Multiple sclerosis (MS) is the most common autoimmune demyelinating disease of the central nervous system (CNS), showing a female preponderance [35]. MS can take a relapsing–remitting or a primary or secondary progressive disease course, the latter with or without active inflammation [111]. A primary manifestation or relapses of MS as myelitis is common and is the most frequent cause of autoimmune myelitis. In individuals with known MS, a new spinal manifestation should therefore primarily be diagnosed and treated as an MS relapse. Spinal cord lesions in MS are typically short, spanning over one or two segments, and localised laterally in the spinal cord (Fig. 6.1). Contrast enhancement is seen regularly in acute lesions. A longitudinal myelitis is not typical for MS and should trigger alternative diagnoses such as neuromyelitis optica spectrum disorder (NMOSD, see below). Patients presenting with a monofocal myelitis and asymptomatic brain lesions without contrast enhancement have a high risk of developing a clinically definite MS in the future [138]. With at least two additional lesions in cranial MRI, one with contrast enhancement, the current diagnostic criteria allow the definite diagnosis of MS [141] and underline the importance of a cranial MRI in patients initially presenting with a clinically isolated myelitis. CSF examination reveals a mild pleocytosis, normally below 50 cells/μL with a predominance for activated lymphocytes. Oligoclonal bands and signs for a polyspecific intrathecal antibody production are found in the majority of MS patients and support the diagnosis. A thorough differential diagnosis should exclude other causes. Treatment of spinal manifestation of MS follows the general recommendations of relapse treatment including high-dose steroids and in the case of steroid-refractory functional deficits the use of apheresis therapies (see Sect. 6.1.11). Long-term treatment of MS is based on the use of immunomodulatory and immunosuppressive strategies.

Neuromyelitis optica spectrum disorder (NMOSD) is a disabling autoimmune condition of the CNS characterised by inflammation predominantly of the optic nerves and the spinal cord. Neuromyelitis optica (NMO), also known as Devic’s disease, was long considered a variant of MS. However, the discovery of highly specific serum autoantibodies against aquaporin 4 (AQP4) in a subset (60–80 %) of patients with NMO has identified NMO as a distinct disease entity completely separate from MS [12, 22, 108, 196]. With characterisation of patients with AQP4 antibodies but not the full clinical picture of NMO, the spectrum of the disease entity has been expanded, and the term NMO spectrum disorder (NMOSD) was introduced [197]. In 2015, the diagnostic criteria of NMOSD were revised and underline the importance of the presence of AQP4 antibodies with stratifying NMOSD in those with and without AQP4 antibodies [198]. The core clinical characteristics required for patients with NMOSD with AQP4 antibodies include clinical syndromes or MRI findings related to optic nerve, spinal cord, area postrema and other brainstem, diencephalic or cerebral presentations. More stringent clinical criteria, with additional neuroimaging findings, are required for diagnosis of NMOSD without AQP4 antibodies or when serologic testing is unavailable.

Spinal cord affection in NMOSD patients shows typically an LETM, which is defined as spanning over at least three vertebral segments (Fig. 6.2). Lesions are often found centrally in the spinal cord. Contrast enhancement is patchy and long lasting. Recently, anti-MOG antibodies were detected in some AQP4 antibody-negative NMOSD patients, constituting approximately 5 % of all NMOSD patients [102, 112, 155]. NMOSD has a strong female preponderance (up to 10:1 depending on geographical region). The occurrence and frequency of myelitis in the first year predicts the long-term course of NMOSD [86]. Contrary to MS, myelitis in NMOSD often leaves residual deficits with complete remissions in only 20 % of cases. Since the outcome of NMOSD attacks is decisive for long-term disability, early escalation of attack treatment is recommended [103]. Apheresis therapies might be superior to high-dose corticosteroids for the first-line treatment of NMOSD myelitis [103]. Concomitant autoimmune or rheumatologic diseases occur in up to 40 % of patients with NMOSD [82]. LETM can also be found of other origin than in NMOSD; therefore, a thorough differential work-up is essential [186]. Long-term treatment of NMOSD is immunosuppressive; first-line therapies are azathioprine or rituximab [187].

Acute disseminated encephalomyelitis (ADEM) is a monophasic (multiphasic possible) inflammatory multifocal disease of the CNS [180]. ADEM typically affects children and young adults. An association with previous infections and vaccination has repeatedly been reported [149]. Clinical presentation ranges from a prodromal phase with fever, headache and nausea to the rapid appearance of multifocal neurological deficits, often accompanied by reduced consciousness and a psychosyndrome. Cranial MRI typically exhibits large lesions in the white and grey matter with perifocal oedema, often of the same age and gadolinium enhancing [203]. The involvement of the spinal cord is frequently observed, showing lesions of longitudinal extent [9]. ADEM is associated with occurrence of anti-MOG antibodies, particularly in children [11, 112].

Diagnosis is based on the combination of clinical presentation, cranial MRI with multifocal lesions of the same age, spinal MRI with longitudinal myelitis and CSF examination revealing mild to moderate pleocytosis and absence of oligoclonal bands. Therapy comprises of high-dose methylprednisolone but can also include therapeutic plasma exchange, intravenous immunoglobulins and immunosuppressants.

The diagnosis of an idiopathic transverse myelitis (ITM) is based on exclusion of other diseases. About 40 % of acute transverse myelopathies remain unexplained [163]. The “Transverse Myelitis Consortium Working Group” (TMCWG) has proposed diagnostic criteria for an idiopathic transverse myelitis [184]. Besides a typical clinical presentation for a spinal cord lesion, the diagnosis requires signs of an inflammatory aetiology either by MRI (hyperintensities in T2-weighted images, contrast enhancement) or in the CSF with a pleocytosis or intrathecal immunoglobulin production (elevated IgG index). Other aetiologies, particularly infectious or autoimmune disease, vascular or metabolic disease and hypovitaminosis, have to be excluded by a thorough differential diagnostic work-up.

ITM usually is monophasic and has a good outcome in the majority of patients [184]. About one third of patients initially diagnosed with an ITM and normal cranial MRI will develop a clinically definite MS within 5 years [138]. Recurring transverse myelitis without other CNS manifestation can occur in about 8 % of patients with an acute isolated ITM [166].

Spinal cord affliction can occur as a complication of multisystem autoimmune or inflammatory disorders, for example, sarcoidosis, Sjögren’s disease, systemic lupus erythematosus (SLE), Behçet’s disease, mixed connective tissue disease, vasculitis and others.

Myelopathies occurring in association with cancer are rare. Spinal cord paraneoplastic syndromes include inflammatory, necrotising or demyelinating myelitis, which may have a focal, transverse or longitudinally extensive dissemination [42]. Myelitis can be accompanied by motor neuron disease, subacute motor neuronopathy or stiff-person syndrome.

The diagnosis of a paraneoplastic myelitis is made by exclusion of other autoimmune or infectious causes of myelitis and CSF or imaging findings supporting acute inflammation, i.e. CSF pleocytosis and IgG index elevation, as well as gadolinium enhancement. Cancers and paraneoplastic antibodies commonly associated with myelitis include small cell lung carcinoma (anti-Hu, anti-Ri, anti-amphiphysin, anti-CRMP5/CV2, anti-GAD, P/Q and N type calcium channel antibodies), breast carcinoma (anti-PCA1, anti-amphiphysin) and ovarian cancer (anti-Ri) [84, 120]. Additionally, AQP4 antibodies are sometimes found positive, particularly in patients with breast carcinoma and in the elderly [130, 140]. Hence, LETM in the context of NMOSD can also represent a cancer-associated aetiology. Other cancers associated with AQP4 antibodies include lung, thymic and cervical carcinomas, leiomyosarcoma and lymphomas. Apart from cancers, demyelinating myelopathy was also described as a rare manifestation of graft-versus-host disease [63]. The paraneoplastic form of stiff-person syndrome occurs in 5–10 % of patients; is characterised by rapidly evolving pain, rigidity and stiffness; and is frequently associated with anti-amphiphysin, anti-GAD65 or anti-glycine receptor antibodies.

Paraneoplastic myelitis is often progressive and may lead to wheelchair dependency and death [57]. Acute paraneoplastic myelitis is treated with high-dose corticosteroids, intravenous immunoglobulins and therapeutic plasma exchange and stiff-person syndrome additionally with antispasticity drugs. Therapy of the underlying tumour is the most important long-term treatment; however, since relapses and progressive courses occur, additional immunosuppressive treatment is often needed.

Myelitis can be associated with concomitant or antecedent viral, rarely bacterial, infections [149]. Patients typically report an upper respiratory tract infection or a nonspecific febrile illness. Para-/postinfectious myelitis may present as isolated, mostly transverse myelitis, or together with a more widespread encephalomyelitis and can range from mild urinary symptoms from a conus/epiconus lesion [143] to severe ADEM and even involvement of the whole peripheral and central nervous system (“encephalomyeloradiculopathy”) [114]. An immune-mediated mechanism, i.e. bystander activation or molecular mimicry, is thought to be the pathogenic mechanism. Specific causes of para-/postinfectious myelitis are discussed under the individual pathogens involved. Typical are herpes viruses, orthomyxo- and paramyxoviruses (influenza, measles, mumps) and rubella virus. As with idiopathic transverse myelitis, diagnosis depends on spinal MRI, typically showing gadolinium enhancement and an inflammatory CSF with pleocytosis, abnormal IgG index and sometimes oligoclonal bands but absent pathogen or specific antibody index. Steroid pulse therapy and plasma exchange are used for remission induction, intravenous immunoglobulins in cases with contraindications for these therapies [172]. Since para-/postinfectious myelitis usually is monophasic, long-term immunosuppressive therapy is rarely needed.

Neurological complications of vaccinations are rare [123]. LETM with local oedema and axonal motor neuropathy was described in a 77-year-old Japanese woman after vaccination against A/H1N1 influenza [156]. In a systematic review of PubMed, EMBASE and DynaMed, 37 cases of transverse myelitis associated with previous vaccinations were found for a period from 1970 to 2009 [1]. Cases were associated with vaccines against hepatitis B, measles–mumps–rubella, diphtheria–tetanus, rabies, poliovirus, influenza, typhus, pertussis and Japanese B encephalitis in decreasing order and typically occurred in the first month after vaccination.

Therapeutic inhibition of the tumour necrosis factor (TNF)-α is associated with CNS demyelination [46, 202]. In a review of 33 patients with neurological complaints which occurred within a median of 10 months after initiation of anti-TNFα agents, 22 had CNS involvement, 16 with encephalitic lesions, 5 with optic neuritis and 8 with transverse myelitis [169]. CSF and evoked potentials frequently are abnormal in patients with CNS involvement. Myelitis associated with anti-TNFα agents usually is monophasic, but relapsing episodes with final diagnosis of multiple sclerosis have been described. Consequently, anti-TNFα therapy should be discontinued when demyelinating myelitis occurs.

Both myelitis after vaccination and as complication of immunotherapy lack specific clinical and ancillary findings. It is discussed controversially whether the temporal association of vaccinations and anti-TNFα therapies with myelitis indicates a causal relationship, triggering of an underlying disease process, or occurs merely by chance.

Patients presenting with signs and symptoms of acute autoimmune or immune-mediated spinal cord affection should be immediately subjected to MRI of the complete spinal axis. First priority is to rule out a compressive aetiology [184]. The appearance and longitudinal extension of intramedullary lesions can guide diagnosis (Table 6.2). Further diagnostic testing (Table 6.3) should include CSF analysis, blood testing and cranial MRI, since most of these diseases can affect the brain as well [162]. A CSF pleocytosis with a cell count over 50 cells/μl should prompt the consideration of an infectious cause (see below), even though a high CSF cell count does not exclude an autoimmune inflammatory aetiology, particularly NMOSD, or even a neoplastic disorder. Additional blood testing aims to find systemic disorders such as SLE, Sjögren’s syndrome or sarcoidosis. A neurological involvement of these disorders should be considered in the setting of a positive serology and typical clinical presentation. The presence of a paraneoplastic antibody should prompt the search for the primary tumour using appropriate imaging techniques and a whole body FDG-PET scan where available. FDG-PET scanning can also be helpful to detect inflammatory lymph nodes in the setting of systemic sarcoidosis.

With the exception of MS where additionally immunomodulatory therapies are used, treatment of spinal cord manifestations of autoimmune disorders is immunosuppressive. For acute attacks, high-dose methylprednisolone pulses are first line, sometimes to be followed by therapeutic plasma exchange, immunoadsorption or intravenous immunoglobulins (Table 6.4). When no complete recovery is achieved, immunosuppressive therapy, e.g. with rituximab, cyclophosphamide or mitoxantrone may be used for further remission induction. In the majority of autoimmune spinal cord diseases, the risk of a relapsing course is given; therefore, long-term treatment is required.