Multiple Sclerosis and Demyelinating Diseases 4

Question 1

Transverse myelitis etiology

Answer 1

Question 2

Evaluation of suspected acute myelopathy

Answer 2

https://www.uptodate.com/contents/image?imageKey=NEURO%2F88920&topicKey=NEURO%2F14088&search=transverse%20myelitis&rank=1~136&source=see_link

Question 3

Potential medical work-up for suspected acute transverse myelitis

Answer 3

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Question 4

Diagnostic tests in transverse myelitis

Answer 4

Question 5

Diagnostic criteria for transverse myelitis

Answer 5

Question 6

Most common antibodies in paraneoplastic myelopathy

Answer 6

anti-Hu and anti-collapsin-responsive mediator protein 5 (CRMP5), and, less frequently, anti-amphiphysin antibodies

Question 7

Differential of longitudinally extensive spinal cord lesions

Answer 7

NMOSD
systemic lupus erythematosus
Sjögren’s disease
neuro-Behçet disease
sarcoidosis
MS
MOGAD
parainfectious disorders (eg, acute disseminated encephalomyelitis)
anti-N-methyl-D-aspartate receptor encephalitis

Question 8

Acute treatment for idiopathic transverse myelitis

Answer 8

*TM without motor impairment – For patients with acute idiopathic TM, we suggest high-dose intravenous glucocorticoid treatment.

*TM with motor impairment – For patients with acute TM complicated by motor impairment, we suggest plasma exchange in addition to glucocorticoid treatment.

Question 9

Acute treatment of myelitis in 1) sytemic autoimmune dirorders 2) paraneoplastic disorders

Answer 9

1) Acute attacks of TM in patients with most types of systemic autoimmune disorders are typically treated with a short course of high-dose intravenous glucocorticoids, with or without plasma exchange, similar to acute idiopathic TM
However, in severe cases of myelitis secondary to systemic lupus erythematosus, cyclophosphamide may be beneficial.

2) Treatment for TM due to a paraneoplastic etiology includes glucocorticoids and PLEX, but long-term remission is based on therapy directed at the underlying malignancy, along with immunotherapy in most cases

Question 10

NMOSD: which sex is most affected

Answer 10

The incidence of NMOSD in females is up to 10 times higher than in males

Question 11

Whith which condition may NMOSD be associated?

Answer 11

NMOSD is frequently associated with systemic autoimmune disorders
these include:

organ-specific disorders such as hypothyroidism, pernicious anemia, ulcerative colitis, myasthenia gravis, and idiopathic thrombocytopenic purpura

nonorgan-specific disorders such as systemic lupus erythematosus, antiphospholipid syndrome, and Sjögren’s disease

In addition, some cases of NMOSD may be associated with neoplasms

Antinuclear autoantibodies are common in patients with NMOSD who lack evidence of a systemic disorder

Question 12

Which is the primary target in NMOSD inflammatory process

Answer 12

The inflammatory processes in NMOSD primarily target astrocytes, leading to immune-mediated inflammation and secondary demyelination

Question 13

NMOSD clinical findings

Answer 13

Hallmark features of NMOSD include acute attacks characterized by:
1) bilateral or rapidly sequential optic neuritis (leading to visual loss),
2) acute transverse myelitis (often causing limb weakness and bladder dysfunction), and
3) the area postrema syndrome (with intractable hiccups or nausea and vomiting).

Other suggestive symptoms include episodes of
1) symptoms related to bilateral hypothalamic lesions (may include symptomatic narcolepsy or excessive daytime sleepiness, obesity, and various autonomic manifestations such as hypotension, bradycardia, and hypothermia)
2) reversible posterior leukoencephalopathy syndrome
3) neuroendocrine disorders
4) (in children) seizures

Question 14

NMOSD diagnostic criteria

Answer 14

Question 15

Comparison of inflammatory demyelinating diseases of the central nervous system

Answer 15

https://www.uptodate.com/contents/image?imageKey=NEURO%2F131849&topicKey=NEURO%2F14089&search=nmo&rank=1~58&source=see_link

Question 16

When to suspect NMOSD

Answer 16

Clinical presentations that should raise suspicion for NMOSD include the following:

●Optic neuritis that is simultaneously bilateral, involves the optic chiasm, causes an altitudinal visual field defect, or causes severe residual visual loss

●A complete (rather than partial) spinal cord syndrome, especially with paroxysmal tonic spasms

●An area postrema clinical syndrome consisting of intractable hiccups or nausea and vomiting

Question 17

Diagnostic tests in patients with NMOSD

Answer 17

● Serum for AQP4-IgG antibody and MOG-IgG antibody testing, using a cell-based assay.

● CSF analysis is not strictly required for the diagnosis of NMOSD but is used to distinguish from other entities such as multiple sclerosis, since for example oligoclonal bands are not usually present in NMOSD, unlike multiple sclerosis.

● MRI, with and without contrast, of the brain and spinal cord. In some cases, spinal arteriography may be needed to confirm the diagnosis of vascular pathologies that can present as acute myelopathies, such as dural arteriovenous fistula.

● Most clinicians also obtain assays for other autoimmune conditions such as systemic lupus erythematosus and Sjögren’s disease, as well as antibodies against HIV as part of the workup.

Question 18

Neuroimaging characteristics of NMOSD

Answer 18

Question 19

Treatment of acute attacks in NMOSD

Answer 19

*Glucocorticoid therapy – For patients with acute or recurrent attacks of NMOSD, we suggest initial treatment with high-dose intravenous methylprednisolone (1 gram daily for three to five consecutive days), with a low threshold for rapid initiation of plasma exchange

*Adjunctive plasma exchange – For patients with severe symptoms or poorly responsive to glucocorticoids, we suggest treatment with plasma exchange. Plasma exchange may be more effective if started early as adjunctive therapy with glucocorticoids

Attack therapy must start as soon as possible

++ NEMOS 2024

Question 20

Preventive therapy for AQP4‑IgG‑positive NMOSD

Answer 20

NEMOS 2024

Question 21

Preventive therapy for double negative NMOSD

Answer 21

Question 22

Preventive therapy for NMOSD duration of treatment

Answer 22

Question 23

NMOSD prognosis

Answer 23

The natural history of NMOSD is one of stepwise deterioration due to accumulating visual, motor, sensory, and bladder deficits from recurrent attacks.
Long-term disability and mortality rates are high

Question 24

Medications to avoid in NMOSD

Answer 24

Increased relapses have been associated with the use of interferon, glatiramer acetate, dimethyl fumarate, alemtuzumab, and natalizumab

++ fingolimod (Uptodate)

Continuum 2019

Question 25

Eculizumab mechanism of action, dosing and adverse effects

Answer 25

Eculizumab is a humanized antibody that binds to the complement component C5 and inhibits the formation of C5b-induced membrane attack complex.

● Dose – Eculizumab is administered intravenously at 900 mg weekly for the first four doses, followed by maintenance dosing of 1200 mg every two weeks beginning at week 5.

● Adverse effects – Eculizumab infusions are generally well tolerated. Commonly reported adverse events in clinical trials included headache, upper respiratory tract infections, back pain, and nausea.
However,eculizumab treatment is associated with an increased risk of infection with Neisseria meningitidis;
patients should be immunized with meningococcal vaccines and receive daily antimicrobial prophylaxis

Question 26

Ravulizumab mechanism of action, dosing and adverse effects

Answer 26

Ravulizumab is a humanized antibody that binds to the same complement component C5 epitope as eculizumab, thereby inhibiting the formation of C5b-induced membrane attack complex.
Ravulizumab has a longer half-life than eculizumab, which permits less frequent maintenance administration for ravulizumab (every eight weeks) compared with eculizumab (every two weeks)

●Dose – For patients with NMOSD and no prior treatment, ravulizumab is given intravenously with a weight-based loading dose of 2400 to 3600 mg on day one, followed by a weight-based maintenance dose of 3000 to 3600 mg once every eight weeks, starting two weeks after the loading dose

●Adverse effects – Meningococcal infections occurred in two patients (3 percent) treated with ravulizumab in the CHAMPION-NMOSD trial despite prior vaccination against Neisseria meningitidis; other common adverse events included COVID-19 and headache

Question 27

Inebilizumab mechanism of action, dosing and adverse effects

Answer 27

Inebilizumab is a humanized monoclonal antibody that binds to the CD19 surface antigen of B cells, thereby depleting a wide range of lymphocytes derived from B cell lineage, including peripheral blood CD20 plasmablasts and plasma cells

●Dose and administration – Inebilizumab is given by intravenous infusion as an initial dose of 300 mg, followed two weeks later by a second 300 mg dose. Thereafter, inebilizumab is given as 300 mg infusion every six months, starting from the first infusion.

●Adverse reactions – The most common adverse reactions in the randomized trial were urinary tract infection, headache, arthralgia, nausea, and back pain
Risk of opportunistic infections (including PML!)

Contraindications to inebilizumab are active hepatitis B infection, active or untreated latent tuberculosis

Question 28

Satralizumab mechanism of action, dosing and adverse effects

Answer 28

Satralizumab is a humanized monoclonal antibody that binds interleukin-6 (IL-6) receptors, thereby suppressing inflammation mediated by IL-6 signaling pathways.

●Dose – Satralizumab is given by subcutaneous injection with a loading dose of 120 mg at weeks 0, 2, and 4, followed by a maintenance dose of 120 mg every four weeks.

●Adverse effects – The most common adverse effects with satralizumab are nasopharyngitis, headache, upper respiratory tract infection, gastritis, rash, arthralgia, extremity pain, fatigue, and nausea.

Satralizumab is contraindicated for patients with active hepatitis B infection, active or untreated latent tuberculosis, or known hypersensitivity to satralizumab.

Question 29

Rituximab mechanism of action, dosing and adverse effects

Answer 29

Rituximab is a chimeric monoclonal antibody that causes B cell depletion by binding to the CD20 antigen of B cell lymphocytes and to Fc receptors.

●Dose – Rituximab is started with two 1 g infusions separated by a two-week interval, followed by a 1 g infusion every six months or earlier if CD19+ lymphocytes are >0.1 percent of total lymphocytes

●Adverse reactions – Potential adverse effects include infusion reactions, hypogammaglobulinemia, infection, reactivation of hepatitis B, and neutropenia.
Risk of opportunistic infections (including PML)

Question 30

ADEM: pathophysiology

Answer 30

ADEM appears to be an autoimmune disorder of the central nervous system that is triggered by an environmental stimulus in genetically susceptible individuals.

One proposed mechanism is that myelin autoantigens such as myelin basic protein, proteolipid protein, and myelin oligodendrocyte protein share antigenic determinants with those of an infecting pathogen. Antiviral antibodies or a cell-mediated response to the pathogen cross-react with the myelin autoantigens, resulting in ADEM.

Question 31

ADEM: enviromental stimulus

Answer 31

1) ADEM is associated with a preceding infection in 50 to 75 percent of adult cases
The list of infectious pathogens associated with ADEM includes rubella (ερυθρά), mumps (παρωτίτιδα), varicella, measles (ιλαρά), smallpox, Epstein-Barr virus, herpes simplex virus, human herpes virus-6, influenza, HIV, and Mycoplasma pneumoniae, coronavirus 2 (SARS-CoV-2)

2) studies have found little or no association between ADEM and immunization

Question 32

Classic ADEM: Clinical features

Answer 32

After a preceding infectious illness in most cases (mean 26 days) acute onset of multifocal neurologic symptoms with
1) encephalopathy
2) motor deficits; these may involve a single limb or result in paraparesis (partial paralysis of both legs) or quadriparesis
3) sensory deficits
4) brainstem involvement (including oculomotor deficits and dysarthria)

Additional signs and symptoms may include headache, malaise, meningismus, ataxia, aphasia, optic neuritis (sometimes bilateral), nystagmus, extrapyramidal movement disorders, urinary retention, seizures, and increased intracranial pressure

** In adults, the presence of encephalopathy is clinically important, as it helps to identify individuals who are less likely to have a different disease, such as multiple sclerosis, and more likely to have ADEM. However, encephalopathy has not always been a required feature for diagnosis (it has been reported in only 20 to 56 percent of adult cases)

Question 33

ADEM: Variant form

Answer 33

1) Acute hemorrhagic leukoencephalitis

2) ADEM with peripheral nervous system involvement

Question 34

Acute hemorrhagic leukoencephalitis: 1) Presentation, 2) Imaging findings 3) Prognosis

Answer 34

1)
- meningismus
- headache
- seizures
- multifocal neurologic signs
- asymmetrical neurologic deficits
- rapid progression to coma

2)
MRI is the gold-standard
- large tumefactive lesions involving the white matter and sparing the cortex
- associated punctate hemorrhages and extensive mass effect and surrounding edema
- possible involvement of ganglia and thalami

Radiopaedia

3) very poor prognosis with the majority of affected individuals succumbing to the disease

Question 35

ADEM with peripheral nervous system involvement

Answer 35

Combined central and peripheral nervous system involvement
(encephalomyeloradiculoneuritis and myeloradiculoneuritis)

Patients with peripheral nerve involvement were significantly older and had a worse prognosis and an elevated risk of relapses compared with those having only central nervous system syndromes

Question 36

When to suspect ADEM

Answer 36

The diagnosis of ADEM should be considered in patients with unexplained acute encephalopathy and multifocal neurologic signs and symptoms.

Question 37

ADEM: imaging findings

Answer 37

●Brain MRI
- Typically bilateral and asymmetric lesions / tend to be poorly marginated
- Hyperintense on T2-weighted and FLAIR sequences
- Large lesions can be slightly hypointense on unenhanced T1 sequences.
- There can be considerable heterogeneity: large confluent lesions, single solitary lesions, and multiple small lesions
- Lesions may be seen in the periventricular and subcortical white matter, including corpus callosum and centrum semiovale, as well as in the gray matter, including the cortex, basal ganglia, and thalamus. Infratentorial lesions in the brainstem, cerebellum, and spinal cord are common

●Spinal cord MRI – Lesions in the spinal cord are common in ADEM Both long and short segment cord lesions have been reported, but large confluent intramedullary lesions that extend over multiple segments are more common, particularly with MOG antibody-associated ADEM.

●Enhancing lesions – Gadolinium enhancement of MRI lesions in ADEM is variable. Enhancing and nonenhancing lesions may appear together in the same scan. Even though ADEM is usually a monophasic illness, repeat imaging early in the disease course has shown fluctuation in the presence of both enhancing and nonenhancing lesions

●Diffusion MRI –
restricted diffusion (ie, decreased apparent diffusion coefficient [ADC] values) in the acute stage, defined as within seven days from symptom onset, whereas increased diffusivity and normalization of the ADC is seen within a few weeks after the initial presentation

●Resolution of MRI abnormalities – Many MRI lesions resolve within 18 months, although some patients have residual lesions on follow-up imaging

Question 38

ADEM: CSF analysis

Answer 38

●Typical findings
– abnormalities are present in 50 to 80 percent of patients.
Typical abnormalities in ADEM are nonspecific and include a lymphocytic pleocytosis, usually with a CSF white blood cell count <100 cells/mL, and a mildly elevated CSF protein, usually <70 mg/dL

●Oligoclonal bands have been reported in 6 to 65 percent of adult patients with ADEM.
Positivity for anti-MOG-IgG antibody rarely occurs in patients with OCBs; thus, both tests are useful in differentiating a MOG antibody-associated disorder with an ADEM phenotype from ADEM as a first attack of MS.

Question 39

ADEM: Which serum antibodies should be tested?

Answer 39

anti-MOG-IgG antibody –> MOG antibody-associated disorder

anti-AQP4-IgG antibody –> neuromyelitis optica spectrum disorder (NMOSD)

Question 40

ADEM: supportive features

Answer 40

The diagnosis of ADEM is supported by the presence of one or more supratentorial or infratentorial demyelinating lesions on brain MRI and the absence of destructive “black hole” lesions on T1-weighted MRI, which suggest prior episodes of inflammation or demyelination as seen in multiple sclerosis
A preceding infection and abnormal CSF (a mild lymphocytic pleocytosis and a mildly elevated protein) are suggestive of ADEM but not required for the diagnosis.

Question 41

ADEM: differential diagnosis

Answer 41

1) myelin oligodendrocyte glycoprotein (MOG) antibody-associated disorder

2) neuromyelitis optica spectrum disorder (NMOSD)

3) a first attack of multiple sclerosis

Other entities to be considered in the differential diagnosis of ADEM include infectious meningoencephalitis, neurologic sarcoidosis, vasculitis, progressive multifocal leukoencephalopathy, and Behçet syndrome

Question 42

ADEM: treatment

Answer 42

Initial therapy:
A typical regimen is intravenous methylprednisolone, 1000 mg daily for three to five days, followed by an oral glucocorticoid taper of variable duration.

Empiric antibiotics for select patients — Some adults with ADEM present with fever, meningeal signs, acute encephalopathy, and evidence of inflammation in blood and cerebrospinal fluid.
For such patients, empiric treatment with acyclovir should be started if the patient has encephalitis without apparent explanation and continued until an infectious etiology is excluded.

Empiric antibiotics for possible bacterial meningitis are not necessary unless the cerebrospinal fluid findings suggest a bacterial inflammatory profile.

Inadequate response to initial therapy — For patients with ADEM who have a poor response to glucocorticoids, therapeutic options include intravenous immune globulin (IVIG) or plasma exchange. In addition, alternate diagnoses should be explored for patients who have suspected ADEM that does not respond well to glucocorticoids.

Among patients with ADEM who have electrodiagnostic or clinical evidence of peripheral nervous system involvement IVIG treatment was associated with a favorable outcome

Other options — Cyclophosphamide, 1 gram given intravenously, has also been used for patients when the response to glucocorticoids is poor. Repeat dosing may be necessary to achieve maximum benefit.

Management of malignant edema — In some cases, fulminant ADEM or acute hemorrhagic leukoencephalitis may progress to develop malignant, space-occupying brain edema with increased intracranial pressure and brain tissue shifts or herniation. This process can lead to neurologic deterioration with signs that typically include decreased arousal, pupillary changes, and worsening of motor responses.

Interventions to reduce intracerebral pressure include elevation of the head of the bed, osmotic therapy, brief periods of hyperventilation as needed, and hemicraniectomy for patients with life-threatening cerebral edema

Question 43

ADEM: prognosis

Answer 43

Complete recovery has been reported in 10 to 46 percent of adults.
Cognitive impairment, mostly affecting attention and concentration, has persisted in some.

Question 44

clinical feature that can help distinguish
anti-MOG ON from that associated with MS or NMOSD

Answer 44

papillitis or swelling of the optic nerve head

papillitis is strongly associated with anti-MOG ON and can be seen by fundoscopy or by orbital MRI.

Question 45

When to suspect MOGAD

Answer 45

Clinical presentations that should raise suspicion for MOGAD include the following:

●Optic neuritis that is simultaneously bilateral, involves the anterior optic pathway, and is associated with optic disc edema.

●Acute disseminated encephalomyelitis (ADEM) or ADEM-like presentations accompanied by large, poorly demarcated T2 hyperintense lesions in the brain and with T2 lesions within the spinal cord.

●Unilateral cortical encephalitis with headache, fever, seizures, encephalopathy, or other focal neurologic findings with cortical T2 hyperintensity and swelling.

●A complete (rather than partial) spinal cord syndrome, especially with prominent bowel, bladder, or erectile dysfunction symptoms.

Question 46

Diagnostic tests in MOGAD

Answer 46

The evaluation of suspected MOGAD on initial presentation entails the following imaging and laboratory studies:

● MRI with and without contrast of any symptomatic region of the neuraxis, and all of the following if there is any diagnostic uncertainty or when encephalopathy confounds the neurologic examination:
*Orbits and with fat saturation images
*Brain
*Spinal cord

●Serum for MOG-IgG, tested using a cell-based assay

●CSF analysis for
1) routine studies (eg, cell count, differential) and oligoclonal bands
2) in select patients, PCR testing for viral infections
3) in select patients with features suggestive of anti-NMDA receptor encephalitis (orofacial dyskinesias, psychosis, seizures) testing CSF for NMDA receptor antibodies

Question 47

MOGAD diagnostic criteria

Answer 47

Question 48

Best discriminators of MOGAD and MS

Answer 48

●MOG-IgG antibody status; the presence of MOG-IgG supports the diagnosis of MOGAD, particularly at higher titers. However, the presence of the antibody alone is insufficient, given that MOG-IgG at low titer can be found in up to 2.5 percent of MS patients

●Cerebrospinal fluid oligoclonal bands; these are absent in most patients with MOGAD and are present in most patients with MS

●Clinical and magnetic resonance imaging features, particularly the evolution of T2 lesions; most MS lesions leave a residual signal abnormality, while most MOGAD T2 lesions resolve over time

Question 49

MOGAD treatment

Answer 49

For patients with acute attacks of MOGAD, we suggest a short course of high-dose glucocorticoid therapy. Our preferred regimen is intravenous methylprednisolone 1000 mg per day for five consecutive days. Observational evidence suggests that most patients with MOGAD respond briskly to glucocorticoids

For patients who are refractory to initial therapy with glucocorticoids, we suggest treatment with plasma exchange or intravenous immune globulin (IVIG)

We advise observation after treatment for a first attack of MOGAD, since 40 to 50 percent of patients will have no further attacks.
Preventive therapy is generally reserved for patients who have relapsing disease; options include azathioprine, mycophenolate, intermittent IVIG, oral prednisone, rituximab, or tocilizumab. However, supporting data are limited

Question 50

MOGAD prognosis

Answer 50

MOGAD may follow a monophasic or relapsing disease course.
Long-term disability rates are lower than with aquaporin-4 positive IgG (AQP4-IgG) NMOSD or multiple sclerosis
Unlike MS, MOGAD is not associated with a primary or secondary progressive course.
Mortality due to MOGAD is low.