CONTENTS
- Inflammatory demyelinating disorders
- Management considerations for inflammatory demyelinating disorders
- Other white matter disorders
- Podcast
- Questions & discussion
- Pitfalls
basics
- Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) encompasses a variety of demyelinating disorders which seem to be causally related to MOG-IgG antibodies (which binds to oligodendrocytes). These are likely different manifestations of a similar underlying process, so they may occur together:
- Acute demyelinating encephalomyelitis (ADEM) involves the brain and spinal cord.
- Transverse myelitis.
- Optic neuritis.
- MOGAD is associated with severe demyelination without astrocyte cell death, which may explain why it tends to be reversible.
epidemiology
- Most often seen in children or young adults.
- Generally occurs following a viral infection, e.g.:
- Herpesviruses (e.g., EBV, HSV, VZV, CMV).
- Influenza.
- Rubella, mumps.
- HIV.
- Enteroviruses.
- West Nile Virus.
- COVID.
- Mycoplasma pneumoniae.
clinical manifestations
- Usually occurs 1-2 weeks after a viral prodrome (especially upper respiratory tract illness).
- Acute disseminated encephalomyelitis (ADEM):
- Typical symptoms include fever, headache, and altered level of consciousness. These may progress to seizures and focal neurological deficits.(Torbey, 2019) Peak severity is usually reached within 2-5 days.(34030191)
- Encephalopathy is common, but frequently absent (unlike pediatric ADEM).
- 🔥 FLAMES syndrome refers to FLAIR-hyperintense lesions in MOG-associated Encephalitis with Seizures. Radiologically, patients have unilateral cortical encephalitis with FLAIR-hyperintense lesions.(33522737)
- Transverse myelitis:
- This is the second most frequent region affected by MOGAD. Transverse myelitis accounts for about a third of presentations in adults.(34024334)
- Transverse myelitis is generally acute, often with severe motor impairment and sphincter dysfunction. This may mimic acute flaccid myelitis due to enteroviral infection.(31162318)
- Prognosis is favorable, with most patients having good recoveries despite severe attacks.
- Optic neuritis.
laboratory evaluation
- Serum testing is usually preferred for MOG-IgG, given increased sensitivity. However, some patients may have isolated CSF MOG-IgG, so this should also be considered.(34024334) The precise sensitivity is unclear, but it's far from perfect. 1.5% of healthy controls test positive for MOG-IgG, so this is not entirely specific (especially at lower titers).(34030191)
- CSF analysis may help exclude alternative diagnoses, but is generally nonspecific (e.g., mild lymphocytic pleocytosis and elevated protein). Cell count may be markedly elevated in ADEM.(34024334)
- CSF oligoclonal bands are only rarely seen (<10%), which may help differentiate this from MS.(Torbey, 2019)
radiological findings of brain involvement (ADEM)
- Usually there are numerous, diffuse, large (>1-2 cm), edematous, asymmetric, poorly demarcated (“fluffy”) lesions.(26595866) Lesions may be confluent. They are located in the supratentorial and infratentorial white matter, as well as the gray matter (especially the basal ganglia and thalami).
- Lesions are hyperintense on T2/FLAIR, with uncommon enhancement. Restricted diffusion with increased apparent diffusion coefficient (ADC) may occur, especially among acute lesions.(Torbey, 2019)
- Optic neuritis may be seen (typically affecting more than half of the optic nerve). Lesions often spare the optic chiasm (unlike neuromyelitis optica spectrum disorders).(33522737)
- Differentiation from multiple sclerosis:
- ADEM may affect the deep gray structures (unlike classic multiple sclerosis lesions).
- ADEM uncommonly has a periventricular distribution (whereas this is characteristic of multiple sclerosis).
- ADEM lesions have a uniform age (whereas multiple sclerosis may produce acute and chronic lesions).
- Hypointense lesions on T1 within the white matter that are nonenhancing are rare in ADEM; these may associate with an increased risk of developing multiple sclerosis.(26595866)
radiological findings of spinal cord involvement
- MRI may initially be normal in 10% of patients, despite severe myelitis.(34619778)
- MRI may show short and/or long T2 expansile lesions, or a coexisting combination of both. The combination of short myelitis without oligoclonal bands suggests MOG-IgG.(34024334)
- T2 hyperintensity is often centrally restricted to the gray matter (“H-sign”). On sagittal images, T2 hyperintensity may be notable along the ventral cord parenchyma (“ventral sagittal line”).
- Lesions are most often located in the thoracic cord and conus medullaris, with the latter being suggestive of MOGAD.(31582425 ; 34619778)
- Lesions are usually nonenhancing (unlike multiple sclerosis or neuromyelitis optica spectrum disorders). If enhancement does occur, it is often mild and patchy.(33522737)
- Brain MRI may be normal, or it may show characteristic lesions of acute disseminated encephalomyelitis (ADEM), as discussed above.
management
- First-line therapy is high-dose steroid (e.g., 1,000 mg methylprednisolone for 3-5 days), followed by a prednisone taper.(Torbey, 2019)
- In steroid-refractory disease, plasma exchange may be preferred over IVIG, based on an RCT showing the utility of plasma exchange in demyelinating diseases. If plasma exchange is not possible, IVIG may be utilized.(10589540)
- Supportive care:
- Most patients may require mechanical ventilation.
- Elevated intracranial pressure may require management.
acute hemorrhagic leukoencephalitis (AHLE), aka Hurst disease
- This is a severe form of ADEM.
- Clinical features:
- Imaging:
- CSF: Unlike most other demyelinating disorders, CSF may show a neutrophilic pleocytosis, elevated erythrocytes, and a more marked elevation in protein.
- Treatment is similar to that of ADEM, with early initiation of steroid and plasma exchange. Additionally, management of intracranial pressure can be necessary. There may be a risk of herniation, with some patients requiring decompressive craniectomy.📖 (31534611)
basics
- NMOSD is an autoimmune process with IgG antibodies against aquaporin-4 on astrocyte foot processes, leading to an inflammatory demyelinating disease.
- Patients typically have chronic, extensive transverse myelitis and/or optic neuritis. However, variants are being discovered with partial syndromes (e.g., recurrent optic neuritis, or recurrent transverse myelitis).
- The disease course is typically relapsing, with relapses that are more severe than MS relapses.
epidemiology
- ~90% of patients are women.(34619778)
- Peak incidence occurs around ~40-55 years old (but the distribution of ages is broad).
- Risk factors:
- (1) Autoimmune disorders, including lupus, antiphospholipid antibody syndrome, Sjogren's syndrome, autoimmune thyroid disease, or type 1 diabetes.(34024334; 33392785) Many patients previously regarded as having myelitis due to lupus or especially Sjogren's syndrome may actually have NMOSD.
- (2) NMOSD may occur as a paraneoplastic disorder, most often in association with breast cancer, lung cancer, cervical cancer, thymoma, or lymphoma.(34798965; 33392785)
clinical manifestations
- (#1) Myelitis
- Myelitis is the most common presentation after age 40.(34024334)
- Presentations may include paraplegia or tetraplegia. Patients often have complete transverse myelitis with symmetric motor and sensory findings as well as bowel/bladder dysfunction.(22284064)
- Recurrent dystonic-like episodes that involve paroxysmal painful spasms after an attack of myelitis are common.(33392785)
- (#2) Optic neuritis may cause visual loss.
- (#3) Brainstem involvement:
- Involvement of the area postrema may cause otherwise unexplained hiccups or nausea/vomiting (this should correlate with lesions in the dorsal medulla).
- More severe lesions may cause coma.(Torbey, 2019)
- Neurogenic respiratory failure may occur (due to extensive brainstem or upper cervical disease that causes respiratory muscle weakness).
- Cranial nerve dysfunction may include diplopia or ophthalmoplegia.(31162318; 31582425)
- (#4) Diencephalic syndromes due to involvement of the thalamus/hypothalamus:
- Hypothermia.
- Narcolepsy.
- Endocrinopathies.
- SIADH.
- Anorexia.
- Other less common manifestations:
- Posterior reversible encephalopathy syndrome (PRES).
- Cerebral involvement.
- Hydrocephalus.(31162318)
laboratory findings
- Serum antibody against aquaporin-4 is present in most patients, but ~20% of patients are seronegative.(33392785) Serum testing (with a sensitivity of 80% and specificity of 99%) is more sensitive and preferred over CSF.(33522737; 31582425) IgG against aquaporin-4 may coexist with other antibodies and their respective clinical syndromes (e.g., anti-NMDA receptor encephalitis and/or GFAP-IgG associated myelitis), often in the context of teratoma.(33522737)
- CSF is generally nonspecific (may see lymphocytic pleocytosis and elevated protein). Neutrophilic or eosinophilic pleocytosis with cell counts higher than those typically seen in multiple sclerosis may be encountered.(26595866) Oligoclonal banding occurs in 15%.(31582425)
radiological findings in the optic nerve & brain
- Optic nerve contrast enhancement and edema may be seen (with T2 hyperintensity and contrast enhancement). This typically affects most of the optic nerve, including the optic chiasm (unlike multiple sclerosis, which often causes shorter involvement).(33522737)
- Brain lesions are not uncommonly seen, usually predominating around the third and fourth ventricles (where aquaporin-4 is highly expressed).(30709470, 34024334) Other areas which may be involved include:
- Dorsal medullary lesions (including the area postrema), which may extend into the cervical spinal cord.
- Hypothalamic and/or thalamic lesions.
- Internal capsule; corpus callosum (either splenium or diffuse involvement).
- Large hemispheric lesions can occur.(Torbey, 2019)
- Linear ependymal enhancement may be suggestive.(33522737) Leptomeningeal enhancement may also occur.(31162318)
radiological findings of spinal cord involvement
- Longitudinally extensive transverse myelitis is characteristic (usually extending over three or more vertebral segments). However, patients may initially present with a short lesion which is misdiagnosed as multiple sclerosis.(33392785)
- The cervical cord is most often affected, with lesions sometimes extending into the thoracic cord or into the brainstem.(34024334) Typically a solitary lesion is seen.(33522737)
- There is a predilection for involvement of the central gray matter, but inflammation may extend transversely across the entire spinal cord.(34619778)
- On T2 sequences the lesions may have pockets of signal intensity similar to CSF, creating a “bright and spotty” appearance.(33522737) If seen, this is fairly specific.(34024334)
- Gadolinium enhancement is seen in >90% of acute lesions, which can be patchy, ill-defined, or ring-like.(34619778) Marked swelling is common.
treatment
- Acute exacerbations are generally treated with pulse dose steroid (e.g., 1,000 mg methylprednisolone daily for five days), followed by a steroid taper.
- Patients may be refractory to steroid. Early use of plasma exchange is thus recommended in combination with steroid, as this may improve the likelihood of complete recovery.(34619778, 34030191)
- Pain may respond to carbamazepine or oxcarbazepine.(34030191)
epidemiology
- Most commonly seen in patients 20-40 years old, of whom 70% are women.(34619778)
clinical presentation
- Acute (with deterioration usually occurring over a few days, followed by recovery over a few weeks).
- Tends to be mild, causing sensory-predominant deficits.
- Usually involves only parts of the spinal cord, leading to asymmetric deficits (“acute partial transverse myelitis”).
- Affects mainly the posterior tracts of the cervical cord.
- Classically is associated with Lhermitte's sign (a shock-like sensation which occurs with neck flexion).
lumbar puncture findings
- Discussed in the section on the approach to myelopathy here.
MRI findings (34619778)
- Short peripheral T2 lesions (<3 vertebral segments).
- Presence of multiple lesions supports multiple sclerosis, if seen.(34619778)
- Usually at the cervical level.
- Most are peripherally distributed in an asymmetric fashion, within the dorsal or lateral columns.
- If acute, lesions may be expansile and marked by ring or homogeneous contrast enhancement. If seen, an “open ring” of C-shaped enhancement is very suggestive of demyelinating disease – similar to tumefactive multiple sclerosis discussed below.(30709470)
- Brain MRI may be very helpful by revealing additional lesions due to multiple sclerosis.
basics
- Demyelinating lesion >2 cm with vasogenic edema, mass effect, and enhancement on MRI (typically in an open ring configuration) that may mimic a tumor.
- Most often occurs at ~20-40 years old, especially in the context of known multiple sclerosis.
clinical manifestations
- Onset is often insidious, similar to a malignancy.
- Findings depend on location of the lesion.
- May cause cortical syndromes that are otherwise atypical for multiple sclerosis (e.g., apraxia, aphasia).
- ICU admission may be necessary due to mass effects causing midline shift and herniation.(34798965)
- Seizures or encephalopathy are less common.(22284064)
differential diagnosis includes
- Malignancy (e.g., high-grade glioma or metastatic disease).
- Primary CNS lymphoma.
- Levamisole-induced leukoencephalopathy due to cocaine use. 📖
- AHLE (acute hemorrhagic leukoencephalitis). 📖
radiology
- Large, tumor-like lesion which is >2 cm in size. Surrounding vasogenic edema and mass effect may lead to midline shift and transtentorial herniation.(22284064)
- Nearly all lesions are contrast-enhancing, but the pattern is variable (including closed rings, open rings, diffuse, homogeneous punctate, or concentric).(Torbey 2019) Open-ring enhancement is typical, with the nonenhancing section of the ring abutting the deep gray matter or cortical ribbon.(22284064) Enhancement generally resolves within 1-2 months; persistent enhancement beyond this time frame suggests an alternative diagnosis.(31582425)
- Restriction of diffusion-weighted imaging may occur at the lesion edge.(26595866)
- The lesion may include dilated central veins. (Tang 2015)
- Finding asymptomatic plaques (e.g., in the spinal cord) may help solidify a diagnosis of underlying multiple sclerosis.
management of tumefactive multiple sclerosis
- Initial therapy is high-dose steroid (e.g., methylprednisolone 1,000 mg daily for 3-5 days).(Torbey 2019)
- Plasma exchange can be considered among patients refractory to steroid.
- Monophasic and fulminant demyelinating disorder with an aggressive course. May lead to death within months.(34798965)
- MRI shows multiple T2-FLAIR hyperintensities that coalesce to form confluent, large plaques throughout the hemisphere and brainstem.(26595866) These are associated with perilesional edema and contrast enhancement.(34798965)
- Differential diagnosis:
- May initially be difficult to distinguish from ADEM.(Torbey 2019)
- Contrast enhancement tends to be homogeneous (which may help differentiate this from tumefactive multiple sclerosis).
- Marburg-variant MS with a single lesion may be very difficult to distinguish from malignancy radiographically.
- Lumbar puncture demonstrates elevated protein, normal or mildly increased cell count, and an absence of oligoclonal bands.(34798965)
basics
- 🧅 Monophasic, rapidly progressive acute demyelinating disease. The hallmark finding is onion-like concentric rings of demyelination.
epidemiology & differential diagnosis
- Mostly affects young adults, with an upper age range of ~70 YO.(22284064)
- Usually associated with multiple sclerosis, but similar lesions have been reported in neuromyelitis optica spectrum disorders, ADEM, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), progressive multifocal leukoencephalopathy (PML), and human herpesvirus 6 infection.(26595866)
- Should be differentiated from levamisole-induced leukoencephalopathy due to cocaine use (which may cause a very similar imaging pattern). 📖
clinical presentation
- Typically presents as a solitary tumor-like lesion that can involve the brainstem or cerebral hemispheres.(Torbey 2019)
imaging
- MRI findings:
- T1: rings alternate between isointense and hypointense.
- T2: rings alternate between isointense and hyperintense.
- Gadolinium usually shows enhancement at the periphery.
- Sometimes diffusion restriction occurs at the edge of the lesion.
- Most patients will have other, additional demyelinating lesions elsewhere that are not due to Balo concentric sclerosis.
management
- Optimal treatment is unknown.
- This is often managed similarly to tumefactive multiple sclerosis.
basics
- This is an autoimmune antibody-mediated disorder which may occur as a paraneoplastic syndrome, or without any associated malignancy.
- Peak age range ~40-50 years old.
clinical presentation
- Evolution is usually chronic, but an acute presentation is possible.
- Viral-like prodrome is common.
- Myelitis rarely occurs in combination with meningoencephalitis.(34619778) Symptoms may include:(31162318)
- Meningitis (headache, nuchal rigidity, photophobia, fever).
- Encephalitis (ataxia, eye movement abnormalities, memory loss, psychiatric symptoms, tremor, seizures, delirium).
- Myelitis (urinary retention, numbness, weakness).
CSF
- >85% of patients will have an elevated CSF white cell count.(31162318)
- CSF may show oligoclonal banding in ~40% of patients.
- GFAP-IgG is ideally tested from the CSF.(33522737) Antibiotics isolated from the serum but not the CSF may represent false-positives.(31162318)
MRI findings
- Spinal cord findings in myelitis:
- Brain MRI in most cases shows radial enhancement around the ventricles (radially oriented linear perivascular enhancement).(34619778) Similar patterns may occur in patients with CNS vasculitis, neurosarcoidosis, Lyme disease, neuromyelitis optica spectrum disease, or intravascular lymphoma.(31162318)
treatment
- Response to steroids is generally rapid.(31162318)
basics
- The precise definition of transverse myelitis is a bit controversial. Transverse myelitis generally refers to inflammation involving the spinal cord bilaterally. However, the entire transverse section of the spinal cord is not necessarily involved (e.g., “partial transverse myelitis”).
clinical manifestations
- Antecedent infectious symptoms are common, suggesting that in some patients this may represent a postinfectious inflammatory event.(34030191)
- Patients commonly present with subacute bilateral weakness and sensory changes, with bowel and bladder dysfunction. Diminished/absent reflexes occur at the level of the lesion, with hyperreflexia below the level of the lesion.
- Respiratory compromise can occur.
- There should not be involvement of the cranial nerves or brain.
differential diagnosis
- Demyelinating diseases (e.g., multiple sclerosis or neuromyelitis optica spectrum disorder).
- Collagen vascular diseases, sarcoidosis.
- Paraneoplastic myelopathies.
- Infectious myelitis (e.g., VZV).
- dAFV (dural arteriovenous fistula).
- Neoplasms (e.g., glioma and ependymoma).
diagnostic criteria for definite idiopathic transverse myelitis
- (⚠️ Note that these are presented to illustrate core features of the disease, rather than necessarily to dictate whether a patient should receive corticosteroid.)
- Bilateral sensory, motor, or autonomic dysfunction referable to the spinal cord, with a clearly defined sensory level that progresses to the nadir over 4 hours to 21 days from onset.
- Neuroimaging must eliminate structural etiologies.
- Evidence supporting an inflammatory etiology is required, either by:
- MRI showing gadolinium enhancement.
- CSF showing pleocytosis or elevation of the immunoglobulin G index (initial CSF may be unremarkable, prompting repeat LP after 2-7 days).
- No history of radiation near the spine for 10 years.
- No serologic evidence of connective tissue disease, infection, or neuromyelitis optica spectrum disorder.
- No brain MRI abnormalities that would suggest multiple sclerosis.
- No history of optic neuritis.
- No clinical evidence of anterior spinal artery infarct.
treatment of idiopathic transverse myelitis
- High-dose steroid therapy is probably justified in most patients.(26595866)
- Treatment shouldn't be withheld while awaiting the results of antibody testing (which may be required to sort out different types of autoimmune myelitis).(33522737)
- More on the management of inflammatory demyelinating disorders below.📖
elevated ICP and/or herniation syndromes
- May result from a large lesion (e.g., tumefactive multiple sclerosis) or multiple smaller lesions (e.g., ADEM).
- Some case reports describe the use of hemicraniectomy for management of focal space-occupying lesions.(22284064)
respiratory failure
- May result from lesions in brainstem or spinal cord.
- Patients with chronic MS are at increased risk of aspiration.
neurogenic pulmonary edema
- May result from acute medullary lesions in the nucleus tractus solitarius of the medulla oblongata.
- Other associated signs of medullary involvement may include: rotary nystagmus, hemifacial numbness, unilateral soft palate paralysis, dysphonia, or diplopia.(22284064)
- Neurogenic pulmonary edema is usually self-limited and improves as the CNS process subsides.(Torbey, 2019)
- More on neurogenic pulmonary edema: 📖
takotsubo cardiomyopathy
- Rare complication that may lead to shock or cardiogenic pulmonary edema.
- More on takotsubo cardiomyopathy: 📖
posterior reversible encephalopathy syndrome (PRES)
- May occur in patients with NMOSD (dysfunction of aquaporin-4 channels leads to altered water regulation).
- Treatment includes general supportive care for PRES as well as steroid to reduce inflammation from NMOSD.(Wijdicks, 2019)
- More on PRES: 📖
hypothermia
- In advanced, chronic MS hypothermia may occur and cause episodic encephalopathy, which is usually not due to acute inflammation.(Wijdicks, 2019)
- Hypothermia may manifest as episodic encephalopathy.
- MRI may show lesions in the hypothalamus.
- Treatment includes supportive therapy for patients with hypothermia: 📖
bowel and bladder dysfunction
- These may be affected, similarly to other patients with spinal cord disorders.
- Usual supportive care should be provided (e.g., bladder scans and Foley catheter placement).
The following describes some general treatments which are often useful for acute inflammatory demyelinating disorders (e.g., multiple sclerosis, ADEM, NMOSD, idiopathic transverse myelitis). Please note that treatments should often be tailored to a specific disease process, in consultation with neurology specialists.
corticosteroid
- Initial treatment is steroid (typically pulse-dose methylprednisolone, 1000 mg daily for 3-5 days).(26595866)
- Empiric therapy may be needed prior to definitive diagnosis.
- For patients with myelitis of unclear etiology, a trial of steroid is generally reasonable once infection or spinal arteriovenous fistula have been reasonably excluded (e.g., 1 gram IV methylprednisolone daily for 3-5 days).(34619778)
- ⚠️ Acute neuroworsening after steroid administration may suggest dural arteriovenous fistula.(34024334)
- Improvement may occur rapidly.
plasmapheresis
- Plasmapheresis is generally second-line therapy for acute fulminant CNS demyelinating disease, if refractory to steroid.(Wijdicks, 2019; 33522737)
- One single-center RCT found plasmapheresis to be beneficial among a group of patients with acute inflammatory demyelinating attacks.(26595866)
IVIG
- IVIG may be useful in steroid-refractory ADEM (e.g., 2 grams/kg divided over 3-5 days).(Wijdicks, 2019)
- IVIG doesn't have a role in the treatment of fulminant MS relapses.(26595866)
fever management
- Among patients with multiple sclerosis, fever may cause acute neurological deterioration (a phenomenon known as Uhthoff phenomenon). This might relate to temperature-sensitive conduction blockade of partially demyelinated neurons.(34798965)
- Fever should be avoided in patients with MS, particularly if it seems to correlate with neurological deterioration.
basics
- Osmotic demyelination syndrome (ODS) was previously known as central pontine myelinolysis (CPM). However, the term central pontine myelinolysis has been replaced by the broader term osmotic demyelination syndrome to reflect that demyelination also occurs outside of the pons.
- Osmotic demyelination syndrome has generally been associated with rapid correction of hyponatremia. However, demyelination can also occur if the sodium begins at a normal level and is then elevated very rapidly.(29277507)
epidemiology: risk factors for osmotic demyelination syndrome
- (1) Baseline sodium:
- Osmotic demyelination usually occurs following rapid correction of chronic hyponatremia (hyponatremia lasting >2-3 days).
- Severe and asymptomatic hyponatremia is the most worrisome (especially <110 mM). In the absence of known baseline sodium levels, lack of symptoms implies chronicity.
- Osmotic demyelination is rare if the initial sodium is >120-125 mM.(31601554) However, osmotic demyelination syndrome can occur in patients with a baseline normal sodium that is abruptly increased.(29277507)
- (2) Rate of rise of sodium:
- >8-10 mM per day on average might cause osmotic demyelination. The rate that may cause demyelination is not precisely known (probably because it varies between patients).
- The greatest risk occurs if patients transition from chronic hyponatremia to hypernatremia. Hypernatremia should be aggressively avoided in patients who are recovering from hyponatremia.
- (3) Other risk factors:(30181129, 29277507)
- Cirrhosis, liver transplantation.
- Alcoholism.
- Malnutrition.
- Malignancy.
- Refeeding syndrome, hypophosphatemia, hypokalemia.
- Pregnancy or postpartum state; hyperemesis gravidarum.
- Severe illness / sepsis.
- Adrenal insufficiency.
classic presentation of pontine demyelination
- (#1) An initial encephalopathic stage often occurs. However, this is generally impossible to discern in the context of patients admitted with hyponatremia or other acute disorders.
- ⚠️ Patients can actually appear to be clinically improving in the first day or two following rapid sodium correction.
- (#2) Flaccid quadriparesis (~2-7 days after sodium rise):
- Dysarthria and dysphagia may be initial symptoms.
- Flaccid quadriplegia or quadriparesis occurs. Rarely this may progress to involve ocular motility, culminating in a locked-in syndrome.(31587708)
- Delirium, obtundation, or coma can occur.
- Movement disorders may occur including ataxia (more on this below).
- (#3) Spastic quadriparesis or quadriplegia (occurring roughly 5 days after symptom onset)(33713026)
- Upper motor neuron signs eventually emerge (including increased tone, hyperreflexia, clonus, and positive Babinski sign).
symptoms caused by extrapontine demyelination
- Extrapontine demyelination may occur together with pontine demyelination, or as an isolated phenomenon. Involvement of structures in the basal ganglia, thalamus, and limbic system may cause a variety of symptoms.
- (1) Movement disorder:
- A movement disorder may be the primary or sole clinical manifestation.(28850553)
- Basal ganglia involvement may cause movement disorders (including tremor, chorea, choreoathetosis, myoclonus, opsoclonus, dystonia, ataxia, mutism, and catatonia). Involuntary slow writhing and jerking movements of the anterior abdominal wall has been reported (“belly dancer's syndrome”).(33713026)
- (2) Neurobehavioral symptoms:(31587708)
- Seizures (which may persist for longer than seizures due solely to acute hyponatremia).
- Depression or mania, emotional lability.
- Frontal lobe dysfunction (e.g., disinhibition, impaired executive function, apathy).
- Encephalopathy, dementia.
- (3) Asymptomatic osmotic demyelination syndrome:
- MRI features of osmotic demyelination may occur without associated clinical deficits.(28850553)
radiology
- Imaging findings may lag behind clinical manifestations, with abnormalities often developing over 1-2 weeks.(33713026; 28850553) If imaging is initially normal, a repeat study may be helpful.
- CT scan is insensitive (~25%), but might reveal hypodensity within the pons.(31587708)
- Pattern of MRI abnormalities:
- The first abnormality to occur is hyperintensity on diffusion-weighted imaging (DWI).(33713026) Subsequently, hyperintensity is seen on T2/FLAIR sequences with hypointensity on T1 sequences (reflecting edema). However, hyperintensity on T1 may rarely occur if there is coagulative necrosis.(28850553)
- Lesions are usually nonenhancing with contrast.
- (1) Pontine abnormalities:
- MRI classically shows a symmetric lesion in the central pons. It may be rounded, triangular, or trident-shaped.(31589567)
- The corticospinal tracts and peripheral pons are typically spared.
- Sparing of the transverse pontine fibers is described, and may be noted as fine lines of normal signal intensity crossing the lesion.(31589567)
- (2) Extrapontine myelinolysis:
- This usually occurs in combination with pontine myelinolysis, but it may occur without pontine abnormalities in ~20% of cases.(31587708)
- Symmetric abnormalities may involve a variety of different structures. The most commonly involved structures are the basal ganglia, thalami, and hemispheric white matter (especially immediately underlying the grey matter).(31589567) Other structures which may be involved include the cerebellum and amygdala.(Torbey 2019)
prevention
- Osmotic demyelination may be prevented by avoiding rapid increases in sodium (when treating chronic hyponatremia, the target rise in sodium is ~6 mEq/L per day, and no more than 8 mEq/L per day).
- More on hyponatremia management here: 📖
management
- Early osmotic demyelination syndrome may be treatable by re-lowering of the sodium.(31601554) This may be effective if initiated within 24 hours of symptom onset, although a precise time cutoff is unclear.(33713026) Relowering of sodium will typically require IV desmopressin in combination with aggressive free water administration and frequent sodium monitoring (i.e., the DDAVP clamp; more on this here 📖).
- Electrolyte repletion and thiamine administration may be beneficial for patients with malnutrition, alcoholism, and/or refeeding syndrome.(33713026)
- Plasmapheresis or intravenous immunoglobulin have been utilized with some reports of success, but there is no high-level evidence supporting this.(33713026)
- Patients with movement disorders due to extrapontine demyelination may be treated in a symptomatic fashion, based on their clinical features and the usual management strategies for their type of movement disorder.
- The long-term prognosis of osmotic demyelination may be good, even among patients requiring mechanical ventilation. With meticulous supportive care, many patients have favorable recoveries.(22036854) This may be analogous to other demyelinating processes such as acute inflammatory demyelinating polyneuropathy (AIDP): with sufficient time, remyelination can occur. It should be noted that severe radiological abnormalities don't necessarily correlate with a poor prognosis.(28850553)
- Levamisole is an anthelmintic agent which commonly contaminates illicit cocaine.
- Clinical presentation of levamisole-induced leukoencephalopathy may initially resemble a stroke. Following neuroimaging, this may be confused with multiple sclerosis.
- Imaging of levamisole-induced leukoencephalopathy reveals a tumefactive demyelinating pattern:(31589567)
- One or more oval lesions within the white matter.
- Absence of mass effect or edema.
- Strong diffusion restriction.
- Incomplete ring-enhancement, with the incomplete portion facing the cortex.
- Concentric layers may be seen on T2 and DWI sequences.
basics
- Mild encephalopathy with reversible splenial lesion (MERS) is a clinico-radiologic syndrome. Some alternative/related terms include:
- “Reversible splenial lesion syndrome” (RESLES), in recognition that it is not invariably mild.(31588684)
- “Reversible splenial lesions during febrile illness” (RESLEF), in recognition that the syndrome is usually preceded by a febrile illness.
- “Cytotoxic lesions of the corpus callosum” (CLOCCS)
- MERS was initially associated with viral infections. More recently, other associations have been recognized as well (listed below). A formal definition of MERS is lacking, so there may be some confusion regarding exactly which patients have this syndrome.
clinical features
- (#1) A prodrome often occurs with symptoms that include fever, headache, cough, or gastrointestinal disturbance.(33839562) Patients are often diagnosed with an identifiable infection during this period (e.g., influenza). Other patients may have an infection that eludes definitive diagnosis.
- (#2) MERS may cause the following symptoms:
- (#3) Recovery without sequelae usually occurs within a month.(31588684)
radiology
- A lesion occurs in the mid-splenium of the corpus callosum with strong diffusion restriction, FLAIR/T2 hyperintensity, and no contrast enhancement.(33839562)
- Two radiological patterns are described:(31588684)
- Type 1 MERS: A small ovoid lesion is isolated in the center of the splenium of the corpus callosum. (However, even in this situation there may be very subtle diffusion restriction in the genu of the corpus callosum – implying the presence of more extensive brain involvement that defies identification on MRI.)
- Type 2 MERS: A lesion in the splenium of the corpus callosum expands into the adjacent white matter and/or anterior portion of the corpus callosum. In many cases, diffusion restriction is confined to the splenium, whereas T2 hyperintensity extends more diffusely.(28523438)
MERS is most often due to infection, including:
- Viral (influenza, parainfluenza, RSV, rotavirus, adenovirus, parvovirus B19, CMV, VZV, EBV, HHV6, HHV7, HIV, measles, mumps, rubella, enterovirus, adenovirus, COVID).(28523438)
- Bacterial (Legionella pneumophila, Streptococcus pneumoniae, Salmonella enteritidis, Escherichia coli, Staphylococcus aureus, Enterococcus faecalis, Klebsiella pneumoniae, Campylobacter jejuni, Mycoplasma pneumoniae).
- Other infections: Malaria, dengue fever.
- (It's probable that MERS may result from a broad range of infectious pathologies that incite significant systemic inflammation. Those listed above may merely represent the most common pathologies, which have been most frequently reported.)
differential diagnosis: other causes of a lesion in the splenium of the corpus callosum(31588684; 28523438)
- Antiseizure medications & epilepsy:
- Antiseizure medication (e.g., carbamazepine, phenytoin, valproate, lamotrigine, levetiracetam).
- Withdrawal from antiseizure medication.
- Status epilepticus.
- Other medications and toxins:
- Corticosteroids.
- Metronidazole, tetracycline.
- Intravenous immunoglobulin.
- Chemotherapy (e.g., methotrexate, 5-fluorouracil, capecitabine).
- Lithium.
- Alcoholism.
- Carbon monoxide poisoning.
- Sympathomimetic-induced kaleidoscopic visual illusion syndrome.
- Metabolic disturbances and associated disease:
- Hypoglycemia.
- Hypoxic-ischemic brain injury.
- Hypernatremia, hyponatremia, osmotic myelinolysis.
- Hyperammonemia.
- Marchiafava-Bignami disease.
- Wernicke encephalopathy.
- Thyroid storm.
- Hemolytic-uremic syndrome.
- Malignancy:
- Lymphocytic leukemia.
- Glioblastoma.
- Spinal meningeal melanocytoma.
- Chemotherapy (5-fluorouracil, cisplatin, carboplatin).
- Radiation therapy.
- Cerebrovascular diseases or vasculitis:
- Subarachnoid hemorrhage.
- Ischemic stroke.
- Cerebral venous thrombosis has been reported to cause a similar splenial lesion on MRI.(29204189)
- Kawasaki disease.
- Traumatic brain injury.
- Inflammatory processes:
- Autoimmune encephalitis (including anti-NMDA-receptor encephalitis, anti-voltage-gated potassium channel antibody syndrome).
- Autoimmune thyroid disease.
- Lupus.
- Multiple sclerosis.
- Miscellaneous:
- Renal failure.
- Preeclampsia.
- Malnutrition; anorexia nervosa.
- Status migrainosus.
- High-altitude cerebral edema.
- Transient global amnesia.
- Charcot-Marie-Tooth disease.
management
- There is no well-defined therapy for MERS. Post-infectious MERS seems to be a benign and self-limiting disorder that may not require any specific therapy.
- Any underlying cause(s) should be sought and managed.
- Many patients have associated seizure, so there should probably be a high index of suspicion for seizures or nonconvulsive status epilepticus.
basics of CLIPPERS (chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids)
- CLIPPERS is a rare, subacute/chronic inflammatory process involving predominantly the brainstem (especially the pons and adjacent areas such as the cerebellum).(33851608) Key features:
- MRI shows post-gadolinium enhancing punctate and curvilinear lesions “peppering” the affected areas.
- Dramatic clinico-radiological resolution following steroid.
- Pathologically, CLIPPERS involves perivascular and parenchymal infiltration of lymphocytes.
- The cause of CLIPPERS remains unknown.
clinical presentation
- Subacute or chronic onset of symptoms related to pontine and cerebellar dysfunction (e.g., cranial nerve abnormalities, ataxia, upper motor neuron signs).
- The average age of onset is ~50 years old, with a very broad age range.(31661071)
laboratory findings
- CSF studies may show mild protein elevation.
- Oligoclonal bands and IgG index may be elevated.
- (Dramatic CSF abnormalities would argue for an alternative diagnosis.)
differential diagnosis includes:
- Primary CNS lymphoma (PCNSL), intravascular lymphoma, CNS lymphomatoid granulomatosis.
- Infection (e.g., tuberculosis, neurosyphilis, Whipple's disease).
- Vasculitis.
- Granulomatous diseases (e.g., neurosarcoidosis).
- MOG-antibody related diseases.
- Multiple sclerosis.
- Hemophagocytic lymphohistiocytosis.
- Langerhans cell histiocytosis.
- autoimmune GFAP astrocytopathy.
imaging
- The radiographic hallmark is punctate gadolinium enhancement in a “pepper-like” pattern centered on the pons. These lesions may extend into the cerebellum or spinal cord (and rarely even further).
- Lesions are usually small (<3 mm).
- T2/FLAIR sequences may be unimpressive. On T2 sequences, there should be homogeneous abnormality that doesn't exceed the size of the area with gadolinium enhancement.(31661071)
- Edema, mass effect, ring enhancement, or diffusion restriction are absent.(31661071)
- Steroid generally eliminates gadolinium-enhancing lesions on MRI within weeks. However, some atrophy may remain within its wake.(28726127)
management
- A typical initial treatment is a five-day pulse of steroid (e.g., IV methylprednisolone 1 gram/day), followed by a maintenance dose of 1 mg/kg/day oral prednisone. (28726127)
- Long-term therapy involves various steroid-sparing agents. These are generally initiated after clinical improvement is observed.(28726127)
epidemiology
- Neuropsychiatric lupus affects about half of patients with lupus, usually within the first five years of disease onset.(33832774)
neuropsychiatric syndromes in lupus relevant to critical care
- Cerebrovascular disease:
- Ischemic stroke is the most common manifestation.
- Potential causes include:
- Hypercoagulable state due to antiphospholipid antibody syndrome.
- Cardioembolic stroke due to Libman-Sacks endocarditis.
- Early atherosclerosis.
- CNS vasculitis (which is extremely rare).(33609799)
- Lupus causes premature atherosclerosis, so strokes occurring >~8 years after diagnosis may be increasingly due to atherosclerosis.(33832774)
- Seizure disorders:
- Generalized or focal seizures may occur in ~5% of patients.
- Potential causes include:
- PRES (posterior reversible encephalopathy syndrome).
- CVT (cerebral venous thrombosis).
- Ischemic stroke.
- Lupus (e.g., direct toxicity from autoantibodies).
- Demyelination, including transverse myelopathy:
- Occurs in ~2% of patients.(33832774)
- Clinical and radiological manifestation may be indistinguishable from multiple sclerosis or NMOSD (neuromyelitis optica spectrum disorders). To confuse matters further, some patients may have both lupus and a second, distinct autoimmune disorder (e.g., NMOSD).
- Movement disorders (especially chorea).
- Chorea is strongly associated with antiphospholipid antibodies.
- Brain MRI is usually normal.(33609799)
- Acute confusional state / delirium.
- Occurs in ~5% of patients.(33832774)
- Alternative etiologies are broad (including infection, metabolic disturbances, medication side-effects).
- Brain MRI may reveal white matter hyperintensities.(33609799)
- Delirium due to lupus usually responds well to steroids and classic immunosuppressants.(33609799)
- Psychosis.
- Psychosis is rare, occuring in ~2% of patients.
- Alternative etiologies include steroid therapy.
- Psychosis due to lupus usually precedes, or occurs early in the course of the disease.
- Aseptic meningitis.
- This is rare, occuring in ~0.5% of patients.
- Alternative etiologies include drug-induced aseptic meningitis (especially due to NSAIDs or immunosuppressants), or infection.
- PRES (posterior reversible encephalopathy syndrome).
- In patients where PRES seems to be precipitated by a lupus flare, treatment may include a combination of blood pressure control and immunosuppression. However, these patients may also have other causes of PRES (e.g., uncontrolled hypertension, cyclophosphamide exposure).(33609799)
- PML (progressive multifocal leukoencephalopathy) – as a complication of immunosuppression (e.g., rituximab).
- CAPS (catastrophic antiphospholipid antibody syndrome).
- CVT (cerebral venous thrombosis).
- HLH (hemophagocytic lymphohistiocytosis).
- Guillain Barre syndrome.
- Myasthenia gravis.
evaluation
- CSF analysis may help exclude alternative diagnoses.
- Antiphospholipid antibody evaluation may be considered.
- Anti-aquaporin 4 antibodies may be helpful if there is concern for intercurrent NMOSD (neuromyelitis optica spectrum disease).
- Neuroimaging may vary depending on specific neurologic manifestations.
factors to consider in determining whether to attribute clinical manifestations to lupus
- Time interval between diagnosis of lupus and neurologic abnormality:
- Neuropsychiatric lupus typically begins within five years of diagnosis.
- Longer durations of time between lupus diagnosis may reduce the likelihood that the neurologic disorder is due to lupus.
- General lupus activity and antiphospholipid antibodies.
- Alternative explanation(s) for neurologic abnormalities.
management
- Ischemic pathway therapies:
- Aspirin may be reasonable for primary prevention among patients with antiphospholipid antibodies.
- For patients with antiphospholipid antibodies implicated in causing focal stroke(s), anticoagulation may be indicated.(33832774)
- Inflammatory pathway therapies:
- Steroid and steroid-sparing agents may be utilized.
Follow us on iTunes
To keep this page small and fast, questions & discussion about this post can be found on another page here.
- Assuming that a spinal lesion is idiopathic transverse myelitis, without an adequate evaluation.
Guide to emoji hyperlinks
- = Link to online calculator.
- = Link to Medscape monograph about a drug.
- = Link to IBCC section about a drug.
- = Link to IBCC section covering that topic.
- = Link to FOAMed site with related information.
- 📄 = Link to open-access journal article.
- = Link to supplemental media.
References
- 22284064 Bunyan RF, Tang J, Weinshenker B. Acute demyelinating disorders: emergencies and management. Neurol Clin. 2012 Feb;30(1):285-307, ix-x. doi: 10.1016/j.ncl.2011.09.013 [PubMed]
- 26595866 Bevan CJ, Cree BA. Fulminant Demyelinating Diseases of the Central Nervous System. Semin Neurol. 2015 Dec;35(6):656-66. doi: 10.1055/s-0035-1564682 [PubMed]
- Tang, Y., Mukherjee, S., & Wintermark, M. (2015). Emergency Neuroradiology: A Case-Based Approach (1st ed.). Cambridge University Press.
- 28523438 Lin D, Rheinboldt M. Reversible splenial lesions presenting in conjunction with febrile illness: a case series and literature review. Emerg Radiol. 2017 Oct;24(5):599-604. doi: 10.1007/s10140-017-1516-4 [PubMed]
- 28545419 Yuan J, Yang S, Wang S, Qin W, Yang L, Hu W. Mild encephalitis/encephalopathy with reversible splenial lesion (MERS) in adults-a case report and literature review. BMC Neurol. 2017 May 25;17(1):103. doi: 10.1186/s12883-017-0875-5 [PubMed]
- 28726127 Zalewski NL, Tobin WO. CLIPPERS. Curr Neurol Neurosci Rep. 2017 Sep;17(9):65. doi: 10.1007/s11910-017-0773-7 [PubMed]
- 29277507 Shah MK, Mandayam S, Adrogué HJ. Osmotic Demyelination Unrelated to Hyponatremia. Am J Kidney Dis. 2018 Mar;71(3):436-440. doi: 10.1053/j.ajkd.2017.10.010 [PubMed]
- 30181129 Rondon-Berrios H, Tandukar S, Mor MK, Ray EC, Bender FH, Kleyman TR, Weisbord SD. Urea for the Treatment of Hyponatremia. Clin J Am Soc Nephrol. 2018 Nov 7;13(11):1627-1632. doi: 10.2215/CJN.04020318 [PubMed]
- 30709470 Kranz PG, Amrhein TJ. Imaging Approach to Myelopathy: Acute, Subacute, and Chronic. Radiol Clin North Am. 2019 Mar;57(2):257-279. doi: 10.1016/j.rcl.2018.09.006 [PubMed]
- 31162318 Flanagan EP. Neuromyelitis Optica Spectrum Disorder and Other Non-Multiple Sclerosis Central Nervous System Inflammatory Diseases. Continuum (Minneap Minn). 2019 Jun;25(3):815-844. doi: 10.1212/CON.0000000000000742 [PubMed]
- 31534611 Sharma A, Foutz TJ, Gonzalez-Cuyar LF, Latimer CS, Longstreth WT Jr, Tirschwell DL, Davis AP. From Herniation to Rehabilitation: A Young Woman With Rapidly Progressive Neurological Deficits. Neurohospitalist. 2019 Oct;9(4):215-221. doi: 10.1177/1941874419832437 [PubMed]
- 31582425 Rosenthal JF, Hoffman BM, Tyor WR. CNS inflammatory demyelinating disorders: MS, NMOSD and MOG antibody associated disease. J Investig Med. 2020 Feb;68(2):321-330. doi: 10.1136/jim-2019-001126 [PubMed]
- 31587708 Lambeck J, Hieber M, Dreßing A, Niesen WD. Central Pontine Myelinosis and Osmotic Demyelination Syndrome. Dtsch Arztebl Int. 2019 Sep 2;116(35-36):600-606. doi: 10.3238/arztebl.2019.0600 [PubMed]
- 31588684 Tetsuka S. Reversible lesion in the splenium of the corpus callosum. Brain Behav. 2019 Nov;9(11):e01440. doi: 10.1002/brb3.1440 [PubMed]
- 31589567 de Oliveira AM, Paulino MV, Vieira APF, McKinney AM, da Rocha AJ, Dos Santos GT, Leite CDC, Godoy LFS, Lucato LT. Imaging Patterns of Toxic and Metabolic Brain Disorders. Radiographics. 2019 Oct;39(6):1672-1695. doi: 10.1148/rg.2019190016 [PubMed]
- 31601554 Rondon-Berrios H. Therapeutic Relowering of Plasma Sodium after Overly Rapid Correction of Hyponatremia: What Is the Evidence? Clin J Am Soc Nephrol. 2020 Feb 7;15(2):282-284. doi: 10.2215/CJN.04880419 [PubMed]
- 31661071 Turnquist C, Pretorius PM, DeLuca GC, Halliday J, Kerr R, Hofer M. CLIPPERS: A case report with radiology, three serial biopsies and a literature review. Clin Neuropathol. 2020 Jan/Feb;39(1):19-24. doi: 10.5414/NP301219 [PubMed]
- 31895125 Moore E, Huang MW, Putterman C. Advances in the diagnosis, pathogenesis and treatment of neuropsychiatric systemic lupus erythematosus. Curr Opin Rheumatol. 2020 Mar;32(2):152-158. doi: 10.1097/BOR.0000000000000682 [PubMed]
- 33392785 Perez Giraldo GS, Ortiz Garcia JG. Immune-Mediated Disorders Affecting the Spinal Cord and the Spine. Curr Neurol Neurosci Rep. 2021 Jan 3;21(1):3. doi: 10.1007/s11910-020-01088-6 [PubMed]
- 33522737 Lopez Chiriboga S, Flanagan EP. Myelitis and Other Autoimmune Myelopathies. Continuum (Minneap Minn). 2021 Feb 1;27(1):62-92. doi: 10.1212/CON.0000000000000900 [PubMed]
- 33609799 Carrión-Barberà I, Salman-Monte TC, Vílchez-Oya F, Monfort J. Neuropsychiatric involvement in systemic lupus erythematosus: A review. Autoimmun Rev. 2021 Apr;20(4):102780. doi: 10.1016/j.autrev.2021.102780 [PubMed]
- 33713026 Bose P. Central pontine myelinolysis and the osmotic demyelination syndromes: an open and shut case? Acta Neurol Belg. 2021 Aug;121(4):849-858. doi: 10.1007/s13760-021-01634-0 [PubMed]
- 33832774 Hanly JG, Inanç M. The neurology of lupus. J Neurol Sci. 2021 May 15;424:117419. doi: 10.1016/j.jns.2021.117419 [PubMed]
- 33839562 Grosset L, Hosseini H, Bapst B, Hodel J, Cleret De Langavant L, Faugeras F, Bachoud-Lévi AC, Seddik L. Mild encephalopathy with reversible splenial lesion: Description of nine cases and review of the literature. Seizure. 2021 May;88:83-86. doi: 10.1016/j.seizure.2021.03.032 [PubMed]
- 33851608 Dyachenko PA, Hramova RA, Dyachenko AG. A RARE BRAINSTEM INFLAMMATORY SYNDROME, CLIPPERS, MYTH OR FACT. CASE REPORT WITH CRITICAL REVIEW. Wiad Lek. 2021;74(1):161-164 [PubMed]
- 34024334 Marignier R. Acute and subacute myelopathy. Rev Neurol (Paris). 2021 May;177(5):557-566. doi: 10.1016/j.neurol.2020.08.003 [PubMed]
- 34030191 Abdel-Wahed L, Cho TA. Immune-Mediated Myelopathies: A Review of Etiologies, Diagnostic Approach, and Therapeutic Management. Semin Neurol. 2021 Jun;41(3):269-279. doi: 10.1055/s-0041-1725152 [PubMed]
- 34619778 Sechi E, Flanagan EP. Evaluation and Management of Acute Myelopathy. Semin Neurol. 2021 Oct;41(5):511-529. doi: 10.1055/s-0041-1733792 [PubMed]
- Louis ED, Mayer SA, Noble JM. (2021). Merritt’s Neurology (Fourteenth). LWW.
- 34798965 Touma L, Muccilli A. Diagnosis and Management of Central Nervous System Demyelinating Disorders. Neurol Clin. 2022 Feb;40(1):113-131. doi: 10.1016/j.ncl.2021.08.008 [PubMed]