Discriptions of Myalgic Encephalomyelitis

Preface to the (Second Edition)

The clinical identity of the "myalgic encephalomyelitis"

An article by David, Wessely and Pelosi entitled ‘Postviral fatigue syndrome: time for a new approach’ (1988) makes it abundantly clear that in my first edition of this monograph entitled ‘Postviral Fatigue Syndrome: The Saga of Royal Free Disease’ 

I failed to draw a clear distinction between "myalgic encephalomyelitis" (M.E.) and "postviral fatigue states".

I have never approved of the term ‘postviral fatigue syndrome’ (PVFS) and accepted it with great reluctance when Gower Medical Publishing insisted that it should be used as a title for my monograph. The fact that it was accepted on both sides of the Atlantic and obviated the disadvantage of an American term ‘epidemic neuromyasthenia’ and a British term ‘myalgic encephalomyelitis’ for the same disease was in its favour. Its disadvantage lay in the fact that it provided too wide a coverage for the many postviral fatigue states that can quite legitimately be included under such a title.

I insisted on using the term ‘myalgic encephalomyelitis’ for my treatise. When, on the occasion of a recent ITV programme on the subject of myalgic encephalomyelitis, an immunologist stated that ‘M.E. and PVFS are regarded as synonymous’, I realised that my objection to the latter term was fully justified and that it was incumbent on me to show that such a statement is blatantly untrue.

It is fortunate that a second edition of my monograph affords me the opportunity to demonstrate that the clinical features of myalgic encephalomyelitis provide a sharp contrast to all forms of postviral fatigue syndrome.

The clinical identity of the myalgic encephalomyelitis rests on three distinct features, namely:

a unique form of muscle fatigability whereby, even after a minor degree of physical effort, three, four or five days, or longer, elapse before full muscle power is restored;

variability and fluctuation of both symptoms and physical findings in the course of a day; and an alarming tendency to become chronic.

If we take the well-known condition of post influenzal debility as an example of a postviral fatigue state, we see that in all these three particulars it constitutes a complete contrast.

The wrongful assumption that M.E. and PVFS are synonymous, now prevalent in the world literature on the subject, serves to blur the true clinical identity of the myalgic encephalomyelitis. 

This can only be remedied when the term PVFS is restored to its rightful context.

Nomenclature

The syndrome to which Royal Free disease belongs is one that follows an infectious disease process which is probably caused by a virus, although no specific aetiological agent has been identified.

An outbreak which occurred in Iceland in 1948-49 was named both 'Iceland disease' and 'Akureyri disease’ after the name of the town in which it first appeared. The use of such names is to be regretted since it tends to limit the disease to particular geographic sites and obscured the fact that the condition is to be found worldwide. I would strongly recommend that such terms be discarded.

The leader writer in The Lancet (1956), under the title ‘A New Clinical Entity?’, suggested that a suitable term might be ‘benign myalgic encephalomyelitis’. The word ‘benign’ can only be justified on the grounds that there is no mortality from the diseases and Dr. Sigurdsson (1956) registered strong objections to its use as it was ‘certainly not benign in other respects’. I have no doubts that many victims who are permanently incapacitated would readily agree.

I therefore suggest that the term ‘epidemic myalgic encephalomyelitis’, put forward by a leader writer in the British Medical Journal in 1978, is preferable. Colloquially, we tend to refer to it as ‘M.E.’ and this is certainly suitable for the many sporadic cases which are endemic and occur unrelated to any epidemic.

In America the term ‘epidemic neuromyasthenia’ was introduced to describe the neuritic and muscle abnormalities and was adopted by the physicians who reported the outbreak at the Great Ormond Street Hospital in 1970 because the neurological findings were sparse. 

The term was used in the symposium held at the Royal Society of Medicine in 1978, in deference to several American colleagues who read papers.

For the purposes of this narrative, I propose to use the term M.E., with which we have all been familiar for so many years past.

LOS ANGELES, 1934

In 1934 an epidemic of what was first considered to be poliomyelitis occurred in Los Angeles. Indeed a number of outbreaks occurred in institutions with features which differed from those usually associated with poliomyelitis. The most important outbreak involved one hundred and ninety-eight members of the medical and nursing staff of Los Angeles County General Hospital. The main features of the illness were described by Gilliam (1938) who found that, although the initial symptoms were similar to poliomyelitis, and localised muscle weakness occurred in 80% of cases, the severe degree of muscle wasting which is an invariable feature of poliomyelitis, did not occur. Moreover, muscle pain and tenderness together with sensory symptoms persisted far longer than would be expected in poliomyelitis. Loss of concentration and lapses of memory, sleep disturbances and emotional lability with hysterical episodes were features of the disease and fatigue on walking short distances was a prominent feature. Recurrence of both systemic and neurological symptoms were frequent and some cases were more disabled by the recurrence than by the original illness. There was no mortality but morbidity was high; indeed 55% of the staff were still off duty six months after the peak of the epidemic.

Wilson and Walker (1936) stated that

vaso-motor and trophic disturbances were almost constant findings among the adult patients. Excessive sweating or abnormal dryness of the skin of the extremities, together with coldness and cyanosis, were the phenomena usually observed. In the cases of more severe involvement, exfoliation of the skin of the affected extremities occurred, followed by glossy atrophy of the skin and trophy of the subcutaneous tissue. 

Hypertrichosis and brittleness of the nails, with retardation or acceleration of growth, were noted. It was the impression of many observers that a generalised disturbance of vaso-motor control occurred in these patients, which best explained the emotional instability and the exacerbations of the symptoms described later.

Between 1948 and 1952, Marinacci & Von Hagen (reported in 1965) examined twenty-one of the cases (that is, about 10%) and found that all had residual muscle pain fatigue and mental changes. They found similar changes in three hundred cases of epidemic neuromyasthenia seen between 1948 and 1965 and observed that recurrences could still occur after seven years of normal health. They concluded that the disease was spread by personal contact with cases or carriers and that the illness may have been a modification of the prevailing illness, namely poliomyelitis, or may have been due to a coincidental infection of the central nervous system of which the cause remained unknown. To that I can only say that muscle weakness without resultant wasting of muscle cannot be poliomyelitis; indeed, the electromyogram which authors mentioned showed no evidence of damage to the lower motor neuron and that in itself excludes poliomyelitis. Hysteria was recognised as a component of the illness but only a few cases were considered to be psychogenic.

Sporadic cases of infection continued to appear in Los Angeles up to 1965. The outbreak in the Royal Free Hospital in 1955 was an almost exact replica of the outbreak in Los Angeles.

DISTRICT EPIDEMIC IN ICELAND, 1948-49

In the autumn of 1948 three cases of what was considered to be ‘classical poliomyelitis’ occurred in the district of Akureyri; one was in the town itself. Thereafter, the clinical picture of epidemic neuromyasthenia developed and the diseases spread to other districts in December 1948 and January 1949 (Sigurdsson et al., 1950). Students at the high school were heavily involved so there was a very high incidence in the 15-19 age group. The systemic form of the illness occurred in 70% of patients with characteristic low-grade fever, muscle tenderness and marked lassitude. The remaining 30% had muscle weakness with pyrexia frequently over 100.4°F (c.38°C). Ulnar and shoulder girdle neuritis as well as radiculitis involving the T1, L5 and S1 nerve roots were described. Mental changes with hysterical episodes were observed. Multiple relapses occurred in some patients with renewal of fever, muscle tenderness and weakness at a fresh site. Virus studies failed to show evidence of infection with poliomyelitis, Coxsackie or known encephalomyelitis viruses.

Now follows the really important feature of the Iceland outbreaks. In 1955 Kjartan Gudmundsson, a neurologist, re-examined thirty-nine patients affected in the 1948 epidemic and found that of those more severely affected, only 25% had recovered completely, while 52% had residual tenderness and 65% had objective neurological signs. Many patients still complained of nervousness, abnormal fatigability of muscles, muscle pain, insomnia and loss of memory. Of those mildly affected in 1948, only 44% had fully recovered, while 50% had muscular tenderness and 19% had objective neurological signs (Sigurdsson & Gudmundsson, 1956).

In the same year there was an epidemic of Type 1 poliomyelitis in Iceland and this spread around the coast, yet failed to become established at centres where epidemic neuromyasthenia occurred in 1948. It would therefore seem that the agent responsible for epidemic neuromyasthenia is able to inhibit the pathological effects of poliomyelitis infection.

THE OUTBREAK IN NORTH WEST LONDON, 1955-58.

In May 1955, we found that we were admitting to the Infectious Diseases Department of the Royal Free Hospital at Hampstead cases which were frankly puzzling, although the degree of muscular weakness at first suggested a diagnosis of poliomyelitis. In 1955 we admitted sixteen such cases, in 1956 there were eighteen and in 1957 another nineteen. Together with a few cases early in 1958, this constituted an outbreak which had lasted almost three years. The initial features generally took the form of an upper respiratory tract infection with low-grade fever, sore throat, enlarged cervical glands or, less commonly, a gastrointestinal upset and, in five cases, acute vertigo. The patients then complained of persistent headache, sometimes both frontal and occipital, and accentuated by movement, while intermittent attacks of vertigo could occur throughout the early period. In addition, patients complained of pain in the limbs, neck and back, paraesthesiae and visual phenomena in the form of blurring of vision, while actual diplopia was by no means an infrequent occurrence.

Muscle cramps, spasms, twitchings and deep muscle tenderness were common but the dominant feature was muscle fatigability; following even a minimal degree of physical exertion there could be delays of between three and five days before muscle power was restored. Lymphadenopathy, affecting mainly the posterior chain of the cervical glands, and exaggerated tendon reflexes were found in over 50% of cases. Impairment of sensation was present in 41% of cases and in and presented as excessive sensitivity of the skin, usually corresponding with areas of deep muscle tenderness, interspersed with areas of hypalgesia. Extensor plantar responses were found in 21% of cases and in two cases these persisted after discharge from hospital. We found nystagmus in 23% of cases and cranial nerve palsies in 10%. Evidence of involvement of the autonomic nervous system was present in most cases. This could take the form of orthostatic tachycardia [which Sotomayer (1969) pointed out does not occur in hysteria], coldness of the extremities and hypersensitivity to climatic change, and a ghastly facial pallor which was first noticed by friends or relatives. A very common feature was bladder disturbance, a phenomenon reported by many observers. Frequency of micturition is a common legacy of these cases yet no evidence of infection of the urinary tract has ever been found. A third component of the clinical picture of M.E. is cerebral involvement which usually takes the form of impairment of memory and powers of concentration, emotional lability and vivid dreams (often in colour) which tended to occur in persons who had had no previous experience of such phenomena. A complaint of hyperacusis (intolerance of loud noise) was by no means infrequent and this could alternate with periods of normal hearing or even deafness.

All the first eight and a large number of subsequent cases were submitted to electrophysiological investigations. These were carried out by Richardson (1956) and his findings were identical with those which he reported in the Royal Free Hospital outbreak. Electroencephalograms were carried out in five patients who had serious behaviour disorders: all were abnormal. At the early stage at which the examinations were made, the changes were probably non-specific and possibly constitutional. However, Pampiglione, Harris & Kennedy (1978), at the Department of Electroencephalography in the Royal Free Hospital, demonstrated abnormalities in 38 patients even after a considerable period from the onset of the disease.

The first eight cases in this outbreak were described by the late Dr. E. O'Sullivan and myself in The Lancet of May 26, 1956. They received very favourable comment in a leading article in the same issue and I have already commented on the suggestions made for the use of the term ‘benign myalgic encephalomyelitis’. In The Lancet of December 14, 1957, I described thirty-four cases of this ‘new entity’. These all conformed to the pattern described in the earlier publication. All cases, whether with or without neurological involvement, showed proneness to fatigue after physical exertion and by this time it was clear that this could persist for weeks or months after the initial attack. Most patients exhibited outbursts of irritability which proved very distressing to those who, previously of a calm and equable temperament, were fully aware of a change in disposition which no effort of will could control. At the symposium held at the Royal Society of Medicine in April 1978, I was able to present the records of fifty-three patients who were involved in this outbreak in North West London. At the same symposium, Dr. Nigel Compston reviewed in detail the events of the outbreak in the Royal Free Hospital and concluded ‘those of the medical staff of the hospital who witnessed the epidemic of 1955 were firmly of the opinion that they were dealing with an organic illness complicated by encephalomyelitis in which a myalgia was a dominant feature. Objective evidence of brainstem and spinal cord involvement was observed.’

In 1978 I was able to report on the clinical and biochemical findings in ten patients with ‘benign myalgic encephalomyelitis’. This enquiry was carried out with the co-operation of Dr. Alan Rundle, consultant pathologist at St Lawrence's Hospital, Caterham, and the results were published in the Postgraduate Medical Journal of December 1979 (see Tables 1 and 2). The investigation was based on blood levels of serum myoglobin and various enzymes and these showed a biochemical pattern closely similar to that found in Duchenne muscular dystrophy, though differing sharply in that we found no rise in creatine phosphokinase (CPK) level in any of the patients. A difference in the molecular weights of myoglobin and CPK might afford an explanation of this. Whereas CPK is a relatively large molecule, with a molecular weight of 81000, myoglobin has a molecular weight of 17500. High levels of serum myoglobin, maintained in two successive estimations in all ten cases, were clearly indicative of muscle damage. Moreover, the level of one of the enzymes (glutamic oxaloacetic transaminase) was raised in all ten cases; in two the elevation was gross. Fasting whole-blood levels of lactate, pyruvate and ATP were estimated in five cases. The ATP level was normal in all five. The serum pyruvate was significantly reduced in all five, but serum lactate was low in only one case.

In a survey of clinical enzymology, Wilkinson (1978) discussed the release of enzymes from cells. He concluded that ‘intracellular energy content is important in the control of membrane permeability’ and gave as examples ‘loss of enzymes from a series of insults such as anoxia, deprivation of glucose, high potassium concentrations, high-energy phosphate, and metabolic inhibitors such as both rat muscle and human erythrocytes’. 

Therefore, if the aetiological factor in M.E. impairs the permeability of the muscle energy content, this could be followed by a differential loss of intracellular proteins.

AN OUTBREAK OF "ENCEPHALOMYELITIS" IN THE ROYAL FREE HOSPITAL

On July 13th 1955, a resident doctor and a ward sister on the staff of the Royal Free Hospital were admitted to the wards with an obscure illness. By July 23rd more than 70 members of staff were similarly affected and it was plain that there was in the hospital an epidemic of a highly infectious nature producing, among other things, manifestations in the central nervous system. Because of the threat to the health of patients and because of the large number of nurses involved, the hospital closed on that date and remained closed until October 5th. By that time the epidemic was almost over although sporadic cases appeared up to November 24th.

Between July 13th and November 24th, 292 members of the medical, nursing, auxiliary medical and administrative staff were affected by the illness and, of these, 255 were admitted to hospital; 37 nurses were looked after at home or admitted to other hospitals from their homes. It is remarkable that, although the hospital was full at the time of the epidemic, only 12 patients who were already there developed the disease.

These are the opening two paragraphs of the report on the outbreak published in the British Medical Journal on October 19 1957, by the medical staff of the hospital who were concerned with the care of these patients. The clinical picture which they described was based on the findings of two hundred of these cases in which the diagnosis seemed certain and in which the records were complete. No analysis was made of the ninety-two cases which were omitted and, with the gift of hindsight, this omission was to prove singularly unfortunate since they contained many instances of nurses who had succumbed to panic at the rapidity with which their friends and colleagues were going down with a ‘mystery illness’. As a result of this, at a later date, Drs McEvedy and Beard were presented with abundant material for their hypothesis of ‘mass hysteria’ (see Chapter 4).

The earliest symptoms were malaise and headache, frequently associated with disproportionate depression and emotional lability. Early symptoms fluctuated markedly, often disappearing for a day or two only to return more severely. A mild sore throat was usual: headache, frontal or occipital, though often transient, could be persistent and severe; and nausea with anorexia was frequent. 

Transient abdominal pain, vomiting and diarrhoea were less common. In a few cases the fully developed picture did not manifest until the second or third week. This consisted of pain in the neck, back or limbs and dizziness. The pain was out of proportion to the general constitutional disturbance which was sometimes present when fever was absent. It was usually confined to one limb, one side of the body or to both legs and, as with other symptoms, pain showed marked variation from day to day or even from one part of the day to another. Pain below both rib margins was common and at times the severity of these pains was such as to require the strongest analgesics for their control. Dizziness, usually a transient feeling of imbalance on sudden movement but in some a true vertigo, characterised the disease in the early stages. Sometimes the vertigo was very marked, being readily induced by slight movement of the head.

During the second and third weeks many of the patients became more severely ill. In addition to the intensification of the earlier symptoms, particularly of the pain, prostration and vertigo, other neurological symptoms and signs developed. One hundred and forty-eight patients out of the two hundred (74%) showed objective evidence of involvement of the central nervous system and the neurological manifestations formed a characteristic picture that distinguishes this disease from other infections of the nervous system. There was heavy involvement of the cranial nerves. Transient blurring of near vision, probably due to weakness of the ciliary muscle, was encountered; the pupils were at times unequal and were sometimes defective in reaction to light and on accommodation. Weakness of the external muscles of the eye was common and sometimes both sides were affected. Paralysis of the face occurred in just under 20% of cases and occasionally both sides were affected. Vertigo could persist, become very severe and could be associated with tinnitus and nystagmus. Paralysis of swallowing occurred in eleven patients, and two of these required tube-feeding.

The limbs and trunk were involved in almost all cases in which the nervous system was involved. Motor weakness was more common than sensory disturbance. Initially, the weakness was accompanied by loss of tone and could be associated with severe and painful muscle spasms that often occurred in limbs in which there was clear objective evidence of sensory disturbance. The slightest attempt at active or passive movement could invoke extreme pain. Loss of power in the affected limbs was more marked in the lower, rather than the upper, muscles and in some cases the paralysis was complete. Sometimes early on, but more commonly during recovery from weakness, a peculiar jerking was noted in a limb on voluntary movement. This is considered to be a distinctive and characteristic feature of nerve involvement in this form of encephalomyelitis.

In addition to spasm, irritative phenomena such as twitching and fasciculation (rippling of muscle under the skin) were noted and all of these became more pronounced when the patient was disturbed by physical movement or nursing treatment. Bladder dysfunction occurred in one quarter of the patients and consisted of difficulty in micturition which could result in retention requiring tidal drainage for a few days.

Spontaneous pain was the commonest sensory manifestation and its part in the clinical picture cannot be over-emphasised. It was usually felt diffusely throughout a weak limb and was associated with marked muscle tenderness. There could be extreme tenderness in the regions below the ribs and attempts at examination sometimes evoked resentment due to pain. Weakness and coarse tinglings, chiefly in the limbs, were further sensory manifestations. Objective sensory loss was usually marked in the lower part of the limbs and this coincided with the motor weakness. In a number of patients there was a complete loss of sensation over one half of the body, although the face usually escaped.

The clinical impression was of a disease producing a diffuse disorder of the nervous system with a combination of irritative and paralytic signs which were frequently transient. The most important evidence of the generalised infectious process was to be found in the involvement of other systems:

Electromyograms carried out on twenty-eight of the patients confirmed that there was involvement of the motor unit at the level of the spinal cord. Intensive laboratory investigations failed to reveal the causal agent. This then was the ‘event’ which became known as ‘Royal Free disease’ and which has since attained notoriety as a suspected outbreak of ‘mass hysteria’, the context in which it occurred being either ignored or forgotten. It may be that the explosive nature of the outbreak and the failure to detect the causal agent, despite intensive investigations, are responsible for it being regarded as an isolated baffling episode. However, I find that there has been a general failure of part of the profession to recognise that:

1. The outbreak in the hospital arose as a direct result of a nest of sporadic cases over a large area of North West London which had been present since the spring.

2. An outbreak of infection of a very extensive nature had commenced in Dalston, Cumbria, in February 1955, and had spread to the north east of the country by July.

3. An outbreak closely similar to that in the Royal Free Hospital had occurred in Addington Hospital, Durban, South Africa, in February of that momentous year.

THE OUTBREAK IN DALSTON, CUMBRIA

Although it was unknown to us at the time of the North West London and Royal Free Hospital outbreaks, an extensive outbreak had commenced in the villages of Dalston, Orton and Thursby in February 1955 and this was fully reported by the general practitioner concerned, Dr. A.I. Wallis (1955, 1957). The first case was recorded in a male adult and by the beginning of February there was an extensive epidemic in the primary school children, the main spread to adults taking place in March and April. The epidemic continued until July by which time two hundred and thirty-three cases had been reported out of the practice population of one thousand six hundred and seventy-five children, an incidence of 14%. The male-female ratio was 1:1. Twenty children boarded at the Carlisle Corporation Home in Dalston, mainly boys aged 5-15 years, all were affected. Secondary attacks in contacts occurred in several families after a primary host relapsed, suggesting that the patient had again become infectious. The possibility of glandular fever was considered but the Paul-Bunnell test was consistently negative. The onset was abrupt after an incubation period of 5-7 days but some of the adults had a delayed onset, with the illness reaching its maximum after more than six weeks. Neurological symptoms occurred in 60% of the patients but the objective signs were mild. There were lesions of the ulnar nerve in eight patients. Non-specific abnormalities were noted in the EEGs in fifteen of the twenty-three patients tested. Virus investigations proved negative.

The characteristic features of the Dalston outbreak are most important and are set out in detail:

1. A system illness with relatively low fever or subnormal temperatures in delayed-onset cases and tenderness over enlarged glands, liver and/or spleen

2. Marked muscle fatigability

3. Mental changes, such as impairment of memory, changes in mood with behavioural changes in children, sleep disorders, irritability or depression

4. Involvement of the autonomic system resulting in orthostatic tachycardia, coolness of the extremities, episodes of sweating or profound pallor, sluggish pupils, constipation and frequency of micturition, possibly as a result of a lesion of the hypothalamus

5. Diffuse and variable involvement of the central nervous system, leading to ataxia, weakness and/or sensory changes in a limb, nerve root or a peripheral nerve such as the ulnar.

6. Muscle pain, tenderness and myalgia

7. Recurrence in about 20% of patients over a period of several years.

By July 1955, the disease had spread eastwards to County Durham where the senior registrar in the electrodiagnostic clinic encountered a dramatic increase in the number of cases of lower motor neuron lesions, particularly ulnar nerve palsies, and of motor weaknesses of an unusual type affecting the shoulder girdle and legs. In August he himself was confined to bed with what was thought to be viral hepatitis without jaundice as there were similar cases in the district. When he was allowed to get up, he noticed weakness of his legs which increased on walking. An attempt to return to work was followed by a more severe illness in October with a pyrexia up to 100.4°F (c38°C) lasting several weeks. Although he returned to work part-time in January 1956 he relapsed the following summer. I saw him with Dr. A.T. Richardson and we found that he had a marked right-foot drop. We diagnosed him as a case of M.E.. 

His history is of great interest as it shows the insidious-onset form of the disease and the type of course with severe relapses (in his case every three or four years) with periods of relatively good health in between. 

However, in the last few years, his disability has become persistent as the result of repeated milder relapses.

"Encephalomyelitis" of Unknown Origin 1955: Cumberland:

Dr. Wallis did autopsies in the 1955 Cumberland epidemic. 

This was an epidemic that once again started with children in a boarding school in the early fall and spread to the near-by residents. 

This publication of one of the most extensive early investigations will appear on our Nightingale website later this year. 

It might be of interest in repeating the onset symptoms of children and adults who fell ill in 1955: 

Wallis' Onset Symptoms

1. The patients usually stated they thought they had caught a chill or a touch of the 

 "flu", the illness starting immediately or on some occasions, a few days after this 

 infectious illness, 

2. Excessive tiredness, finding normal work a burden to them, 

3. Difficulty in walking due to legs feeling a loss of power, 

4. Sweating, unrelated to work done or the ambient temperature, 

5. Difficulty in keeping warm, 

6. Bouts of dizziness and unsteadiness, 

7. Intermittent headaches and neuralgic pains, often around the eye or down the neck, 

8. Insomnia, 

9. Loss of clarity of thought and concentration, 

10. Aching in the legs and back of an intermittent nature, 

11. Pins and needles in hands and feet, 

12. Blurred Vision. 

Wallis' Frequent, Later Neurological Signs and Symptoms

1. Paraesthesiae (burning, prickling or formication often in the absence of an 

 external stimulus),

2. Hyperaesthesia (increased pain to touch) and hyperthesiae (increased pain),

3. Impairment of taste or smell,

4. Vertigo,

5. Blurred vision,

6. Loss of concentration or depression,

7. Poor recent memory, diminished powers of abstract thought,

8. Impairment of co-ordination and unsteadiness,

9. General weakness,

10. Inversion of sleep rhythm,

11. Abnormal perception of taste and smell,

12. Visual acuity considered impaired but no objective evidence,

13. Diplopia (double vision) in upward and lateral gaze,

14. Sluggish pupil reactions to light and accommodation,

15. Motor dysfunctions, generally muscular weakness,

16. Ataxia with positive Romberg,

17. Syncope without any epileptic evidence,

18. Tremor in half the cases that usually disappeared after several months,

19. Co-ordination impaired with breaking of crockery, difficulty walking through a doorway, pouring a cup of tea,

20. Reflexes: normal or decreased initially, normal or increased or brisk later. 

Anyone with Myalgic Encephalomyelitis will recognize these epidemic features as a 

classical example of M.E.

The clinical features of "Myalgic Encephalomyelitis" (1988) - (Verbatim Transcript from "second edition" of book)

The onset of the disease is similar to those described in the various recorded outbreaks. Thus it may be sudden and without apparent cause, as in cases where the first intimation of illness is an alarming attack of acute vertigo, but usually there is a history of infection of the upper respiratory tract or, occasionally, the gastrointestinal tract with nausea and/or vomiting. Instead of an uneventful recovery, the patient is dogged by persistent and profound fatigue accompanied by a medley of symptoms such as headache, giddiness, muscle pain, cramps or twitchings, muscle tenderness and weakness, paraesthesiae, frequency of micturition, blurred vision and/or diplopia, hyperacusis (sometimes alternating with deafness or normal hearing), tinnitus and a general sense of ‘feeling awful’. Some patients reported the occurrence of fainting attacks relieved by a small meal or just eating a biscuit; these attacks are the result of hypoglycaemia and we are reminded of the three young women in the outbreak in Finchley who were admitted to hospital in an unconscious state, the result of acute hypoglycaemia. All cases run a low-grade pyrexia, seldom exceeding 100ºF (c 38ºC) and usually subsiding within a week. A very thorough examination of the central nervous system should be made and this should be accompanied by a careful estimation of muscle power, especially in the limbs and neck. A search for enlarged lymph nodes should never be omitted. If muscle power is found to be satisfactory, a re-examination should be made after exercise; a walk of half a mile is sufficient, as very few M.E. cases can manage more. Once the syndrome is fully established the patient presents a multiplicity of symptoms which can most conveniently be described in three groups.

Muscle phenomena

Muscle fatigability whereby, even after a minor degree of physical effort, three, four or five days, or longer, elapse before full muscle power is restored constitutes the sheet anchor of diagnosis. Without it I would be unwilling to diagnose a patient as suffering from M.E., but it is most important to stress the fact that cases of M.E. of mild or even moderate severity may have normal muscle power in remission. In such cases, tests for muscle power should be repeated after exercise. In severe cases of M.E., muscle spasms and twitchings are a prominent feature and give rise to swollen bands of muscle which are acutely tender. In less severe cases, muscle tenderness may not be so readily elicited but careful palpitation of the trapezii and gastrocnemii (the muscle groups most commonly involved) with the tip of the forefinger should enable the examiner to detect minute foci of exquisite tenderness. It is interesting to note that Dr Garnet Simpson in Sydney, Australia (1986), without any prior knowledge of my writings, devised the identical technique and found that detection of these foci ‘will make the patient yelp’. In the aftermath of the disease, patients frequently fumble with relatively simple manoeuvres such as turning a key in a lock or taking the cork out of a bottle.

Circulatory impairment

Most cases of M.E. complain of cold extremities and hypersensitivity to climatic change but the most striking illustration of this condition is the observation by relatives or friends of an ashen-grey facial pallor, some twenty or thirty minutes before the patient complains of feeling ill.

Cerebral dysfunction

Impairment of memory, impairment of powers of concentration and emotional lability are the cardinal features. Failures to recall recent or past events, difficulty in completing a line of thought, thus becoming tongue-tied in the middle of a sentence, and a strong inclination to use wrong words, saying ‘door’ when they mean ‘table’ or ‘hot’ when they mean ‘cold’ (two doctors have testified to this), are all common deviations from normal cerebral function. A complete inability to comprehend a paragraph even after re-reading is a further example of this defect. This may be accompanied by bouts of uncontrollable weeping which can prove very embarrassing to those who pride themselves on a stoical temperament. Alterations of sleep rhythm or vivid dreams, or both, are common and occurred in patients with no previous experience of such phenomena. In a very tragic case, complete reversal of sleep rhythm in a young university student led to suicide. Frequency of micturition and hyperacusis are an almost invariable accompaniment of the cerebral features and, together with episodic sweating and orthostatic tachycardia, they can only be attributed to involvement of the autonomic nervous system. Though less frequently encountered, and usually in severe cases episodic, sweating is a very striking event. I encountered this phenomenon fifteen years ago in a patient who used to waken in the night to find himself lying in a pool of water. His wife is a nurse and reports that his temperature in these episodes is 94 or 95ºF. His condition remains unchanged and the sweating episodes are still occurring. Variability and fluctuation of both symptoms and physical findings in the course of a day is a constant feature in the clinical picture of myalgic encephalomyelitis.

The chronicity of "myalgic encephalomyelitis"

While most cases of M.E. make a complete recovery within a few years, the alarming tendency of the disease to become chronic is the final distinguishing feature in all forms of postviral fatigue syndrome. It is now possible to give figures regarding the number of M.E. patients who have had the disease for ten years or longer. At a conservative estimate, this is about 25%. In a group of one hundred and fifty members in the north of England, thirty-six have had the disease for ten years or more. Of fifty-five members of a small group in Surrey, England, twenty-nine have had the disease for ten years or more; four have had it for over twenty years, and four for over thirty years. One member in each group has had it for over forty years. The circumstances of individual lives may play an important part in this. A young mother with several children is in an especially unfortunate position as she cannot possibly get the rest essential for her recovery. Absolute rest in the early stage of the disease can prove a strong determining factor in the outcome. Relapses resulting from excessive physical or mental stress, or both, or after a further virus infection, are an accepted feature of the disease. One doctor who contracted the infection in 1955 informs me that his relapse follows a definite periodicity and this can occur when he is not under any physical or mental stress. His remissions have lasted as long as four years; his last relapse was severe and incapacitated him for six months, compelling him to take early retirement.  A senior consultant physician who was a victim of the 1955 outbreak tells me that it was ten years before she was restored to normal health. A busy general practitioner bravely battled on for twenty-one years before she realised that the disease was, at last, abating. One of the most severe cases I have encountered is the wife of a doctor in a northern England industrial town; she was a prominent amateur athlete until the age of twenty-two when she contracted ‘flu’. Since then she has battled with the muscle fatigability of M.E. for over forty years; during that time she has been seen by several consultant physicians who could find no cause for her symptoms and virtually pronounced her neurotic; one of her daughters has developed the same condition. Another severely incapacitated patient was a senior technician in the Blood Transfusion Service and her chief tells me she was the author of several important papers which are regarded as ‘classics’ in that speciality. He now finds that he can hardly recognise her for the active person she once was. I made the diagnosis of M.E. in 1969 when I was asked to see her and her twelve-year-old son by their doctor in Sutton, England. I have already referred to the tragic suicide of the son while a university student. His mother applied for invalidity benefit and was seen by a senior neurologist who considered her to be a case of ‘near-delusional self-deception’ and described M.E. as a ‘figment of the imagination both on the part of the patients who think they are suffering from it and the doctors who make the diagnosis. The prejudice harboured against those of us who hold the view that M.E. is an organically-determined disease defies rational explanation. The chronic case can take two different forms. In the first there is a recurring cycle of remission and relapse. In three doctors who contracted the infection between 1955 and 1958, the alternation of remission and relapse continues. The patient lives a very restricted existence, unable to walk more than a short distance, and that with considerable difficulty, unable to read for any length of time and in many cases subject to disturbance of sleep rhythm or vivid dreams, or both with constant frequency of micturition and dizzy spells. A few of these chronic cases are compelled to sleep in an upright position as a result of permanent weakness of the intercostal and abdominal recti muscles.

THE GLASGOW RESEARCH PROJECT (M.E. vs ADEM)

At the symposium held at the Royal Society of Medicine in April 1978, Dr. Peter Behan presented a paper on the subject of ‘Post infectious encephalomyelitis’ in which he showed that acute disseminated encephalomyelitis (ADEM) and myalgic encephalomyelitis or epidemic neuromyasthenia may share a common pathogenesis. He referred to the views of Miller, Stanton & Gibbons (1956) that ADEM usually occurs after a banal virus infection yet the disease receives little attention in textbooks of neurology, is mentioned only briefly in textbooks of medicine and is rarely considered in textbooks of psychiatry. Nevertheless it is relatively common, constituting one-third of all cases diagnosed as encephalitis (Scott, 1967) and is often clinically indistinguishable from multiple sclerosis. Dr. Behan stressed that ADEM ‘has a wide spectrum of clinical presentation’ since ‘it may present as a fulminating encephalitis ending fatally after a few day’ or ‘it can be an illness clinically indistinguishable from epidemic myalgic encephalomyelitis’.

Behan's initial research showed that patients with "epidemic myalgic encephalomyelitis" had immunological abnormalities consisting of: 

(1) atypical peripheral lymphocytes; 

(2) mild eosinophilia and anti-complementary activity; 

(3) increased IgM; 

(4) decreased or deficient IgA; 

(5) reduced complement factor C4 concentrations; 

(6) serum anti-complementary activity; and 

(7) a suggestion of increased titres to Coxsackie virus (in some patients specific IgM to Coxsackie virus type A9). 

Increased serum lactic dehydrogenase (LDH) concentrations, abnormal cerebrospinal fluid results, and abnormalities in electromyography and visual evoked-response testing represented a body of circumstantial evidence that supported the hypothesis of an organically determined disease.

This became the basis of a research project (Behan & Behan, 1980) in which they considered a series of forty-three outbreaks that had occurred between 1950 and 1977. 

They then reported their findings in a series of twelve patients who presented with the symptoms and physical signs that corresponded with those found in the various outbreaks (see Chapters 2 & 3). 

The symptoms included headache, pain in the neck, back and limb muscles, fatigue, exhaustion, emotional lability, irritability, poor memory, difficulty in concentration, dizziness, sore throat, diarrhoea and general malaise; physical findings included muscle tenderness, neck stiffness, paresis, lymphadenopathy, increases tendon reflexes, muscle twitching, sensory loss, extensor plantar responses, conjunctivitis, nystagmus, cranial nerve palsies, urinary retention and respiratory failure; in brief, all the features that characterised the North-West London and Royal Free outbreaks. Nevertheless, Behan & Behan stated that had it not been for the immunological studies which they carried out ‘it would have been easy to concur with McEvedy & Beard that the illness is entirely a manifestation of hysteria’. 

But they added, ‘the presence of generalised lymphadenopathy is strongly in favour of an infective process’. 

Moreover, the presence of atypical lymphoblasts (immunocytes) in the peripheral blood of two of the patients was suggestive of a persistent antigenic stimulation, possibly caused by a virus, and this corresponded with the findings of Dillon and co-workers (1974) who found that lymphocytes from four children grew and multiplied in culture tissue, a phenomenon strongly suggestive of a persistent virus.

The presence of eosinophils in the peripheral blood of three patients suggested an allergic element in the reaction. 

Increased concentrations of IgM and decreased concentrations of IgA were found in half the cases. 

Autoantibodies were also commonly found, adding further support to the possibility of disturbance in the immune system. 

The complement results together with the anti-complementary activity suggested the presence of circulating immune complexes which is in line with the findings of Dillon and co-workers (1974).

Increased serum lactic dehydrogenase was found in nine of the twelve patients and this corresponded with the findings of Rundle & Ramsay (as reported in Lyle & Chamberlain, 1978). This is clearly indicative of muscle involvement. All routine tests on the cerebrospinal fluid were normal but in three cases there were ‘faint but definite oligoclonal bands on electrophoresis of concentrated CSF’. 

This finding, together with abnormal evoked visual responses, indicated involvement of the white matter of the central nervous system. 

It is well known that Coxsackie viruses have a predilection for cardiac and skeletal muscle and in the 1965 Coxsackie Group B5 outbreak in Europe both carditis and meningitis were found (British Medical Journal, leading article, 1967); Coxsackie viruses are also the aetiological agents of Bornholm disease.

Behan & Behan found that two patients in their series had very high antibody titres to Coxsackie A9 virus and two had increased titres to Coxsackie B1. The husband and two sons of one of the patients developed an illness similar to M.E. in one of her relapses and the muscle biopsy of the husband showed the characteristic features of dermatomyositis. Behan & Behan (1977) pointed out that ‘activation of the complement system and the presence of circulating immune complexes’ had been described by them where there was muscle damage thought to be due to a vasculopathy secondary to immune-complex deposition. 

They therefore suggested that in M.E. the pathogenesis may be that of a persistent virus with the formation of immune complexes and widespread deposition of antigen-antibody aggregates in the blood vessels, the central nervous system and muscle.

---

The Clinical Features of Myalgic Encephalomyelitis

Melvin Ramsay, M.D., 1986-1988

In the textbook, Ramsay began with the symptoms of the disease at its onset, then followed with the symptoms of chronic M.E. 

The onset of the disease

The onset of the disease is similar to those described in the various recorded outbreaks. Thus it may be sudden and without apparent cause, as in cases where the first intimation of illness is an alarming attack of acute vertigo, but usually there is a history of infection of the upper respiratory tract or, occasionally, the gastrointestinal tract with nausea and/or vomiting.

Instead of an uneventful recovery the patient is dogged by:

All cases run a low-grade pyrexia (fever), seldom exceeding 100°F (c. 38°C) and usually subsiding within a week.

- Persistent and profound fatigue accompanied by a medley of symptoms such as: 

- Headache

- Giddiness

- Muscle pain, cramps, or twitchings

- Muscle tenderness and weakness

- Paraesthesiae [numbness or tingling in the extremeties]

- Frequency of micturition [urination]

- Blurred vision and/or diplopia [double vision]

- Hyperacusis [sensitivity to noise sometimes alternating with deafness or normal hearing]

- Tinnitus [constant sound in the ears], and a

- General sense of “feeling awful.”

A search for enlarged lymph nodes should never be omitted. 

Some patients report the occurrence of fainting attacks relieved by a small meal or just eating a biscuit; these attacks were the result of hypoglycaemia...

A very thorough examination of the central nervous system should be made and this should be accompanied by a careful estimation of muscle power, especially in the limbs and neck. 

If muscle power is found to be satisfactory, a re-examination should be made after exercise; a walk of half a mile is sufficient, as very few M.E. cases can make more.

Disease in chronic state

Once the syndrome is fully established the patient presents a multiplicity of symptoms which can most conveniently be described in three groups.

1. Muscle phenomena

- [Muscle Fatiguability]: Muscle fatigability, whereby, even after a minor degree of physical effort, three, four or five days, or longer, elapse before full muscle power is restored and constitutes the sheet anchor of diagnosis. Without it I would be unwilling to diagnose a patient as suffering from M.E., but it is most important to stress the fact that cases of M.E. or mild or even moderate severity may have normal muscle power in a remission. In such cases, tests for muscle power should be repeated after exercise.

- [Pain:] In severe cases of M.E., muscle spasms and twitchings are a prominent feature and give rise to swollen bands of tissue which are acutely tender. In less severe cases, muscle tenderness may not be so readily elicited but careful palpation of the trapezii and gastrocnemii (the muscle groups most commonly involved) with the tip of the forefinger should enable the examiner to detect minute foci or exquisite tenderness...

- [Clumsiness:] In the aftermath of the disease patients frequently fumble with relatively simple manoevres such as turning a key in a lock or taking the cork of a bottle.

2. Circulatory impairment

Most cases of M.E. complain of:

- Cold extremities and

- Hypersensitivity to climactic change...

- Ashen-grey facial pallor, some twenty or thirty minutes before the Patient complains of feeling ill

3. Cerebral dysfunction

The cardinal features:

- Impairment of memory

- Impairment of powers of concentration and

- Emotional lability

[Other] common deviations from normal cerebral function:

- Failure to recall recent or past events,

- Difficulty in completing a line of thought...

- Becoming tongue-tied in the middle of a sentence, and a

- Strong inclination to use wrong words, saying “door” when they mean “table” or “hot” when they mean “cold”...

- Complete inability to comprehend a paragraph even after re-reading it

- Bouts of uncontrollable weeping...

- Alterations of sleep rhythm or vivid dreams, or both...

[Accompanying] features [that] can only be attributed to involvement of the Autonomic nervous system:

- Frequency of micturition (urination)

- Hyperacusis (hypersensitivity to noise)

- Episodic sweating

- Orthostatic tachycardia...

Variability and fluctuation of both symptoms and physical findings in the course of a day is a constant feature in the clinical picture of myalgic encephalomyelitis.

An alarming tendency to become chronic. [Added in the 2nd edition, 1988]

[A. Melvin Ramsay, M.A., M.D. Myalgic Encephalomyelitis and Postviral Fatigue States: The saga of Royal Free disease (London, 1st ed. 1986, 2nd ed. 1988). Ramsay died in 1990. Thanks to Connie Nelson of the UK for making this available to me.]