
 neuromyelitis optica ( nmo ) is an inflammatory disorder restricted to the spinal cord and optic nerves .
contrary to multiple sclerosis ( ms ) , relapses of nmo are often strikingly severe and most nmo patients present stepwise neurological impairments .
nmo treatments are aimed to prevent the relapses with the administration of various promising immunosuppressive drugs .
since the largely used steroid treatment usually fails to control severe attacks , specific add - on treatments have to be considered in order to limit the stepwise increase of residual impairment .
given that a strong humoral response characterizes nmo physiology , one might assume plasma exchange ( plex ) to be particularly well adapted in severe nmo relapses .  
we here propose to outline the rationale of the plex treatment based on physiological grounds and summarize the relevant data of plex studies in the setting of nmo spectrum disorder , assessing the results obtained in each type of attacks .
finally we will try to build up an original concept linking the inner dynamic of the lesion , the timing of plex , onset , and the expected clinical results .
a vasculocentric pattern of activated complement and immunoglobulin of igg and igm types is observed that mirrors the normal expression of aqp4 .
aqp4 expression is definitely reduced in normal appearing white matter and lost throughout the lesions .
these modifications are the hallmark of nmo and could occur alone or associated with a wide range of lesions from mild demyelination to large necrosis .
this pattern of lesion was classified in the pattern ii of the lassmann classification of the inflammatory lesions [ 1 , 2 ] .
contrary to ms , t cells are rare in nmo lesions and probably have no major effect on the formation of the lesions . however , t cells are probably involved upstream in physiopathological cascade in the earlier phases of the disease where a complex interplay leads to antigen sensitization and possibly in the initial opening of the blood - brain barrier ( bbb ) .
moreover , the pattern associating vasculocentric deposition of ig and complement , cells ( eosinophils / lymphocytes ) infiltration and aqp4 loss is sometimes fully dissociated from demyelination .  
this antibody is detected with tissue - based immunofluorescence assays with a sensitivity and specificity for clinically defined nmo of more than , respectively , 60% and 90% .
clinically diagnosed nmo patients share clinical common and evolutional characteristics regardless of their nmo - igg status . beyond the surrogate marker value of nmo - igg , this marker is now used as a major diagnostic criterion   and delineates the nmo spectrum disorders that gather in a same entity both typical nmo and unusual or truncated clinical forms .
aqp4 is a transmembrane protein expressed in the apical domain of the membrane feet expansions of the astrocytes close to the surrounded blood vessels .
this protein is critically involved in the homeostasis of the water in the brain and interfaces with blood vessels , especially in the clearance of free water .
loss of perivascular aqp4 in the basal state results in cellular swelling , ostensibly due to a failure to eliminate water generated from cellular metabolism .
thus in nmo , since the interaction of nmo - igg and aqp4 leads to a functional knockout phenotype of aqp4 , edema develops as a result of functional impairment of aqp4 although bbb is expected to be still intact , which may explain the paradoxical lack of gadolinium enhancement in most nmo lesions .
apart from water homeostasis , the removal of aqp4 from astrocytes membrane is associated with an impaired homeostasis of glutamate via the loss of function of eaat2 , a major glutamate transporter associated with aqp4 in a macromolecular complex .
the disruption of glutamate homeostasis initiates an excitotoxic mechanism damaging oligodendrocytes and ultimately leading to demyelination .
virtually all the cns astrocytes express aqp4 , however , some regions are enriched in aqp4 .
those regions are the spinal cord gray matter , the posterior optic nerve , the floor of the fourth ventricle and the circumventricular organs especially the area postrema , explaining the restriction of the sites of lesion characterizing nmo .
interestingly circumventricular organs are also the only sites of the cns expressing fenestrated capillaries favoring local passive diffusion of circulating antibodies
nmo - igg detection is a strong predictor of recurrence after an initial spinal or optic attack [ 1315 ] . in few patients ,
nmo - igg was high during flares and became negative during the stabilized disease following treatment , and , in contrary , an initially seronegative patient became positive during a further attack [ 16 , 17 ] .
that is to say that nmo - igg negative sera are not always nmo - igg negative patients on long term . in the seminal work of takahashi et al .
, nmo - igg levels were positively correlated with both clinical severity ( i.e. , blindness ) and radiological severity . moreover
, a strong positive correlation was obtained between the nmo - igg titres at the nadir of exacerbations and the spinal cord lesion length on mri .
in contrast , low nmo - igg titres were observed during remission induced by immunosuppressive maintenance therapy .   in vitro , the binding of nmo - igg to the extracellular domain of aqp4 reversibly downregulates its plasma expression . in the presence of active complement ,
nmo serum igm is not aqp4-specific and abundant igm deposits in the nmo lesions may have passively diffused after the bbb disruption by the seminal focal complement activation initiated by nmo - igg .   in an animal model of eae with passive transfer of nmo - igg ,
the transfer exacerbated eae signs and the typical pathological characteristics were reproduced in treated rats [ 20 , 21 ] .
direct injection of nmo - igg in mice brains could reproduce the pathology , but only when complement is coinjected . the nmo - igg ability to lesion aqp4-transfected cells in the presence of complement
the percentage of cells lesioned by complement was strongly higher in presence of sera from patients with severe attacks , although lesion induced by sera from patients with mild attacks did not differ from negative controls or ms patients .
thus , the severity of the disease may be partly determined by intrinsic nmo - igg characteristics to activate the complement .
as we already described , nmo lesions are associated with a strong igg , igm and complement deposition , typical of the pattern ii in the lassmann classification .
the nmo - igg is involved in a complement - dependant toxicity against the astrocytes .
all of these components  igg , igm , and complement  are targeted by plasma exchanges . by means of 5 exchanges , all the exchanged molecules will drop to less than 20% of their initial level [ 24 , 25 ] .
by this way , antibodies and complement , which are the core of the pattern ii lesions , are excluded from the circulating pool and can not migrate anymore to the lesions .   although plex has long been used in various demyelinating disorders , there is some clue that the pattern is a key determinant of plex efficiency . in a retrospective study ,
keegan et al .   reported that all the patients suffering from demyelinating disorders and improved by plex had a biopsy proven pattern ii lesion .
however all these patients were ms without nmo - igg and none were nmo .  
all the aforementioned findings stress that circulating nmo - igg and complements are the two main actors of the nmo pathogeny and why clearing them from blood with plex should be appropriate for special benefits .
plex or plasmapheresis is the filtration of the plasma , which is removed , replaced by artificial plasma and reinfused to the patient  the plasma exchange . basically , the goal of the filtration step is to remove a given volume of patients plasma and to return an artificial plasma substitute in its place .  
two high flow rate accesses are mandatory : an input line from patient to device (  artery  ) and a return line from device to patient (  vein  ) . in continuous filtration ,
two needles are placed in both arms or groins in order to drawn out the blood of the body through an extracorporeal line connected to one needle , then blood is processed and reinfused continuously through the other needle . in case of discontinuous filtration , the separation and remixing are done in small batches through a single venous access in the groin where in and out cycles may alternate .
anticoagulation ( citrate or heparin ) is added to the blood preplasma filter to prevent from clotting .
the removed blood is processed ( apheresis procedure ) in a cell separator that continuously separates plasma from cellular components ( consisting of red and white blood cells and platelets ) either by a centrifugation ring with permanent in and out flow , or by filtration through a porous membrane .
small molecules like cytokines as well as large molecules , such as albumin and immunoglobulin , are easily extruded from the blood compartment with a reported sieving coefficient > 0.95 at a blood flow rate of 100  ml / min .
the cleared cellular components are then combined with the replacement fluid ( donor plasma or artificial albumin mixed with a saline solution ) and returned to the patient through the needle in the other arm .
a plex session is usually performed in 2 to 6 hours , depending on patient 's height , weight , viscosity of the blood , and technical parameters .
all the targeted components are distributed in the interstitium ( extra - vascular compartment ) by variable part .
the relation curve of the achieved concentration of a plasma component ( c ) after a unique exchange of a given plasma volume is exponential inverse , following a single kinetics .
the larger volume of plasma exchanged during each session clears a larger amount targeted circulating component .
an exchange of one body plasma volume leads to the immediate clearance of 50% of the circulating component .
a 1.3 body mass volume exchange that removes about 72% of the concentration is generally agreed .
beyond , the volume to process increases massively for too little gain .   however , according to the distribution of c in the interstitium , the achievement of the clearance of c will necessitate the use of multiple plex sessions separated by the time necessary for the equilibration of c concentration between interstitium and vascular spaces .
the number and frequency of sessions should be evaluated according to the biological characteristics of the components to remove ( synthesis level , vascular distribution , diffusion ability ) .
the durability of the immunomodulatory effect after plex is difficult to assess and will depend on the turnover rate of the targeted humoral components .
concomitant intensive immunosuppressive therapy ( i.e. , steroids , mitoxantrone , mycophenolate mofetil , and rituximab ) will be required to sustain the obtained depletive effect .
plex are contraindicated in case of ongoing infectious disease , precarious hemodynamics , and active hemorrhage ( heparin ) .
immediate side effects are related to the extracorporeal line : hemodynamic instability , vasovagal syndrome , numbness or tingling , venous puncture hazards with excessive local bleeding , septicaemia , or allergy .
since blood coagulation factors are all depleted by plex , hemostasis is affected in variable ways : first , a hypocoagulation state is immediately achieved by the global depletion of all the coagulation factors for half a day ; at day 2 , short - life procoagulant factors are regained but antithrombin - iii synthesis is delayed leading to a hypercoagulable state until day 3 .
persistently low fibrinogen levels have been described with the concomitant use of high dosage steroid infusion . in summary ,
methylprednisolone pharmacokinetics is characterized by a very short half - life ( about 2 hours ) and although steroid binding to plasma protein is about 75% , the volume of distribution is very large ( about 1.5  l / kg ) .
these factors are the key of the negligible plex effect upon steroids biodisponibility [ 30 , 31 ] .
when used the same day as plex procedure , steroids were infused at the end of each plex session .
various regimens of high doses of intravenous methylprednisolone are used in first line of treatment ranging from 3  g infused in 3 days , to 10  g in 5 to 10 days , depending on authors .
there is no evidence in favor of one regimen or another and efficacy assessment has never been addressed .
moreover , even if steroids reduce the inflammatory cellular response by triggering apoptosis of lymphocytes , they are clearly not sufficient because poor outcomes are still a common issue even when steroid treatment is given immediately after onset .
we wish to develop here the evidence for the effectiveness of plex that we have been largely using as an add - on therapy for more than 10 years .  
plex proved to be efficient in central demyelinating diseases in a randomized sham - controlled study [ 32 , 33 ] .
reviewed the clinical data from 59 patients who received plex for inflammatory demyelinating diseases , including 10 nmo and 6 acute transverse myelitis ( atm ) cases .
a moderate or marked improvement was obtained in half of nmo and atm patient groups .
the late final outcome at one year was more or less obtained during the first month after treatment in both groups , without regard to success or failure of treatment [ 26 , 34 ] .
a small number of case reports and few small studies were reported with variable issues .
judging improvement is even more complex due to the subjective classification of improvement in mild / moderate / marked instead of a quantified clinical exam [ 26 , 3436 ] .
moreover the natural history of single spinal relapse in nmo has never been addressed , so any improvement bias after plex is inappreciable in the absence of a control group . finally , most authors used plex as a rescue treatment given late after the onset .
for example plex was delayed from onset by a mean of 33  30 days in brunot et al .   and a median of 30 days ( 6 to 90 days ) in llufriu et al . .
although a synergistic effect of steroids and plex was long expected due to their complementary action , none of these studies compared conventional steroid treatment alone with add - on plex - treated attacks .  
we previously refined these results in a study of outcome after severe spinal attacks associated with nmo spectrum disorders .
we included 96 spinal attacks from 43 patients , divided in two groups : ( 1 ) a steroid - only group designed from historical patients treated with steroids alone ; ( 2 ) an active group treated with both plex and steroids .
plex decision was raised at the same time and started as soon as possible during the two days later . as a major difference with other groups ,
plex was never initiated as a delayed rescue treatment after a standard steroid treatment failure .
since plex therapy is mainly expected to minimize residual impairment , we used the edss ( calculated as the difference between residual and basal edss ) as the main outcome .
if we except 5 plex delayed due to difficult medevac reasons , plex was initiated by a mean of 5.4  3.1 days after attack onset with a median of 4 sessions .
there was no significant difference between the plex - treated and steroid - only groups for basal and acute edss ( 3.9  2.9 versus 4.2  2.9 , and 7.9  1.0 versus 8.0  1.4 ; p = ns ) , however , residual edss ( 5.1  2.4 versus 6.8  1.9 , p < 0.01 ) and mean edss ( 1.2  1.6 versus 2.6  2.4 , p < 0.01 ) were significantly lower in the plex - treated group than in the steroid - only group .  
basal edss dramatically influenced therapy outcome ( table 1 ) . during the first attack , although acute edss were similar in both groups ( 7.6  1.2 versus 7.1  1.5 , p = ns ) , edss and residual edss were dramatically reduced in the plex - treated group ( 2.1  1.9 versus 5.9  2.0 , p < 0.01 ) given that acute edss was similar in this sub - group .
in the two other sub - groups of basal impairment ( edss 1.0 to 5.5 and edss  6.0 ) , residual edss and edss tended to be lower in plex - treated attacks but no statistical signification could be obtained due to the small size of these groups .   the classical lazarus effect , defined as a very short - term dramatic improvement , was rather unusual in our group but our study was not designed to analyse short - term improvement .
the patients who experienced this effect have all received a very early treatment ( less than 2 days ) . however , in magaa et al .
's paper , patients who exhibited functional improvement did so within a median of 4 days ( third plex ) , although a minority ( 6% ) exhibited a delayed response ( more than 2 months ) .
minor side effects occurred in 24% of plex - treated attacks and resulted in plex interruption once ( 84-year - old patient with pulmonary embolism ) .   in summary
, plex - treated patients achieved a significantly better outcome after a spinal attack , especially if plex was given during the first attack .
the exact effect of plex in previously impaired patients should be validated in a larger multicentric cohort . as plex proved to be a promising treatment in spinal attacks
, it would now be unethical to design a study with a sham - treated control group .  
predictors of good outcome were studied in a large group of plex including 26 nmo patients .
surprisingly a short plex delay was associated with a good outcome in a first study   but had no effect in a second study , although one should remind that median plex delay was long ( 23 days ) in this later compared to our group .
the same plex response rate was obtained irrespective of nmo - igg serostatus in our cohort and in the mayo clinic cohort . as a practical consequence , faced with a patient suffering from a severe relapse , the knowledge of nmo - igg status should not be required to start plex as soon as possible , since plex was found efficient in nmo - igg negative patients .
we previously showed that an immediate unilateral blindness occurred in a third of patients after the first optic neuritis ( on ) , and generally two attacks are sufficient to cause a definitive loss of vision .
few plex were undertaken after on and a quick dramatic recovery is usual as we also observed [ 41 , and unpublished results ] .
depending authors , plex were used immediately   or as a delayed add - on therapy [ 4245 ] .
after pooling severe ( acute visual acuity < 1/10 ) on patients ( either nmo or in the nmo spectrum ) from available studies [ 41 , 42 , 45 , 46 ] with ours ( unpublished results ) , data were gathered for 39 eyes .
plex were given in a median of 19 days in patients who recovered a visual acuity more than 1/10 ( considered here as a treatment success ) but 41 days in treatment failure . a clear effect of plex delay was observed since success rate was 8/8 ( 100% ) during the first 11 days , then 4/7 ( 57% ) from days 12 to 22 , and 7/13 ( 53% ) from days 23 to 73 . moreover , even when patients recovered , averaged residual va tended to be lower in delayed plex patients .
interestingly , the spontaneous recovery ( > 1/10 ) after severe on treated by steroids alone was about 40% in our cohort ( from ) , which is very close to the recovery obtained in the two last groups of late plex . in conclusion ,
strong clues support that plex change the outcome of severe on only when they are given early , however broader studies using carefully chosen patients are still lacking to confirm this hypothesis .  
apart from opticospinal attacks , severe brain attacks are described in nmo , especially involving hypothalamus and medulla oblongata .
those lesions are usually severe and associated with blindness , central endocrine disorders , or quadriplegia with respiratory failure .
nonspecific telencephalic lesions are common but are mostly asymptomatic . however , symptomatic lesions involving supratentorial white matter are exceptional and extensive . even if a favourable outcome after plex has been reported in a few severe cases [ 48 , 49 ] , comparative data are still lacking .  
posterior reversible encephalopathy syndrome ( pres ) is an encephalopathy with consciousness and visual disturbances with rapidly reversible changes on mri consistent with vasogenic edema .
it seems to occur more often than coincidental in nmo patients : 5 out of 70 consecutive nmo - igg patients evaluated at mayo clinic ; 2 out of 5 in hadassah medical school , israel .
authors proposed that the autoimmune - mediated disruption of the aqp4 water channel function may predisposes to pres at comparable levels of acute illness .
plex was involved as a trigger in one case with a good final outcome . in few cases ,
plex were implemented as curative treatment with an overall good outcome [ 50 , 51 ] .
besides knowing plex are effective and safe , the central question remains : is plex necessary as soon as and as often as possible ?
prospective , randomised , multicentre clinical trials would be required to definitively answer the question . for most authors ,
to date plex are considered as an add - on rescue treatment after steroid failure .
the european recommendation from efns is to start with an early steroid course no matter the severity .
early escalation with plex is only recommended after a failure of a second course of steroids , that is to say that plex initiation may be postponed for more than a week .   as we demonstrated before , plex efficiency depends on the timing of initiation , ranging from immediate dramatic improvement ( the lazarus effect ) to no effect according to whether they are given early or very late .
we propose to regress to the dynamic of the inflammatory nmo lesions to explain why plex efficiency is strongly dependant of the timing of their onset .  
as we described above , lesion is the consequence of a cascade of reversible events , susceptible to an external action .
one could abruptly divide this cascade into two main points : ( 1 ) firstly , the binding of nmo - igg to aqp4 triggers the functional impairment of astrocytes , quickly completed by a complement - mediated cell destruction ; ( 2 ) the dysfunction of eaat2 transporters , as a bystander effect , impairs the clearance of free glutamate which progressively accumulates and initiates an excito - toxic mechanism upon oligodendrocytes , ultimately leading to oligodendrocytes apoptosis and demyelination [ 11 , 53 ] .
this excito - toxicity is reversed in vitro by adding a competitive antagonist of the nmda receptor .
the time sequence of these events was studied in lesions induced by direct mouse brain injection with nmo - igg and complement .
loss of aqp4 and gfap , and myelin breakdown were evident 7  h following the injection .
finally , one could suppose that a very early intervention targeting astrocytes dysfunction may prevent the progression to the bystander effect .   the influence of treatment delay upon outcome has been addressed in a single study of first on receiving steroid treatments .
the outcomes were both visual acuity and the width of the retinal fibers layer evaluated with optic tomography ( oct ) .
patients were divided into two groups : one group with a good visual outcome , including a high residual visual acuity and high rfl ; a second group with a poor visual outcome in terms of low acuity and low rfl . very interestingly , the two groups were similar in all the parameters except one : patients with a good outcome received steroids with a lower mean delay after on onset , by a mean of 1.8  1.1 days compared to  7.8  3.8 days in patients with a poor outcome .
this study is the first proof that a delayed infusion of steroids is associated with a poorer outcome . a similar effect of treatment delay ,
treated with plex , early initiation of treatment was one out of the predictors of good outcome . in a larger study encompassing attacks from various demyelinating disorders , success rates were stratified by delay : improvement occurred in 83% when given before day 15 , but fell to 43 after 2 months . moreover the dramatically very short - term improvement , called the lazarus effect , is sometimes observed after severe attacks receiving a very early treatment with plex and steroids . however , this earliness responsibility on the lazarus effect remains elusive since no study is available on this rather unusual effect . in the light of the available data , we postulate a link between the staging of nmo lesion and the plex effect upon clinical and radiological outcome ( figure 1 ) .
stage 1 ( first hours ) : acute attack provokes for hours an astrocyte dysfunction ( by nmo - igg binding on aqp4 leading to internalization ) mainly expressed by an edema .
this purely edematous lesion could be immediately reversible by the clearance of nmo - igg preventing the loss of astrocytes and the excitotoxic cascade .
stage 2 ( days ) : the underexpression of eaat2 induces an excitotoxic effect of glutamate on oligodendrocytes leading progressively to demyelination and axonal loss .
astrocytes loss initiates a self - sustained excitotoxic process henceforth independent from nmo - igg persistence . even if the extraction of nmo - igg and complement by plex ends the astrocytes aggression .
a variable amount of them has been already lost and excitotoxic effects upon oligodendrocytes are evident .
stage 3 ( weeks ) : atrocytes , oligodendrocytes , and axonal loss are prominent , engulfed in large areas of necrosis .
we propose to reconsider plex as a major part of the treatment of severe nmo attacks and suggest that plex could be given systematically in severe relapses of nmo , extended transverse myelitis or bilateral severe on resistant to steroids .
since nmo - igg positivity is both predictive of attacks and severity , achieving a low concentration of plasmatic antibodies remains a goal to achieve . besides immunosuppressive drugs
, weekly plex have been used to achieve a sustained depletion of nmo - igg and complement .
miyamoto and kusunoki   proposed to use plex as preventive treatment as an add - on therapy after immunosuppressive drugs failure .
the natural history of nmo leads all the patients to a deep impairment in a stepwise fashion without progressive phase . in our study , 5 years after the onset , 70% of patients suffered from a unilateral loss of vision and almost half of them from a bilateral loss of vision .
after 8 years , half of the patients had suffered from a severe myelitis and had become chairbound .
the mortality rate was very high before immunosuppressive drugs but dramatically dropped since they are largely used .
the exact role of recurring plex along the remaining attacks to tune the outcome to a low impairment has not yet been addressed but remains most probable considering this striking epidemiological change of mortality in french west indies .
immunosuppressive drugs are necessary to prevent further relapses but no recommendation is yet available concerning therapeutic escalation . since the lesion severity mostly depends on the initial and definitive depth of the loss of aqp4 and astrocytes , future treatments strategies may be directed upon aqp4 preservation .
small molecules or monoclonal antibodies could be used to prevent nmo - igg binding to aqp4 and to block the physiopathological cascade upstream .
another strategy may deplete pathogenic antibodies by apheresis using dedicated immunoadsorption systems as previously described in myasthenia gravis   and in various extra neurological disorders .
however , if the value of this technique is less clear in disorders like ms [ 60 , 61 ] , where pathology is broader than a specific antibody , it could be especially suitable to nmo since anti - aqp4 seems to be the pathological core .
the strength of these techniques is the specificity of the antigenic absorption with no regard to the class or subclass of antibodies and no fluid replacement .
this alternative therapy may be considered in plex - resistant relapses and should be better studied in severe relapses as an alternative of steroids and plex .
a complementary approach may target the complement system with newly developed anticomplement recombinant antibodies at various levels , with preliminary promising results .
plex , in synergy with steroids , could be a major treatment of relapses , aimed at preventing cumulative disability .
these preliminary results suggest that plex may modify the short prognostic of nmo relapses , as long as given early .
those models should be able to confirm that early therapeutic intervention directed to halt the ongoing lesions should be even more dramatic in an early narrow therapeutic window .
the next steps should be to concentrate upon large multicentric therapeutic trials in order to validate the therapeutic procedure and to determine the time opportunity window .
however , we are aware that good trials against placebo could now be difficult to accept since this is an extremely devastating disease .
 
 background . 
 neuromyelitis optica ( nmo ) attacks are poorly controlled by steroids and evolve in stepwise neurological impairments . 
 assuming the strong humoral response underlying nmo attacks , plasma exchange ( plex ) is an appropriate technique in severe nmo attacks . objective . presenting an up - to - date review of the literature of plex in nmo 
 . methods . 
 we summarize the rationale of plex in relation with the physiology of nmo , the main technical aspects , and the available studies 
 . results . 
 plex in severe attacks from myelitis or optic neuritis are associated with a better outcome , depending on plex delay (  time is cord and eyes  ) . 
 nmo - igg status has no influence . 
 finally , we build up an original concept linking the inner dynamic of the lesion , the timing of plex onset and the expected clinical results . conclusion . 
 plex is a safe and efficient add - on therapy in nmo , in synergy with steroids . 
 large therapeutic trials are required to definitely assess the procedure and define the time opportunity window . 
1. Introduction
2. Physiopathology of NMO
3. Plasma Exchange Procedure
4. PLEX in Severe Attacks
5. Timing of PLEX: Evolving to a Key Concept
6. PLEX as Preventive Treatment
7. Preventive Treatments and Future Avenues
8. Conclusion