Acute Demyelinating Disorders

June 22, 2022 by Josh Farkas

Acute Demyelinating EncephaloMyelitis (ADEM) & MOGAD

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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:

 Initial symptoms often include headache, nausea/vomiting, seizures,

encephalopathy, and multifocal neurologic
deficits. (31534611) Patients often deteriorate acutely, with evolution
from encephalopathy to coma.

 Death often occurs due to cerebral edema and herniation.(26595866)

 Imaging:

 Lesions are often large and confluent, sometimes with tumefactive

necrosis.

 Lesions predominantly involve the supratentorial white matter. The

cortex is spared, but lesions frequently involve the basal ganglia,
thalamus, and pons.(31534611)

 Punctate hemorrhages may occur.(34798965)

 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)

NeuroMyelitis Optica Spectrum Disorders (NMOSD)

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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)

Multiple Sclerosis myelitis

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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.

tumefactive MS
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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.
 acute multiple sclerosis (Marburg variant)
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 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)

Balo Concentric Sclerosis

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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.

GFAP-IgG associated meningoencephalomyelitis

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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:

  Faint, long T2 lesions are longitudinally extensive, potentially
extending over the entire spinal cord.(34619778)

 Punctate parenchymal enhancement, enhancement of the central

canal, and/or leptomeningeal enhancement are common.(34619778)

 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)

Idiopathic Transverse Myelitis

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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.

emergency complications of demyelinating disorders

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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).

treatment
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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.

Osmotic Demyelination Syndrome (ODS)

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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-induced leukoencephalopathy
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 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.

mild encephalopathy with reversible splenial lesion (MERS)

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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:

 Core features may be altered consciousness, delirium, headache,

and/or seizure.(33839562; 28545419)

 Other features which may be seen include dysarthria, aphasia, ataxia,

nystagmus, sensory abnormality, hemiparesis, and/or urinary
retention.(31588684; 28545419)

 Hyponatremia is often seen.(28545419)

 (#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.

CLIPPERS
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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)

lupus
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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.

Pitfalls

 Assuming that a spinal lesion is idiopathic transverse myelitis, without an adequate

evaluation.