Multiple Sclerosis - Diagnosis

Of particular interest is the hypothesis based on epidemiological data, according to which clinically manifested multiple sclerosis is only the final stage of a process that begins long before the onset of adulthood. In accordance with this hypothesis, an induction phase is distinguished, which occurs before the age of 15 in people with a genetic predisposition due to the influence of an unknown immunogenic external factor. This is followed by an asymptomatic latent period, during which signs of demyelination may be detected, but clinically obvious symptoms are absent. The clinical debut ("first attack") of the disease may develop acutely or subacutely. The interval from the onset of the disease to its clinical manifestation may last from 1 to 20 years. Sometimes MRI, performed for other purposes, reveals a typical picture of demyelination in a patient who does not have any clinical manifestations of demyelinating disease. The term "latent multiple sclerosis" is also used to describe cases where signs of a demyelinating process are detected, but which, however, is not clinically manifested.

A careful history of patients presenting with a first full-blown episode of the disease may reveal one or more episodes of transient symptoms in the past, such as mild visual disturbances, numbness or tingling, or unsteadiness in walking, which may not have been considered significant at the time of their occurrence. Other patients may have a history of previous episodes of extreme fatigue or difficulty concentrating.

The acute episode for which the patient seeks medical attention may not be associated with any precipitating factor. However, many patients report a temporary association with infection, stress, trauma, or pregnancy. In some cases, symptoms may peak immediately upon becoming apparent to the patient, such as upon awakening, but sometimes they build up over a period of time, from minutes to days. Patients often report a gradual progression of symptoms, while a “stroke-like” onset is rare.

The onset of symptoms of multiple sclerosis as a result of the inflammatory demyelinating process is called an "attack", "exacerbation" or "relapse". The course characterized by repeated attacks is called relapsing or remitting. The degree of recovery (completeness of remission) after an attack varies considerably. In the early stages of the disease, recovery begins soon after symptoms reach their peak, with the attack ending in complete or almost complete recovery within 6-8 weeks. In cases where neurological symptoms develop gradually, a chronic progressive course is noted, in which functional recovery is unlikely, but more or less long-term stabilization is possible. The first attack of multiple sclerosis must be differentiated from acute disseminated encephalomyelitis (ADEM), in which episodes of demyelination do not recur.

In a study of 1096 patients, a connection was noted between the age of the patients and the type of disease progression. The results of this study show that people over 40 years of age more often have a progressive course with a gradual increase in paresis.

[ 1 ], [ 2 ], [ 3 ], [ 4 ], [ 5 ], [ 6 ]

Diagnostic criteria for multiple sclerosis

Several classification schemes for multiple sclerosis have been proposed, but all provide the same definition of clinically significant multiple sclerosis, according to which, according to the anamnesis or examination, there must be at least two exacerbations with lesions of the white matter of the central nervous system, separated by time and location. Therefore, the diagnosis of multiple sclerosis requires establishing the temporal and spatial dispersion of foci. Moreover, the episodes must be separated from each other by intervals of at least 1 month, during which there is no steady deterioration in the condition, and the symptoms cannot be explained by the presence of a single anatomical lesion of the nerve axis (as, for example, in the case when ocular symptoms are combined with unilateral contralateral motor impairment in the limbs or contralateral decreased sensitivity in the face and trunk and can be caused by an isolated focal lesion of the brainstem). However, such a definition does not allow us to consider recurrent optic neuritis in the same eye as a separate episode of multiple sclerosis.

Diagnostic criteria for "clinically reliable" multiple sclerosis according to Schumacher (according to A. E. Mi11er, 1990)

• Age of onset from 10 to 50 years
• During examination, objective neurological symptoms are revealed.
• Neurological symptoms indicate white matter damage to the central nervous system
• Dispersion in time:
  • two or more exacerbations (lasting at least 24 hours) with an interval of at least 1 month (an exacerbation is defined as the appearance of new symptoms or an increase in previously existing ones) or
  • increasing symptoms over a period of at least 6 months
• Spatial disorganization: two or more anatomical areas isolated from each other are affected
• There is no alternative clinical explanation.

To account for progressive forms of multiple sclerosis, the criteria require progressive neurological dysfunction over a period of at least 6 months, in the absence of other causes that could explain the symptoms. Since there is no single specific test that can accurately diagnose multiple sclerosis, the diagnosis is made by a combination of clinical manifestations, neuroimaging, and laboratory data. The terms "probable" and "possible" multiple sclerosis have been introduced into the classification to denote cases in which there is only one attack or one lesion, or when attacks cannot be confirmed by objective examination data.

Since the publication of these classifications, several diagnostic tests have increased the sensitivity and specificity of the diagnosis of multiple sclerosis. The diagnostic value of MRI and evoked potentials has already been discussed. The most characteristic changes in the CSF include the presence of intrathecally produced immunoglobulin. This is usually detected using an index defined as the ratio of the IgG level in the CSF to that in serum, corrected for the immunoglobulin level. A qualitative indicator is 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 are detected in the CSF that are absent from the serum. These and other tests are included in the diagnostic criteria for multiple sclerosis developed by Poser et al. (1983). According to Poser's criteria, paraclinical data can be taken into account when establishing the spatial dispersion of lesions necessary for making a diagnosis of multiple sclerosis. Moreover, the term “laboratory-confirmed” reliable multiple sclerosis has been introduced, which is used in cases where the criteria for “clinically reliable” multiple sclerosis are not met, but elevated levels of IgG or oligoclonal antibodies are detected in the cerebrospinal fluid.

Research methods that may be useful in diagnosis and treatment selection in patients with multiple sclerosis

• Research method

1. Clarifications of MRI of the brain and/or spinal cord
2. T1, T2, proton density, FLAIR, gadolinium enhanced images

• Cerebrospinal fluid examination

1. Cytosis, protein level, glucose, syphilis test, neuroborreliosis, IgG index, oligoclonal antibodies

• Evoked potentials

1. Visual, auditory potentials of the brainstem, somatosensory
2. Neuropsychological research

• Urodynamics study
• Serological studies

1. Test for antinuclear antibodies with extracted nuclear antigens (rho, 1a, mр), antibodies to cardiolipin, antiborreliosis antibodies, angiotensin-converting enzyme and vitamin B12 levels

[ 7 ], [ 8 ], [ 9 ]

Diagnostic significance of additional research methods

More than 90% of patients with clinically significant multiple sclerosis have abnormal MRI findings, and more than two-thirds of patients have elevated CSF gamma globulin levels or oligoclonal antibodies. Although MRI findings are not required to confirm the diagnosis of clinically significant multiple sclerosis, neuroimaging is a more sensitive method than CSF or evoked potential studies in examining patients suspected of having multiple sclerosis. MRI criteria for diagnosing multiple sclerosis include:

• the presence of three or four zones of altered signal intensity on proton density or T2-weighted images;
• foci in the periventricular region;
• lesions larger than 5 mm;
• 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 the sensitivity was 81%. Other MRI changes characteristic of multiple sclerosis include elliptical lesions adjacent to the lateral ventricles and oriented perpendicular to the anterior-posterior axis of the brain, which correspond to Dawson's fingers, and lesions in the corpus callosum adjacent to its inferior contour.

CSF indicators in multiple sclerosis

Total protein content

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

Cytosis

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

Lymphocyte subtypes

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

Glucose content

• Normal

Immunoglobulin (IgG)

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

Fabric markers

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

Diagnostic criteria for multiple sclerosis

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

MRI data also have prognostic value in individuals at risk of developing multiple sclerosis who have clinically experienced one attack with symptoms characteristic of a demyelinating disease. In this case, both the presence of lesions in the white matter of the brain and their number have prognostic value.

Although brain and spinal neuroimaging data are an important adjunct to the clinical diagnosis of multiple sclerosis, diagnosis cannot rely solely on them. Their misinterpretation may lead to misdiagnosis, since a number of other conditions have similar MRI appearances. Moreover, in individuals over 40 years of age, hyperintensities on T2-weighted images are more likely to be detected.

[ 10 ], [ 11 ], [ 12 ]

Some aspects of differential diagnosis of multiple sclerosis

Important clinical and pathomorphological variants of demyelinating diseases of the central nervous system include ADEM and Devic's neuromyelitis optica, which differ from multiple sclerosis in prognosis and treatment.

Acute disseminated encephalomyelitis. Acute disseminated encephalomyelitis (ADEM) is clinically and pathologically indistinguishable from the onset of multiple sclerosis. Differentiation is possible when a clinically isolated episode of demyelination occurs after an acute infectious disease or vaccination. However, ADEM may also occur in the absence of an obvious provoking factor. The disease is most often provoked by measles infection, less often it occurs following chickenpox, rubella, mumps, scarlet fever or whooping cough. ADEM most often occurs in childhood and young adulthood. Acute optic neuritis, which occurs within the framework of ADEM, is most often bilateral. More pronounced inflammatory changes are usually detected in the cerebrospinal fluid, including higher cytosis, sometimes with a predominance of neutrophils, and a higher protein content. Oligoclonal antibodies in the cerebrospinal fluid in ADEM are usually not detected or they appear for a short time in the acute phase.

Although ADEM is usually a monophasic disorder that responds to glucocorticoids or adrenocorticotropic hormone therapy, cases of multiphasic or relapsing ADEM have been reported. Multiphasic ADEM is characterized by one or more clinically distinct attacks that follow an initial acute episode. Relapsing ADEM is characterized by subsequent episodes that are clinically identical to the initial episode.

In ADEM and its variants, MRI reveals small multifocal hyperintense changes in T2 mode, but large lobar volumetric lesions involving gray matter are also possible. At the same time, in ADEM, as a rule, lesions in the periventricular white matter or corpus callosum characteristic of multiple sclerosis are absent.

Neuromyelitis optica. Neuromyelitis optica, also known as Devic's disease, is a variant of multiple sclerosis with unique clinical and pathological changes. The clinical picture includes manifestations of acute or subacute optic neuritis and severe transverse myelitis. The interval between visual loss and spinal cord involvement is usually no more than 2 years, but may be longer. Pathological changes are limited to demyelination in the optic nerves and severe necrosis, which may involve most of the spinal cord. There are no changes in the brain (except for the optic nerves and chiasm). Cerebrospinal fluid examination reveals normal pressure, variable pleocytosis of up to several hundred leukocytes with a predominance of neutrophils and an elevated protein level. Oligoclonal antibodies and signs of increased IgG synthesis in the cerebrospinal fluid are usually absent. The disease can be monophasic or multiphasic. There are reports that neuromyelitis optica may also occur in the context of ADEM, as well as in systemic lupus erythematosus, mixed connective tissue disease, and tuberculosis. Devic's disease is more commonly observed in Japan and appears to have unique immunogenetic characteristics. The prognosis for recovery of neurological functions is poor. Attempts have been made to treat with various agents (alkylating agents, including cyclophosphamide, corticotropin, glucocorticoids, plasmapheresis) - with varying success.

Although a number of systemic inflammatory diseases may involve white matter, neurologic symptoms are rarely the only or initial manifestation. Such conditions are usually recognized by the presence of somatic symptoms. CNS involvement in systemic lupus erythematosus may include infarctions or hemorrhages due to thrombosis or vasculitis. Psychotic disorders, seizures, confusion, or somnolence may occur primarily or as a complication of infections or failure of other organs. Myelitis, sometimes with concomitant optic nerve involvement (resembling Devic syndrome), may also be associated with systemic lupus erythematosus, as may the presence of oligoclonal antibodies in the cerebrospinal fluid. Oligoclonal antibodies in the cerebrospinal fluid are also found in sarcoidosis and Behcet's disease. On the other hand, antinuclear antibodies, characteristic of systemic lupus erythematosus, are found in about one third of patients with multiple sclerosis.

Neuroborreliosis. Neuroborreliosis is a nervous system disorder caused by Lyme disease, which is caused by Borrelia burgdorferi. Neuroborreliosis may present with meningitis, encephalomyelitis, and peripheral neuropathy. Encephalomyelitis is a rare complication of Lyme disease, occurring in less than 0.1% of patients. In areas where Lyme disease is endemic, patients with typical clinical and laboratory manifestations of multiple sclerosis but no objective evidence of CNS involvement by Borrelia are sometimes mistakenly treated with long courses of antibiotics. Borrelia encephalomyelitis usually presents with memory impairment and other cognitive functions, although cases of multifocal involvement, primarily involving the white matter of the CNS, have been reported. Oligoclonal antibodies may be detected in the cerebrospinal fluid. Objective signs of neuroborreliosis include intrathecal production of specific antibodies, positive CSF culture results, and detection of B. burgdorferi DNA using polymerase chain reaction.

Tropical spastic paraparesis (TSP) and HIV-associated myelopathy (HAM) are terms for a chronic demyelinating inflammatory disorder of the spinal cord caused by a retrovirus, the human T-cell lymphotrophic virus (HTLV-I). The virus is endemic in parts of Japan, the West Indies, and South America. TSP and HAM resemble multiple sclerosis in a number of ways, including the presence of oligoclonal antibodies and elevated IgG levels in the cerebrospinal fluid, white matter changes on brain MRI, and a response (usually partial) to immunotherapy. However, TSP and VAM can be differentiated from multiple sclerosis by the presence of antibodies to HTLV-I or by detection of HTLV-I DNA using polymerase chain reaction, as well as by peripheral nerve damage, the presence of oligoclonal antibodies in serum, the presence of multinucleated lymphocytes in the cerebrospinal fluid and blood, positive serologic tests for syphilis, dry syndrome, or pulmonary lymphocytic alveolitis.