Multiple Sclerosis - Symptoms.

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

Visual pathways

Inflammation and demyelination of the optic nerves and chiasm are common in multiple sclerosis. In approximately 20% of patients, symptoms of optic neuritis are the first manifestation of the disease, and in 70% of cases they occur at some stage of the disease. 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 clinical symptoms of multiple sclerosis within 15 years of their first episode of optic neuritis. In other studies, the proportion of patients who subsequently developed multiple sclerosis was 20-30%, but over a shorter period of time. In these studies, the risk of developing multiple sclerosis after optic neuritis was also higher in women than in men.

Optic neuritis often presents with acute visual impairment that develops over several days (up to 1 week). Mild discomfort or pain with movement of the affected eye or in the periorbital region is common, preceding or accompanying the visual impairment. Most often, only one nerve is involved, but two nerves may be affected simultaneously or sequentially. Vision loss is usually characterized by decreased visual acuity, impaired color perception, sometimes in combination with a limited visual field or widening of the central scotoma. In acute optic neuritis, direct ophthalmoscopy may reveal pallor or edema of the nerve head in the affected eye, depending on the proximity of the affected segment to the nerve head. Other changes may be detected by extended indirect ophthalmoscopic examination. These include: pallor around the peripheral retinal venules (perivenous cuffs), localized fluid leakage on fluorescent angiograms, and the presence of cells in the vitreous. These changes occur despite the absence of myelinated fibers in the retina, indicating that changes in vascular permeability may occur primarily in multiple sclerosis and are not a complication of demyelination.

The study of visual evoked potentials is a highly sensitive method for diagnosing optic neuritis in the acute stage, which also allows for verification of previous episodes that resulted in complete restoration of vision and did not leave behind nerve atrophy. The value of visual evoked potentials in the diagnosis of multiple sclerosis is in the detection of subclinical damage to the visual pathways, which allows for the multifocal nature of damage to the central nervous system to be established, which is especially important in differential diagnostics with spinal cord diseases, as well as in cases of possible or probable multiple sclerosis.

A useful symptom of multiple sclerosis associated with subclinical damage to the optic nerve is the Uthoff phenomenon. Although it manifests itself in many ways, it is most often associated with demyelinating damage to the visual pathways. The Uthoff phenomenon is characterized by visual impairment in one or both eyes due to a rise in temperature, such as fever, physical exertion, hot weather, etc. It can also manifest itself in other situations, such as exposure to bright light, emotional stress, or fatigue. If the provoking factor is eliminated, vision returns to normal.

The Marcus Gunn phenomenon, which is the dilation of both pupils when the light source is moved from the healthy eye to the affected eye, may also be a sign of acute, chronic or subclinical optic neuritis. The presence of the phenomenon indicates unilateral damage to the afferent part of the pupillary arc, both direct and consensual. It is best detected in a darkened room when moving the light source from one eye to the other. When the light source is applied to the unaffected eye, the pupil will constrict, both on the stimulation side (due to the direct reaction) and on the contralateral side (due to the consensual reaction). When the light source is brought to the affected eye, the constriction of the pupils will change to dilation due to damage to the afferent part of the arc of both direct and consensual reactions. Like changes in visual evoked potentials, the Marcus Gunn phenomenon may persist persistently after an episode of optic neuritis even with complete recovery of vision or may be detected in subclinical optic nerve damage.

Optic neuritis may not only be idiopathic or associated with a demyelinating disease, but may also be caused by infections (syphilis, Lyme disease, tuberculosis, sinusitis, various viral infections, some of which are associated with AIDS) or other systemic inflammatory diseases (sarcoidosis, Behcet's disease, systemic lupus erythematosus). Severe bilateral vision loss due to simultaneous or sequential damage to the optic nerve occurs in Leber's hereditary optic neuropathy, a mitochondrial disease that predominantly affects men. Interestingly, the mitochondrial DNA mutation characteristic of Leber's disease has been 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 prognosis for recovery is generally good. Recovery usually occurs within 4-6 weeks. In relatively mild cases, complete recovery of vision within 6 months is observed in 70% of patients. This outcome does not appear to be affected by treatment with corticotropin or glucocorticoids. However, the likelihood of recovery of vision in moderate to severe cases is significantly affected by corticosteroid therapy. The effectiveness of this treatment may depend on its timeliness - early therapy is more effective than delayed therapy.

Spinal cord

Spinal cord involvement is common in multiple sclerosis and may be acute or slowly progressive. Symptoms such as decreased sensitivity, paresthesia, and paralysis, especially if bilateral, may be attributed to spinal cord involvement. Unsteadiness when walking, urinary and bowel dysfunction, sexual dysfunction, and pain may also be associated with spinal cord involvement. Dystonia and myoclonus have been reported in spinal cord involvement, but are more common in brainstem lesions.

Spinal cord dysfunction may develop acutely (as in transverse myelitis), subacutely, or gradually. The cervical spine is affected in 2/3 of cases, while the thoracic spine is less commonly affected. Sensory loss due to incomplete transverse myelitis occurs in almost half of patients as the first symptom of the disease. Sensory loss usually begins in the distal extremities and then spreads proximally. It peaks over several days or 1–2 weeks and regresses over approximately the same period in the reverse order in which it appeared. Tingling and numbness sensations spread from the distal lower extremities up the trunk or involve the arm and leg on the same side of the body. Sensory loss is rarely complete and is usually manifested by moderate objective changes during examination. Paresthesia is observed in almost all cases. Some patients complain of involuntary urge to urinate or difficulty initiating urination; deep reflexes may be brisk, normal, or, less commonly, decreased. Babinski's sign may or may not be present. Loss of superficial abdominal reflexes (not related to weakness of the abdominal wall, such as due to abdominal surgery) also suggests spinal cord damage.

Patients may complain of sharp pain or paresthesias radiating from the neck down the back to the arms or legs when moving their head. This is known as Lhermitte's sign, which indicates damage to the cervical spinal cord. The symptom is caused by irritation of the spinal cord as a result of its slight stretching when the head is tilted. Although Lhermitte's sign may indicate multiple sclerosis, it is not pathognomonic for it and can occur with other diseases, including spinal cord injury, vitamin B12 deficiency, radiation myelopathy, herpes zoster infection, or spinal cord compression.

Other manifestations of multiple sclerosis include acute or gradually developing spastic monoparesis, paraparesis or hemiparesis, which, like sensory disturbances, are rarely complete at first. As a rule, there is a combination of motor disturbances with sensory disturbances, especially disturbances of vibration and joint-muscle sense. Pyramidal signs are often bilateral, even if the paresis is limited to only one limb.

MRI is the method of choice for studying spinal cord lesions. It allows diagnosing intramedullary processes, vascular malformations, developmental anomalies, and extramedullary compression of the spinal cord. Demyelination foci are usually well visualized on sagittal images obtained in the T2 mode or proton density mode as delimited hyperintense zones oriented parallel to the long axis of the spinal cord. Such a zone may involve one or more adjacent segments of the spinal cord, but sometimes several foci are noted in different segments. Axial images may reveal foci in the central zone of the spinal cord, involving both gray and white matter or the posterior, anterior, or lateral funiculi. On transverse sections of the spinal cord, foci often have a heterogeneous or mosaic structure. In the acute phase, foci may be contrasted with gadolinium and cause mild edema of the spinal cord, which can be a reason for erroneous diagnosis of a tumor in cases of single foci. Spinal cord atrophy, probably due to axonal degeneration in demyelination foci, correlates with the overall severity of the neurological defect. As with optic neuritis or brainstem syndromes, the risk of progression to the development of a full-blown clinical picture of multiple sclerosis after isolated spinal cord damage increases sharply in the presence of lesions in the white matter of the brain.

In cases where transverse myelitis is incomplete and therefore does not cause paraplegia, the probability of developing multiple sclerosis is higher than with complete transverse spinal cord injury. The presence of oligoclonal antibodies in the cerebrospinal fluid will differentiate the onset of multiple sclerosis from postinfectious myelitis. Viral myelitis is accompanied by a higher cytosis and protein level in the cerebrospinal fluid than demyelinating disease. In cases where multiple sclerosis selectively involves the spinal cord, the disease is much more often progressive rather than remitting. Diagnosis of multiple sclerosis can be difficult in cases where MRI of the brain does not reveal changes or reveals nonspecific changes in the white matter, reminiscent in nature of those often observed in elderly individuals.

Brainstem and cerebellum

Compared with foci of other localization, foci 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 number. Damage to this localization causes the classic Charcot triad: nystagmus, intention tremor, scanned speech. According to the pathomorphological study 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 midbrain, in 13% of cases - in the cerebellum, in 12% of cases - in the medulla oblongata, in 7% of cases - in the pons. For comparison, changes were absent in the optic nerves, cerebral hemispheres and spinal cord in 1, 3 and 1% of cases, respectively. Although damage to the brainstem manifests itself with the same symptoms as damage to other parts of the brain (for example, hemiparesis, paraparesis, or sensory disturbances), more characteristic symptoms of multiple sclerosis are possible, associated with the impairment of specific functions of the brainstem - including disorders of conjugate eye movements, articulation, swallowing, and breathing. Lesions in the subcortical parts of the cerebellum and cerebellar tracts can cause ataxia of the limbs and trunk, nystagmus, dizziness, and scanned speech. Some patients with preserved muscle strength are deeply disabled due to severe ataxia of the trunk and limbs.

Oculomotor disorders

Although there are no pathognomonic oculomotor disturbances characteristic of multiple sclerosis, some of them are often observed in this disease. The most characteristic sign is a disturbance of the coordination of eye movements in lateral abduction due to internuclear ophthalmoplegia. This syndrome can be unilateral or bilateral, complete or incomplete. It occurs due to damage to the medial longitudinal fasciculus (MLF), a tract connecting the nucleus of the third cranial nerve (controlling adduction of the ipsilateral eye) with the nucleus of the sixth cranial nerve on the opposite side (controlling abduction of the ipsilateral eye). When looking at the side contralateral to the lesion, the patient cannot adduct the eye on the side of the lesion, or slowly brings it to the middle position, while the contralateral eye is completely abducted, but at the same time, due to hypermetria, a coarse horizontal monocular nystagmus may occur in it. Isolated oculomotor disorders are rare and are most often associated with damage to the third or sixth cranial nerves.

Large hemispheres

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

Other symptoms of multiple sclerosis

Trigeminal neuralgia may occur at the onset of the disease or during its course. In large clinical series, it is noted in 2% of patients. In some cases, mild paresis of the facial muscles is noted, resembling facial nerve neuropathy. A rare symptom that is possible with multiple sclerosis and some other diseases is facial myokymia. It is characterized by wave-like fasciculatory twitching of the facial muscles. Involvement of the respiratory centers of the trunk, leading to respiratory failure, usually occurs at a late stage of the disease, but is also possible in the acute phase of exacerbation.

Course and natural development of multiple sclerosis

Several different variants of the disease course have been identified, according to which the disease is classified into separate forms. The 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 hand, by a steady non-remitting progression of neurological disorders. These two forms are designated respectively as remitting (relapsing-remitting) and primarily progressive. The latter should be distinguished from the secondary progressive form, which develops in patients with a remitting course, as well as from the progressive-relapsing form, which is characterized from the very beginning by steady progression with infrequent exacerbations. The term "benign multiple sclerosis" is excluded from the new classification.

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

Clinical and pathological 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 symmetrical zones of demyelination in the semiovale center (the area of white matter located above the lateral ventricles), accompanied by smaller isolated foci or without them. Such cases are more often observed in children. Clinically, the disease is manifested by dementia and other mental disorders, the presence of exacerbations and remissions, increased intracranial pressure, imitating the clinical picture of a brain tumor (pseudotumor course). Histologically, clearly demarcated zones of demyelination with fibrillary gliosis, giant multinucleated or edematous astrocytes, perivascular infiltration and axonal damage are detected.

Marburg disease is an acute fulminant form of multiple sclerosis characterized by a massive hemispheric lesion, brainstem involvement, pleocytosis, and oligoclonal antibodies in the cerebrospinal fluid. Edema is evident early on, and widespread myelin destruction and a sharp decrease in the number of axons are also noted.

Concentric sclerosis of Balo is another variant of the fulminant monophasic course of multiple sclerosis, in which a lesion is formed consisting of concentrically located layers of demyelinated and myelinated tissue.

Two other variants of demyelinating disease, acute disseminated encephalomyelitis (ADEM) and neuromyelitis optica (Devic's disease), are more common and are discussed in more detail below.

Experimental allergic encephalomyelitis

Although other mammals do not have a disease similar to human multiple sclerosis, a demyelinating disease, experimental allergic encephalitis (EAE), can be artificially induced in them. The creation of an experimental model is important not only for understanding the pathogenesis of the immune process in multiple sclerosis, but also for searching for and evaluating the effectiveness of potential drugs. Pathomorphological changes in EAE are similar to those in MS and are characterized by perivenous inflammatory infiltration and variable demyelination. EAE is induced by immunization with preparations containing myelin antigens, including untreated brain and spinal cord homogenate, myelin proteins or their fragments with or without the addition of adjuvant and pertussis toxin. The disease can also be passively transferred between syngeneic mouse lines using T lymphocytes sensitized to myelin antigens. In this case, additional administration of antibodies to myelin is required to develop more pronounced demyelination. Typically, EAE is a monophasic disease with complete or almost complete recovery. However, recurrent EAE can be induced in guinea pigs and mormosets. EAE has also been studied in mice with a transgenic T-cell receptor to a specific amino acid sequence of the myelin basic protein. Although EAE is not an absolute analogue of multiple sclerosis and is imperfect as a model, the data obtained in its study have allowed us to better understand the biology of T-cell receptors and MHC, autoantigens and autoantibodies presumably involved in multiple sclerosis, regulation of the immune response, and the genetics of CNS demyelination.

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