Matthew Hotopf et al.
Meningitis is not a single disease, but rather an inflammation of the brain or spinal cord, caused sometimes by bacteria, sometimes by virus, and sometimes by cancerous growth. Viral meningitis, usually milder than the bacterial form, used to be a common result of mumps. Nowadays, as incidence of mumps has decreased, it is mostly caused by enteroviruses, which dwell in the alimentary canal.
These researchers hypothesized that enteroviral infection was frequently associated with chronic fatigue syndrome (CFS) and that viral meningitis, involving as it does the central nervous system, would show a particularly large effect. Of the two previous large studies of the effects of viral meningitis, one showed evidence of fatigue, clumsiness, and headaches three months after the illness, but recovery after one year. The other study looked for psychiatric effects but found none.
This study recruited 83 patients who had recovered from viral meningitis in the last two years. Patients were excluded from this sample if non-viral meningitis, HIV, preexisting psychosis, substance abuse or eating disorder was suspected. These patients had all shown meningitis symptoms, such as neck stiffness and photophobia (adverse reaction to light), and all had eventually resolved spontaneously.
The researchers also assembled 76 controls. These had all suffered from viral infection in the same period, but not at the hands of enteroviruses. Those whose disease had shown too many meningitis symptoms were excluded from the control group.
To establish the psychiatric state of the subjects and the degree of fatigue, a postal survey was carried out. This included the Beck depression inventory, a standardized instrument in very common use, plus a general health questionnaire and a questionnaire on quality of life and functional impairment.
There is more than one set of criteria for diagnosing chronic fatigue syndrome. In this study they used three. Simple chronic fatigue was determined by a score higher than four on the fatigue questionnaire, with a duration of at least six months, and no obvious medical explanation. CFS involves the same criteria, but must be present at least 50% of the time, and must cause measured functional impairment. Finally, the U.S. Centers for Disease Control (CDC) has a more rigourous definition, which involves all the usual criteria for CFS, plus the presence of at least four other symptoms from a list including myalgia, memory/concentration problems, headache, sore throat, transient joint pain, and unrefreshing sleep.
In a nutshell, there was no significant difference between patients and controls in rates of fatigue or psychiatric disorder. The hypothesis that enteroviral infection is peculiarly linked to chronic fatigue syndrome had to go by the board. One-quarter of patients and one-fifth of controls had chronic fatigue. A further 14% of patients and 10% of controls had chronic fatigue syndrome proper, while 10% of patients and 4% of controls met the CDC criterion for severe CFS. It will be noted that the patients did have higher rates of these conditions than the controls. Since, however, the difference was not strong enough to reach statistical significance, according to scientific convention the authors must declare their hypothesis unsound. The meningitis patients did not score higher at all in terms of neurological symptoms like headache.
Out of 159 patients and controls, 16 met the criteria for chronic fatigue alone, a further nine for chronic fatigue syndrome, and 11 more for CFS+, the CDC version. The 20 patients with CFS were compared to the 139 without, in an effort to divine what factors produced fatigue symptoms after viral illness. Age and sex made little or no difference, nor did the duration of hospital stay, which was used as an indicator of disease severity. Time taken off work or convalescing after discharge from hospital, however, showed a definite correlation with a tendency to develop fatigue symptoms. The 20 CFS patients had taken an average 62 days off work, nearly twice as much as those without CFS. The obvious conclusion to be drawn from this finding is that the patient's perception of the disease's severity may be more important than the reality. It has also been shown in diseases like mononucleosis that excessive convalescence can be counterproductive.
The other factor that appeared to predispose people to fatigue was previous psychiatric history. In total, 55% of CFS patients had such a history, compared to only 21% of non-CFS patients. The prevalence mounted sharply among those with the worst fatigue symptoms. Thus, those with simple chronic fatigue were 1.3 times as likely as the average to have a psychiatric history, while those with CFS were 3.6 times as likely, and those with CFS+ were 7.8 times as likely. CFS patients generally were also three times as likely to register depression on the Beck test as those without CFS.
Because the rates of fatigue were higher overall in this survey than would be expected in the population, it is tempting to conclude that all viral diseases can contribute to fatigue symptoms, in the manner of mononucleosis, and perhaps to temporary depression, as does influenza. However, there was no apparent correlation between disease severity and degree of fatigue, and there was little tendency for the fatigue symptoms to fade with time after the disease was gone. This suggests that the predisposition of the patient is more important in determining fatigue than the nature of the viral disease.
Questions for Dr. Hotopf:
1. What other viruses or infections can cause CFS symptoms?
Many acute viral illnesses are associated with fatigue, muscle aches and mood changes characteristic of CFS. However, this is not the same as saying they cause CFS, which by definition has to be chronic. The only viral illnesses which have been shown to be associated with CFS with what I would call "reasonable" evidence (i.e. following people up from the time of the illness -- cohort design) are glandular fever and hepatitis. My study showed high rates of CFS following a mixed bag of severe viral illnesses (ones which have led to hospitalization) but is not able to formally prove that these cause CFS. By far the biggest cohort study of CFS following viral illness found milder viral illnesses were not associated with any increase in risk of chronic fatigue (Wessely et al.).
2. Do you think convalescence is a bad thing after some diseases?
It depends on what you mean by convalescence. There is increasing evidence that bed rest and avoidance of normal activities is a bad thing in many physical diseases. Of course, during an acute viral illness everyone feels like retiring to bed, but after the acute phase the best approach is probably to gradually increase activities back to normal levels.
There is no doubt that bed rest is dangerous. If it were a medical drug we would severely limit its use! Even after relatively short periods of bed rest healthy, fit young subjects have changes to cardiovascular function, reduced muscle strength and a reduced desire to exercise. It's not difficult to see how quickly one can get into a cycle of deconditioning.
There are very, very few illnesses for which bed rest is a good prescription. I have just done a review of fatigue in physical illnesses, and the overwhelming pattern is that to reverse fatigue, you should gradually attempt more exercise. This has been shown for cancer, heart failure, and more recently CFS itself.
3. Why do you think meningitis leaves lasting fatigue?
Meningitis is an appalling illness. It affects young people who were previously fit and well. It would be surprising if some people did not have lasting psychological changes, including depression and fatigue. My study was not able to examine what it was about meningitis which made people fatigued. Most cases of viral meningitis are not associated with anatomical changes in the brain, although it is of course possible that the acute inflammation sets up a chain of neurological events leading to the experience of chronic fatigue.
4. What kind of patient is most likely to develop fatigue or depression following a virus?
The clearest answer to this is people with a previous history of difficulties. I found that people who had previously seen a doctor for emotional problems were more likely to run into trouble. There is a growing literature on this, and it is fairly consistent in showing that previous depression is a risk factor for having a poor recovery from viral illnesses. There is also evidence that depression worsens the outcome of other physical diseases. The exact mechanisms are uncertain. It may be that people with depression are more likely to enter into the cycle of deconditioning, or they may be more vulnerable to neurological insults.
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