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#Infografía
enero 2023

Severity and Unpredictability of NMOSD

enero 2023
​ Neuroscience
​

MS and NMOSD disease course

Refresh your memory on the difference in typical disease course between NMOSD and MS

Patients with NMOSD frequently experience a relapsing disease course, with repeated attacks leading to accumulating neurological disability1,2

The disease course differs between NMOSD and MS

  • Unlike in MS, it is rare for patients with NMOSD to experience a progressive, subtle accumulation of disability3
    • Instead, inflammation and the accumulation of neurological damage in NMOSD are tied to relapse events3
  • Residual disability, or incomplete recovery, is common with relapses in NMOSD1

MS, multiple sclerosis; NMOSD; neuromyelitis optica spectrum disorder.  

Summary

NMOSD attacks vary in their severity, with more severe attacks carrying a higher risk of causing permanent disability 

Relapses occur frequently, often in clusters of attacks, leading to the rapid accumulation of disability

Early diagnosis and initiation of maintenance treatment for NMOSD may reduce long-term disability 

A number of characteristics, such as AQP4-IgG serostatus and disease history, may help to predict patients’ risk of relapse

AQP4-IgG, aquaporin-4 immunoglobulin G; NMOSD, neuromyelitis optica spectrum disorder. 

Referencias

  1. Oh J Levy M. Neurol Res Int 2012;2012:460825.
  2. Kessler RA et al. Neurol Neuroimmunol Neuroinflamm 2016;3:e269.
  3. Kawachi I et al. J Neurol Neurosurg Psychiatry 2017;88:137–145.

Introduction to the EDSS - Relapses and their symptoms

Understand that NMOSD attacks vary in frequency and severity, and how that affects disability accrual

Disability in MS and NMOSD can be measured using the Expanded Disability Status Scale

  • The EDSS, originally developed for MS, is an instrument that enables neurologists to score patients’  disability out of ten
    • Higher scores indicate greater disability
       
  • A patient’s EDSS score is based on measures of impairment across eight functional systems:
    • Visual 
    • Cerebellar
    • Brainstem
    • Sensory
    • Bowel and bladder
    • Cerebral or mental
    • Pyramidal motor function
    • Other
       
  • To view a copy of the full EDSS assessment criteria, please click here2

EDSS, expanded disability status scale; MS, multiple sclerosis; NMOSD; neuromyelitis optica spectrum disorder.  

A single NMOSD attack can cause permanent disability and/or bilateral vision loss3,4

One in four patients with NMOSD experience significant, long-term disability (EDSS score ≥6) as a result of their first attack3

The first NMOSD attack may be so severe that 41% and 21% of patients develop blindness in one or both eyes, respectively3

Severe NMOSD attacks (i.e. those that cause an increase in EDSS score of ≥3 points) are significantly more likely to cause permanent disability than less severe attacks4

However, for most patients with NMOSD, multiple relapses are required in order to accumulate significant disability3,5

EDSS, Expanded Disability Status Scale; NMOSD, neuromyelitis optica spectrum disorder.  

In general, the symptoms associated with NMOSD relapses are more severe than with MS relapses 

  • Acute NMOSD attacks of optic neuritis and/or transverse myelitis can be severe or fatal6-8
  • The symptoms of NMOSD attacks are often more disabling than in MS, with poorer recovery if untreated6,8
  • In contrast with MS, progression independent of relapse activity (PIRA) is not thought to be a driver of disease worsening in NMOSD9

Optic neuritis
 

Optic neuritis in NMOSD is usually more severe and more extensive than in MS

  • Attacks are more likely to be bilateral and recurrent,7,10 and result in more severe residual vision loss11,12

Longitudinally extensive transverse myelitis (LETM)

Transverse myelitis in NMOSD is frequently severe, leading to motor, sensory, and/or bowel and bladder dysfunction13

  • In contrast to MS, myelitis in NMOSD tends to span ≥3 vertebral segments (LETM), and often affects the motor, sensory, and autonomic neurological pathways simultaneously14

Area postrema syndrome 


Area postrema syndrome is also relatively common in NMOSD but rare in MS, with patients developing intractable hiccups and/or nausea/vomiting10

EDSS, expanded disability status scale; LETM, longitudinally extensive transverse myelitis; MS, multiple sclerosis; NMOSD; neuromyelitis optica spectrum disorder. 

Summary

NMOSD attacks vary in their severity, with more severe attacks carrying a higher risk of causing permanent disability 

Relapses occur frequently, often in clusters of attacks, leading to the rapid accumulation of disability

Early diagnosis and initiation of maintenance treatment for NMOSD may reduce long-term disability 

A number of characteristics, such as AQP4-IgG serostatus and disease history, may help to predict patients’ risk of relapse

AQP4-IgG, aquaporin-4 immunoglobulin G; NMOSD, neuromyelitis optica spectrum disorder. 

Referencias

  1. Kurtze JF. Neurology 1983;33:1444–1452;
  2. Kurtzke Expanded Disability Status Scale (EDSS). National MS Society. http://www.nationalmssociety.org/nationalmssociety/media/msnationalfiles/brochures/10-2-3-29-edss_form.pdf. Accessed October 2020.
  3. Palace J et al. Brain 2019:142;1310–1323;
  4. Banerjee A et al. Mult Scler Relat Disord 2019;28:60–63;
  5. Sellner J et al. Eur J Neurol 2010;17:1019–1032.
  6. Wingerchuk DM et al. Lancet Neurol 2007;6:805–815;
  7. Kawachi I, Lassmann H. J Neurol Neurosurg Psychiatry 2017;88:137–145;
  8. Jarius S et al. Clinical and Experimental Immunology 2014;176:149–164;
  9. Akaishi T et al. Scientific Reports 2020;10:13890;
  10. Wingerchuk DM et al. Neurology 2015;85:177–189;
  11. Finke C et al. JAMA Neurol 2018;75:296–303;
  12. Levin MH et al. Prog Retin Eye Res 2013;36:159–171;
  13. Kim S-M, et al. Ther Adv Neruol Disord 2017;10:265–89;
  14. Romeo AR et al. Curr Opin Rheumatol 2019;31:250–255;

Unpredictability of relapses 

Learn that relapses are unpredictable, and tend to occur in clusters of several attacks of a similar phenotype

NMOSD relapses can occur frequently and without warning, leading to the rapid accumulation of disability 

  • Occurrence of relapses can be random,1 with the time between attacks lasting anywhere from weeks to years2

  • Up to 90% of patients with NMOSD show a recurrent episodic attack disease course2
    • Of these patients, up to 60% relapse within 1 year and 90% relapse within 3 years2,3
       
  • Several cohort studies identified a mean annualized relapse rate of 0.8–1.3, with an average time to first relapse of 10–17 months3–5

  • Because patients with NMOSD can experience relapses at a relatively high frequency, they can accrue disability more quickly than in MS6

EDSS, expanded disability status scale; NMOSD; neuromyelitis optica spectrum disorder.  

While NMOSD relapses remain clinically unpredictable, some attacks have been shown to cluster in timing and anatomical region 

NMOSD relapses are highly unpredictable2,1,7

  • It is not possible to accurately predict the timing or CNS location of future NMOSD relapses2,1
  • However, some patients with NMOSD show unpredictable periods of frequent ‘clustered’ relapses, separated by ‘non-clustered’ intermittent periods with sparse relapses2,1,7

Clustered relapse periods

  • Clustered relapses often occur within 6–12 months of the previous attack1
  • Clinical attacks may manifest in the same anatomic region and display the same attack phenotype, for example, in the optic nerve (optic neuritis) or spinal cord (myelitis)1

Non-clustered periods

  • Relapses are entirely unpredictable in nature, with limited or no relation to previous NMOSD attacks in CNS location1

Cases with ≥3 clinical attacks (in the order of onset age)

Reproduced from Akaishi T, et al. 2020.1

AQP4-IgG, aquaporin-4 immunoglobulin G; CNS, central nervous system; NMOSD, neuromyelitis optica spectrum disorder.  

No correlation has been observed between the occurrence of a severe relapse and the severity of the preceding relapse 

  • Around three-quarters of patients (74%) will have had a mild or moderately severe relapse prior to their most recent severe relapse
    • Two-thirds (66%) experience a severe relapse within 12 months of their previous relapse
       
  • The severity of the most recent relapse cannot predict the severity of the subsequent relapse

Increasing disability and disease burden in NMOSD are driven by multiple severe relapses and incomplete recovery 

  • Most relapses develop quickly, worsen over the course of a few days, and then plateau, before slowly improving in the following weeks–months7–9

  • For myelitis, the rate of no or incomplete recovery after the first event is high (76%), and worsens with the number of subsequent relapses9

  • In line with the increasingly low rate of recovery from myelitis, a median EDSS of 4* is notable even early in the disease course9

*Indicating a restricted walking range. EDSS, Expanded Disability Status Scale; NMOSD, neuromyelitis optica spectrum disorder.

AQP4-IgG seropositive patients with NMOSD may experience more severe relapses than patients who are AQP4-IgG seronegative

A number of clinical features that are reflective of increased disease severity occur more frequently in AQP4-IgG seropositive (AQP4-IgG+) NMOSD than in the seronegative disease9 , including:

  • Severe reduction in vision during acute optic neuritis
  • Motor symptoms (e.g. paraparesis)
  • Significant muscle weakness
  • Higher total spinal cord lesion load
  • Larger lesions (≥6 vertebral segments), sometimes extending to entire spinal cord involvement

The AQP4-IgG seronegative population can be split into two categories, depending on the presence of antibodies against myelin oligodendrocyte glycoprotein (MOG-IgG)

‘Double-seronegative’ (DSN) NMOSD

Most AQP4-IgG seronegative patients are DSN (negative for both AQP4-IgG and MOG-IgG)10

  • These patients relapse at similar rates to AQP4-IgG+ patients, but are more likely to experience simultaneous optic neuritis and transverse myelitis (TM), compared with TM only in AQP4-IgG+ patients11

MOG-IgG seropositive (MOG-IgG+) NMOSD 

Up to 42% of AQP4-IgG seronegative patients are MOG-IgG seropositive10; these patients have similar relapse rates to AQP4-IgG+ and DSN patients, but tend to show less disability11

  • Compared with DSN NMOSD, MOG-IgG+ patients have different clinical phenotypes – they are more likely to have optic neuritis only, or TM plus brain involvement11
  • MOG-IgG+ patients’ disease course appears to differ depending on the age of the patient12

AQP4-IgG, aquaporin-4 immunoglobulin G; EDSS, expanded disability status scale; NMOSD; neuromyelitis optica spectrum disorder.  

Summary

NMOSD attacks vary in their severity, with more severe attacks carrying a higher risk of causing permanent disability 

Relapses occur frequently, often in clusters of attacks, leading to the rapid accumulation of disability

Early diagnosis and initiation of maintenance treatment for NMOSD may reduce long-term disability 

A number of characteristics, such as AQP4-IgG serostatus and disease history, may help to predict patients’ risk of relapse

AQP4-IgG, aquaporin-4 immunoglobulin G; NMOSD, neuromyelitis optica spectrum disorder. 

Referencias

  1. Akaishi T et al. Neurol Neuroimmunol Neuroinflamm 2020;7:e640;
  2. Wingerchuk DM et al. Lancet Neurol 2007;6:805–815; 3.
  3. Kitley J et al. Brain 2012;135:1834–1849;
  4. Ghezzi A et al. J Neurol 2004;251:47–52;
  5. Seok JM et al. J Neurol Sci 2016;368:209–213;
  6. Jarius S et al. Clinical and Experimental Immunology 2014;176:149–164.
  7. Sellner J et al. Eur J Neurol 2010;17:1019–1032;
  8. Wingerchuk DM et al. Neurology 1999;53:1107–1114;
  9. Jarius S et al. J Neuroinflammation 2012;9:14.
  10. Narayan R, et al. Mult Scler Relat Disord 2018;25:66–72.
  11. Kim HW, et al. Presented at ECTRIMS 2019;278294:P10924. Cobo-Calvo A, et al. Ann Neurol 2020: doi: 10.1002/ana.25909
  12. Cobo-Calvo A, et al. Ann Neurol 2020: doi: 10.1002/ana.25909.

Risk factors for relapses

Evaluate some of the prognostic factors that help predict NMOSD relapse risk, and understand why early diagnosis and treatment is vital

The exact cause of relapse events in NMOSD is unknown, but a number of prognostic factors can be used to predict the risk of relapse 

Suggested triggers for relapse events in NMOSD include infections, vaccinations, and systemic autoimmune diseases1–3

The presence of AQP4-IgG antibodies does not appear to affect relapse risk, but attack severity appears to be greater in AQP4-IgG seropositive vs seronegative patients1

The following factors have all been associated with increased risk of relapse, disability, and fatality in NMOSD4–9

  • A history of other autoimmune diseases
  • Older age at onset
  • Female gender
  • Caucasian or African ethnicity
  • Higher attack frequency during the first 2 years of disease
  • Incomplete recovery from the index event

 Recently developed prognostic models use combinations of these factors to predict the likelihood of developing attacks and disability in individual patients, according to their baseline features and disease history8

Reproduced from Kitley J et al. 2012.9

AQP4-IgG, aquaporin-4 immunoglobulin G; NMOSD, neuromyelitis optica spectrum disorder. 

Early diagnosis and initiation of maintenance treatment for NMOSD may reduce long-term disability 

  • Because a single relapse in NMOSD can have devastating consequences, the prevention of relapses is the primary goal of long-term NMOSD treatment10
    • Reducing the severity of relapses may also limit disability accrual Reproduced from Kitley J et al. 2012.9
       
  • Relapses can occur in quick succession, so it is important to provide patients with a rapid and accurate diagnosis after their onset attack, so that they can begin treatment as soon as possible8

  • Most patients require multiple attacks to accumulate significant disability (EDSS score ≥6, or blindness in one/both eyes), so preventing future relapses can greatly affect patient outcomes8

EDSS, expanded disability status scale; NMOSD; neuromyelitis optica spectrum disorder. 

Summary

NMOSD attacks vary in their severity, with more severe attacks carrying a higher risk of causing permanent disability 

Relapses occur frequently, often in clusters of attacks, leading to the rapid accumulation of disability

Early diagnosis and initiation of maintenance treatment for NMOSD may reduce long-term disability 

A number of characteristics, such as AQP4-IgG serostatus and disease history, may help to predict patients’ risk of relapse

AQP4-IgG, aquaporin-4 immunoglobulin G; NMOSD, neuromyelitis optica spectrum disorder. 

Referencias

  1. Jarius S et al. J Neuroinflammation 2012;9:14;
  2. Wingerchuk DM et al. Neurol 1999;53:1107–1114;
  3. Wingerchuk DM et al. Lancet Neurol 2007;6:805–815;
  4. Sellner J et al. Eur J Neurol 2010;17:1019–1032;
  5. Wingerchuk DM, Weinshenker BG. Neurol 2003;60:848–853;
  6. Bichuetti DB et al. Mult Scler 2009;15:613–619;
  7. Cabre P et al. J Neurol Neurosurg Psychiatry 2009;80:1162–1164;
  8. Palace J et al. Brain 2019:142;1310–1323;
  9. Kitley J et al. Brain 2012;135:1834–1849.
  10. Palace J et al. Presented at MSVirtual 2020. FC.01.03;
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