BACKGROUND (1814-1901) in 1850, and Jacob Augustus Lockhart Clarke

BACKGROUND

 

History

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Neuromyelitis optica (abbreviated NMO) is a rare CNS condition
often affecting both the spinal cord and the optic nerve. While the majority of
advancements in this field has been made only in the past two decades,
neuromyelitis optica traces its roots all the way back to the early 19th
century. In 1804, Louis XVIII’s physician Antoine Portal (1742-1832) reported
visual loss in a patient with spinal cord inflammation but no brain pathology;
this represented the first ever account of its kind in Western literature (Jarius
and Wildemann, 2012). From then on, various physicans have reported cases of
similar symptoms in their patients: Giovanni Battista Pescetto (1806-1884) in
1844, Christopher Mercer Durrant (1814-1901) in 1850, and Jacob Augustus
Lockhart Clarke (1817-1880) in 1862. It wasn’t until 1894, however, when French
neurologist Eugène Devic (1858-1930) finally gave this syndrome (characterised
by optic neuritis and acute myelitis) a name: “neuromyelitis optica” (Jarius
and Wildemann, 2013). Devic’s contribution to the discovery of this condition
is still recognised to this day; neuromyelitis optica is also known as ‘Devic’s
disease’ or ‘Devic’s syndrome’. Devic believed that neuromyelitis optica was a
disease in its own right;
however, over the years, people have only considered it to be a variant of
multiple sclerosis (Papadopoulos and Verkman, 2012). It wasn’t until after the
turn of the century when a major discovery definitively distinguished NMO from
multiple sclerosis.

 

Clinical Features
& Demographics

Traditionally,
neuromyelitis optica could be diagnosed when the following were present: optic
neuritis, acute myelitis, and at least two of three supportive criteria
(contiguous spinal cord MRI lesion extending over ³3 vertebral segments; brain MRI not meeting
criteria for multiple sclerosis; NMO-IgG seropositive status) (Wingerchuk et al., 2006). According to Papadopoulos
and Verkman’s review article (2012), neuromyelitis optica affects approximately
0.3-4.4 per 100,000 individuals. It is much more prevalent in women than in men;
up to 90% of all NMO patients are female (Wingerchuk et al., 2007).

 

Comparison to
Multiple Sclerosis

While neuromyelitis optica and multiple sclerosis
share a number of clinical and radiological features (Jarius and Wildemann,
2013) such as transverse myelitis and spinal cord lesions, there are many
differences between them. A review article by Wingerchuk et al. (2007) described the median age of onset for neuromyelitis
optica to be 39 years-old, compared to 29 for multiple sclerosis; the majority
(80-90%) of NMO patients have relapsing episodes of myelitis and optic
neuritis, whereas MS patients usually have milder attacks with good recovery (only
15% of MS patients are primary-progressive). Wingerchuk et al. also expressed that the distinction of neuromyelitis optica
from multiple sclerosis can be made further by the use of laboratory studies,
specifically the analysis of the cerebrospinal fluid: NMO-specific myelitis is
characterised by prominent cerebrospinal fluid pleocytosis (>50´106
leucocytes/L) with a predominance of neutrophils; on the other hand, attacks of
multiple sclerosis typically involve much milder CSF pleocytosis with a high
proportion of lymphocytes instead of neutrophils. Finally, excessive
oligoclonal bands of IgG (indicating intrathecal immunoglobulin synthesis) is
found in the cerebrospinal fluid of 15-30% of NMO patients, compared to 85% of
MS patients (Wingerchuk et al.,
2007).

 

Discovery of
NMO-IgG

In the year 2004, Lennon et al. discovered a
circulating autoantibody in a group of patients with neuromyelitis optica which
was absent in MS patients; this biological marker was termed NMO-IgG (or
AQP4-IgG). This breakthrough not only revolutionised our understanding of the
disease (Papadopoulos and Verkman, 2012), but it also gave conclusive evidence
that neuromyelitis optica was distinct from multiple sclerosis. In their study,
Lennon et al. tested serum samples
from North American and Japanese patients with suspected neuromyelitis optica
and multiple sclerosis. They found that NMO-IgG was present in 73% of those
diagnosed with NMO, 46% of those classified as high risk candidates for NMO,
and 0% of those diagnosed with classic MS or miscellaneous autoimmune and
paraneoplastic neurological disorders; furthermore, they concluded that NMO-IgG
binds at the blood-brain barrier (specifically microvessels in the CNS, pia,
subpia, and Virchow-Robin space) (Lennon et
al., 2004). It wasn’t particularly surprising to find that neuromyelitis
optica was an antibody-mediated disease, however; 78% of all patients with
autoimmune diseases are women (Fairweather, Frisancho-Kiss and Rose, 2008),
which is similar to the demographics of neuromyelitis optica.

 

Discussion of Aquaporins

Aquaporins are integral
membrane proteins that selectively allow the passive transport of water
molecules. While there are thirteen known classes of aquaporins, the most
abundant water channel in the central nervous system is aquaporin-4 (AQP4),
which is found in the perimicrovessel astrocyte foot processes, glia limitans,
and ependyma (Saadoun and Papadopoulos, 2010). The structure of aquaporin-4
consists of four monomers, each with six helical transmembrane domains and two
short helical segments surrounding an aqueous pore (Verkman et al., 2013). A key article by Saadoun et al. (2005) discovered that aside from
facilitating water movement into and out of the brain, aquaporin-4 plays a key
role in enhancing astroglial cell migration in glial scar formation. The significance
and relevance of this to neuromyelitis optica will be discussed further in the
article.

 

Discussion of Astrocytes

Astrocytes (astron = star and kytos = cell in Greek) are star-shaped glial
cells found in the central nervous system. Also known as astroglia, they
consist of a cell body (soma), a high number of branched processes, and end
feet at the end of each process. Astrocytes are arguably one of the most
important cells of the central nervous system; a few of their many functions
include providing structural support for neurons and other glial cells, maintaining
interstitial fluid homeostasis by regulating ion concentration, clearing
synapses of used neurotransmitters, forming a glial scar as a response to
injury, and contributing to the blood-brain barrier.

 

Discussion of the Complement System

The complement system is a
part of the innate immune system that promotes inflammatory responses and opsonises
pathogens to fight infection; its name comes from the fact that it ‘complements’
and enhances the action of antibodies and phagocytic cells (Janeway et al., 2001). This system consists of
many different plasma proteins, called “complement proteins”, which activate a
large-scale complement cascade at the onset of infection. Due to the
potentially dangerous nature of a pathway that leads to such potent
inflammation and destructive effects, tight regulatory mechanisms must be put
in place; for this reason, complement regulators are present at many points in
the complement cascade (Janeway et al.,
2001).

 

PATHOPHYSIOLOGY

 

Pathogenicity of NMO-IgG

A study by Hinson et al. (2007) evaluated the selectivity
and consequences of immunoglobulins binding to target cells expressing aquaporin-4.
Using confocal microscopy and flow cytometry, they not only found that serum
IgG (but not IgM) from patients with neuromyelitis optica binds to aquaporin-4
and initiates both aquaporin-4 endocytosis/degradation and also complement
activation, but also found that aquaporin-4 is highly expressed at paranodal
astrocytic endfeet; from these results, they concluded that NMO patients’ serum
IgG has a selective pathologic effect on cell membranes expressing aquaporin-4
(Hinson et al., 2007).

 

Binding of NMO-IgG to Aquaporin-4

In humans, aquaporin-4
channels are expressed as two different isoforms formed by alternative splicing:
a full-length isoform (named M1) with translation initiation at Met-1, and a
short isoform (named M23) with translation initiation at Met-23 (Jin, Rossi and
Verkman, 2011). The significant difference between these two isoforms is that while
M23 forms supramolecular assemblies called orthogonal arrays of particles
(OAPs), M1 does not do the same, unless it coassembles with M23 (Jin, Rossi and
Verkman, 2011). Multiple studies have found that in the serum of patients with
neuromyelitis optica, binding of NMO-IgG occurs more with cells expressing M23
than with M1; these studies suggest that NMO-IgG preferentially binds to OAPs (Papadopoulos
and Verkman, 2012).

 

NMO-IgG and Complement Activation

While the NMO-IgG antibody is
the main marker for neuromyelitis optica, there is one other key component that
must also be present for the formation of NMO lesions: complement proteins. A
study by Saadoun et al. (2010)
involving mouse models discovered that NMO-IgG alone was unable to produce
lesions in mouse; however, once human complement was co-injected, they observed
lesions with the following characteristic histological features of human NMO
lesions: inflammatory cell infiltration, demyelination, loss of aquaporin-4 and
GFAP (glial fibrillary acidic protein) expression, and perivascular deposition
of activated complement components. Furthermore, since NMO-IgG with human
complement did not produce NMO-like lesions in AQP4-null mice, it was confirmed
that autoantibodies to aquaporin-4 were indeed responsible for these lesions,
instead of another autoimmune component of the IgG preparations (Saadoun et al., 2010).

 

Downstream Effects of Complement Activation

Both complement-dependent
and antibody-dependent cell-mediated cytotoxicities are thought to be present
in the pathogenesis of neuromyelitis optica (Nishiyama et al., 2016). Thought to be the principal mechanism of
cytotoxicity in neuromyelitis optica, complement-dependent cytotoxicity is
greatly enhanced in aquaporin-4 channels assembled in OAPs; on the other hand,
antibody-dependent cell-mediated cytotoxicity involves natural killer cells and
was found not to be dependent on OAP formation (thus can be present in both M1
and M23-expressing cells) (Phuan et al.,
2012). This complement-dependent cytotoxicity pathway of neuromyelitis optica
begins with the multivalent interaction between complement protein C1q and
array-assembled NMO-IgG (Phuan et al.,
2012).

 

The activation of the
classical complement pathway at the perivascular astrocytic end-feet results in
a number of downstream effects. A study by Lucchinetti et al. (2002) proposed that this complement activation leads to the
recruitment of activated macrophages that locally generate cytokines, proteases
and oxygen/nitrogen free radicals; this results in the non-selective
destruction of both grey and white matter, including axons and
oligodendrocytes. This explains the demyelinating feature of neuromyelitis
optica, as oligodendrocytes are glial cells responsible for the myelination of
neuronal axons in the central nervous system. As shown by Lucchinetti et al., this axonal degeneration leads
to neuronal necrosis. Furthermore, there is intense perivascular and meningeal
infiltration by eosinophils and neutrophils in the spinal cord; these activated
eosinophils release cytotoxic granule proteins such as MBP, eosinophil-derived
neurotoxin, eosinophil cationic protein and eosinophil peroxidase (Lucchinetti et al., 2002).

 

Animal Models

Ever since the discovery of
the NMO-IgG auto-antibody (Lennon et al.,
2004), many animal models have been developed to further investigate the
pathogenesis of neuromyelitis optica. However, it is surprisingly difficult to
mimic this disease in other organisms; for instance, the simple transfer of
AQP4 antibodies into naïve animals was insufficient to induce experimental NMO
(similar to how human patients may possess anti-AQP4 antibodies for many years
before showing any clinical signs of NMO) (Bradl and Lassmann, 2014).
Furthermore, NMO-IgG only recognises conformational epitopes of aquaporin-4
that require immunogen consisting of properly folded AQP4 (which is insoluble
and can only be solubilised by toxic concentrations of triton); this can’t be
achieved by using recombinant proteins during immunisation (Bradl and Lassman,
2014). Despite these challenges, many models have crucially improved our
understanding of this disease: autoimmunity to myelin oligodendrocyte
glycoprotein (MOG) in rats was found to mimic the pathology in classic multiple
sclerosis and neuromyelitis optica (Storch et
al., 1998); in addition to antibodies to AQP4, complement proteins must
also be present for the formation of NMO lesions (Saadoun et al., 2010); and more recently, interleukin-1 beta released in
NMO lesions was found to facilitate neutrophil entry and blood-brain barrier
breakdown (Kitic et al., 2013).

 

CLINICAL IMPLICATIONS

 

Importance of Understanding Pathophysiology for Developing Treatments

Understanding the
pathophysiology of neuromyelitis optica is essential for the development of
novel treatments, as it gives us insight into where potential therapeutic
targets may be. For example, our understanding of the presence of anti-AQP4
antibodies led to the routine usage of plasmapheresis in treating this disease;
one trial found that anti-AQP4 levels decreased by 85% after plasmapheresis was
used in acute attacks (Kim et al.,
2013). Next, the discovery that complement was required for the formation of
lesions suggested that complement inhibitors such as C1 inhibitor may be an
effective way to limit CNS injury in neuromyelitis optica (Saadoun et al., 2010). Finally, recent evidence have
pointed to B-cell-mediated humoral immunity in the pathogenesis of
neuromyelitis optica; this led to the usage of Rituximab, an antibody against
the CD20 antigen on B-cells, which profoundly depletes B-cells and decreases
the frequence and severity of NMO attacks (Etemadifar et al., 2017).

 

While the treatment methods
above have led to marked improvement in patients with neuromyelitis optica, new
treatment options are constantly being explored. One of the most prominent approaches
still in their preclinical phase would be aquaporumab, a highly-selective,
nonpathogenic human monoclonal antibody that competes against NMO-IgG to bind
to aquaporin-4 channels; aquaporumab greatly reduced NMO-IgG-dependent
cytotoxicity in animal and in vitro
models of neuromyelitis optica (Papadopoulos, Bennett and Verkman, 2014). Some
existing therapeutic strategies that target complement proteins, neutrophils,
and eosinophils (initially developed for other indications) are currently under
clinical evaluation for the repurposing for neuromyelitis optica (Papadopoulos,
Bennett and Verkman, 2014).

 

Modified Diagnostic Criteria

Recent advancements in the
field of neuromyelitis optica research had rendered the previous diagnostic
criteria from 2006 inadequate for contemporary practice; the International
Panel for NMO Diagnosis (IPND) was thus assembled to develop revised diagnostic
criteria that included non-opticospinal clinical and MRI characteristics
(Wingerchuk et al., 2015).
Furthermore, the term ‘neuromyelitis optica’ would be merged with
‘neuromyelitis optica spectrum disorder’ (NMOSD), which was previously used for
patients who didn’t necessarily fit under the traditional criteria of NMO but
were vulnerable to future attacks.

 

Table 1. (Wingerchuk et al., 2015) NMOSD diagnostic criteria
for adult patients

 

Seronegative NMO & Anti-MOG Antibodies

Patients who don’t test
positive for the anti-AQP4 antibody may still be diagnosed with neuromyelitis
optica, but are referred to as being ‘seronegative’. As it has been many years
since the initial discovery of AQP4-IgG, anti-AQP4 assay sensitivity has been
improved to near 90%; thus the concept of seronegative NMO has been challenged
(Levy, 2014). Scientists and clinicians have attempted to explore this
so-called ‘seronegative NMO’ by identifying a subpopulation of patients with
clinical features of neuromyelitis optica while testing positive for antibodies
against myelin oligodendrocyte glycoprotein (MOG); they appeared to have a
slightly different disease phenotype with a demographic and clinical profile
more similar to patients with acute demyelinating encephalomyelitis: while
females comprised the vast majority of the anti-AQP4-seropositive group,
anti-MOG seropositivity was more common in males; episodes were more severe in
the anti-MOG-seropositive group but recovery was better and more likely to be
monophasic, compared to those with anti-AQP4 seropositivity (Levy, 2014). While
the ambiguity of seropositive vs. seronegative NMO had posed as an issue, the
newly-revised diagnostic criteria for NMOSD in 2015 have tackled this problem
by clarifying the requirements for the diagnosis of NMOSD without the presence
of AQP4-IgG.

 

Organs Outside the Central Nervous System

In addition to the central
nervous system, aquaporin-4 channels are also expressed in the epithelium of
many organs in the human body such as the kidney, intestine, salivary glands,
sensory organs, and skeletal muscles (Gleiser et al., 2016). However, these peripheral organs are usually
unaffected in patients with NMOSD. This phenomenon can be explained by the role
of complement regulators. Astrocytic end-feet in normal brain lack complement
regulators CD46, CD55 and CD59, while the kidneys, stomach and skeletal muscle
express one or more of these complement regulators; this suggests why these
peripheral organs are generally spared from AQP4-IgG and complement-mediated
damage (Saadoun and Papadopoulos, 2015). However, the impact of NMOSD on
peripheral organs warrants further investigation, as a recent study has found
that muscle damage occurs in patients with NMOSD and is aggravated during the
acute phase (Chen et al., 2017).

 

Neuromyelitis Optica and Pregnancy

As the vast majority of NMOSD
patients are female, it’s important to discuss how NMOSD affects pregnancy. A
passive mouse transfer study proposed that AQP4-IgG increases miscarriage rates
by binding to the placental syncytiotrophoblast of fetal villi and activating
the classical complement pathway; this is followed by the deposit of C5b-9 onto
the syncytiotrophoblast plasma membrane, thus causing damage and loss of AQP4
expression, followed by leukocyte infiltration into the placenta, releasing
elastase and other proteases that inflame and necrotise the placenta,
ultimately causing fetal death (Saadoun et
al., 2013). The link between neuromyelitis optica and pregnancy outcome was
further investigated in a retrospective study by Nour et al. (2016), where they found the miscarriage rate to be higher
after NMOSD onset (42.9% compared to 7.04% before NMOSD onset). They concluded
that pregnancy after NMOSD onset is a risk factor for marriage (Nour et al., 2016) and provided further
evidence pointing to the destructive effects of AQP4-IgG on the placenta.

 

FUTURE DIRECTIONS

 

While the field of
neuromyelitis optica research has rapidly evolved over the past one-and-half
decades, there is still major room for further development. It will be
interesting to explore whether there are other antibodies that cause
AQP4-IgG-like damage; the presence of anti-MOG antibodies in some patients
suggests that even more types of antibodies may be present. In addition, since
neuromyelitis optica is currently incurable, the development of novel therapeutic
drugs (e.g. aquaporumab, as mentioned earlier) is essential. Another
possibility is to modify complement regulators in order to protect the central
nervous system from complement-mediated astrocytopathy.

 

Other questions to explore
may be how AQP4-IgG gains entry into the blood-brain barrier, why AQP4-IgG
forms in the first place, and whether there are other aquaporinopathies
elsewhere in the body. A link between neuromyelitis optica and myasthenia
gravis (a chronic, autoimmune neuromuscular disease characterised by skeletal
muscle weakness) shoud be studied. Since the thymus is often enlarged in
patients with myasthenia gravis, it will be interesting to observe how the
thymus differs in patients with NMOSD from those without. Since no treatment
has been proven to be safe and effective for NMOSD in any clinical trials
(Weinshenker et al., 2015), more
interventional studies must be done in order for the development of novel
viable therapeutic agents to be effective. Perhaps the biggest challenge of implementing
placebo-controlled trials is the severity of NMOSD attacks; however, innovative
approaches such as shared placebo groups may overcome the hurdles associated
with designing such trials (Weinshenker et
al., 2015).

Furthermore, another major
difficult aspect of designing NMOSD clinical trials is the rarity of this
disease; since more common autoimmune disorders (such as multiple sclerosis)
often overshadow neuromyelitis optica, it deserves more attention and awareness
than it is currently getting.