Idiopathic inflammatory demyelinating diseases

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]


Diseases included in this category

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

  • Standard multiple sclerosis, the most known and extended variant.
  • Optic-spinal MS, or Opticospinal, variant 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,[6] currently is considered outside the scope of Multiple Sclerosis and inside the scope of Devic's disease,[7] though is not sure if this applies to all cases.[8]
  • Devic's disease, currently considered a separate disease
  • Acute disseminated encephalomyelitis or ADEM, a closely related disorder in which a known virus or vaccine triggers autoimmunity against myelin.
  • Acute hemorrhagic leukoencephalitis, possibly a variant of Acute disseminated encephalomyelitis
  • Balo concentric sclerosis, an unusual presentation of plaques forming concentrenic circles, which can sometimes get better spontaneously.
  • Schilder disease or diffuse myelinoclastic sclerosis: is a rare disease that presents clinically as a pseudotumoural demyelinating lesion; and is more common in children.[9][10]
  • Marburg multiple sclerosis, an aggressive form, also known as malignant, fulminant or acute MS.

Other variants have been proposed:

  • Tumefactive Multiple sclerosis: lesions whose size is more than 2 cm, with mass effect, oedema and/or ring enhancement[11][12]
  • Pediatric and pubertal MS: 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[13]
  • Venous multiple sclerosis: A relationship has been proposed between MS and Chronic cerebrospinal venous insufficiency. The hypothetical MS variant produced by CCSVI is called Venous Multiple Sclerosis. If this hypothesis is confirmed, this variant would account for most of MS cases.

Some others include in the list also other conditions associated with the presence of the scleroses[14]

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[15]), Myalgic encephalomyelitis (aka Chronic fatigue syndrome)[16] or autoimmune variants of peripheral neuropathies like Guillain-Barré syndrome or Progressive inflammatory neuropathy could be included assuming the autoimmune model.

Multiple sclerosis definitions

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 [2]. 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"[3].

The Unified Medical Language System also gives very loose definitions of MS [4]. 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" [5]. 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 [6]. Clinical definitions refer to the lesions and their location, but not to the nature of the lesions and this kind of definitions are potentially heterogeneous. As with any definition, patients have to be considered non-affected until the definition conditions are satisfied.

Clinical vs. pathological definitions

Probably the most implicitly used definition can be found into the McDonald criteria proposal, which is the currently considered as the gold standard for MS diagnosis. These authors state that "MS is a clinical entity and therefore should be diagnosized with clinical and paraclinical criteria"[17] . 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. According to Hans Lassmann, the pathological definition should be preferred because clinical definitions have problems with differential diagnosis.[18] 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 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""[19]

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

Variants inside standard MS

Progressive variants

Some authors also think that primary progressive multiple sclerosis should be considered a different entity from standard MS.[20][21] Others maintain the opposite.[22] In any case, the lesions in PPMS can be diffused instead of the normal focal ones.[23] Finally, also a dual classification of these diseases has been proposed, according to the shape of edges of the scars, in MS-like and ADEM-like[24]

Subclinical, preclinical, CIS and CDMS

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 a 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.[25] Preclinical MS refers to cases after the CIS but before the confirming second attack.[26] After the second confirming attack the situation is referred to as CDMS (clinically defined multiple sclerosis).[27]

Aggressive multiple sclerosis

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.[28]

See also


  1. ^ Fontaine B (2001). "[Borderline forms of multiple sclerosis]" (in French). Rev. Neurol. (Paris) 157 (8-9 Pt 2): 929–34. PMID 11787357. 
  2. ^ Wingerchuk DM, Lucchinetti CF (2007). "Comparative immunopathogenesis of acute disseminated encephalomyelitis, neuromyelitis optica, and multiple sclerosis". Curr. Opin. Neurol. 20 (3): 343–50. doi:10.1097/WCO.0b013e3280be58d8. PMID 17495631. 
  3. ^ Poser CM, Brinar VV (October 2007). "Disseminated encephalomyelitis and multiple sclerosis: two different diseases - a critical review". Acta Neurol Scand. 116 (4): 201–6. doi:10.1111/j.1600-0404.2007.00902.x. PMID 17824894. 
  4. ^ Weinshenker B, Miller D (1998). "Multiple sclerosis: one disease or many?". In Thompson AB, Siva A, Kesselring J. Frontiers in Multiple Sclerosis (2nd ed.). London: Taylor & Francis Group. pp. 37–46. ISBN 1-85317-506-4. 
  5. ^ Hartung HP, Grossman RI (May 2001). "ADEM: distinct disease or part of the MS spectrum?". Neurology 56 (10): 1257–60. PMID 11376169. 
  6. ^ Kalanie H, Kholghie Y, Shamsai GR, Ghorbani M (October 2008). "Opticospinal multiple sclerosis in Iran". J Neurol Sci. 276 (1-2): 130–2. doi:10.1016/j.jns.2008.09.038. PMID 18962726. 
  7. ^ Kira J (October 2008). "Neuromyelitis optica and asian phenotype of multiple sclerosis". Ann NY Acad Sci. 1142 (1): 58–71. doi:10.1196/annals.1444.002. PMID 18990121. 
  8. ^ Matsushita, T; Isobe, N; Matsuoka, T; Shi, N; Kawano, Y; Wu, XM; Yoshiura, T; Nakao, Y et al. (2009). "Aquaporin-4 autoimmune syndrome and anti-aquaporin-4 antibody-negative opticospinal multiple sclerosis in Japanese.". Multiple sclerosis (Houndmills, Basingstoke, England) 15 (7): 834–47. doi:10.1177/1352458509104595. PMID 19465451. 
  9. ^ Garrido C, Levy-Gomes A, Teixeira J, Temudo T (2004). "[Schilder's disease: two new cases and a review of the literature]" (in Spanish). Revista de neurologia 39 (8): 734–8. PMID 15514902. 
  10. ^ Afifi AK, Bell WE, Menezes AH, Moore SA (1994). "Myelinoclastic diffuse sclerosis (Schilder's disease): report of a case and review of the literature". J. Child Neurol. 9 (4): 398–403. doi:10.1177/088307389400900412. PMID 7822732. 
  11. ^ Lucchinetti CF, Gavrilova RH, Metz I, et al. (July 2008). "Clinical and radiographic spectrum of pathologically confirmed tumefactive multiple sclerosis". Brain 131 (Pt 7): 1759–75. doi:10.1093/brain/awn098. PMC 2442427. PMID 18535080. 
  12. ^ Given CA, Stevens BS, Lee C (1 January 2004). "The MRI appearance of tumefactive demyelinating lesions". AJR Am J Roentgenol 182 (1): 195–9. PMID 14684539. 
  13. ^ Chabas D, Castillo-Trivino T, Mowry EM, Strober JB, Glenn OA, Waubant E (September 2008). "Vanishing MS T2-bright lesions before puberty: a distinct MRI phenotype?". Neurology 71 (14): 1090–3. doi:10.1212/ PMID 18824673. 
  14. ^ Paul O'Connor, James Marriott, Differential Diagnosis and Diagnostic Criteria for Multiple Sclerosis: Application and Pitfalls
  15. ^ Minagar A, Jy W, Jimenez JJ, Alexander JS (2006). "Multiple sclerosis as a vascular disease". Neurol. Res. 28 (3): 230–5. doi:10.1179/016164106X98080. PMID 16687046. 
  16. ^ ; "The following test results... are seen consistently...: Brain MRI showing swelling in the brain or destruction of part of the nerve cells (demyelination)
  17. ^ McDonald WI, Compston A, Edan G et al. (2001). "Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis". Ann. Neurol. 50 (1): 121–7. doi:10.1002/ana.1032. PMID 11456302. 
  18. ^ H. Lassmann, Acute disseminated encephalomyelitis and multiple sclerosis, doi: 10.1093/brain/awp342, [1]
  19. ^ McDonald WI, Compston A, Edan G, et al. (2001). "Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis". Ann. Neurol. 50 (1): 121–7. doi:10.1002/ana.1032. PMID 11456302. 
  20. ^ Vukusic S, Confavreux C (2003). "Primary and secondary progressive multiple sclerosis". J. Neurol. Sci. 206 (2): 153–5. doi:10.1016/S0022-510X(02)00427-6. PMID 12559503. 
  21. ^ Dressel A, Kolb AK, Elitok E, Bitsch A, Bogumil T, Kitze B, Tumani H, Weber F (2006). "Interferon-beta1b treatment modulates cytokines in patients with primary progressive multiple sclerosis". Acta Neurol. Scand. 114 (6): 368–73. doi:10.1111/j.1600-0404.2006.00700.x. PMID 17083335. 
  22. ^ Ebers GC (2004). "Natural history of primary progressive multiple sclerosis". Mult. Scler.. 10 Suppl 1 (3): S8–13; discussion S13–5. doi:10.1191/1352458504ms1025oa. PMID 15218804. 
  23. ^ Zwemmer JN, Bot JC, Jelles B, Barkhof F, Polman CH (April 2008). "At the heart of primary progressive multiple sclerosis: three cases with diffuse MRI abnormalities only". Mult Scler. 14 (3): 428–30. doi:10.1177/1352458507084591. PMID 18208890. 
  24. ^ Poser CM, Brinar VV (2004). "The nature of multiple sclerosis". Clinical neurology and neurosurgery 106 (3): 159–71. doi:10.1016/j.clineuro.2004.02.005. PMID 15177764. 
  25. ^ Hakiki B, Goretti B, Portaccio E, Zipoli V, Amato MP. (2008). "Subclinical MS: follow-up of four cases". European Journal of Neurology 15 (8): 858–61. doi:10.1111/j.1468-1331.2008.02155.x. PMID 18507677. 
  26. ^ Lebrun C, Bensa C, Debouverie M, et al. (2008). "Unexpected multiple sclerosis: follow-up of 30 patients with magnetic resonance imaging and clinical conversion profile". J Neurol Neurosurg Psychiatry 79 (2): 195–198. doi:10.1136/jnnp.2006.108274. PMID 18202208. 
  27. ^ Frisullo G, Nociti V, Iorio R, et al. (December 2008). "The persistency of high levels of pSTAT3 expression in circulating CD4+ T cells from CIS patients favors the early conversion to clinically defined multiple sclerosis". J Neuroimmunol. 205 (1-2): 126–34. doi:10.1016/j.jneuroim.2008.09.003. PMID 18926576. 
  28. ^ Sazonov, DV; Malkova, NA; Bulatova, EV; Riabukhina, OV (2009). "Combined therapy of aggressive remitted multiple sclerosis with mitoxantrone in combination with copaxone". Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova / Ministerstvo zdravookhraneniia i meditsinskoi promyshlennosti Rossiiskoi Federatsii, Vserossiiskoe obshchestvo nevrologov [i] Vserossiiskoe obshchestvo psikhiatrov 109 (12): 76–9. PMID 20037526. 

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