Idiopathic inflammatory demyelinating diseases of the central nervous system

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Idiopathic inflammatory demyelinating diseases (IIDDs), sometimes known as borderline forms of multiple sclerosis,[1] is a collection of multiple sclerosis variants, sometimes considered different diseases,[2][3] but considered by others to form a spectrum differing only in terms of chronicity, severity, and clinical course.[4][5]

Multiple Sclerosis could be considered among the acquired demyelinating syndromes with a multiphasic instead of monophasic behaviour.[6]

Diseases included in this category[edit]

The list of these diseases depends of the author, but usually are included:

  • Standard multiple sclerosis, the most known and extended variant, normally consisting of two distinct clinical phases (Remitent-Recidivant, RRMS, and Secondary Progressive, SPMS)
  • Primary progressive MS, PPMS, very similar to the previous one but showing only a clinically progressive phase. There is an ongoing discussion if it represents the same entity than standard MS, though recent findings seem to point that it is pathologically a very different disease[7]
  • KIR4.1 multiple sclerosis. Hypothetical variant reported in 2012[8] and later reported again,[9] which could be considered a different disease (as Devic Disease did before), and can represent up to a 47% of the MS cases.
  • Optic-spinal MS, or Opticospinal, variant of multiple sclerosis which often include visual symptoms and have a more severe course than typical MS. Though multiple scars (scleroses) are present in CNS, and sometimes Poser criteria classifies it as clinically definite multiple sclerosis,[10] currently is considered outside the scope of Multiple Sclerosis and inside the scope of Devic's disease,[11] though is not sure if this applies to all cases.[12]

Some inflammatory conditions are associated with the presence of the scleroses.[24] Optic neuritis (monophasic and recurrent) and Transverse myelitis (monophasic and recurrent)

As MS is an active field for research, the list is not closed or definitive. For example, some diseases like Susac's syndrome (MS has an important vascular component[25]), leukoaraiosis, Myalgic encephalomyelitis (aka Chronic fatigue syndrome)[26] or autoimmune variants of peripheral neuropathies like Guillain-Barré syndrome or Progressive inflammatory neuropathy could be included assuming the autoimmune model. Also Leukodystrophy (which see) and its sub-conditions: Adrenoleukodystrophy and Adrenomyeloneuropathy could be in the list. Venous induced demyelination has also been proposed as a hypothetical MS variant produced by CCSVI.

Clinical situations inside standard MS[edit]

Also inside standard MS different clinical courses can be separated.

Primary progressive variant[edit]

Some authors also think that primary progressive multiple sclerosis should be considered a different entity from standard MS (MS with two phases, recurrent-recidivant and secondary progressive, RRMS+SPMS).[27][28] Others maintain the opposite.[29] In any case, the lesions in PPMS can be diffused instead of the normal focal ones,[30] and are different under MR spectroscopy.[31][32] RRMS and PPMS patients also show differences on the retinal layers yields examined under OCT.[33]

Some authors have proposed a dual classification of PPMS, according to the shape of edges of the scars, in MS-like and ADEM-like[34] Proteomic analysis have shown that two proteins, Secretogranin II and Protein 7B2, in CSF can be used to separate RRMS from PPMS[35]

Recently, the hypothesis of PPMS being apart from RRMS/SPMS is taken further credibility due that it was shown that CSF from PPMS patients can carry the disease to other animals, producing neurodegeneration in mice[7]

It has also been proposed than PPMS could be heterogeneous. An antibody (immunoglobulin M) oligoclonal bands would be the biomarker for an specific kind of PPMS, in a similar way to what AQP4-IgG is for NMO.[36]

Preclinical MS: CIS and CDMS[edit]

The first manifestation of MS is the so-called Clinically isolated syndrome, or CIS, which is the first isolated attack. The current diagnosis criteria for MS does not allow doctors to give an MS diagnosis until a second attack takes place. Therefore the concept of "clinical MS", for an MS that can be diagnosed, has been developed. Until MS diagnosis has been established, nobody can tell whether the disease dealing with is MS.

Cases of MS before the CIS are sometimes found during other neurological inspections and are referred to as subclinical MS.[37] Preclinical MS refers to cases after the CIS but before the confirming second attack.[38] After the second confirming attack the situation is referred to as CDMS (clinically defined multiple sclerosis).[39]

RIS, subclinical and silent MS[edit]

Silent MS has been found in autopsies before the existence of MRI[40] showing that the so called "clinical definitions" cannot be applied to around 25% of the MS cases.[41] Currently a distinction is made between "silent" and subclinical.

In absence of attacks, sometimes a radiological finding suggestive of demyelination can be used to stablish a pre-diagnosis of MS. This is often named "Radiologically Isolated Syndrome" (RIS). Cases before the first attack or CIS are subclinical in the sense that they do not produce clinical situations.

If a second radiological event appears, the clinical situation is named "Silent MS" (Okuda criteria).[42]

It has been noted that some aspects of the MS underlying condition are present in otherwise healthy MS patients relatives[43] suggesting a wider scope for the "silent MS" term.

In these cases Interleukin-8 is a risk for clinical conversion[44]

Aggressive multiple sclerosis[edit]

Relapsing-Remitting MS is considered aggressive when the frequency of exacerbations is not less than 3 during 2 years. Special treatment is often considered for this subtype.[45]

Pediatric and pubertal MS[edit]

MS cases are rare before puberty, but they can happen. Whether they constitute a separate disease is still an open subject. Anyway, even this pubertal MS could be more than one disease, because early-onset and late-onset have different demyelination patterns[46]

Controversy for the definition[edit]

Clinical vs. pathological definitions[edit]

There is no agreement if MS should refer to a clinical course or to a pathological condition. Even assuming a pathological definition it is not clear if MS should refer to the presence of scars in CNS tissue or to the underlying condition that produces them, characterized by some yet unknown biomarkers.

Probably the most implicitly used definition is clinical, and can be found in the McDonald criteria proposal. This author state that "MS is a clinical entity and therefore should be diagnosized with clinical and paraclinical criteria".[47] Currently the McDonald criteria are considered a clinical definition of MS.

Some other authors consider MS as a pathological entity instead, and propose a pathological definition.[48] According to Hans Lassmann, the pathological definition should be preferred because clinical definitions have problems with differential diagnosis.[49] Of course, using a pathological definition would not prevent performing clinical diagnosis, but would require to calibrate any diagnosis criteria against it.

McDonald et al. do not agree with this, and they remark on the clinical character of MS. They state that "Whereas it might be said that the only proved diagnosis of MS can be made upon autopsy, or occasionally upon biopsy, where lesions typical of MS can be directly detected through standard histopathological techniques, MS is essentially a clinical problem and can be diagnosed using clinical and paraclinical criteria""[47]

At this moment, both definitions are currently used by each of their supporters and the relationship among them is not well documented.

Current definitions[edit]

The list of diseases included in the MS-spectrum is not closed because no formal definition of MS is normally given. For example, the World Health Organization does not give any explicit definition with ICD-10 MS entry [1]. In ICD-9 it used to say "chronic disease characterized by presence of numerous areas of demyelination in the central nervous system with symptoms such as weakness, incoordination, paresthesis, and speech disturbances"[2].

The Unified Medical Language System also gives very loose definitions of MS [3]. The Medline medical dictionary defines it as "a demyelinating disease marked by patches of hardened tissue in the brain or the spinal cord and associated especially with partial or complete paralysis and jerking muscle tremor" [4]. It uses the anatomical hallmark of the lesions, but also imposes the existence of clinical problems (paralysis and jerking muscle tremor).

Assuming a definition as weak as the previous ones, several diseases could be included inside the MS-spectrum. Other authors use a definition for MS based in its clinical course.[50] Clinical definitions refer to the lesions and their location, but not to the nature of the lesions and this kind of definition is potentially heterogeneous.

Even leaving aside the clinical definitions, some pathologysts consider that MS is the presence of demyelinated scars in the CNS tissue[48] while others consider that MS is the unknown underlying condition that produces those scars.[51] These subtle differences can affect statistics and the reader should be aware of the definition in which each paper is based.

See also[edit]


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