Rheumatoid Arthritis, for example, may be either mild or severe throughout its course or show great fluctuations including complete remission.
Some chronic infections such as Tuberculosis can remain dormant for many years before eventually causing overt disease.
Parallels can therefore be drawn from other diseases but none approaches the vagaries of the natural history of MS that never cease to surprise the Neurologist even after a lifetime of experience.
The course of MS varies from that of an obviously grave disease to a literally imperceptible condition discovered accidentally after death from unrelated causes in ripe old age.
Between these two extremes lie the great majority of cases, but even here there is great variation in the speed of progression and eventual outcome. I shall therefore begin by describing the typical course of a moderately severe case.
A patient, most often a woman around the age of 30, has an initial attack as described in the last chapter, RetroBulbar Neuritis, Numbness, Weakness, Double Vision, or any of a great number of other less frequently encountered symptoms, either seperately or in different combinations.
Recovery is complete within a few weeks and all is apparently well. A diagnosis may not have been made or even suspected and the disease has now become latent.
After an interval of several months to several years, new symptoms develop, usually different from those of the initial attack.
Thus RetroBulbar Neuritis may be followed by Numbness or Weakness of the Legs and again recovery is complete.
A further relapse, this time more severe and often including Weakness of Both Legs, occurs within the succeeding year or two and this time recovery is not complete.
There are permanent symptoms and permanent slight disability amounting perhaps to Weakness of one Leg when tired, and Inability to Run.
This pattern of successive relapses once or twice a year or once in two years may persist for a further three or four years, each time with less complete recovery and increasing residual symptoms.
Eventually a stage is reached in which there is persistent difficulty in Walking due to a combination of the Spastic Weakness and Ataxia.
The hands may also be a little Tremulous and Unsteady. Eyesight is usually normal but there will by now almost certainly be symptoms of that most distressing disability, failure of the normal control of the Urinary Bladder.
Control is exercised by the Brain through connections in the Spinal Cord and it is these that are damaged in MS. A usual result is that Reflex emptying of the Bladder takes place, that is to say, when filling reaches a certain pressure the Bladder automatically empties.
In the early stages voluntary control is not entirely lost. The Reflex activity is heightened so that the desire to pass Urine becomes urgent when there is only a small quantity in the Bladder.
This Urgency may lead to Incontinence if there is no convenient lavatory. Less often it becomes difficulty to start to pass Urine in spite of a strong desire to do so or the two conditions, Urgency and Hesitancy, may alternate.
At this stage Sexual Potency in the male often declines. There is no reduction in desire but ability to Sustain an Erection fails and intercourse becomes infrequent and unsatisfactory.
MS is not an intrinsically painful disease but in certain circumstances pain may be experienced. Backache is common and is due to the strain and excessive use put on the back muscles by walking with weak and spastic legs.
It is seldom severe or persistent. If Spasticity is severe in later stages of the disease there may be sudden Spasms in which the Legs either shoot out straight or bend sharply at the Knee and Hip, particularly in bed at night.
Usually these are no more than annoying but the latter form, Flexor Spasms, are sometimes painful. Neither the Spasm nor the Backache are specific for MS but may occur in any condition causing Spastic Weakness of the Legs.
There are a number of similar Paroxysmal symptoms in MS. They include brief episodes of Unsteadiness, Slurred Speech or Cramp like Contractions of the Hand or Foot.
A symptom recently recognized is Paroxysms of intense Itching confined to some isolated area of skin.
They all have the same characteristics of being Triggered by Movement, lasting no more than a minute or two and occurring with great frequency for a few weeks then going into remission.
It is likely that all result from a similar effect of DeMyelination: There seems to be excessive conduction of Nerve Impulses where many Axons fire off abnormally and simultaneously.
The Nerve Impulses carried along an Axon is normally effectively isolated or insulated from neighboring Axons and, indeed it is difficult to imagine that the Nervous System could function if this was not so.
Loss of the Myelin sheath from Axons still capable of conducting could lead to the Nerve Impulse spreading sideways to other Axons, causing a sudden massive discharge and the Paroxysm of Pain, Itching, or Muscle Contraction.
Many patients become aware of a pronounced effect of Temperature on their symptoms. A hot day, a hot bath, exertion, or even a hot drink may cause temporary Weakness or Blurring of Vision.
The beneficial effect of cold is less obvious, partly because this may actually aggravate Spasticity so that any improvement in strength would be masked and such patients actually perfer hot weather.
These effects of heat are rapidly explicable as there is evidence that even a minute rise in temperature will increase the proportion of DeMyelinated Axons that cannot conduct at all. The effect is not harmful and these brief reversible increases in symptoms are quite different from an acute relapse.
A natural concern of any patient with MS is whether it will affect the mind. It is undeniable that in the terminal stages of the severe form there is some impairment of Memory and of the Power of Reasoning.
The great majority of those with MS are mentally normal throughout virtually the whole course of the disease.
Other symptoms may be described more briefly. MS does not cause permanent Deafness and only rarely has even any temporary effect on Hearing.
Severe and permanent damage to the Vision in both Eyes is rare. Epileptic Fits hardly ever result from MS and persistent recurrent Epilepsy probably does not occur.
#1 - After the active stage of relapse and remission lasting for about five years the pattern changes. There are no more acute attacks and no more spontaneous recovery.
Symptoms and actual capacity for such exertions as climbing the stairs often flucuate a great deal from day to day and in the course of the day, being influenced by Fatigue, Temperature, and other unknown factors.
These variations are quite different in timing and in significance to the acute relapse lasting for several weeks.
Many patients now experience a long period extending over many years during which their symptoms and the degree of disability do not change significantly beyond these usual expected fluctuations. Life is a struggle but, by no means has it become intolerable.
#2 - Eventually if the disease is indeed in the severe form, this static period will be followed by a Progressive Stage. Walking becomes increasingly difficult.
Canes are no longer adequate support and recourse must be had to a walking frame or to holding on to furniture. A wheelchair becomes necessary for outdoor excursions and eventually at home as well.
Bladder control is increasingly lost with resulting Incontinence but some degree of Bowel control is usually retained, although Constipation may be more common.
The Hands and Arms become increasingly Shaky and Ataxic in such activities as holding a cup or a spoon.
This may become a severe disability quite Out Of Proportion To Any Weakness of the Limbs. It is referred to as Intention Tremor because it becomes evident or increases whenever some Voluntary Action is attempted.
Eyesight may deteriorate, either because of further damage to the Optic Nerves or because the Eyes Oscillate instead of remaining fixed on the object of regard.
This is called Nystagmus and in MS is due to damage to the Cerebellum or the tracts connecting it to the BrainStem, producing a sort of Ataxia of movements of the Eyes.
#3 - I have hesitated to describe the final stages of the severe form of MS, but the purpose of this book is to convey the facts of what is already known to be potentially a grave disease.
With increasing damage to the Spinal Cord and Brain the patient becomes bedridden and helpless and, at this stage, mental powers are undoubtedly affected.
Memory and Concentration fail and the so called Euphoria may be seen. This literally means a sense of well being, which must indeed be rare but it is common to see patients cheerful and apparently indifferent to severe disabilities.
With careful nursing, the risks inherent in the Bedridden and Incontinent state can be held at bay for many years but eventually infection spreads from the paralysed Bladder to the Kidneys, Pneumonia assails the Lungs, or Intractable Bedsores develop and in turn become infected.
It is these complications that are the immediate cause of death.
At the other extreme of recognizable MS is the Benign form. The symptoms at the Onset are entirely typical of MS but are often confined to attacks of RetroBulbar Neuritis and of Numbness and Tingling of the Limbs and Trunk.
Remission is complete, even after many relapses, and severe disability or indeed any form of permanent disability at all does Not develop.
I have known people who come to regard it as quite normal that they should have one or two episodes of Loss Of Sensation of some part of the Limbs or Trunk two or three times a year.
Other patients may have no more than two relapses or perhaps even a single attack, typical of the disease, but entirely without recurrence. Others again may have infrequent relapses at intervals of many years.
In one of my patients 25 symptom free years elapsed between two typical attacks of MS. In a rather less benign form some permanent symptoms, such as Dragging of one Leg, are present after a few years but are insufficient to interfere with work or with the enjoyment of life.
Every patient with MS will rightly want to know the eventual outcome, but it is seldom possible to be in any way precise in the early years of the disease. Certainly there are definite indications of a relatively bad result.
When MS is Progressive from the Onset without remission and relapse it usually takes the severe form. As these people are often older than the average age for the onset of the disease.
It follows that in general, the older the age of onset, the worse the outlook, but there are exceptions. Another indication of a poor prognosis is an initial severe attack with Incomplete Recovery.
The indications of a Benign course are less certain. Symptoms confined to those of damage to the Optic Nerve or the Sensory Pathways of the Spinal Cord, with little or No Weakness or Ataxia are, in general, favorable signs.
But unfortunately only in a statistical sense, rather than providing a individual forcast for each patient.
Figures are indeed available but these are of little use or interest to the patient who has just recovered from a second relapse and wants to plan for the future. These figures are also necessarily an approximation.
Diagnosis of the mild or early case or of progressive disease is often very difficult and figures are bound to be weighted by the severe cases where the diagnosis has been established for many years.
The conclusions are in broad agreement. The average duration of life after the onset of symptoms is at least 25 years.
In 5% or less the disease takes on a particularly severe form in which death may result within 5 years from involvement of centers in the BrainStem, which control Breathing and other vital functions but this form is very rare.
The proportion of patients with the Benign form, show some decline with the increasing duration of the disease; showing that the benign form may after many years eventually become progressive.
By one estimate, 10 years after the first symptom; one third will have little or no disability, reducing to one quarter after 15 years and to one in five after 20 years.
These figures are almost certainly unduly pessimistic as another investigator found that 50% of men with MS lived for more than 35 years after the onset.
If disability remains slight 5 years after the first symptoms, the disease often remains mild but, as usual, there are exceptions.
Possible Causes Of Multiple Sclerosis
Infectious diseases are caused by the invasion of the body by minute forms of living organizms, of which the most common are Bacteria and Viruses.
Bacteria exist virtually everywhere, particularly in the soil and the great majority of species live and multiply without ever invading humans or any other living creature. Others exist harmlessly in the content of our intestines.
Those that cause disease can nearly always be easily identified, since Bacteria can be seen under an ordinary microscope, particularly when stained by appropriate dyes.
They can also be grown in suitable material, usually something resembling soup or jelly.
The presence of invading Bacteria can also often be inferred from AntiBodies against them that are produced by their involuntary host. There has been no recent suggestion that any form of Bacterial infection is responsible for MS.
They can be photographed under an Electron Microscope (EM) but this is very different from the intensive microscopic hunt that can be done when looking for Bacteria.
EM photographs of Viruses do not at first sight suggest any living organizm, as most Viruses when seen this way, look like crystals or some other form of inanimate object.
They are however, alive in the sense that they can reproduce themselves by simple replication. Viruses can only multiply within living cells.
Compared with Bacteria, they are smaller, simpler forms of life and most importantly in the context of MS research, much harder to find.
Viruses induce AntiBodies in the same way as Bacteria but, there is no possibility of growing them in the laboratory in the sort of broth and gelatine, favored by Bacteria.
Some forms of Virus can be induced to infect living cells in tissue culture or in the embryo in a fertile hen's egg.
It is quite likely that certain Viruses exist in forms different from those that can be recognized in EM pictures and much remains mysterious about their mode of existence in the body.
Difficulties of identification are such that it was only in recent years that the Virus of such a well known disease as German Measles or Rubella was actually isolated. The difficulties inherent in such research in MS are indeed formidable.
We must first consider a possible relationship of MS with a form of infection even more mysterious.
In 1936 a naturally occurring disease of sheep known as Scrapie, was shown to be transferable from one sheep to another by injecting an extract from the affected sheep's Brain.
There was nothing remarkable about this at first sight as many diseases are infective, but Scrapie had not even been thought to be any kind of infection at all.
The Nervous System showed no sign of inflammation or any of the usual reactions to an infecting agent. Also, in the laboratory, the incubation period was remarkably long.
This was the beginning of an era of research that has so far shown that a small group of diseases of the CNS, two occurring naturally in animals and two rare diseases in humans, can be transmitted in the laboratory by agents with very strange properties, different from those of ordinary Viruses.
They cannot be seen even with an EM and they cause no AntiBody formation in the infected subject. In fact the presence of the agent can only be detected because it causes the disease.
Another unpleasant feature is that the agents, called Slow Viruses, are very difficult to destroy, being resistant to many antiseptics and to heat. To what extent these diseases are naturally infective as opposed to transmissible in the laboratory is still not known.
The possibility that MS might be due to a Slow Virus was naturally considered particularly because of the undeniably slow progress of the disease but, as mentioned above, MS cannot be transmitted to animals.
The next step was to see whether MS might be due to one of the already discovered Sow Viruses. When looked at under the microscope, the disease processes of Scrapie and MS, are not at all similar and Scrapie is not a Disease of DeMyelination.
The most promising infective candidate still under suspicion is the familiar Measles Virus, familiar in the sense that it causes a disease we all expect to get, rather than some outlandish veterinary disorder. The first hint that Measles might be involved came from studies of AntiBodies to common Viruses in the blood of MSers compared with the general population.
The concentration of AntiBodies to Measles is higher than expected in MSers. The difference is not great and is only detectable when results are taken from quite large groups of subjects so that this finding cannot be used as a diagnostic test for MS.
There have been a few reports of increased AntiBodies to other Viruses but these are much less consistent. AntiBodies are formed during acute infections such as Measles as part of the body's defenses - an Immune Reaction.
Usually when the infection has been overcome the level of AntiBodies falls, although often not as low as in subjects who have never been invaded by the particular Virus.
A persistently raised level is a hint that the infection may also be persistent and that active Virus might still be present.
It is now known that the Measles Virus can indeed persist within the CNS, although the disease in which this has been recognized is not MS, but a form of chronic inflammation of the Brain (Encephalitis) that affects children.
These children have all had Measles, usually at an early age, and only several years later do the progressive symptoms appear. The pathology does not closely resemble that of MS and is not a primary DeMyelinating disease.
AntiBodies to Measles are enormously increased in both the Blood and CSF, also the actual Measles Virus in the Brain can be shown by special staining methods.
Why Measles should occasionally behave in this way is unknown; but the important fact is that the Virus does persist, silently in the Brain for a latent period of some years before causing Encephalitis. Perhaps if it persisted into adulthood the result might be MS, or so the argument has gone.
A possible reason for such persistence might be some defect in the body's defenses to Measles, thus allowing the Virus to persist in some form without being destroyed.
There is no clinical evidence that patients with MS react differently to Measles from anyone else and it is quite possible for an adult with MS who has escaped Measles in childhood to have a typical attack of the disease.
There is some evidence from specific laboratory tests that the Immune Reaction to the Measles Virus is defective in MSers, but it now seems likely that this test is less reliable than was at first thought.
Much additional evidence of a highly technical nature has been found, suggesting that AntiBodies to Measles are actually manufactured in the Brain of MSers and appear in the CSF in the increased ImmunoGlobulin fraction of the Proteins.
However, this is by inference and the final step of demonstrating the Measles Virus itself in the CNS has not been achieved.
The idea that MS may be caused by some enviromental effect which occurred at a particular period of life many years before the onset of symptoms, receives support from a study of migrants.
The results show that those who move in adult life take their high risk with them, while those who migrate in childhood acquire the low risk of their new home.
The cut-off was at first thought to be around the age of 15 but up to date results suggest that it may be much younger and perhaps only those who migrate below the age of 5 escape the high risk of their native land.
Whichever figure is correct the implication is plain; something happens in early life that determines the chance of acquiring MS.
This event does not occur at birth or apparently in the first few years of childhood, because it can largely be avoided by leaving the high risk area within those years. Afterwards it is too late; the event, which seems to depend on enviroment in high risk places, has already occurred.
An obvious strong candidate for such an enviromental factor is the entry of some infective agent.
Many now believe that the future development of MS is determined by infection in childhood either by some unknown Virus or by some common Virus such as Measles behaving in an abnormal way.
MS behaves like PolioMyelitis, which is found in areas where hygiene is good the chance of childhood infection is much reduced, so that there are many adults who have never been infected and are still susceptible.
Where hygiene is poor all infants are infected and some will develop Infantile Paralysis, but those who survive into adult life are immune to further attacks of the disease. There is no evidence of MS being an infective disease in early life, comparable to Infantile Paralysis.
This pattern would explain the relatively high risk of MS within a given country with better socio-economic conditions and generally better hygiene. This was certainly observable in PolioMyelitis epidemics in which the officers would be infected while the troops were not.
The Relapsing and Remitting nature of the early symptoms of MS in most patients could also result from periodic activity of a Virus. There is a very familiar example in the behavior of the Herpies Simplex Virus that causes cold sores.
In those affected, every cold and sometimes other causes such as sensitivity to drugs reactivate the Virus and the sores break out again.
Why should MS be more common in family members of MSer? Members of a family might be exposed to the same external risks and this remains a possible explanation.
It is also possible that what might be handed down in families is not the disease itself but something in the makeup of the body that increases the risk of developing MS, if exposed to the noxious agent in the enviroment.
All the cells in all the tissues of any individual contain many antigenic substances in an individual pattern inherited through the patients' Genes.
They are Antigenic because they are capable of stimulating the production of AntiBodies if introduced into the body of someone who does not carry the same particular Antigens.
This was untill recently a most unusual event, but Kidney and other organ transplants are now common and it is the matching of these Antigens as closely as possible between donor and recipient that is so important for the survival of the graft.
This is not directly relevant to MS but the importance attached to these individual differences has drawn attention to the association of certain individual Antigens belonging to a system known as HLA and specific diseases.
Among these is MS where it has been reported that a higher proportion of individuals carry certain Antigens than would be expected in the general population.
Here again the proportions are not so abnormal as to be of any use in diagnosis and the possible implications are in relation to functions of these HLA Antigens. What is not clear is the role they play in the normal workings of the body.
It is possible that they are involved in elaborating the defenses against infections and that certain combinations of Antigens may be associated with a defect in these reactions, a defect that could permit the persistence in the body of a virus that would normally be destroyed.
All these theories are based on the idea that some poison or infetion, deficiency, allergy, or inherent defect has a direct effect on the Nervoue System and causes MS.
This is natural enough as there is no convincing evidence of any abnormality in any other part of the body. Recently, the theory has been revived that the trouble originates in the small Blood vessels suppling the Brain.
Some diseases affecting Blood vessels can indeed produce scattered areas of damage to the brain and produce symptoms very much like those of MS.
The plaques of the disease can often be seen to have formed around small veins and in the 1930's it was suggested that this happened because the Veins had somehow become blocked with Blood clot.
The most recent extention of this theory is that Blood vessels in the Brain may be blocked by tiny globules of fat circulating in the Bloodstream.
This fat embolism is indeed known to occur, particularly after severe bone fractures, but whether anything of this kind happens in MS is at present a matter for fierce argument.
I think it is fair to say that most people who have examined MS plaques and blood vessels in a knowledgeable way under the microscope do not believe that fat embolism occurs.
As will be seen in the next chapter there are implications of possible significance for the treatment of MS.
A general theory of the cause of MS has recieved much support although it must be recognized that much of the evidence is flimsy and capable of different interpretations.
We may suppose that inborn defects in Immune Reactions permit the persistence in the Nervous System of a Virus, perhaps the Measles Virus, acquired in childhood.
By direct attack of the Virus or by stimulating AutoImmunity to Myelin, MS plaques are formed. The trigger that initiates the first attack and subsequent relapses remains unknown and this is but one of the many gaps in knowledge.
The theory may be wrong, but there is continuing intense research activity directed to the detection and identification of an infective agent.
How far this and other theories of caustion have led to rational or effective treatment is considered in the next chapter.