Under healthy conditions, AQP4 is coexpressed with the excitatory amino acid transporter 2, which enables glutamate uptake by astrocytes. Loss of AQP4 in AQP4-Ab-positive NMOSD may lead to an excessive accumulation of glutamate in the extracellular space. In the context of neuroinflammation and dysregulation of sensory neurons, persistent excessive BDNF, and glutamate concentrations affect vulnerable inhibitory alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and gamma-aminobutyric acid (GABA) neurons, respectively (72, 73). The resulting imbalance between excitation and inhibition can then facilitate the development of chronic pain (3, 74, 75). In addition, astrocytes release endocannabinoid 2-arachidonoylglycerol (2-AG), which strongly enhances GABAergic inhibition. Loss of astrocytes in NMOSD leads to 2-AG reduction, likely leading to nociceptive pain and hyperalgesia (28).

Structural cerebral alterations may also affect chronic pain perception in NMOSD. Recently, a study on subcortical abnormalities in female NMOSD patients showed smaller hippocampus and pallidum volumes in patients with neuropathic pain compared to patients without neuropathic pain, as well as a negative correlation between pain intensity and volumes of the accumbens nucleus and thalamus (56). A study on pain-related morphological abnormalities in AQP4-Ab-positive NMOSD described an association of the ventral posterior nucleus (VPN) volume with several measures of pain intensity (76). Both studies suggest that subcortical structures are substantially involved in cognitive, emotional, and modulatory pain processing in AQP4-Ab-positive NMOSD (56, 76).

While AQP4-Abs target astrocytes, MOG-Abs bind to myelin-forming oligodendrocytes. Therefore, inflammation in MOGAD primarily causes demyelination with a loss of the microtubule cytoskeleton of oligodendrocytes (13, 77–79). Under healthy conditions, the neuropeptide nerve growth factor (NGF) has a high affinity to bind MOG. Moreover, NGF is part of the nociceptive system: It binds tropomyosin receptor kinase A (TrkA). TrkA is expressed on unmyelinated nociceptive axons of the spinal cord and regulates synaptic strength and plasticity of sensory neurons. Thus, the loss of MOG by antibody-mediated destruction in MOGAD may cause abundant NGF concentrations in the CNS, leading to aberrant sprouting of unmyelinated nociceptive fibers in the posterolateral tract of the spinal cord and hence nociceptive pain (80).

Spinal cord lesions in NMOSD are typically extensive and occur predominantly in the cervical and thoracic spinal cord (17, 81–83). As AQP4 is mainly expressed in the gray matter, lesions concentrate around the central canal, and the adjacent gray matter in the dorsal and ventral horns, as well as in the dorsal root entry zone (84). Ascendant and descendent white matter tracts, including the spinothalamic tract (STT) (52, 85, 86), are affected by severe lesions (87). Tackley et al. report a significant relationship between persistent thoracic myelitis lesions and the severity of neuropathic pain. The presence of cervical lesions, in contrast, were predictive of lower pain scores (53).

In the brainstem, the dorsal medulla oblongata and area postrema have the highest distribution of AQP4 (74, 88). It has been shown that 27% of NMOSD patients with cervical longitudinally extensive transverse myelitis (LETM) showed lesions involving the brainstem (89). Such a distribution could include trigeminal nucleus or periaqueductal gray (PAG) pathology, causing headaches in affected patients (74). The PAG is considered to be a migraine generator and a modulator of headache in NMOSD. Moreover, the hypothalamospinal tract, localized in the dorsolateral medulla, activates the hypothalamus, and the trigeminovascular system. Both regions are considered to be involved in the pathogenesis of headache (90, 91).

Dorsal lesions of the medulla oblongata lead to substance P release, a transmitter that can cause and maintain nociceptive activation of the trigeminal tract nucleus (92). Besides headache, neuropathic pain was also reported more frequently in NMOSD patients with medulla oblongata lesions (85.7% AQP4-Ab positive) than in patients without such lesions (31.8 vs. 11.1% and 65.9 vs. 29.4%) (93). Increased neuropathic pain frequency could be explained by the severe and extensive spinal cord involvement associated with the medulla oblongata (93).

Moreover, AQP4-Ab-positive NMOSD has a predilection to affect the optic nerve (94–96). Astrocytes surrounding the optic nerve express high levels of AQP4, but the unmyelinated optic nerve head also expresses AQP4. Moreover, a high density of retinal astrocytic Müller cells, expressing AQP4, are located in the parafoveal area (97–101).

For a further and more detailed pathophysiological background of possible mechanisms explaining pain in NMOSD, we refer to a review by Bradl et al. (3).

Spinal cord lesions in MOG-Ab-positive myelitis are not always longitudinal and extensive but can still cause sensory symptoms like pain and dysesthesia (38). The axial lesion extension may be crucial for the risk of pain. Depending on the level of the lesion, aberrant nerve fiber sprouting could lead to occipital neuralgia or to more distal neuropathic pain syndromes. Moreover, it has been shown that central neuropathic pain can be induced by oligodendrocyte death and axonal pathology in the spinothalamic tract (102).

The brainstem is a critical region in the pathophysiology of headache. Brainstem lesions are present in up to one-third of patients suffering from MOGAD and could promote the risk for migraine and trigeminal neuralgia (103, 104).

MOG is highly expressed by oligodendrocytes myelinating the optic nerve (105) and is consequently a predominant target in MOG-Ab-related ON. ON-related pain is particularly severe in MOGAD and can present as a migraine-like headache (54). In these cases, severe edema may lead to irritation of the meningeal nerve sheath, which surrounds the optic nerve and contains nociceptive fibers of trigeminal origin (106–108). The trigeminal nerve provides sensory innervation to the ocular and periocular area, and its recurrent branches innervate the intracranial dura, venous sinuses, and cerebral vessels, likely leading to headache (109, 110).

Optic neuritis is an inflammation of the optic nerve characterized by severe visual loss or blindness associated with ocular pain (111) and occurs in the context of many inflammatory diseases (112–116). ON-related eye pain and pain on eye movement is more common in MOGAD, with reports ranging from 65 to 86% (46, 117, 118), compared to AQP4-Ab-positive ON (28.6–50%) (46, 117) and idiopathic Ab-negative ON (10–46%) (117, 119).

AQP4-Ab-positive ON is typically accompanied by retrobulbar pain often worsened by eye movement (2, 27, 46).

MOGAD-related ON pain seems to be particularly severe, sometimes accompanied by migraine-like headaches that precede the visual deficit (54, 120).

Headache is an unspecific but common symptom in NMOSD (2, 74) and has also been described in MOGAD, here mainly associated with optic neuritis (2, 38, 54). It can occur as a first symptom or persist during the disease course (2, 38, 74). NMOSD-related headache can occur as a cervicogenic-like headache (2, 58, 74), neck pain (60, 68), paroxysmal hemicrania (62), or in the context of meningoencephalitis (74, 121). It is typically a mixed pain condition with neuropathic and nociceptive components (74).

Neuropathic pain is particularly severe (2, 53) and patients typically characterize neuropathic pain as agonizing, shooting, and distressing (57). Neuropathic pain occurs more frequently in NMOSD (83% AQP4-Ab positive) than in MOGAD (80 vs. 40%) (2, 27). It can occur as an early myelitis-related symptom or develop during the disease course (3, 50, 53). Medication is currently not sufficient to control neuropathic pain (2, 27), particularly in patients with AQP4-Ab-positive NMOSD (51). A higher dosage of pain medication was not associated with being free of pain but rather with greater cognitive dysfunction and fatigue (27).

Neuropathic pain can be permanent or intermittent like Lhermitte's sign (27, 81, 124) and is localized either on the extremities or on the trunk, the latter often defined as a girdle sensation (18, 26, 28, 124, 125).

Lhermitte's sign is often painful and occurs in 35–60% of AQP4-Ab-positive NMOSD patients (27, 81, 124). It is defined as a brief, electric-shock-like sensation that runs from the back of the head down the spine, provoked by inclining the neck forward (124). It has been proposed that Lhermitte's sign occurs because demyelinated sensory fibers are hyperexcitable to percussion or elongation (124).

The girdle sensation describes an often burning sensation on the skin, localized with an extension of three or four dermatomes between T3 and T11 (124). It has been reported in 45.8–69% of NMOSD (83% AQP4-Ab positive) patients and can sometimes be misdiagnosed as acute abdomen (27, 124). Schöberl et al. describe an AQP4-Ab-positive NMOSD patient presenting with typical area postrema syndrome who developed an unusual painful segmental erythema resulting from a dorsolateral spinal cord lesion at C6/7 level. A dysregulated A-beta-fiber-evoked vasodilation has been discussed as a possible underlying pathophysiological mechanism (126). Pelvic pain has been reported to occur as an unusual presentation of AQP4-Ab-positive NMOSD, following a lesion of the conus medullaris (61).

Brainstem pathology can also cause neuropathic pain syndromes like trigeminal (2, 16, 74, 127) and occipital neuralgia (2, 128) in NMOSD and MOGAD. Trigeminal neuralgia is defined by pain in the area of the trigeminal innervation (usually V3 and/or V3 division). It is typically characterized by paroxysmal, sudden attacks of short severe stimulus-triggered and electric-like pain episodes (74). Interestingly, NMOSD patients with trigeminal neuralgia rarely show MRI pathology affecting the trigeminal root entry zone (129). It has been discussed whether or not a dual mechanism including pontine plaques and consecutive neurovascular compression may contribute to the pathophysiology (74). Neuropathic pruritus has also been described following brainstem and spinal cord lesions (52). Pruritus is defined as “an unpleasant cutaneous sensation provoking the desire to scratch.” Neuropathic pruritus is caused by affected pruritogenic neurons in the absence of a pruritogenic substance (52). Neuropathic pruritus associated with myelitis has been observed in 27.3% of ACQP4-Ab-positive NMOSD patients, either as a first symptom or a few days after the onset of other myelitis-related symptoms. It has a sudden onset of high intensity with a duration from seconds to minutes, associated with superficial sensory deficits and/or pain. It can occur on the trunk, the extremities, or the occipital region of the head (52). An inflammation-related demyelination involving second-order itch neurons in the dorsal horn of the spinal cord has been discussed as an underlying pathophysiological mechanism. The role of brainstem lesions affecting the spinal nucleus of the trigeminal nerve or periaqueductal pathways has also been discussed (52, 130).

Very few studies have focused on neuropathic pain in MOGAD. Lhermitte's sign (38, 45), band-like girdle sensations (131), trigeminal and occipital neuralgia, and neuropathic extremity pain (2, 38) have been mentioned but have so far not been studied in detail. Myelitis in MOGAD may have a better tendency to recover (83) and therefore cause less severe central neuropathic pain syndromes than in NMOSD.

Spasticity is defined as “disordered sensorimotor control resulting from an upper motor neuron lesion, presenting as intermittent or sustained involuntary activation of muscles.” At the patient level, it can be defined as an “unusual tightening of muscles that feels like leg stiffness, jumping of legs, a repetitive bouncing of the foot, muscle cramping in the legs or arms, legs going out tight and straight or drawing up” (140). More than 50% of NMOSD patients are reported to suffer from moderate to severe spasticity (25), but very little is known about spasticity in MOGAD (1, 38).

Painful tonic spasms are defined as paroxysmal, recurrent muscle spasms in one or more limbs and/or the trunk, lasting seconds to minutes, accompanied by intense pain and dystonia (29, 30, 65). Several case reports and small series describe PTS in NMOSD (18, 29, 29–31, 65–67, 136, 141–144), but no reports were identified mentioning PTS in MOGAD. Abboud et al. reported that all patients with tonic spasms had associated neuropathic pain (145). PTS and pain occur more frequently in NMOSD than in MS (18, 29), and PTS-associated myelitis in AQP4-Ab-positive NMOSD has been described with a specificity of 98.7% compared to MS (143). Kim et al. showed that transverse myelitis at disease onset, but not optic neuritis, was predictive of future occurrence of PTS. PTS develop mainly during recovery from the first myelitis attack within a mean of 48 days without occurrence of new MRI lesions (3, 29, 30). A spinal cord syndrome with paroxysmal tonic spasms may be particularly suggestive for NMOSD (29, 81). PTS may occur following the loss of inhibitory motor neurons in the central gray matter of the spinal cord (142). Abnormal demyelination can cause ephaptic transmission between the tracts causing spasms (65). As nerve damage does not affect somatosensory pathways, PTS are not considered to be of neuropathic origin (146).

Like headache, back pain is an unspecific syndrome but occurs frequently in NMOSD and MOGAD (1, 38, 131, 147, 148). It can emerge in the context of myelitis following radiculitis as described above but is often a mixed syndrome including central and peripheral neuropathic as well as nociceptive pain components. Malposition and axial instability following paresis or spasticity, reduced mobility with wheelchair dependence, or long-term corticoid therapy leading to osteoporosis are important secondary aspects to consider in these disorders and can enhance pain, especially back pain (5).

Up to 45% of patients with NMOSD and ~10% of patients with MOGAD suffer from autoimmune comorbidities (13), including connective tissue disease, dermatomyositis, rheumatoid arthritis, Sjoegren's syndrome, systemic lupus erythematodes, vasculitis, and myasthenia gravis (2, 51, 148–155), which can themselves be associated with pain (156). A careful diagnostic workup is necessary to detect potentially overlapping pathologies.

Attack-related treatment aims to reduce pain by reducing the destruction of the CNS. In NMOSD, as well as in MOGAD, acute attacks are usually treated with 1,000 mg intravenous methylprednisolone (IVMP) for 3–5 days (163). Prompt treatment initiation should also be considered in patients who present with pain as their only symptom, in order to avoid rapid progression and attack-related disability (148). Of note, attack-related disability can cause the development of secondary pain, e.g., paresis- and malposition-related pain, reflecting attack-independent disease progression. Rapid corticoid therapy showed prompt recovery from pain in NMOSD (120), and Jarius et al. showed nearly complete recovery in 50% of IVMP-treated MOG-Ab-related attacks (38). In cases of poor outcome, IVMP therapy can be increased to 2,000 mg/day. Such a high-dose IVMP therapy, however, seems to be less effective than plasma exchange or immunoadsorption (13, 164–166). Especially in isolated myelitis, it has been shown that clinical response to immediate plasma exchange (PLEX) was better compared to high-dose steroid therapy (166). This could be of relevance in the treatment of patients presenting with neuropathic pain.

Bradl et al. suggest a multidrug treatment at an early disease stage to limit the previously discussed complex interactions of proinflammatory and pronociceptive molecules in order to avoid pain instauration. They propose an approach similar to the treatment for traumatic brain injury, involving minocycline, peroxisome proliferator-activated receptor agonists, cell cycle inhibitors, statins, and progesterone (3). However, currently, there are no data on possible preventive effects on pain development in NMOSD or MOGAD in this regard.

Immunosuppressive therapy is essential to reduce disease activity and to avoid relapses in NMOSD and MOGAD, again with the aim to reduce the risk of future CNS damage. Up to now, although recommendations for treatment of NMOSD are available, these are not based on a high level of evidence (163, 167, 168). It is strongly recommended that patients suffering from AQP4-ab-positive NMOSD should receive immunotherapy after the first attack. Currently used preventative treatments in NMOSD include prednisone, azathioprine, rituximab, MMF, intravenous immunoglobulins (IVIGs), eculizumab, and methotrexate (163, 168, 169). Data on the efficacy of IVIG, however, are scarce (13). Of note, in Canada, the USA, and Europe, Eculizumab is currently the only approved therapy for the treatment of NMOSD, and all other medications are used off-label and empirically. In clinical trials, the positive effects on relapse rates of inebelizumab and satralizumab NMOSD have been described (13, 160, 169–173). Satralizumab has shown no benefit on pain intensity in two phase III studies (171, 174), and no data on pain are available for eculizumab and inebilizumab (169, 170, 173). As mentioned above, tocilizumab and MMF in contrast have shown positive effects on pain in AQP4-Ab-positive NMOSD. Still, evidence has to be proven in prospective studies focusing on pain as a primary outcome.

Tocilizumab is an antibody against IL-6, a major cytokine involved in NMOSD pathophysiology (175). It has been shown that NMO-IgG binding to AQP4 on astrocytes selectively induces internalization of AQP4 and production of IL-6 (70), which is thought to enhance the survival time of plasmablasts, which generate anti-AQP4 antibodies (71). IL-6 is a pronociceptive cytokine, which plays an important role in the development of neuropathic pain (176). Treatment with tocilizumab leads to reduced immunological activity, as well as neuropathic pain reduction (59, 125, 160), and should therefore be considered in patients at risk for neuropathic pain.

MMF is an immunosuppressant inhibiting the inosine monophosphate dehydrogenase. Consequently, the synthesis of guanosine nucleotide is reduced, which leads to an inhibition of B- and T-lymphocyte proliferation. MMF can be administered in both NMOSD and MOGAD, in the latter preferably in combination with steroids (13, 162). MMF reduces immunological activity and has a positive effect on pain intensity in AQP4-Ab-positive NMOSD patients (162). Unfortunately, the type of pain was not defined in this study.

Of note, pain can occur as a side effect of some immunosuppressive therapy. Eculizumab, inebilizumab, MMF, and rituximab can lead to headache, MMF can cause abdominal pain (13, 120, 170), and inebilizumab can cause back pain, extremity pain, and chest pain (173).

It has to be kept in mind that NMOSD and MOGAD are distinct nosologic entities regarding their underlying pathogenesis (36). In MOGAD, long-term immunotherapy is often considered and recommended only after a second attack in light of the presumably high proportion of monophasic cases and the overall good recovery. Empirical data suggest oral steroids as mainstay of treatment, and slow tapering is crucial to avoid recurrence of disease activity (33, 177, 178). In contrast to NMOSD, the efficacy of rituximab in MOGAD is controversial. Two recent studies showed that up to 45% of the patients under rituximab treatment still relapsed, despite an effective biological effect of rituximab. Consequently, memory B-cell depletion seems to be unable to prevent relapses in a subset of patients suffering from MOGAD (179, 180). Currently, a long-term treatment with intravenous immunoglobulins, or in some cases with methotrexate, may be preferred (13, 38). Like in NMOSD, treatment of MOGAD with classical MS drugs should be avoided, as they can worsen the disease course (181). Up to now, no treatment guidelines with high grade evidence are available for the treatment of MOGAD, and all medications are used off-label and empirically. Of note, none of the immunotherapies have been studied with regard to a potential effect on pain in MOGAD.

Symptomatic therapies aim to treat pain. Of note, the efficacy of the following treatment strategies have not been specifically demonstrated in NMOSD or MOGAD-related pain.

Pain is more than just an unpleasant physical sensation. It can comprise emotional, social, and spiritual suffering. Therefore, treatment strategies should not only directly target pain relief. Besides psychotherapy or behavioral therapy, exercise programs for physical reconditioning, relaxation techniques, and patient education should be considered to target functional, affective, social, and spiritual consequences affecting the patients' quality of life (182, 207, 208). Currently, pain syndromes in NMOSD and MOGAD are insufficiently controlled by medication, and multidrug therapy has been associated with worse fatigue and depression (2, 27, 209). Therefore, future studies should explore the efficacy of a multimodal and multidisciplinary approach of pain management (27).