Neuromyelitis optica

Pathogenesis and pathophysiology
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By Tiffani Stroup DO and Adil Javed MD PhD

Aquaporin-4 receptors are present throughout the body, including the retina, renal distal collecting tubules, gastric mucosa, lung, cerebral gray matter, and cerebellum. However, neuromyelitis optica preferentially targets the receptors in the optic nerves and spinal cord, for reasons that are unclear (Kira 2011).

The NMO-IgG antibody is directed against aquaporin-4, a water channel that is a component of the dystroglycan protein complex (Lennon et al 2005). Aquaporins have a ubiquitous distribution in the body, including exocrine glands, gastrointestinal tract, kidneys, and brain. Aquaporin-4 is the predominant water channel expressed in the CNS. Indirect immunofluorescence shows a distinctive NMO-IgG pattern of binding in pia and subpia, Virchow-Robin space, and microvessels in white and gray matter of the cerebellum, midbrain, and spinal cord. It binds to subependymal white matter in a mesh pattern. NMO-IgG binds to the abluminal face of cerebral microvessels. Dual labeling with glial fibrillary acidic protein reveals juxtaposition of aquaporin-4 to astrocytic foot processes. NMO-IgG also binds to distal urine-collecting tubules in the renal medulla and to basolateral membranes of gastric parietal cells (Lennon et al 2005). Many authors suggest that neuromyelitis optica should be described as an astrocytopathy rather than a demyelinating disorder due to selective destruction of astrocytes with relative preservation of myelinated fibers in acute lesions. The proposed pathway of astrocyte destruction involves a 2-step process. First, circulating NMO-IgG antibodies bind to aquaporin-4 receptors on the astrocyte foot processes. Next, there is opening of the blood-brain barrier, likely by a T-cell-dependent mechanism. Internalization of aquaporin-4 down-regulates pathways for glutamate homeostasis, which promotes further blood-brain barrier permeability. Binding of NMO-IgG to AQ4 in the presence of complement leads to complement activation, chemo-attraction of granulocytic white blood cells, and astrocyte injury via antibody-dependent cytotoxicity (Saikali et al 2009; Jacob et al 2013). During an acute attack, serum IL-6 is elevated, which is a growth factor for plasmablast survival that promotes further secretion of aquaporin-4 antibody (Jacob et al 2013).

NMO-IgG is likely a pathogenic antibody, causing damage primarily due to complement activation. Other sites, such as the kidney and gut epithelium, are not clinically affected by NMO-IgG, perhaps due to complement inhibitors present in these areas. Interestingly, transfer of NMO-IgG to rats does not induce neuromyelitis optica unless rats have been previously immunized with EAE. This suggests that opening of the blood-brain barrier is a prerequisite for disease activity. Along these lines, AQ4 antibody has been detected in patients years before disease manifestations. In patients who are aquaporin-4 antibody-negative with NMOSD, there may be an undiscovered pathological antibody (Jarius and Wildemann 2010).

Lesions in neuromyelitis optica show perivascular and parenchymal leukocyte infiltration, deposition of IgG, IgM, and complement, loss of GFAP and AQ4 staining, hemorrhagic exudation, edema, capillary proliferation, vascular fibrosis, hyalinization, tissue necrosis, and cavitation (Jarius and Wildemann 2010). Both white and gray matter is affected. Lesions are more similar to necrotizing vasculitis than to the demyelinating lesions of multiple sclerosis or acute disseminated encephalomyelitis.

Neuromyelitis optica is sometimes grouped with other demyelinating diseases that also include multiple sclerosis and acute disseminated encephalomyelitis. However, neuromyelitis optica is distinct from the other demyelinating diseases. Table 1 shows demographic, radiological, and pathological differences between neuromyelitis optica and the other 2 common primary demyelinating diseases, multiple sclerosis and acute disseminated encephalomyelitis. Lesions in neuromyelitis optica, multiple sclerosis, and acute disseminated encephalomyelitis all contain T cells and macrophages. Distinct to neuromyelitis optica is prominent infiltration of neutrophils, eosinophils, and IgM deposition in the lesions. Complement products are also seen in lesions from neuromyelitis optica. Hence, unique to neuromyelitis optica is activation of multiple types of immune responses, including activation of Th1 cell-dependent immune responses (IgG-complement activation), Th2 cell-dependent responses (eosinophils), and T cell-independent responses (IgM deposition). In acute disseminated encephalomyelitis lesions, T cells and macrophages play a dominant role, and humoral mechanisms are involved to a lesser degree. Multiple sclerosis lesions are heterogeneous, with at least 4 pathologic patterns. Pathologic patterns I and II in multiple sclerosis show T cells and macrophages, but immunoglobulin deposition and complement activation are unique to pattern II. Both pattern I and II lesions are seen in experimental autoimmune encephalomyelitis, depending on the genetic background of animals. Pattern III and IV lesions show prominent loss of oligodendrocytes either by apoptosis or necrosis, and these patterns have not been observed in the experimental autoimmune encephalomyelitis model.

Table 1. Comparison of Demyelinating Diseases

Characteristics

Neuromyelitis

optica

Multiple sclerosis

Acute disseminated encephalomyelitis

 

Age (median, estimate) years

 

40

30

15

Sex F:M

4:1 (relapsing)

 

3:1 (relapsing)

1:1

Ethnicity

Greater incidence in Japanese and Blacks

 

White >> Blacks

Sporadic

Clinical course

 

 

 

Monophasic

30%

 

NA

>95%

Relapsing

70%

 

80%

5% to 20% *

Progressive (secondary and primary

 

NA

10% to 15% primary from onset; more than 50% become secondary progressive

 

NA

MRI features

 

 

 

Brain lesions

Usually absent

Oval, usually perpendicular to ventricles

 

Large, oval, disseminated and periventricular

Spinal cord lesions

Longitudinal extensive > 3 vertebral body length

 

Punctate lesions, < 3 vertebral body length

Transverse myelitis < 3 vertebral body length†

Optic nerve lesions

Can be bilateral, poor recovery

Usually unilateral with good recovery

 

Can be bilateral with good recovery

CSF findings

 

 

 

White blood cell

Polymorphonuclear cells >> lymphocytes

 

Primarily lymphocytes

Lymphocytes > polymorphonuclear cells

Protein

Elevated

 

Typically normal

Elevated

Oligoclonal bands

Usually absent‡

 

> 90% present

Usually absent‡

MMP-9

Decreased

Elevated

NA (serum elevated)

 

   IL-6     Increased     Normal     Increased

Pathology

 

 

 

Gray matter

Necrosis

 

Demyelination

Demyelination

White matter

Necrosis

 

Demyelination

Demyelination

Lesion immunopathology

 

 

 

Macrophages

+++

 

+++

+++

T cells

+++

 

+++

+++

B cells

++

 

++ (pattern I, II)

+

Eosinophils

++

 

None

None

Neutrophils

+++

 

Rare

Rare

Antibodies

+++

 

++ (pattern II)

+

Complement

++

 

++ (pattern II)

+

Coexisting autoimmune diseases

 

30% to 50%

Infrequent

Not seen

Disability progression

Attack related

Can be attack independent

Attack related

* relapses occur based on ethnic background and duration of steroid taper
† longitudinal extensive myelitis can occur
‡ when positive, become negative later

In This Article

Introduction
Historical note and nomenclature
Clinical manifestations
Clinical vignette
Etiology
Pathogenesis and pathophysiology
Epidemiology
Prevention
Differential diagnosis
Diagnostic workup
Prognosis and complications
Management
Pregnancy
Anesthesia
References cited
Contributors