Multiple sclerosis: symptoms

The main symptoms of multiple sclerosis, depending on the location of the lesion

Visual paths

Inflammation and demyelination of the optic nerves and chiasma are often observed with multiple sclerosis. In about 20% of patients, the symptoms of optic neuritis are the first manifestation of the disease, and in 70% of cases they occur at one or another stage of the disease of multiple sclerosis. A significant number of patients with optic neuritis subsequently develop multiple sclerosis. In a prospective study, it was noted that 74% of women and 34% of men developed a clinical picture of multiple sclerosis in the next 15 years after the first episode of optic neuritis. In other studies, the proportion of patients who later developed multiple sclerosis was 20-30%, but in a shorter period of time. In these studies, the risk of developing multiple sclerosis after neuritis of the optic nerve in women also was higher than that of men.

Neuritis of the optic nerve is often manifested by a sharp decrease in vision, developing for several days (up to 1 week). Often there is slight discomfort or pain in the movements of the affected eye or in the periorbital area that precede or accompany a visual impairment. The involvement of only one nerve is more often noted, but simultaneous or sequential defeat of two nerves is possible. Visual loss is usually characterized by a decrease in visual acuity, a violation of color perception, sometimes in combination with the limitation of the field of vision or the expansion of the central scotoma. With acute optic neuritis, direct ophthalmoscopy can detect blistering or edema of the nerve disc in the affected eye, depending on the proximity of the affected segment to the nerve head. Other changes can be detected with an expanded indirect ophthalmoscopic examination. These include: blanching around the peripheral retinal venules (perivenovenous clutches), local leakage of fluids on fluorescent angiograms, the presence of cells in the vitreous. These changes occur, in spite of the fact that the myelinated fibers are absent in the retina - this indicates that the change in vascular permeability can occur primarily in multiple sclerosis rather than a complication of demyelination.

The study of visual evoked potentials is a highly sensitive method of diagnosing the optic neuritis in the acute stage, which also allows to verify the previous episodes, which resulted in the complete restoration of vision and did not leave atrophy of the nerve. The value of visual evoked potentials in the diagnosis of multiple sclerosis lies in the detection of subclinical lesion of the visual pathways, which allows us to state the multi-focal character of the lesion of the central nervous system, which is especially important in differential diagnostics with diseases of the spinal cord, as well as in cases of possible or probable multiple sclerosis.

A useful symptom of multiple sclerosis associated with subclinical lesion of the optic nerve is the Uttoff phenomenon . Although it manifests itself in a variety of ways, it is most often associated with the demyelinating lesion of the visual pathways. Uttoff's phenomenon is characterized by a visual impairment of one or both eyes due to a rise in temperature, for example, with fever, physical exertion, hot weather, etc. It can manifest itself in other situations, for example, under the influence of bright light, emotional stress or fatigue. If the provoking factor is eliminated, vision returns to normal.

An attribute of acute, chronic or subclinical neuritis of the optic nerve may be the phenomenon of Marcus Hunn - the expansion of both pupils when the light source moves from the healthy eye to the affected. The presence of the phenomenon indicates a one-sided damage to the afferent part of the arc of pupillary reactions, both direct and friendly. It is better to detect it in a darkened room by transferring a light source from one eye to another. When the light source is applied to the unaffected eye, the pupil will narrow, both on the side of stimulation (due to direct reaction) and on the contralateral side (due to a friendly reaction). When the light source is brought to the affected eye, the narrowing of the pupils is replaced by their enlargement due to affection of the afferent link of the arc as a direct and friendly reaction. Like the changes in visual evoked potentials, the phenomenon of Marcus Hun can persist after the episode of optic neuritis even with a complete restoration of vision or can be detected in subclinical lesion of the optic nerve.

Neuritis of the optic nerve can not only be idiopathic or associated with a demyelinating disease, it can be caused by infections (syphilis, Lyme disease, tuberculosis, sinusitis, various viral infections, some of which are related to AIDS) or other systemic inflammatory diseases (sarcoidosis , Behcet's disease, systemic lupus erythematosus). Severe bilateral loss of vision due to simultaneous or sequential lesion of the optic nerve occurs with hereditary neuropathy of the optic nerves of Leber, a mitochondrial disease that mainly affects men. Interestingly, the mitochondrial DNA mutation inherent in Leber's disease was found in a small group of patients with typical clinical manifestations of multiple sclerosis and severe vision loss, but it does not predispose to the development of multiple sclerosis.

After the initial episode of optic neuritis, the recovery forecast is generally favorable. Recovery usually occurs within 4-6 weeks. In relatively mild cases - a full recovery of vision for 6 months is noted in 70% of patients. This result is apparently not affected by treatment with corticotropin or glucocorticoids. However, the probability of restoring vision with a moderate or severe impairment of corticosteroid therapy has a significant effect. The effectiveness of this method of treatment may depend on its timeliness - early therapy is more effective than delayed.

Spinal cord

Spinal cord injury is often observed in multiple sclerosis and can take the form of an acute or slowly progressive disease. Defeat of the spinal cord can explain such symptoms as decreased sensitivity, paresthesia, paralysis, especially if they are bilateral. Shaky walking, urination and bowel function, sexual dysfunction, pain can also be associated with a spinal cord injury. There have been reports of cases of dystonia and myoclonus with spinal cord injury, but they often occur with lesions of the trunk.

Dysfunction of the spinal cord can develop sharply (as with the transverse myelitis), subacute or gradual. The cervical region is affected in 2/3 of the cases, the thoracic spinal cord is less likely to suffer. Disturbance of sensitivity due to incomplete transverse myelitis occurs in almost half of patients as the first symptom of the disease. Sensitivity disorders usually begin with the distal extremity, and then spread in the proximal direction. They peak at several days or 1-2 weeks and regress for about the same time in reverse sequence than they appeared. Sensations of tingling and numbness spread from the distal sections of the lower extremities upward on the trunk or involve the arm and leg on the same side of the body. Disturbance of sensitivity is rarely complete and is usually manifested by moderate objective changes during examination. Paresthesias are observed in almost all cases. Some patients have complaints of involuntary urination or difficult urination initiation, deep reflexes can be lively, normal, or, more rarely, reduced. Symptom Babinsky may be present or absent. The loss of superficial abdominal reflexes (not associated with weakness of the abdominal wall, for example, due to abdominal surgery) also indicates a lesion of the spinal cord.

Patients can complain about the fact that when they move their head they have acute pains or paresthesias, extending from the neck down the back to the hands or feet. This is the so-called Lermitt symptom, indicating the defeat of the cervical spinal cord. The symptom is caused by spinal cord irritation as a result of its slight stretching when the head is tilted. Although the symptom of Lermitt may be indicative of multiple sclerosis, he is not pathognomonic for him and can occur in other diseases, including spinal cord injury, vitamin B12 deficiency, radiation myelopathy, herpes zoster infection or spinal cord compression.

Other manifestations of multiple sclerosis are acute or progressively developing spastic monoparesis, paraparesis or hemiparesis, which, like sensitivity disorders, are rarely complete at first. As a rule, there is a combination of motor disorders with sensitive, especially disorders of vibrational and joint-muscle feelings. Pyramid signs are more often two-sided, even if the paresis is limited to only one limb.

MRI is the method of choice for the study of lesions of the spinal cord. It allows to diagnose intramedullary processes, vascular malformations, developmental anomalies, extramedullary compression of the spinal cord. The centers of demyelination are usually well visualized on sagittal images obtained in T2-mode or proton-density regime, in the form of delimited hyperintensive zones oriented parallel to the longue of the spinal cord. A similar zone can capture one or more adjacent segments of the spinal cord, but sometimes several foci are seen in different segments. On axial images, foci in the central zone of the spinal cord can be identified, involving both gray and white matter or the posterior, anterior or lateral cords. On the transverse sections of the spinal cord, the foci often have a heterogeneous or mosaic structure. In the acute phase, the foci can be contrasted with gadolinium and cause a slight swelling of the spinal cord, which is the reason for the erroneous diagnosis of the tumor in cases of single foci. Spinal cord atrophy, probably due to degeneration of axons in the foci of demyelination, correlates with the overall severity of the neurological defect. As with neuritis of the optic nerve or stem syndromes, the risk of progression with the formation of an expanded clinical picture of multiple sclerosis after an isolated lesion of the spinal cord increases dramatically in the presence of lesions in the white matter of the brain.

In cases where the transverse myelitis is not complete and, therefore, does not cause paraplegia, the likelihood of developing multiple sclerosis is higher than with complete transverse damage to the spinal cord. The presence of oligoclonal antibodies in CSF will allow to differentiate the debut of multiple sclerosis from postinfection myelitis. Viral myelitis is accompanied by a higher cytosis and protein level in the CSF than a demyelinating disease. In cases where multiple sclerosis selectively involves the spinal cord, the disease is much more likely to have a progressive rather than remitting course. Diagnosis of multiple sclerosis is difficult in cases where an MRI scan of the brain does not detect changes or exhibits nonspecific changes in white matter, reminiscent of the nature of those that are often observed in elderly people.

The trunk of the brain and the cerebellum

In comparison with the centers of other localization, the centers of demyelination in the structures of the posterior cranial fossa (brainstem or cerebellum) often cause a severe neurological defect, which often does not correspond to their own size or quantity. The defeat of this particular localization causes the classical triad of Charcot: nystagmus, intentional tremor, chanted speech. According to the pathomorphological studies of Ikuta and Zimmerman (1976), changes in the structures of the posterior cranial fossa are not detected quite often: in 16% of cases they were absent in the middle brain, 13% in the cerebellum, 12% in the medulla oblongata, 7% of cases - in the bridge. For comparison, in the optic nerves, the cerebral hemispheres and the spinal cord, changes were absent in 1, 3 and 1% of cases, respectively. Although the damage to the brainstem manifests itself with the same symptoms as the damage to other parts of the brain (for example, hemiparesis, paraparesis, or sensitivity disorder), however, more characteristic symptoms of multiple sclerosis are associated with a violation of the specific functions of the trunk - including violations of friendly eye movements, articulation, swallowing, breathing. Foci in the subcortical areas of the cerebellum and the cerebellar tract can cause ataxia of limbs and trunk, nystagmus, dizziness, chanting speech. Some patients who have a strong muscular strength are deeply disabled due to severe ataxia of the trunk and extremities.

Oculomotor disorders

Although for multiple sclerosis there are no pathognomonic oculomotor disorders, some of them are often observed in this disease. The most characteristic sign is a violation of the friendliness of movements of eyeballs with lateral leads due to internuclear ophthalmoplegia. This syndrome can be one-sided or bilateral, complete or incomplete. It occurs as a result of a lesion of the medial longitudinal bundle (MPP), a path connecting the nucleus of the third cranial nerve (controlling the reduction of the ipsilateral eye) to the nucleus of the sixth cranial nerve on the opposite side (controlling the retraction of the ipsilateral eye). When viewed in a contralateral lesion the patient's side can not bring the eye to the side of the focus, or slowly bring it to the middle position, while the contralateral eye is completely removed, but due to the hypermetry, a coarse horizontal monocular nystagmus can arise. Isolated oculomotor disorders are rare and are most often associated with third or sixth cranial nerve damage.

The Great Hemisphere

Many foci, visualized in the subcortical white matter, are localized in the "silent" areas of the brain and, accordingly, are asymptomatic. Nevertheless, foci in the large hemispheres occasionally cause, as in stroke, hemiparesis, hemygipesthesia, cortical blindness or aphasia. Cognitive impairment in multiple sclerosis is associated not only with the total lesion, but also with local damage to the corpus callosum. Cognitive defect in multiple sclerosis is usually characterized by a weakening of short-term memory, a violation of abstract and conceptual thinking, a decrease in speech activity, and visual-spatial disorders. Extrapyramidal syndromes are rare, but can be caused by foci localized in subcortical gray matter, for example, basal ganglia (caudate nucleus or subthalamic nucleus).

Other symptoms of multiple sclerosis

Neuralgia of the trigeminal nerve can occur in the onset of the disease or in the course of its course. In large clinical series, it was noted in 2% of patients. In some cases, a slight paresis of mimic muscles is noted, reminiscent of facial nerve neuropathy. A rare symptom, which is possible with multiple sclerosis and some other diseases, is facial mycobia. It is characterized by wave-like fasciculatory twitches of facial muscles. Involving the respiratory centers of the trunk, leading to respiratory failure, usually occurs at a late stage of the disease, but it is also possible in the acute phase of exacerbation.

The course and natural development of multiple sclerosis

Several different variants of the course are distinguished, according to which the disease is classified into separate forms. Different forms form a kind of clinical spectrum, which, on the one hand, is represented by repeated exacerbations with complete or almost complete remissions, and on the other - a steady, non-mutating progression of neurological disorders. These two forms are designated respectively as remitting (relapsing-remitting) and primarily progressive. The latter should be distinguished from a secondarily progressive form, which develops in patients with a remitting course, as well as from a progressively recurrent form, for which a steady progression with infrequent exacerbations is characteristic from the very beginning. The term "benign multiple sclerosis" is excluded from the new classification.

The nature of the course of multiple sclerosis is affected by the age of onset of the disease and the nature of its initial manifestations. The remittent course of multiple sclerosis is more often observed in women, with the onset of the disease at an earlier age with impaired sensation or optic neuritis. Progressive course of multiple sclerosis is more often observed in men, with late onset of the disease (on the 5th-6th decades of life) with gradually developing paralysis.

Clinico-pathomorphologic variants of multiple sclerosis

There are several variants of multiple sclerosis, differing in clinical and pathomorphological changes. Schilder's diffuse myelinoclastic sclerosis is characterized by the presence of extensive bilateral symmetric demyelinating zones in the semiovalicular center (white matter region located above the lateral ventricles), with or without smaller isolated foci. Such cases are more common in children. Clinically, the disease manifests itself as dementia and other mental disorders, the presence of exacerbations and remissions, increased intracranial pressure, imitating a brain tumor clinic (pseudotumoric course). Histologically, clearly demarcated zones of demyelination with fibrillar gliosis, giant multinucleate or edematous astrocytes, perivascular infiltration and axonal damage are clearly identified.

Marburg's disease is an acute lightning-fast form of multiple sclerosis, characterized by the presence of a massive hemisphere focus, brain stem involvement, pleocytosis and oligoclonal antibodies in the cerebro-spinal fluid. At an early stage, edema is expressed, there is also a widespread destruction of myelin and a sharp decrease in the number of axons.

Concentric sclerosis Balo is another variant of the lightning-fast monophasic course of multiple sclerosis, in which a focus is formed, consisting of concentrically arranged layers of demyelinated and myelinated tissue.

Two other variants of demyelinating disease - acute disseminated encephalomyelitis (OPEM) and opticemia (Devik's disease) occur more often and are discussed in more detail later.

Experimental allergic encephalomyelitis. Although other mammals do not have a disease similar to human multiple sclerosis, they can artificially trigger a demyelinating disease - experimental allergic encephalitis - EAE. The creation of an experimental model is important not only to understand the pathogenesis of the immune process in disseminated sclerosis, but also to search for and evaluate the effectiveness of possible drugs. Pathomorphological changes in EAE are similar to changes in PC and are characterized by perivennous inflammatory infiltration and variable demyelination. EAE is induced by immunization with preparations containing myelin antigens, including untreated brain and spinal cord homogenates, myelin proteins or fragments thereof with or without addition of an adjuvant and pertussis toxin. The disease can also be passively transferred between the syngeneic lines of mice with T-lymphocytes sensitized to myelin antigens. In this case, additional administration of antibodies to myelin is required to develop more pronounced demyelination. In a typical case, EAE is a monophasic disease with complete or almost complete recovery. But guinea pigs and mormozetok can cause recurrent EAE. EAE has also been studied in mice with a transgenic T-cell receptor for the specific amino acid sequence of the main myelin protein. Although EAE is not an absolute analogue of multiple sclerosis and as a model it is not perfect, the data obtained in its study made it possible to better know the biology of T-cell receptors and MHC, autoantigens and autoantibodies presumably involved in multiple sclerosis, regulation of the immune response, and genetics of demyelinating the CNS.

[1], [2], [3], [4], [5], [6], [7], [8], [9]