patients in the first group of 76 with positive cultures were examined again and the same virus was isolated from five. 13 still had enterovirus-specific IgM anti- bodies and nine were positive for vP1 antigen in the serum. These findings pro- vide strong evidence for the persistence of a virus infection for at least a year, and that chronic infection with enteroviruses occurs in many patients with this con- dition. The detection of enterovirus antigen in the serum may well be a satisfactory method for investigating infection in these patients, as Coxsasckie B has certainly been associated with the syndrome. YOUSEF and colleagues stress that viral antigen detection in the serum may be a more sensitive test for demonstrating the infection than virus isolation. In fact clinical monitoring showed that there was a high correlation between clinical improvement and disappearance of both vP1 antigen and IgM complexes from the circulation. Such tests undoubtedly will be a help in confirming that many patients

with myalgic encephalomyelitis are suffering from a present or past virus infection, especially Coxsackie B virus. This may be associated with defective immunoregulation, producing damage to intracellular enzymes and resulting in abnormal muscle metabolism, particularly during exercise' l .

FEGAN et al." found a difference in Coxsackie B antibody status between myalgic encephalomyelitis patients and the normal adult population, compatible with an immunological abnormality and a persistent virus infection. WAKEFIELD and L L O Y D ~ ~ suggest that the local cell- mediated immune response to intracellular pathogens in muscle and neural cells may elicit increased local interferon activity, without producing a detectable change in circulatory interferon levels. Lymphokines such as interferon induce alterations to skeletal muscle-cell membrane potentials, and altered cellular energy metabolism in vitro and in vivo. It may be that the dysfunction of muscle membrane is the pathophysiological basis of the exercise- aggravated muscle fatigue. Interferons have also been recognised as causing increased psychiatric morbidity among patients receiving recombinant Q-

interferon for chronic hepatitis B virus infections17.

Endemic and epidemic incidence World-wide, there have been over 50 reports of outbreaks of this condition and both endemic and epidemic incidences have been reported. Characteristically the symptoms can recur over a number of years, with some sufferers remaining permanently affected. The syndrome occurs among both children and adults, and the epidemics particularly effect those living in communities such as hospitals and schools. Sporadic cases have been reported among the general population, particularly in areas surrounding epidemics.

Outbreaks have occurred during epidemics of poliomyelitis, but, oddly, myalgic encephalomyelitis seems to convey some protection against infection with the poliomyelitis virus**. This could be due to the protection given by a previous enterovirus, since enteroviruses are known to be mutually an tag on is ti^^^. It is also strange how selective it can be;

for example in the Great Ormond Street Hospital epidemic, staff in the hospital were affected, but no children12. There is not complete agreement, however, that in d every epidemic the nature of the illness has been the same. 2

23 There is no doubt that hysteria is a component of the post-viral fatigue syn- drome, as it can be of multiple sclerosis B and acute disseminated encephalomyelitis, 2

2 myalgic encephalomyelitis being of 0 psychogenic origin has been considered. 2 outbreaks and thought that a lot of them 8 P increased medical vigilance with an c

community, and an illness not E immediately diagnosable as something -3

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r and the possibility of outbreaks of

MCEVEDY and BEARD~O. 21 reviewed 15 ul .P

were to due to mass hysteria; but also to

altered medical perception of the 2

L 4 else being regarded as '? polio'. In the

case of the outbreak at the Royal Free Hospital, they based the diagnosis of hysteria on the fact that the majority of patients were young females living in an environment of social segregation, the intensity of the malaise compared with the slight temperature, that many of the symptoms were similar to those produced by hysterical hyperventilation, the glove- and-stocking distribution of the sensory impairment, and the normal findings on most of the special tests, including the deliberate reproduction among normal controls of the EMG changes recorded among patients at the Royal Free Hospital2'. Hyperventilation as a result of anxiety was considered to be the primary disorder, but more attention might have been paid to the positive clinical signs recorded in some epidemics. It seems that no one can contend that every patient in all outbreaks described has been hysterical22.

RAh4SAY3 argues that the diagnosis of mass hysteria is untenable in the Royal Free epidemic because 89 per cent of the patients were pyrexial, 79 per cent showed lymphadenopathy, 43 per cent had ocular palsy and 19 per cent had facial palsy. Fair comment, but this does not exclude individual patients with similar symptoms, particularly if they do not suffer these in the context of an epidemic, being wrongly diagnosed . as instances of myalgic encephalomyelitis rather than hysteria. 679

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Certainly epidemics of hysteria do occur. In a girls’ secondary school there was an epidemic of overbreathing, the stage being set by a recent outbreak of poliomyelitis and a parade during which several pupils had fainted. The possibility of an organic illness with an hysterical overlay was considered, but owing to lack of evidence this was not accepted23.

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Differential diagnosis The differential diagnosis of a number of conditions from hysteria can be very difficult; for example even with a disease such as myasthenia gravis, for which there are reasonably conclusive tests, mistakes are made in both directions. When there are no tests to provide proof of a diagnosis the dilemma is especially acute. The repertoire of symptoms which the human body can produce is limited, so it is not surprising that similar patterns can be produced by different causes.

The diagnosis of myalgic encephalo- myelitis has to be considered in the presence of a relapsing illness with muscu- lar weakness and emotional disturb- ances”, and in childhood after other possibilities such as migraine variants, including hemiplegic migraine, and the so-called periodic syndrome have been excluded. It must also be realised that an acute illness can trigger a depressive syndrome, especially among susceptible people, and a high incidence of depressive episodes prior to the onset of myalgic encephalomyelitis has been found25.

Demyelinating disorders can cause particular difficulties; initially symptoms can occur without signs and, as already mentioned, can suggest hysteria. It is suggested by B E H A N ~ ~ that myalgic encephalomyelitis and acute disseminated encephalomyelitis may share a patho- genesis, and various psychiatric symptoms are common to both, which may cause diagnostic difficulties. The latter con- dition, presumably a vasculopathy, may occur after a viral infection, with headache, anorexia, tiredness, muscle and joint pains and low-grade fever. There may be depression, progressive impair- ment of the level of consciousness, difficulty in concentration and memory disorders. Other neurological abnorm- alities such as hemiplegia, impaired vision 680

and bladder disturbances often develop. THOMAS*’, from his personal experience

of following up patients with myalgic encephalomyelitis, has found that those with stable neurological signs have a likely diagnosis of acute disseminated encephalo- myelitis, and those with relapsing multifocal CNS disease one of multiple sclerosis. The majority with persisting or relapsing symptoms, especially of muscle pain and fatiguability, showed no evidence of structural disease and tests were negative. The weakness was of volitional type, the EMG confirming reduced effort by demonstrating low motor-unit firing rates on maximal volition.

Management and treatment The differential diagnosis therefore covers a wide range of possibilities, factual, functional or fictional2*, but arguments about whether a condition is organic or reactive are apt to be sterile exercises. Energies may be better employed in considering the predicament of the individual, and in what ways the situation can be helped with a multi- factorial approach. The comment: ‘All your tests are normal: therefore nothing is wrong with you’ is a sad reflection on the medical profession3. The remark: ‘it’s all in the mind’ is almost equally unhelpful, as most things are all in the mind, especially one’s reaction to an illness, whatever it may be; and it is essential to get away from the idea that a psychiatric illness is not an illness. TAYLOR29 pleads for more time to be spent in listening to the patient, and that the diagnosis not be limited to finding a disease. Diagnosis must extend into the patient’s context; if that is done it is often possible to help, even if there is no ‘specific treatment’.

It is obviously important to assess psychological factors and to try and establish whether the psychiatric symptoms are related to a pre-existing disturbance or are secondary to the disease. In the first case there is a greater chance, especially with sporadic cases, that myalgic encephalomyelitis will be the wrong diagnosis. If a virus is identified, it may be some time yet before this infection can be treated. Inosine pranobex and other anti-viral agents, immunoglobulins and

immunosuppressants have been tried, without any proven effect. Rest is strongly recommended, particularly after exercise, and patients may have to adapt their life-style, at least for a while. Caffeine and alcohol are said to have an adverse affect on symptoms and are best avoided. Rehabilitation is important, and symptoms can be treated as and when they arise with analgesics, anxiolytics and antidepressants. Symptoms such as depression and anxiety may need advice from a psychiatrist, although once the possibility of a virus infection has been raised it may be necessary to overcome a marked resistance to accepting psychiatric support. Perhaps it is not surprising that patients turn to unconventional treatments when orthodox medicine has relatively little to offer30. It can be important to patients that a name be given to a con- dition causing distressing symptoms, and if these are compatible with the syndrome of myalgic encephalomyelitis, in spite of the difficulties of case definition, the diagnosis should be made and the patients managed according to their needs.

The lesson to be learned from all the controversy over the past 30 years or more is surely that this condition does exist as an entity, although sometimes it is difficult to define and diagnose; it contains components some of which are organic and some of which are not; and to support one to the exclusion of the other is a great disservice to the patient. The lack of controls in most studies in the past has been a major hindrance to a greater understanding of myalgic encephalo- myelitis and the plea by DAVID et a1.* for well-structured epidemiological studies is the greatest hope for the future.

NEIL. GORDON Booth Hall Children’s Hospital, Charlesto wn Road, Blackley, Manchester M9 2AA.

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syndrome.’ Lancet, 1, 218-219. 28. Ball, A. P. (1978) ‘Disease due to echovirus type

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