Multiple sclerosis: diagnosis

Diagnosis of multiple sclerosis

Of particular interest is the hypothesis, based on epidemiological data, according to which clinically manifested multiple sclerosis is only the final stage of the process, which begins long before the onset of the adult period of life. In accordance with this hypothesis, an induction phase is identified that occurs up to 15 years of streets with a genetic predisposition due to the effect of an unknown immunogenic external factor. This is followed by an asymptomatic latent period, during which signs of demyelination may be detected, but there is no clinically clear symptomatology. Clinical debut ("first attack") of the disease can develop sharply or subacute. The interval from the moment of the disease to its clinical manifestation can take from 1 to 20 years. Sometimes an MRI performed for other purposes reveals a typical picture of demyelination in a patient who does not have any clinical manifestations of a demyelinating disease. The term "latent multiple sclerosis" is also used to refer to cases when signs of a demyelinating process are detected, which, however, does not appear clinically.

With careful collection of anamnesis in patients who are applying for the first developed episode of the disease, one or more episodes of transient symptoms can be identified in the past in the form of mild visual impairment, numbness or tingling, unsteadiness during walking, which at the time of their occurrence could not be given much importance. Other patients have a history of previous episodes of extreme fatigue or impaired concentration.

An acute episode, about which a patient consults a doctor, may not be associated with any provoking factor. However, many patients report a temporary connection with infection, stress, trauma or pregnancy. In some cases, the symptoms can peak right away as soon as the patient's attention has been noticed, for example, on awakening, but sometimes they build up within a certain time - from a few minutes to several days. Patients are more likely to report gradual progression of symptoms, while "stroke-like" onset is rare.

The appearance of symptoms of multiple sclerosis as a result of the inflammatory demyelinating process is referred to as "attack," "exacerbation," or "relapse." The current, characterized by the repeated development of attacks, is called relapsing or remitting. The degree of recovery (completeness of remission) after an attack varies considerably. At an early stage of the disease, recovery begins shortly after the symptoms peak, and the attack ends with a complete or almost complete recovery within 6-8 weeks. In those cases when neurologic symptoms develop gradually, a chronic progressive course is established, in which restoration of functions is unlikely, but more or less prolonged stabilization is possible. The first attack of multiple sclerosis must be differentiated with acute disseminated encephalomyelitis (OREM), in which episodes of demyelination are not repeated.

In the study of 1096 patients, the relationship between the age of the patients and the type of course of the disease was noted. The results of this study show that people older than 40 years are more often marked by a progressive course with a gradual increase in paresis.

[1], [2], [3], [4], [5], [6], [7], [8], [9], [10], [11]

Criteria for diagnosis of multiple sclerosis

Several classification schemes for multiple sclerosis are suggested, but they all give the same definition of clinically reliable multiple sclerosis, according to which, according to the history or examination, there must be at least two exacerbations with white matter lesions of the central nervous system, separated by time and location. Consequently, the diagnosis of multiple sclerosis requires the establishment of temporal and spatial scattering of foci. In this case, episodes should be separated from each other by intervals of not less than 1 month, during which there is no steady deterioration of the condition, and the symptoms can not be explained by the presence of an anatomical lesion of the neural axis (as, for example, when eye symptoms are combined with unilateral contralateral movement disorders in the extremities or contralateral decrease in sensitivity on the face and trunk and can be caused by isolated focal lesion of the trunk). However, this definition does not allow us to consider recurrent neuritis of the optic nerve in the same eye as a separate episode of multiple sclerosis.

Criteria for diagnosing "clinically reliable" multiple sclerosis Schumacher (according to AE Mi11er, 1990)

• Age of the beginning from 10 to 50 years
• When examined, objective neurological symptoms are revealed
• Neurological symptoms indicate a white matter lesion of the central nervous system
• Scattering in time:
  • two or more exacerbations (angry for at least 24 hours) with an interval of at least 1 month (exacerbation is defined as the appearance of new symptoms or the growth of pre-existing ones) or
  • the increase in symptoms for at least 6 months
• Scattering in space: two or more isolated anatomical regions are affected
• There is no alternative clinical explanation

To take into account the progressive forms of multiple sclerosis, the criteria establish the need for neurological dysfunction to increase for at least 6 months - in the absence of other causes that could explain the symptoms. Since there is no one specific test that can correctly diagnose multiple sclerosis, the diagnosis is established with a combination of clinical manifestations, neuroimaging and laboratory data. The terms "probable" and "possible" multiple sclerosis are included in the classification to refer to those cases where there is only one attack or one lesion or when attacks can not be confirmed by objective survey data.

Since the publication of these classifications, several diagnostic tests have increased the sensitivity and specificity of the diagnosis of multiple sclerosis. The diagnostic significance of MRI and evoked potentials has already been discussed. The most characteristic changes in cerebrospinal fluid include the presence of intrathecally produced immunoglobulin. This is usually detected using an index, defined as the ratio of the level of IgG in cerebrospinal fluid and serum with the correction for the level of immunoglobulin. Qualitative indicator - the presence of oligoclonal antibodies in the gamma-globulin spectrum, detected by immunofixation or isoelectric focusing. The test results are considered positive when two or more types of oligoclonal antibodies that are absent in the serum are detected in the CSF. These and other tests are taken into account in the criteria for the diagnosis of multiple sclerosis, developed by Poser et a1 (1983). According to Poseur's criteria, when observing the spatial dispersion of the foci necessary for the diagnosis of multiple sclerosis, paraclinical data can be taken into account. Moreover, the term "laboratory-reinforced" reliable multiple sclerosis has been introduced, which is used in those cases when the criteria for "clinically significant" multiple sclerosis are not met, but in the cerebrospinal fluid an increased level of IgG or oligoclonal antibodies is detected.

Research methods that can be useful in diagnosing and selecting treatment in patients with multiple sclerosis

Method of research

• Refinement of MRI of the brain and / or spinal cord
• Images in modes T1, T2, proton density, FLAIR, with contrasting gadolinium

Investigation of CSF

• Cytosis, protein level, glucose, syphilis, neuroborreliosis, IgG index, oligoclonal antibodies

The evoked potentials

• Visual, auditory potentials of the trunk, somatosensory
• Neuropsychological study  

Investigation of urodynamics

Serological tests

• Study for antinuclear antibodies with extracted nuclear antigens (rho, 1a, mp), for antibodies to cardiolipin, antiborrelytic antibodies, angiotensin-converting enzyme level and vitamin B12

[12], [13], [14], [15], [16], [17], [18], [19], [20], [21]

Diagnostic significance of additional research methods

More than 90% of patients with clinically significant multiple sclerosis are diagnosed with pathological changes with MRI and more than two-thirds of patients - an increase in the level of gamma globulin in the cerebrospinal fluid or the presence of oligoclonal antibodies. Although MRI data are not required to confirm a diagnosis with clinically significant multiple sclerosis, neuroimaging is a more sensitive method than investigation of cerebrospinal fluid or evoked potentials when examining patients with suspected multiple sclerosis. MRI criteria for the diagnosis of multiple sclerosis include:

• presence of three or four zones of the changed intensity of a signal on images in a mode of proton density or T2-weighted images;
• foci in the periventricular region;
• foci of more than 5 mm in size;
• infratentorial foci.

In a study evaluating MRI data in 1500 patients with clinical manifestations of multiple sclerosis, the specificity of these criteria was 96%, and sensitivity was 81%. Other changes that are characteristic of multiple sclerosis in MRI include elliptical foci adjacent to the lateral ventricles and oriented perpendicular to the anterior-posterior axis of the brain, which correspond to Davson's fingers, as well as foci in the corpus callosum, adjacent to its lower contour.

Rates of cerebrospinal fluid in multiple sclerosis

Total protein content

• Normal in 60% of patients with multiple sclerosis
• > 110 mg / dL - very rarely

Cytosis

• Normal in 66%
• > 5 lymphocytes in 1 ml in 33%
• Variable correlates with exacerbation

Subtypes of lymphocytes

• > 80% of CD3 +
• The ratio of CD4 + / CD8 + 2: 1
• 16-18% of B lymphocytes
• Plasma cells are rarely detected

The content of glucose

• Normal

Immunoglobulin (IgG)

• Content increased
• The IgG index (> 0.7)
• The speed of synthesis of IgG (> 3.3 mg / day)
• Oligoclonal IgG antibodies
• Increased kappa / lambda-light chain ratio
• Free kappa-light chains

Tissue markers

• Increased the content of MBM-like material in the active phase

Criteria for diagnosis of multiple sclerosis

•   Clinically Reliable Multiple Sclerosis
  • Two exacerbations and clinical manifestations of two separate lesions
  • Two exacerbations: clinical manifestations of one focus and paraclinic signs (CG, MRI, VP) of another focus
  • Laboratory confirmed reliable multiple sclerosis
• Laboratory confirmation is the detection of oligoclonal antibodies (OA) or increased IgG synthesis in the cerebrospinal fluid (serum antibody structure and IgG level should be normal). Other causes of cerebro-spinal fluid changes should be excluded: syphilis, subacute sclerosing panencephalitis, sarcoidosis, diffuse connective tissue diseases and similar disorders
  • Two exacerbations, clinical or paraclinic signs of one focus and detection in CSF or elevated levels of IgG
  • One exacerbation, clinical signs of two separate foci and detection in CSF or elevated levels of IgG
  • One exacerbation, clinical signs of one focus, paraclinic signs of another focus and detection in CSF CSF or elevated levels of IgG
• Clinically probable multiple sclerosis
  • Two exacerbations and clinical signs of a single focus
  • One exacerbation and clinical signs of two separate foci
  • One exacerbation, clinical signs of a single focus and paraclinic signs of another focus
  • Laboratory-confirmed probable multiple sclerosis
  • Two exacerbations and detection in the cerebrospinal fluid OA or elevated levels of IgG

MRI data are also of prognostic value in people at risk of developing multiple sclerosis, who clinically had one attack with symptoms typical of demyelinating disease. In this prognostic value as the very fact of the presence of foci in the white matter of the brain, and their number.

Although neuroimaging data from the brain and spinal cord is an important addition to the clinical diagnosis of multiple sclerosis, the diagnosis can not rely solely on them. Their misinterpretation can lead to erroneous diagnosis, since a number of other conditions have similar MRI manifestations. Moreover, individuals over the age of 40 are more likely to detect hyperintensive zones on T2-weighted images.

[22], [23], [24], [25], [26]

Some aspects of differential diagnosis of multiple sclerosis

Important clinical and pathomorphological variants of demyelinating CNS diseases include OPEC and Devic's optic duets, which differ from multiple sclerosis by prognosis and treatment.

Acute disseminated encephalomyelitis. Acute disseminated encephalomyelitis (OREM) is clinically and pathomorphologically indistinguishable from the debut of multiple sclerosis. Differentiation is possible in the event that a clinically isolated episode of demyelination occurs after an acute infectious disease or vaccination. But OREM can arise in the absence of an obvious provocative factor. The disease most often provokes a measles infection, less often it occurs after chickenpox, rubella, mumps, scarlet fever or whooping cough. Most often OREM occurs in childhood and young age. Acute optic neuritis arising in the OREM is most often bilateral. In CSF, more pronounced inflammatory changes usually occur, including higher cytosis, sometimes with a predominance of neutrophils, and a higher protein content. Oligoclonal antibodies in the cerebrospinal fluid with OREM are usually not detected or they appear for a short time in the acute phase.

Although OREM is usually a monophasic disease that reacts to glucocorticoids or adrenocorticotropic hormone preparations, cases of multiphase or recurrent flow are noted. Multiphase OREM is characterized by one or several clinically different attacks that occur after the initial acute episode. The recurrent variant is characterized by the presence of subsequent episodes, which are clinically identical to the original one.

With OREM and its variants, MRI reveals small multi-point hypertensive changes in T2-mode, but large lobar volume foci involving gray matter are also possible. At the same time, as a rule, with OREM, there are no focal lesions typical for multiple sclerosis in periventricular white matter or callosity.

Optimichelite. Optiocoelitis, also known as Devik's disease, is a variant of multiple sclerosis with peculiar clinical and pathomorphological changes. The clinical picture includes manifestations of acute or subacute neuritis of the optic nerve and severe transverse myelitis. The interval between loss of sight and spinal cord lesion is usually not more than 2 years, but may be more prolonged. Pathomorphological changes are limited by demyelination in the optic nerves and severe necrosis, which can involve most of the spinal cord. In the brain (with the exception of optic nerves and chiasma), there are no changes. In the study of cerebrospinal fluid, normal pressure, variable pleocytosis to several hundred leukocytes with a predominance of neutrophils and an elevated protein level is revealed. Oligoclonal antibodies and signs of increased synthesis of IgG in CSF are usually absent. The disease can be monophasic or multiphase. There are reports that opticomelitis may occur within the OREM, as well as in systemic lupus erythematosus, mixed connective tissue disease, tuberculosis. Devik's disease is more often observed in Japan and, apparently, has some kind of immunogenetic characteristics. The prognosis of recovery of neurological functions is poor. Attempts were made to treat with various agents (alkylation drugs, including cyclophosphamide, corticotropin, glucocorticoids, plasmapheresis) with varying success.

Although a number of systemic inflammatory diseases can cause white matter damage, neurological symptoms in these cases are rarely their only or debut manifestation. Such conditions are usually recognized by the presence of somatic symptoms. The defeat of the central nervous system in systemic lupus erythematosus can be manifested by heart attacks or hemorrhages due to thrombosis or vasculitis. Psychotic disorders, epileptic seizures, confusion or somnolence can arise primarily as a complication of infections or insufficiency of other organs. Myelitis, sometimes with concomitant defeat of the optic nerves (which resembles Devik's syndrome) can also be associated with systemic lupus erythematosus, as well as the presence of oligoclonal antibodies in the cerebrospinal fluid. Oligoclonal antibodies in CSF are also detected in sarcoidosis and Behcet's disease. On the other hand, antinuclear antibodies, characteristic of systemic lupus erythematosus, are found in about a third of patients with multiple sclerosis.

Neuroborreliosis. Neuroborreliosis is a lesion of the nervous system in the Lime disease, caused by Borre1ia burgdorferi. Neuroborreliosis can be manifested by meningitis, encephalomyelitis, peripheral neuropathy. Encephalomyelitis is a rare complication of borreliosis that occurs in less than 0.1% of patients. In endemic zones of Lyme disease, patients with typical clinical and laboratory manifestations of multiple sclerosis, but who do not have objective signs confirming borreliosis lesion of the central nervous system, are sometimes mistaken for long courses of antibiotics. Borreliosis encephalomyelitis is usually manifested by impaired memory and other cognitive functions, although there have been reports of multifocal lesions, mainly involving white matter of the central nervous system. In the cerebrospinal fluid, oligoclonal antibodies can be detected. Objective signs of neuroborreliosis include intrathecal production of specific antibodies, positive results of cereus sowing, and detection of B. Burgdorferi DNA by polymerase chain reaction.

Tropical spastic paraparesis (TSP) and HIV-associated myelopathy (VAM) are terms used to denote chronic demyelinating inflammatory lesions of the spinal cord caused by retrovirus -human T-cell lymphotrophic virus (HTLV-I). The virus is endemic for some areas of Japan, the West Indies and South America. For a number of signs, TSP and VAM resemble multiple sclerosis, including the presence of oligoclonal antibodies and elevated levels of IgG in liquor, changes in white matter with MRI of the brain, and reaction (usually partial) to immunotherapy. However, TSP and VAM can be differentiated from multiple sclerosis by the presence of antibodies to HTLV-I either by detecting HTLV-I DNA by polymerase chain reaction, as well as peripheral nerve damage, the presence of oligoclonal antibodies in the serum, the presence of multinuclear lymphocytes in the CSF and blood, positive serological tests for syphilis, dry syndrome or pulmonary lymphocytic alveolitis.