Acquired demyelinating syndromes encompass both acute and chronic immune-mediated disorders of the central nervous system (CNS) and include acute disseminated encephalomyelitis (ADEM), optic neuritis (ON), transverse myelitis, multiple sclerosis (MS), and neuromyelitis optica (NMO). These disorders are all characterized by CNS inflammation. Although these syndromes overlap in their neurologic symptoms, the clinical severity, radiologic features, response to treatment, and prognosis for neurologic recovery vary between the disorders.
Given the complexity of acquired demyelinating syndromes, pediatric providers must have a high index of suspicion for these disorders. Subtle neurologic symptoms may be difficult to identify in young children. For example, sensory and visual symptoms are often difficult for young children to describe and may not be brought to the attention of a care provider or parent unless they are severe or impacting activities of daily living.
Patients with symptoms concerning for an acute or chronic demyelinating disorder require prompt evaluation so that a diagnosis can be confirmed and treatment initiated. This chapter reviews clinical features, differential diagnosis, and management of demyelinating disorders in the inpatient setting and then describes the prototypical acquired demyelinating syndromes in greater detail, highlighting the unique features of the disorders.
Acquired demyelinating syndromes cause various symptoms that localize to the CNS. Common symptoms include vision loss or visual disturbance (such as blurry or double vision), sensory abnormalities (including numbness or tingling), weakness, balance difficulties, gait abnormalities, and bowel and bladder dysfunction. Neurologic symptoms may localize to one particular area of the CNS (termed monofocal); however, symptoms and signs can affect various regions (polyfocal) and reflect the presence of diffuse inflammation throughout the CNS.
The differential diagnosis for an acute neurologic event in a previously well child is extensive and must be tailored to the individual’s clinical history and exam findings. Acquired demyelinating syndromes are diagnosed based on clinical criteria, with accompanying supportive laboratory and radiographic features. The prototypical demyelinating disorders are listed in Table 122-1 and discussed in greater detail later in the chapter. However, diagnosis of a demyelinating syndrome is often difficult at presentation, and other etiologies, such as infection, rheumatologic processes, and malignancy must be carefully considered prior to making the diagnosis. Table 122-2 provides a differential diagnosis that may be considered in the appropriate clinical context as well as supportive laboratory and imaging features to determine whether an alternative diagnosis exists.
| Diagnosis | Clinical Features | Radiographic Features | CSF and other Labs | Demographics |
|---|---|---|---|---|
| Acute disseminated encephalomyelitis (ADEM) | Acute encephalopathy with polyfocal neurologic symptoms Seizures, fever, headache can occur Typically monophasic | Lesions are asymmetric, large, and often have poorly defined borders Visible lesions in the deep gray matter are common | Oligoclonal bands are rarely positive | Common in children and young adults |
| Multiple Sclerosis (MS) | Neurologic features are variable; encephalopathy and seizures are rare Typically a relapsing course | Periaqueductal, corpus callosum, and periventricular white matter often involved T1 hypointense lesions present commonly at onset | Oligoclonal bands are typically positive (>95% in post-pubertal patients) | Commonly presents in adolescence and young adulthood Female predominance |
| Optic neuritis (ON) | Vision loss Pain with eye movement Change in color vision | Increased T2 signal, swelling, or Gd enhancement of the optic nerves | Can see elevated CSF WBC, CSF protein/glucose is typically normal | Can occur at any age Bilateral ON is more common in younger children (<10 years of age)4 |
| Transverse myelitis (TM) | Weakness Paresthesias Bowel/bladder dysfunction | Increased T2 signal, swelling, or Gd enhancement of the spinal cord | CSF pleocytosis and/or elevated protein seen in at least half of cases | Can occur at any age |
| Neuromyelitis optica (NMO) | Must have ON and TM | Spinal cord lesions extending over 3 cord segments (longitudinally extensive myelitis) Brain lesions, if present, tend to occur in the hypothalamic region or midbrain | Positive NMO IgG in serum and/or CSF CSF WBC often very elevated (can be >100 cells) | Females predominantly affected5 |
| Diagnostic Category | Characteristic Clinical Features | Additional Investigations |
|---|---|---|
Infectious/peri-infectious Bacterial, viral, fungal, or parasitic infections, such as: Herpes virus (HSV, VZV, CMV) EBV Mycoplasma Enterovirus Neuroborreliosis HIV Neurosyphilis Tuberculosis (TB) JC virus HTLV-1 Hepatitis A, B, and C Cryptococcus | Fever Meningsmus Rash (such as petechiae in bacterial meningitis or vesicles in herpes viruses) Systemic evidence of infection Alteration in mental status | Blood and CSF cell counts and cultures PCR testing for infection in CSF TB testing Fungal culture |
Rheumatologic Primary CNS angiitis Sarcoidosis Sjogren syndrome System lupus erythematosus Bechet syndrome Anticardiolipin or antiphospholipid antibody syndrome | Persistent and prominent headache Systemic evidence of vasculitis (not required) Note: Clinical, laboratory, and radiographic evidence of systemic disease may be absent in CNS vasculitis | ESR, ANA profile ACE level Antiphospholipid and anticardiolipin antibodies MRA of head Cerebral angiography Brain biopsy |
Malignancy CNS lymphoma Glioma | History of prior malignancy and/or chemotherapy Systemic symptoms (weight loss, night sweats, fever) Note: With CNS lymphoma, symptoms may improve with administration of steroids | Blood smear CSF cytology Brain biopsy |
Neuroimmune disorders Anti-NMDA receptor encephalitis | Encephalopathy Vital sign instability Movement abnormalities Psychiatric symptoms | Anti-NMDA receptor antibody from CSF and blood Abdominal ultrasound in females; testicular ultrasound in males (evaluate for teratoma) Consider other paraneoplastic antibody testing (based on clinical symptomatology) |
| Macrophage activation syndromes | History of similarly affected sibling Systemic signs of liver, skin, renal, or bone marrow involvement Persistent fever | Serum ferritin and triglycerides Soluble IL-2 receptor level Blood, CSF, and bone marrow evaluation for hemophagocytosis |
| Metabolic or mitochondrial disease | Symptomatic worsening with fever Pre-existing progressive neurologic deterioration, developmental delay, or cognitive dysfunction | Serum and CSF lactate/pyruvate MR spectroscopy Consider plasma amino acids, urine organic acids, ammonia, acylcarnitine profile |
Vascular Cerebral Autosomal Dominant Arteriopathy with Subcortical Infracts and Leukoencephalopathy (CADASIL) | Prominent headaches Cognitive and psychiatric symptoms are common Family history of migraines, early onset dementia, and strokes | NOTCH3 genetic testing |
The evaluation of a child with acute neurologic symptoms begins with a detailed history that includes information about the timing and duration of symptoms. Although a thorough neurologic examination should be performed to help localize neurologic dysfunction, asymptomatic inflammation (lesions that do not cause symptoms or findings on exam) is also common in these disorders. Similarly, a normal sensory or ophthalmologic examination does not preclude the possibility of CNS demyelinating lesions. Therefore extensive imaging (brain, cervical and thoracic spine) is often indicated, even without symptoms or examination findings that specifically localize to these areas of the CNS. Though magnetic resonance imaging (MRI) is required to determine the extent of CNS inflammation, computed tomography (CT) of the brain may be performed acutely if there are signs of elevated intracranial pressure, altered mental status, or new focal neurologic deficits.
In all children with suspected CNS inflammation, cerebrospinal fluid (CSF) analysis should be considered. In addition to obtaining CSF cell count, protein, glucose, Gram stain and culture, and other clinically indicated tests (i.e. for infectious etiologies), and evaluation for immunoglobulin synthesis within the CNS should be performed. The intrathecal synthesis of immunoglobulins is a hallmark of CNS inflammation but not specific to demyelinating diseases. To interpret these studies, CSF and blood should be drawn at the same time and sent for an oligoclonal band profile, which includes a qualitative test to visualize the oligoclonal bands through isoelectric focusing as well as quantitative measures of these immunoglobulins through an immunoglobulin G (IgG) index and IgG synthesis rate.
In severe cases, acute demyelination may be life threatening and can impair respiration (especially if upper cervical cord or brainstem lesions are present). As a result, assessment of vital signs is a key part of the initial management of any patient with acute demyelination. Airway, breathing, and circulation should be assessed and respiratory support should be quickly obtained if needed.
It is not always possible at the onset of CNS inflammation to determine the diagnosis. For example, inflammation of the optic nerves causing visual loss (ON, described below) may occur without any other clinical or radiographic neurologic findings (termed a clinically isolated syndrome) or may be a feature of ADEM, MS, or NMO. Therefore acute therapy, targeting the CNS inflammation, is similar at presentation regardless of diagnosis. Most clinicians initiate a short course of corticosteroids to reduce inflammation. Other therapies include intravenous immunoglobulin or plasma exchange in severe or refractory cases.
Though the optimal dose has not been established for pediatric patients, most clinicians prescribe 20 to 30 mg/kg/day (with a maximum of 1000 mg/day) of intravenous methylprednisolone for 3 to 5 days for initial treatment of an acquired demyelinating syndrome requiring hospitalization. The use of a steroid taper is physician-dependent.7 If symptoms resolve after intravenous treatment, additional treatment with oral prednisone may not required. For children with improvement but ongoing deficits, oral prednisone, starting at a dose of 1 mg/kg/day (max of 60 mg), can subsequently be administered and tapered over a few weeks.8,9
Often treatment with corticosteroids is delayed due to concern for infection. Of note, corticosteroids are often used to treat patients with Haemophilus influenzae type b and pneumococcal meningitis, and have been safely given in severe case of herpes encephalitis.10 Therefore delaying treatment with corticosteroids due to concern for infection may not be necessary and is under further investigation. While steroids may be safe even in the presence of a viral or bacterial CNS infection, corticosteroids are contraindicated in fungal infections.
When administering high-dose corticosteroids, it is important to remember to also treat with an H2 blocker or a proton pump inhibitor for gastrointestinal prophylaxis. Other less common side effects of corticosteroids to consider include hyperglycemia, hypertension, psychiatric symptoms (anxiety, psychosis), insomnia, and weight gain. Avascular necrosis can also occur and has been reported in a patient treated with corticosteroids for less than 1 month.11
Intravenous immunoglobulin (IVIg) has been reported to be effective in some children with acquired demyelinating syndromes who do not respond to corticosteroids, or in some patients who experience recurrence of neurological deficits upon corticosteroid withdrawal. The typical dose administered is 2 g/kg divided over 2 to 5 days, though faster infusions can be safely used.
For patients with acquired demyelinating syndromes and severe neurologic deficits who fail to demonstrate clinical improvement by the third to fifth day of corticosteroid treatment, or children with life-threatening demyelination or paralysis at onset, plasma exchange (PE) should be considered.9,12 A typical PE regimen consists of 5 to 7 exchanges over a 2-week period.
Physiatrists and physical, occupational, and speech therapists play a major role in the recovery of patients with CNS inflammation and should be consulted as early as appropriate during an admission. Some children will require transfer to a rehabilitation facility after discharge from the acute care setting, depending upon their clinical recovery.
In summary, acquired demyelinating syndromes occur in children and often require hospitalization at symptom onset to fully evaluate the CNS and exclude alternative diagnoses. Treatment of CNS inflammation is often initiated before all of the diagnostic studies are obtained in the inpatient setting. The prototypical acquired demyelinating syndromes are described in more detail below.
Approximately 25% of all children with an acquired demyelinating syndrome will manifest with ADEM, which is defined by the International Pediatric Multiple Sclerosis Study Group (IPMSSG) as a clinical CNS event with a presumed inflammatory cause characterized by polyfocal neurologic deficits and encephalopathy not explained by fever or systemic illness.13 Though ADEM is typically a monophasic (isolated illness followed by recovery and no recurrence) pediatric disorder, multiphasic forms have been reported. Rarely, an ADEM-like initial attack can be the first presentation of a chronic demyelinating disorder, such as MS or NMO.
In order to meet consensus criteria for ADEM, a patient must present with encephalopathy, which can be manifested by behavioral change, profound irritability, or altered consciousness (including coma), and polyfocal neurologic deficits.13,14 Prodromal systemic symptoms such as fever, headache, and malaise can occur in the days prior to the onset of neurologic symptoms. The initial symptoms of ADEM may occur spontaneously without antecedent illness, but more typically begin within days to weeks of a febrile illness of presumed viral etiology. Upper respiratory tract infections are the most commonly reported preceding illnesses, followed by gastrointestinal infection, and then nonspecific febrile illnesses.14 Once neurologic symptoms begin, the clinical course progresses quickly and patients typically develop maximal symptoms over the following 3 to 5 days.14
Neurologic symptoms in ADEM can vary and correspond to the sites of CNS inflammation in a particular patient. The most common neurologic features in ADEM include upper motor neuron symptoms (such as weakness, increased tone, and hyperreflexia), followed by ataxia and cranial nerve palsies.
In a patient with encephalopathy and neurologic symptoms, with or without a recent fever or illness, investigations are initially directed toward excluding active CNS infections and evaluating for recent viral exposures. The presence of fever, meningismus, rash, or systemic illness should raise suspicion for an infectious process rather than ADEM, although it may often be difficult to differentiate infections from post-infectious disorders if the neurologic symptoms coincide with the fever and systemic illness. Other symptoms and signs are particularly relevant, such as pain over a dermatome (with or without vesicular lesions), which may be caused by herpes infections. Adenopathy is present in cat-scratch disease and other infections. A patient presenting with encephalopathy and psychiatric symptoms or a movement disorder should raise concern for anti-NMDA-R encephalitis.
A lymphocytic CSF pleocytosis (>10 cell/μL) and/or elevation of CSF protein is present in more than half of cases of ADEM. Oligoclonal bands detected in CSF but not detected in concurrent serum are rare but have been reported to be present acutely in up to 19% of patients with ADEM.2,15,16 Presence of CSF oligoclonal bands in this population is nonspecific, as intrathecal immunoglobulins can also be seen with CNS infection, but it is still recommended as part of the diagnostic evaluation in patients presenting with ADEM.7
Radiologically, ADEM is typically characterized by multifocal T2/FLAIR hyperintense lesions in both the white and gray matter of the brain and spinal cord. Lesions are typically large with poorly demarcated margins. Visible lesions in the deep gray matter (thalamus and basal ganglia) are frequently noted. Typical radiologic features of ADEM are demonstrated in Figure 122-1. Though ADEM is thought to be an acute disorder, it is rare for all lesions to enhance with gadolinium, and some patients have no enhancing lesions.17 Meningeal enhancement, the presence of completely ring-enhanced lesions,18 and lesions that are persistently T1 hypointense are uncommon in ADEM and suggest alternative diagnoses.
FIGURE 122-1.
Common radiologic features of ADEM: (a) axial and (b) coronal fluid-attenuated inversion recovery (FLAIR) images demonstrating typical radiologic features of ADEM. Lesions are typically large, asymmetric, and have poorly demarcated borders. Deep gray lesions are often visualized (arrow).
Treatment is based on the severity of neurologic symptoms. If the encephalopathy and polyfocal symptoms have resolved by the time of medical evaluation, acute treatment may not be necessary. For children with neurologic deficits, intravenous corticosteroids should be initiated. Typically, intravenous methylprednisolone is given for 3 to 5 days, during which time clinical improvement often occurs. An oral prednisone taper may be used subsequently if there is improvement but some persistent neurologic deficits remain.
If the symptoms do not improve with intravenous steroids or children have life-threatening demyelination at onset, plasma exchange can be considered. IVIg has been reported to be effective in some children with ADEM who do not respond fully to corticosteroids, or in some patients who seem to experience recurrence of neurological deficits upon corticosteroid withdrawal. Additional details can be found in the Treatment section above.
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