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Diagnosis of Multiple Sclerosis

Diagnosis of MS is dependent upon the recognition of symptoms and neurological findings typically accompanying exacerbations of MS and affecting different parts of the nervous system over time [7-9]. The importance of an accurate history and physical examination cannot be overemphasized. The senior author’s own observation is that a relative’s recognition of early manifestations of MS is likely to lead to the diagnosis of MS in a family member, rather than the contrary as is commonly believed.

Diagnostic Criteria The recognition of MS was easy for experienced neurologists in the past. However, long delays in diagnosis were common and many patients were incorrectly diagnosed. The need for standardized criteria for patients entering treatment studies led to the formation of an NIH committee headed by Dr. George Schumacher. Diagnostic criteria have evolved from the 1965 Schumacher criteria [7], that were established primarily for the selection of research subjects for MS studies, to the 1983 Poser criteria [8] which for the first time included laboratory support (magnetic resonance imaging [MRI], evoked response testing, as well as spinal fluid examination). The 2001, 2006, and now 2010 McDonald criteria are based on the original criteria but include validated specific MRI features [9, 10]. These new criteria (Table 2.1) allow the identification of “clinically isolated syndromes” (optic neuritis and brain stem or acute myelitis) with very high (80%)

Table 2.1 2010 RRMS McDonald diagnostic criteria

Clinical attacks

Objective

lesions

Additional requirement to make diagnosis

>2

>2

Clinical evidence is enough

>2

1

Disseminated in space by MRI or + CSF and > 2MRI lesions consistent with MS or additional clinical attack in different site

1

>2

Disseminated in time by MRI or 2nd clinical attack

1

Mono-symptomatic

1

Disseminated in space by MRI or await a 2nd attack implicating a different CNS site and disseminated in time by MRI or 2nd attack

0 Progressive from start

  • 1 in brain
  • 2 in spinal cord

1 year of disease progression plus two of three of the following:

Disseminated in space by MRI evidence of 1 or more T2 brain lesions or > 2 cord lesions + CSF

probability of MS. Imaging provides the additional evidence required to establish the presence of dissemination of lesions both in time and space. Early diagnosis of MS with earlier introduction of treatment portends a better outcome in the shortterm and prolonged survival, at least for interferon-beta-1a [18, 19]. Consensus definitions of the clinical subtypes of MS were released by the US National Multiple Sclerosis Society Advisory Committee on Clinical Trials in Multiple Sclerosis in 1996 and revised in 2013 [20, 21].

Relapsing MS is characterized by clearly defined relapses with either full recovery or residual deficit, representing about 85% of patients at the outset. Progressive MS is characterized clinically by the gradual accrual of disability independent of relapses and can occur with disease onset (primary progressive) or can be preceded by a relapsing disease course (secondary progressive). In most cases, SPMS is diagnosed retrospectively after several years of gradual worsening after a period of clinical relapses. Currently, there are no clear criteria to mark the transition from RRMS to SPMS. The basis of separating the primary versus secondary progressive forms of MS was derived from a meta-analysis of the COP1 trial in progressive MS as an antecedent of the PROMISE trial [22]. The criteria formulated by Thompson et al. grouped suspected PPMS patients into “definite,” “probable,” and “possible” [21, 23-25]. Multiple sclerosis may be seen as a spectrum with an intense focal inflammatory component in RRMS and more neurodegenerative features with concomitant chronic inflammation and axon loss in progressive forms of MS [26]. Currently, clinical diagnostic criteria exist for both forms. A recent publication provides clear differences in the neuropathological findings separating RRMS, SPMS, and PPMS [27].

Another issue impacting on early diagnosis of MS is the quality of spinal fluid examinations. Importantly, the FDA laboratory standard for oligoclonal banding testing - isoelectric focusing on agarose gel followed by immunoblotting or immu- nofixation for IgG with paired spinal fluid and serum - avoids technically inadequate studies. The quality of antihuman antibody used in the testing has a major

2 Multiple Sclerosis: Clinical Features, Immunopathogenesis, and Treatment

Table 2.2 Differential diagnosis of MS

Acquired diseases

1. ADEM vs. CIS (MS)

2. Infectious disease

Syphilis

Retroviral infection

HIV

HTLV-I/II

3. CNS vasculitis

Granulomatous vasculitis - sarcoid, HIV, etc.

Primary CNS vasculitis

4. Autoimmune diseases - SLE

5. Tumors of the CNS

6. Trauma to CNS

7. Psychiatric illness

Hereditary diseases

1. Leukodystrophies

2. Spinocerebellar diseases

3. Hereditary spastic paraparesis

31

impact on the results. Evoked response testing is relied upon less, but can be helpful, especially visual evoked responses [9].

Diagnostic criteria for PPMS were also updated in 2010 and include (1) a minimum of 1 year of disease progression plus two of three of the following: dissemination in space in the brain or spinal cord or positive CSF, defined as the presence of OCBs, and/or elevated IgG index [10].

Differential Diagnosis There is a large differential diagnosis, outlined in Table 2.2. In the past meningovascular syphilis was the “great imitator” and topped the list. Today a variety of granulomatous diseases and other diseases are considered in the differential diagnosis, but sarcoidosis and systemic lupus erythematosus (SLE) are the major differential diagnosis considered. The retroviruses human immunodeficiency virus (HIV) and HTLV-I/II can rarely present as a granulomatous disease or mimic MS.

Central nervous system lymphoma may require brain biopsy to establish a diagnosis, but a positive test for HIV ordinarily rules out the diagnosis of MS. Biopsy is ordinarily required to make a diagnosis of primary central nervous system vasculitis (CNS vasculitis). The disorder “CNS vasculitis” is rare and like progressive multifocal leukoencephalopathy (PML) is associated with MS-like attacks resulting in increasing neurological deficit progressing in a stepwise fashion. Unlike PML there may be at least temporary partial resolution of neurological deficit with high-dose steroids or pulse cyclophosphamide therapy in patients with CNS vasculitis. Despite its rarity, establishing a diagnosis of CNS vasculitis is important because it is regularly fatal if not treated aggressively with chronic systemic immunosuppression.

Multiple sclerosis may occasionally present with prominent sensory complaints and marked, symmetrical weakness of the lower extremities and be mistakenly diagnosed as an acute demyelinating polyneuropathy (Guillain-Barre syndrome). Albumino-cytological dissociation, however, is rarely found in MS.

Symptoms of MS must last 24 hours at a minimum. To be considered a new relapse, a new symptom or a relapse of a prior symptom must occur at least 1 month after the previous exacerbation. The symptoms and findings should be of a type recognized as associated with multiple sclerosis. The diagnosis of multiple sclerosis is accepted only if it is established by a neurologist [7-10].

PPMS is a more difficult diagnosis to establish. This form of MS presents most commonly in midlife (about 40±5 years on average), and distinguishing this form of MS from other potentially treatable illness may be extremely difficult [11, 28]. Manifestations of neurological disease should be observed for at least 6 months before acceptance as evidence supporting a diagnosis of PPMS. Multiple other disorders must be ruled out of the differential diagnosis. Syphilis, vitamin B-12 deficiency (subacute combined myelopathy), and retrovirus-associated myelopathy (HIV-associated myelopathy and human T-cell leukemia-associated myelopathy (TSP/HAM)) [2, 11, 29] can be easily ruled out by laboratory testing. Antibody testing by Western blot for HTLV-I/II, if indeterminate, may not be sufficient [30]. Genetic (“PCR,” polymerase chain reaction) testing in a reliable laboratory test is the most sensitive and specific test for this purpose. In our experience this test is positive in up to 20% of patients who are Western blot indeterminate but who are infected with either HTLV-I/II virus [31]. Radiation myelopathy continues to be an important differential diagnosis in patients with a history of radiation therapy to the head and neck.

Neuroimaging should be carried out to eliminate spinal cord compression, congenital abnormalities, and intraparenchymal tumors from consideration. At times, imaging will not reveal the presence of one or more intraparenchymal spinal cord lesions that are evidenced by clinical examination, however. The finding of hypothyroidism is common in MS, and myelopathy should not be attributed to thyroid disease alone. Adrenocortical leukodystrophy and hereditary spastic paraplegia are easily distinguished from primary progressive multiple sclerosis by the patient’s infantile age of presentation and presence of a family history [2, 32].

It cannot be overemphasized that repeated clinical visits and examinations over time, as well as repeated imaging, may clarify the nature of the illness in difficult cases. This is particularly important when cognitive and emotional issues dominate and obscure the presentation [3, 11]. The McDonald criteria, however, greatly assist early diagnosis and justify the institution of treatment. It should be noted that in using the criteria for a clinically isolated syndrome (CIS), the majority will be correctly diagnosed as having MS, but about 20% of patients may never meet criteria for clinically definite MS. On the other hand, we regularly document relapses within weeks to months in many patients with CIS who initially had no evidence of brain lesions in their MRI scans at clinical presentation. Multiple sclerosis remains a clinical diagnosis [9, 10].

 
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