Alberto Freddi

Multiple Sclerosis: an “Orphan” Disease?

Among the many diseases which may affect the various human organs, systems and apparatuses, there are some which have become (also among outsiders) significantly well-known; on the other hand, there are others which have remained within some sort of limbo of indifference, accessed only by a small number of specialists and zealous scholars.
For the former (that is for the most renowned diseases, those which affect many people) a great and incessant work of popularisation and information is carried out, combined with a battle for prevention and dogged search for therapeutic and rehabilitative resources; for the latter (for those which affect a fewer number of people, even though they involve very severe prognoses) the rather gloomy term of “orphan diseases” has been coined, to describe affections which have not found sufficient sponsorship for research work to be conducted and for specific treatments to be found to oppose them.
In 1886, Jean Martin Charcot published his « Leçons sur les maladies du système nerveux » and described the demyelinization areas of Multiple Sclerosis, together with the typical symptomatological triad accompanying this disease (intentional tremor, dysarthria, nystagmus). Subsequently, Cruveilhier and Carswell recognised it as an autonomous morbid entity.
A new disease was born which was bound to remain orphan, as it was rare, complex and incurable. Besides, the neurophysiologists of the time still debated about the issue “where does thought come from?” and had just abandoned the theories of mesmerizers, homeopaths and phrenologists (such as Franz Joseph Gall or Mariano Cubi y Soler who, in 1857, published in Paris the treaty “Leçons de phrenologie scientifique et pratique”, in which he outlined complicated mappings of the head, with a detailed description of the relations existing between “cranial prominences and faculties of the mind”).
This was more or less the time in which Gaetano Perugini and Alois Alzheimer illustrated a typical form of insanity, in which Heinrich Quincke carried out the first lumbar puncture, whilst Otto Westphal described rotulian reflex and Joseph Babinski the (pathological) plantar reflex. A few years later, Waldeyer was the first person to talk about the “neuron” and, in the early years of the 20th century, with the studies conducted by Golgi and Ramon y Cajal, the bearing structure of a new framework, bound to support modern research, was consolidated.

And what about Multiple Sclerosis? This disease also conformed to the times, changed its symptomatological semblances, it offered the occasion for a new clinical, instrumental and laboratory semiology. But it remained “orphan”, with its aura of distressful resignation and of honest grief, which are never denied to those whose fate is sealed by an incurable disease. In fact, up to that stage, a great number of neurological diseases had not yet obtained a rigorous nosographic arrangement, as they tended to be confused with psychiatric diseases, owing to that often indefinite relationship between body and mind, between thought and motor action, between somatic perceptions and the perceptions “of the soul”. Therefore you would quite often find, lumped together with hysteria and “functional” disorders, events which on the other hand had unknown organic roots.
The diagnostic means used to establish the existence of a form of multiple sclerosis where basically those offered by the clinical background. Indeed, up to a few decades ago, experts referred to “certain, possible or probable forms” (and among these you would often find the most unexpected pathologies, that is those that the neurologist failed to place within the proper setting and which bore an even vague resemblance to multiple sclerosis).
Today things stand quite differently: the disease has now been set within the proper clinical framing, we have diagnostic means that eliminate great part of the doubts and very effective therapeutic resources have made their appearance. And multiple sclerosis is no longer numbered among orphan diseases.

Numbers and Distribution

How many people suffer from multiple sclerosis in the world? How many in Italy? How is the disease distributed among the various geographical areas of the planet? Which causal and concausal factors underlie it? Today we can state, with reasonably accurate approximation, that the patients affected by M.S. are approximately 3 million, 400,000 of whom in Europe. In Italy there are over 50,000: which means that out of every 1000 people, there is one affected by this disease. To give substance to these numbers, think of a town like Rome, where a whole district with 5,000 inhabitants is affected by M.S. (and where, every year, 180 new cases develop!). Equally striking are the social costs involved by this disease: for days of work lost, for direct expenditures (drugs and health-care assitance) and indirect costs (domiciliary adaptive solutions, purchase of aids), a financial commitment of not less than 2,500 billion/year is calculated. These figures are really impressive and have contributed to attracting attention towards demyelinizing diseases. The first epidemiological studies had already demonstrated that the disease spreads more frequently in the mild climate zones, whereas in the countries with a very cold climate or in tropical and sub-tropical regions, it is definitely more rare. There are two other major and well-known factors, which relate to sex and age of onset. M.S. prevalently affects women (with a 2:1 ratio compared to the opposite sex) and it usually develops at an early age, with a distinct prevalence in the 20 to 30 year age bracket. To enrich our knowledge from an etiological point of view, in addition to the already mentioned risk factors, (age, sex, climate), researchers have also worked on diet, lifestyle, luxury activities, environmental pollution, ethnical-genetic factors, familial relations, possible co-morbility, traumas and several other parameters.

The Plaque

Multiple Sclerosis (in Italian also referred to as “Plaque Sclerosis”) is an autoimmune disease brought about by the synergic action of genetic and biological/environmental causes, whose exact etiology is still in great part wrapped in mystery. The demyelinization plaque is the pathognomonic feature of the morphostructural alteration of multiple sclerosis.
It is the indication that myelin has been damaged and it presents itself in different forms, depending on whether it is an active plaque or a lesion dating back in time. In structural terms, we have known for many years (Geren, 1954) that the myelin sheath of the peripheral nervous fibres is represented by the plasmatic membrane of the Schwann cell which envelops the axon in several layers, thus creating muffs of myelin coating, spaced out by areas of discontinuity (Ranvier’s nodes) and by intralamellar cavities (Schmitt-Lanterman’s fissures). In the central nervous system, the myelinogenic function is carried out by the glia’s cells (in particular by the oligodendrocytes), which envelop the axon in a way that is very similar to what happens with peripheral fibres (even though with a reduced number of Ranvier’s nodes).
It ought to be stressed, however, that whilst peripheral nervous fibres appear surrounded by connectival structures and are quite well separated and independent of each other, central myelin fibres appear more adhesive to each other. In the myelin fibre, the impulse travelling along the axon, “jumps” from a Ranvier’s node to the next, therefore the propagation of the impulse does not take place in a continuative manner, but rather “hops along”.
This means that the multilayer myelin covering that wraps the axon does not limit its function to that of an enveloping muff, but rather represents the means that guarantees the functional integrity of the neuron activity, in that if an axon is not provided with a myelin covering it ends up by losing its ability to carry the messages which normally travel along it. In other words, if the myelin protection is damaged, the nervous impulse transmission speed is gradually reduced and the signal’s energy weakens until it disappears, dissipating in the environmental medium. In multiple sclerosis, the multilayer lipoproteic structure enveloping the axon is attacked by an inflammatory infiltration which damages the fundamental myelin units, with consequent damages within the white matter of the encephalon and of the spinal marrow but with a relative indemnity of axons and of the cell bodies. In actual fact, in old lesions, in addition to the disappearance of myelin (which is replaced by sclerotic tissue), the axons will also appear obviously damaged, which is what usually takes place at a later stage, and causes, unless this has not yet happened, a complete neurofunctional suppression.
Therefore the plaque is some sort of memorial tablet commemorating the death of a more or less extended area of white matter, and it bears different histologic connotations depending on whether it is a recent lesion (with the presence of cellular infiltrates and the disappearance of oligodendrocytes, and with reactive astrogliosis) or a chronic lesion (where the glial hyperplasia is more evident and where the involvement of the axonal component is also more evident).

Symptoms

It is quite obvious that the possibility of attacking the white matter in different areas of the encephalon and of the spinal marrow may lead to a diversified range of symptoms, which are to be regarded as a direct result of the lesion. The size of the lesion is not always related to the entity of the symptoms, because we can have large-sized plaques resulting in limited clinical evidence and, at the same time, there can be a considerable symptomatology brought about by plaques which are smaller in size but situated in more “vital” areas of the central nervous system.
As mentioned, the dislocation of the plaques (even though there are some preferential seats, such as the brain preventricular zones) accounts for the great variability of the clinical signs. As a rule, the symptomatological sequence opens with the appearance of motor deficits, prevalently affecting the lower limbs (often preceded by a vague sense of fatigue), even though quite often the disease shows through the appearance of sensitive disorders, equilibrium disorders and other signs belonging to the cerebellar series, or through alarming vision disorders (owing to the existence of retrobulbar optic neuritis) which usually tend to resolve in a relatively short time.
In addition, there can be other onset symptoms (or symptoms appearing at a later stage), such as the presence of paroxysmal pain or of neuralgic pain (especially affecting the fifth cranial nerve), diplopia caused by paresis of the extrinsic ocular musculature, vesico-sphincteric and sexual activity disorders, problems relating to the superior noetic and emotional-affective functions, critical convulsive episodes, etc. As known, the disease may have a variable evolution, since it may evolve in a progressive manner or (more frequently) through remissions and relapses. The most recent classification (Lublin and Reingold, 1996) provides for the following course variants:
- Relapsing-remitting MS
- Secondary progressive MS
- Progressive-relapsing MS
- Primary progressive MS

Modern Diagnostic Resources

As mentioned, in the not too distant past, the diagnosis of (certain, probable or possible) forms of M.S. was only reached through the analysis of the personal symptoms, as related by the patient, and the detection of the clinic semiology. There were very few aids to support these diagnostic options, such as for instance the ophthalmoscope to explore the eyeground, the possibility of carrying out certain aspecific laboratory test on blood or on cerebrospinal fluid. Today things have changed considerably, since we can rely on a really significant range of diagnostic resources, which enable us to carry out early diagnosis and to widen the number of the definite forms (whilst, of course, reducing the number of those for which we have to adopt an open diagnostic approach, possibly awaiting for further clinical or instrumental symptoms to support a vague suspicion). It is extremely important to be able to carry out, with reasonable accuracy, an early diagnosis. There are several reasons for this, but some deserve to be emphasised.
First of all, as mentioned, the disease prevalently attacks young people, people who are going through a stage of their lives in which projects are made to direct one’s work and family choices.
Being able to know in good time that “something has changed” is not certainly good news, but at least it enables one to eventually change track, to adjust one’s resources (and possible deficits) in view of the future existential conditions. Knowing things early enough, enables one to better cope with the event. Secondly, producing an early definite diagnosis means resorting in good time to the modern therapeutic resources available nowadays, thus definitely improving the prognosis for these patients. A third reason is to allow researchers to acquire, from the very onset, the new cases of this pathology: a wider series allows broader and deeper analyses than could be conducted on a sporadic case (which, on its own, is unable to have an impact on the scientific conclusions or on the indications to be given). At the same time, it is worthwhile pointing out that, also for this disease, an effort has been made to adopt a diagnostic approach which is as objective as possible, by narrowing as much as possible the margins of subjective variability.
As early as in 1983, Poser had introduced criteria fit to restrict the diagnostic options to the definite and probable form categories, with and without the support of adequate laboratory tests, with the aim of removing the diagnostics of the demyelinizing affections from the vast territory of indefiniteness that had been prevailing up to that stage. In more recent times, there is a preference in resorting to the McDonald criteria (2001), whereby adequate appreciation is made of the magnetic resonance findings, which were obviously not taken into account by the criteria suggested by Poser. Also on the clinical side, experts adopt today calibrated and shared quantification criteria, based on specially devised disability assessment scales, such as the Kurtzke scale, in its latest version (EDSS). Also useful are the ISS scale (Inability Status Scale) and the ESS scale (Environmental Status Scale). Of course, the multifaceted symptomatological range of the disease is the very reason for the existence of numerous other scales devised to picture the deficits of the various damaged functions, including those relating to the superior noetic activities. At this stage I am anxious to point out that the physiatric estimate of the resulting impairment has been significantly readjusted, in recent times, with the launch of the ICIDH-2 (“International Classification of Functioning and Disability - 2”). According to this new classification, the terms impairment, disability and handicap, have been replaced by impairment, activity and participation: this means that the physiatric assessment (unlike the neurological one) no longer takes place through the “dosing” of the impairment resulting from the disease, but rather through that of the resources which remain intact, and it allows to assess the residual activity and the possibilities for the patient to take part in the opportunities offered by the social framework in which he/she belongs. As already mentioned, the diagnosis of M.S. has significantly profited from the improvement of new instrumental and laboratory techniques. The conventional Magnetic Resonance techniques (double-echo “spin-echo” sequences and T1-weighted sequences, with the administration of gadolinium-DTPA) have undoubtedly provided great diagnostic advantages, by displaying the presence of plaques disseminated in the encephalon. Although these tests still display some limitations (length in testing time, possibility of artifact-related circumstances, especially in claustrophobic patients, lack of peculiar specificity versus other demyelinization events affecting the white matter of the CNS), no doubt exists as to the fact that they have made it possible to detect asymptomatic lesions and, above all, have offered the possibility to monitor (though periodic controls) the development of the disease and of the effectiveness of the therapies adopted. Researchers have recently devised certain techniques (“turbo spin-echo”) which speed up the test, as well as the turbo gradient spin-echo sequences (which however appear less effective in identifying the lesions, especially the smaller ones). The resources offered by neuroimaging are equally useful to detect lesions affecting the spinal marrow, in at least two thirds of the clinically ascertained forms of M.S. The detection of these plaques, prevalently situated in the cervical area, may be facilitated by resorting to magnetization transfer gradient recalled-echo sequences.
Lastly, through sequences of the inversion recovery (STIR) type, it is possible to document any lesions affecting the optical nerve, in the event that a secondary optic neuritis is present. In summary, with the MR techniques, it is possible today to timely detect the existence of lesions (occasionally also at a pre-clinical stage), monitor the evolution of the pathologic process, and, to a certain extent, facilitate the predictive possibilities relating to the clinical evolution of the disease. Among the para-clinical tests, the test of the cerebrospinal fluid undoubtedly represents one of the most reliable aids for the diagnostical assessment. Approximately two thirds of the patients affected by M.S. display an excess number of inflammatory cells in the cerebrospinal fluid (T lymphocytes, macrophages, plasmocytes, polymorphfonuclear leukocytes). However, the most typical cerebrospinal fluid-related finding is represented by the increased concentration of immunoglobulin (IgG species), whose numerous fractions in oligoclonal bands become visible following electrophoresis or electrofocusing. The possibility rate of a 4-5 % of false positive cases certainly does not invalidate the great diagnostical value of this test, whose reliability as a support to diagnosis is ultimately equivalent to that of the data obtained through MR. Finally, the electrophysiological surveys also appear interesting, especially those carried out through (visual, trunk and somatesthetic) stimulus-related evoked potentials, even though the neurophysiological tests are of an aspecific and variable nature, which diminishes, even though only in part, their diagnostical significance.

Therapies

As mentioned, M.S. is characterised by an inflammatory event, having an autoimmune etiology, which attacks the myelin in certain areas of the CNS, giving rise to demyelinizing (plaques) and, subsequently, also to an axonal damage. To provide further details, we may add (now that war metaphors have sadly come back into fashion) that the responsibility for the act of aggression lies on two parties: the T cells (myelin-specific lymphocytes) which, activated by an exogenous and probably viral agent, are the first to break through the netting of the hemato- encephalic barrier and attack the target; subsequently, from (aspecific) lympho-mononucleae cells that intervene to assist the T cells, pro-inflammatory cytokines are released, which have a highly toxic effect on myelin. Based on this, the therapeutic logic should consist of attacking, to stay with Steinmann’s metaphor, the assaulters’ maniple (specific myelin-toxic activated T cells), or the “infantry” that follows to support and complete the inflammatory devastation, employing weapons represented by Th1 cytokines. Besides, the aggression process relies on the complicity of gamma interferon, which is capable of activating the T lymphocytes and the macrophages. In other words, it is possible to adopt specific antigen immunotherapies or else resort to molecules capable of blocking the Th1 cytokines responsible for pro-inflammatory activity. After the treatment with cortisonic agents and ACTH and the employment of immunoglobulin, in relatively recent times the employment of certain substances (interferons) has been resorted to: these substances are naturally produced by the fibroblasts and by the epithelial cells during a viral infection, and can be obtained through genetic engineering laboratory techniques (recombining IFN). Among these “immunomodulating” drugs, the most active for the purpose of inhibiting the proliferation of T lymphocytes, to reduce their ability to break through the hemato-encephalic barrier (and to reduce the production of gamma interferon), is certainly the beta recombining IFN, whereof the types currently employed are beta 1a (marketed under the Avonex and Rebif names) and beta 1b (Betaferon).
The clinical results obtained so far appear very encouraging and the effectiveness in relapsing-remitting MS as well as in secondary progressive MS has been demonstrated through numerous international multicentric studies, supported by a prolonged follow-up period. Further drugs are being developed in the field of immunomodulating therapies specifically devised for MS, even though their tests on animals date back to several years ago: the synthetic copolymer “glatiramer acetate” (Copaxone) and an immunosuppressive agent called Mitoxantrone (Novantrone), on which the results of the first clinical trials are already being compared both in Europe and in the United States. It should also be stressed that with MS we do not simply have myelin damage but, as previously mentioned, there is a concomitant axonal damage. Therefore, an objective we could set, once the inflammatory assault has been reduced or overcome, would be that of remedying the damages caused by the inflammation in the neuronal circuitry, attempting to restore the various connections that had been interrupted.
But is neuroregeneration possible in the central nervous system? As you know, up to a few years ago, the reply would have been peremptorily negative. The damaged cells were regarded as irremediably lost and the brain was not able to self-repair itself, so to speak However, recent researches have shown that regeneration can also take place in the central nervous system (and that even “neurogenesis” may take place, that is the formation of new neurons). This is the great new age of the plasticity of the nervous system, which is no longer regarded as a rigidly predefined structure but rather as a structure cable of remodelling, depending on the new functional requirements brought about by the pathological events. As known, if a neuron is damaged to death by a lesion, there are other contiguous neurons, which have remained untouched, which start sprouting, trying to take possession of the functions of the deceased neuron. Or else, by extending, certain health neurons attempt to establish contact with a damaged neuron, creating some sort of life-belt, which prevents the damaged neuron from dying (collateral sprouting). Or, lastly, there are some central neurons that, although partially damaged, may start a process of regrowth and resume their functions (regenerative sprouting). In other words, in our central nervous system there are self-repairing possibilities, even though latent and complex, and one of the fascinating tasks of modern research is that of analysing all possible solutions to speed up this process of nervous plasticity and regeneration. Unfortunately, this desirable neuroregeneration finds a very hostile environment within the Central Nervous System, since in the periaxonal myelin sheath there are numerous protein factors that inhibit neuronal regrowth. Among these is the MAG oligodendrocytic protein (Myelin Associated Glycoprotein), the “januscina” and certain myelin-associated molecules produced by the oligodendrocytes (NI35/250). The neutralisation of such molecules with specific antibodies allows axonal grown in vitro and, even though to a smaller extent, also in vivo (for instance in spinal marrow sectioned models). This is confirmed by the fact that the employment of anti-MAG anti-bodies is capable of reducing the inhibition of axonal regrowth. Of course, the inhibition of the oligodendrocytes is not the only reason why axons have difficulties in regenerating, in an adult’s CNS. Astrocytes are also capable of inhibiting axonal sprouting through numerous molecules on their membrane surface (such as, for instance, tenascine, kertan, condroitin-sulphate-proteoglicans etc.).
In addition, it should be recalled that when a lesion produces a solution of continuity of an axon, a glial scar develops and this represents an obstacle (which is not only mechanical) to axonal regrowth, and in order to restore a connection between the area above and the area below the lesion some obstacles exist which at the moment appear materially insurmountable. Indeed, it would be necessary for factors stimulating axonal regeneration to find a way around the cicatricial barrier, and through a “bridge” type course, reconnect with the underlying fibres to reconstruct the complex architectonic structure representing the pre-lesion circuit. It is over 25 years now that attempts of reactivating medullary continuity thorough the “Schwann bridge” have been attempted in mice, by resorting to the inoculation of Schwann cells taken from the same animal, attempting to create some sort of bridge capable of conveying the regenerated sprouting towards the area beneath the lesion.

Recent researches by Xiao Ming Xu have suggested resort to a special “bridge” to facilitate axonal regeneration. This researcher from the Saint Louis University School of Medicine, has arranged a “polymer guidance channel”, that is some sort of muff in whose cavity he has inserted Schwann cells and basal lamina proteins (which stimulate axonal growth). If we managed to replace damaged or lost cells with other specific and operating cells (thus triggering or aiding a regeneration process) this would certainly be one of the most significant victories in the neurobiological and therapeutic field. In actual fact, research work in this sector started several years ago and a great contribution has been provided to this field by Rita Levi Montalcini, with her studies on neurotrophines and, above all, on NGF (Nerve Growth Factor). These are substances which facilitate nerve growth (especially in sympathetic and cutaneous-sensorial neurons) and several research groups have thought that they could be therapeutically employed to support axonal growth and neuronal regeneration. Neurotrophines (NGF, BDNF or brain-derived neurotrophic factors, GDNF, NT-3, etc.) can play an important role also in pathologic conditions. Indeed, it has been established that when a neuron is damaged and is about to die, it sends out some sort of biochemical SOS, calling up the neurotrophines to try and survive and to recreate its connections with the other neurons. Here, however, we have a huge problem (to be honest there are several problems, but this appears to be more serious than the others): when a damaged central neuron starts to be replaced by another neuron, what guides these newly-formed axons towards their “target”? How can the newly formed or recovered neuron know which way to go to correctly reconnect to the other neurons? In other words, it is not sufficient for a neuron to regenerate; the important thing is that it is able to restore proper connections with the other neurons (as per the primitive genetic imprinting), avoiding erroneous contacts, which may lead to dangerous “short circuits”. As regards the central nervous system (where we are trying to facilitate the axonal regrowth process) this is one of the most complex problems, since it is difficult (if not impossible) to correctly address the axonal regrowth towards the vacant areas, with the creation of new connections. Indeed, it is known that the post-lesion axonal growth (and, above all, the creation of new synapses) must take place in a functional way: in other words it is not only important for the two “cables” to connect to each other, but it is important that the new connection produces an efficient circuitry and that no directional errors take place in axonal neo-development (as these would certainly be useless and dangerous). At the moment, we do not possess the knowledge required to recreate conditions such as those existing at the time in which the N.S. is first developed. During that time of formation, there is a complex genetic regulation that is in charge of neuronal proliferation and migration routes, ensuring that the growth cones of the various axons proceed towards precise destinations dictated by the genetic imprinting.
The development of synaptic connections (and, therefore, the creation of the complex neuronal networks) is also the result of a prearranged and genetically regulated mapping, even though today the mechanism regulating the routes of the cellular migrations and of the axonal growth are still virtually unknown (“axon guidance”). As early as in 1910, Harrison conjectured the presence of an axon with a “pioneer” role, capable of establishing some sort of “axonal path” (label pathway) along which other axons would subsequently follow (follower axons), following in the pioneer’s footsteps and grouping together (fasciculation) (Raper et al. 1983., Goodman et al., 1996). However, according to more recent hypotheses, it would not be the axon’s responsibility to “know where to go” (as per genetic information); in fact, the growth cones are now thought to move towards one target or the other based on chemoattractive (or chemorepulsive) activities, capable of attracting or rejecting the contact with the axon endings, creating “permissive” or “repulsive” substrates (Gundersen 1987, Lemmon 1992). Recently (Kolodkin, 2000), certain proteins (which have been named “semaphorins”) have been studied and these are capable of piloting the congruity of the new connections, since they carry out a repulsive action towards certain fibres in the process of being regenerated (thus preventing the new fibres from choosing the wrong track and from creating erroneous connections).
Lastly, we should not neglect the very important role played by the extracellular environment and, above all, by certain cellular surface protein molecules, capable of modulating the axonal growth (CAMs and NCAM, Neural Cell Adhesion Molecules, RTPKs e RTPTs, receptor protein tyrosine kinases and phosphatases).(Cunningham et al. 1987, Takeshida et al. 1993, Suter et al. 1995). The field of neuroregeneration appears at the moment rather problematic, even though pharmacological treatments and genetic engineering (neurotrophic factors stimulating neuronal plasticity and axonal growth) as well as surgical treatment (autologous transplantation of Schwann cells, neuroblast transplantation) represent – together with the resources offered by neurogenetics – the most radical and fascinating course for the following decades. As known, as early as in 1980 in a number of laboratories immortalized cell lines were developed: these were cells which had the ability to continue to replicate up to the time in which it was decided to direct them towards a specific final configuration. This was possible by adding CNS indifferent tissues of the modified tumorous gene, which led the cells to endless replication. At the time of their employment, the cell lines had to be able to become CNS cells, whereas the tumorous gene had to be suppressed (to avoid neoplastic reproductions). Therefore, in very recent times, to attempt repairs following medullary lesions, researchers thought of resorting to solutions based on cell replacement therapies, that is on the implant in the damaged seat of stem cells, indifferentiated ancestors of the future specialised cells for one type of tissue or the other. These stem cells may be of two types: totipotent cells, which can form all the necessary cells to give life to a new organism, and multipotenti cells, which are in a position to generate many (but not all) types of cells. The most modern strategies therefore consist of the employment of stem cells to replace the lost nerve cells, even though the problem remains as to how to get the newly-forming growing neurones to bypass the damaged area (as well as serious perplexities which still exist in connection with bioethical implications). An extremely recent publication by Canadian researchers, led by F. Miller (Nature Cell Biology, Sept. 2001) reports the results obtained through the sampling of indifferentiated cells from the dermis of a young and of an adult mouse (“Skp Super-cells”), capable of evolving into specialised cells (neurons and glial cells). These multipotenti stem cells, unlike the mesenchymal cells (employed so far to generate osseous and cartilaginous tissue) are therefore capable of evolving into different tissues (nervous and muscular), thus providing hope as to new possibilities of neurogenesis. Waxman and his partners (from the Neurology Department of the Yale University School of Medicine) are experimenting new strategies to remyelinize the demyelinized axons of the spinal marrow by means of “myelin-forming cells” (Schwann cells) transplanted into the damaged area. The most actual researches relate to the possibility of carrying out xenografts with the employment of myelin-forming cells from transgenic pigs, and the first results appear, according to such researchers, very encouraging. We cannot close this section dedicated to therapies without mentioning neuromotor rehabilitation (and the physiatric contribution as a whole) whose principles are based on the following general considerations: When a system is damaged, the physiatrist approaches the situation with the following objectives: - Eliminating the cause and (if possible) restoring proper operation of the system; - Stimulating the residual function (motorial, proprioceptive, equilibrium, vesico-sphincteric functions, superior cortical functions, etc.) - Adapting the ambient to the system affected by this damage. o The first option (the most radical and conclusive, but at the moment the most difficult to pursue) is represented by the attempt to “repair” the damage through the regeneration of the demyelinized fibres or their recoating with myelin; in this case, the physiatrist’s task would be that of preparing the patient for his new conditions, associated with the recovery, and to facilitate – by means of adequate therapeutic exercises – the recovery process; o The second option (which is certainly not as conclusive) is that of stimulating the residual post-lesion abilities, attempting to get the functions which have not been damaged to engage in a vicarious role, also through the employment of specific aids; in this case (which at present is the most frequent), the role of the physiatrist is a prominent one, and is started from the very first phase of maximum severity up to the reintroduction of the patient into his social environment; o The third (so far rather neglected) option is based on the fact that every system operates within an environment: if the system is damaged, the environment can be remodelled so as to adapt it to the operating deficit of the damaged system. In this circumstance, the fundamental role is carried out by the patient, who holds all the information and experiences related to his state, who will have to place at the disposal of various professionals (physiatrists, rehabilitation and occupational therapists, ergonomists, architects, etc.) his requirements and suggestions for a solution. Today, the role of the rehabilitator has acquired a significant importance in the management of the problems associated with M.S. disabilities, which of course do not simply relate to motorial deficits, but also to a whole range of specific interventions on the various functions deteriorated by the pathogenic noxa. Depending on the affected system (pyramidal, neo, paleo- and archicerebellar, proprioceptive, etc.) there will be disorders affecting the specific function (motor, postural, equilibrium function, etc.) against which it is possible to come into action with the various compensating rehabilitative strategies. In addition, also in the case of certain specific deficits (such as, for instance, that relating to cognitive faculties, to vesico-sphincteric disorders, to breathing dysfunctions, etc.) we have available today physiatric approach techniques that limit the progress of the disability or manage to speed up the restoration of the function during the remissions phases.

A Few Closing Comments

Based on what has been said, there is no doubt as to the fact that the degree of attention devoted to M.S. from a research, therapy and rehabilitation point of view, confirms that this disease is no longer confined to the field of the so-called ”orphan” diseases. In this regard, a key role has been played by voluntary associations (above all AISM), which have devoted to this field an absolutely commendable effort, through a whole set of initiatives aimed at awakening public opinion, in order to raise funds to be invested in research work and in improved welfare solutions. Of course we still have a long way to go, with the expectable enthusiasms provided by research work and the depression caused by possible apparent successes that may prove short-lived. But we have struck the right road and it is only a matter of time. (trad.Interpres-GiussaNO)
Alberto Freddi
Direttore del Dipartimento
di Neuroscienze e Neuroriabilitazione
Azienda Ospedaliera “S. Maria” - Terni