OVERVIEW: What every practitioner needs to know
Are you sure your patient has demyelinating disease? What are the typical findings for this disease?
Demyelinating diseases are a class of related disorders in which the immune system, both B- and T-cells, inappropriately targets myelinated neurons and resulting in damage to the myelin sheath around neurons, injury to the glial cells supporting the myelin, and even the neurons themselves can also be damaged or even killed in the most severe manifestations of the disease.
As a whole, these diseases are sporadic, generally acute or sub-acute in onset and in their fulminant presentation their symptoms are readily correlated with neuroimaging of the affected central nervous system tissue which will usually reveal evident white matter lesions. These diseases can be treated with corticosteroids to reduce inflammation and eventually degrade the autoimmune response; chronic manifestations of these diseases have many emerging therapies but the mainstay of treatment is immune suppression.
In general, the following symptoms are shared to varying degrees across all demyelinating diseases but all symptoms may not be present in a given patient at the same time:
Altered mental status/encephalopathy
Reduced visual acuity or blindness in the affected eye(s)
Cerebellar findings (ataxia, dysdiadochokinesia)
Often, multiple neurological deficits will be present initially. Clinical examination, radiological findings, and serial follow-up are typically needed to differentiate between specific sub-types of these demyelinating diseases as discussed below.
Taxonomy and Descriptions of Demyelinating Diseases
The initial presentation of a demyelinating disease entity, without encephalopathy and devoid of findings specific to variants (see below) is termed a “clinically isolated syndrome.” The presence of encephalopathy is required for a diagnosis of acute disseminated encephalomyelitis (ADEM.)
A child with multiple sclerosis, or a clinically isolated syndrome, often will present with solitary or multiple neurological findings, and based on retrospective studies these findings would typically include some combination of weakness, sensory changes, visual changes, and/or cerebellar findings.
Demyelinating diseases of the nervous system in children includes multiple sclerosis (“MS”) and its various progressions and variants, including the following:
Balo’s concentric sclerosis is a rare multiple sclerosis variant notable for the appearance of rings of demyelination within the visualized lesions of the affected brain. Clinically, patients will resemble others with multiple sclerosis or a clinically isolated syndrome and this diagnosis requires neuroimaging. Serologic testing of the CSF may reveal pleocytosis without oligoclonal bands in these forms. Balo’s concentric multiple sclerosis disease has a benign course described in the few published studies of longitudinal follow-up in children.
Marburg variant multiple sclerosis (also termed “Marburg’s Disease”) is typified by multiple demyelinating lesions noted deep within the white matter of the brain. There are no published studies of Marburg variant multiple sclerosis in children but the published data from adult patients would suggest that a child presenting with variant would have multiple neurological findings and a more severe clinical phenotype. Based on adult data, mortality or chronic disability would be predicted outcomes. Laboratory studies are typically unrevealing and not specific to this disease, and the diagnosis is based on clinical appearance (typically more severe than typical multiple sclerosis) and (possibly serial) radiological findings.
Opticospinal multiple sclerosis is a multiple sclerosis variant described in Asian populations characterized by a higher proportion of patients with involvement of the optic nerves and the spinal cord. This disease has been described in Asian children and patients presenting with visual changes and neurological findings localizable to the spinal cord. Testing for the aquaporin-4 antibody can distinguish this MS variant from Neuromyelits Optica (see below).
Schilder’s disease also referred to as “myelinclastic diffuse sclerosis” or merely “diffuse sclerosis” is a benign multiple sclerosis variant seen in children discussed in its own chapter. Briefly, Schilder’s disease is typified by open ring enhancing solitary lesions of the brain and requires adrenal function testing to rule out adrenoleukodystrophy which is a known mimic.
Other demyelinating diseases include the following:
Neuromyelitis optica (“NMO”, also referred to as “Devic’s Disease”) is a neuroimmune disease with an identified serological marker, auto-antibodies directed against the aquaporin-4 molecule. In children, the typical presentation is severe, rapidly progressive optic neuritis with possible spinal cord lesions, predominantly in the cervical spinal cord. Severe longitudinal transverse myelitis is not atypical.
Transverse myelitis and its variants will present with acute or sub-acute onset of weakness, numbness, loss of bowel or bladder control readily localized to the spinal cord.
Optic neuritis is described at length in its own chapter. Patients will present with deterioration of, change in, or total loss of vision in one or both eyes.
Acute disseminated encephalomyelitis (ADEM) is discussed at length in its own chapter. This diagnosis requires the presence of encephalopathy with other neurological symptoms including, most typically, weakness and sensory changes which follow an infection or vaccination.
Schilder’s disease and ADEM are discussed in separate entries.
What other disease/condition shares some of these symptoms?
Aside from the overlap in symptoms and manifestations between the demyelinating diseases themselves, other conditions can mimic their appearance. Encephalitis, brain malignancy, granulomatous disease, cerebral vasculitis, cerebral manifestations of sarcoidosis or lupus, mitochondrial diseases, and adrenaleukodystrophy can also mimic demyelinating disease presentations.
In a survey of consultations for demyelinating disease referrals, migraines, major depressive disorder, and arteriovenous malformations were also potential mimics. The use of clinical criteria (i.e., the McDonald Criteria, the Poser’s criteria), severity of the presentation, progression, and the appearance of brain and spinal lesions on neuroimaging can assist in differentiating demyelinating diseases from these other conditions though there is clinical and radiological overlap even among demyelinating diseases themselves that can sometimes cloud definitive diagnosis.
What caused this disease to develop at this time?
The precise cause for the acute onset of demyelinating diseases is unknown. Younger patients acquiring these diseases do so without regard for the usual ethnic (e.g., genetic) distribution seen in adults, and this observation has led to speculation a specific environmental trigger plays a more prominent role in children.
The genesis of demyelinating diseases is thought to represent destructive autoimmunity. The animal model of demyelinating diseases is the “Experimental Autoimmune Encephalomyelitis” (“EAE”) model in which experimental animals receive injections of purified brain homogenates with outcomes of clinical and brain pathology similar to demyelinating diseases. Based on this model and other pathological studies, what is thought to occur in demyelinating diseases is a combination of autoimmunity possibly attributable to a prior infection and loss of regulation of the native immune response.
In the majority of cases, what is believed to occur is a form of “molecular mimicry” in which a preceding infection has antigens that resemble self-derived epitopes, which in turns leads to inappropriate immune activation against both invading and native structures. Preceding infection can also disrupt the normal process of prevention of self-immunity by removing regulatory cells that would otherwise have prevented inappropriate autoimmune responses. Finally, some viruses have been shown to directly damage or even inhabit myelin and therefore lead to identification of myelin as an appropriate immune target.
What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?
In most cases, laboratory testing will fail to yield a primary cause for presentation of a demyelinating disease and diagnosis will be derived largely from history, physical examination, and radiology findings. It is important, however, to assess for such causes as, when identified, they can provide potential treatment options.
In the case of parainfectious demyelinating diseases like ADEM, testing is imperative given the morbidity and mortality of potentially treatable encephalitis. Transverse myelitis has a differential diagnosis that includes several treatable causes and thus the diagnosis of this disease mandates additional testing. For other diseases such as multiple sclerosis, the diagnostic criteria include serologic findings, though no specific marker exists to differentiate MS and its variants from ADEM. Finally, in cases of NMO, there is a specific and sensitive marker for diagnosis.
Tests to consider if a diagnosis of a demyelinating disease is suspected to be secondary to another diagnosis may include the following, divided into sub-categories to guide assignment of resources:
The following should be obtained in any patients presenting with demyelinating disease:
Cerebrospinal fluid (CSF) studies including white blood cell count, protein, glucose, Gram stain, and culture. These studies are usually normal in optic neuritis although a CSF pleocytosis and mildly elevated protein can be present in cases of fulminant disease. Oligoclonal bands and IgG Index will be abnormal as a requirement of MS diagnostic criteria, but these are less likely to be positive in MS presenting in childhood or early adolescence than in adulthood.
Vitamin D (25-hydroxy-vitamin D). Vitamin D deficiency has a complex role in adult demyelinating disease and deficiencies have been identified in pediatric patients with MS.
The following should be evaluated in any patient with spinal cord and/or optic nerve pathology:
Aquaporin-4 antibody. This is a specific assay for NMO, a demyelinating disease which typically presents with optic neuritis and transverse myelitis. The test can be obtained for serum or CSF antibody, with the latter being diagnostic if serum antibodies are absent.
Vitamin B12 level with methylmalonic acid level.
To rule out readily treatable cause of transverse myelitis:
Copper level. Copper deficiency is a rare but treatable cause of myelopathies that sometimes mimic transverse myelitis symptoms.
Vitamin E level. Vitamin E deficiency rarely produces a myelopathic appearance.
To evaluate for infectious causes:
Blood culture and a viral studies (if available): especially important in ADEM to identify potential etiology. Specific viruses of interest include influenza and para-influenza species as these are known risk factors for development of ADEM.
Mycoplasma pneumoniae PCR. There are reports of mycoplasma-related transverse meylitis.
Bartonella henselae IgM of serum if cat scratch disease is suspected based on exposure to domestic or wild felines.
Rapid plasma reagin (RPR). If syphilis is suspected this is a necessary diagnostic test. Anti-treponemal antibody titer in CSF would be required for a diagnosis of neurosyphilis.
Complete blood count with differential to assess for leukocytosis and presence of infection or active autoimmune process.
C-reactive protein (CRP). If elevated, this study is further evidence of infection.
To evaluate for systemic inflammation:
Erythrocyte sedimentation rate (ESR) which, if markedly elevated, may indicate a systemic inflammatory process.
Anti-nuclear antibody (ANA) screen, anticardiolipin, antiphospholipid antibodies. An elevated, significant autoantibody titer is suggestive of a systemic rheumatologic disease with neurological manifesations.
Angiotensin-converting enzyme (ACE). An elevated ACE is suggestive of a neurological manifestation of sarcoidosis, especially with other systemic findings such as lung granulomas.
Ferritin and triglycerides. An elevated fasting triglyceride level of >265 mg/dL and a serum ferritin >500 ng/ml are diagnostic of Macrophage Activation Syndrome (MAS), a rare cause of systemic autoimmune activation.
To evaluate for congenital/mitochondrial disease:
Serum lactate, serum acelycarnitine profile, serum amino acids, urine organic acids, CSF lactate, CSF neurotransmitters. If a mitochondrial disease or amino acidopathy is suspected, these optional assays would be useful diagnostically. A biopsy of muscle or skin fibroblasts may be necessary to confirm or to identify enzymatic-based disease.
Other testing to consider:
Adrenal gland function testing (serum cortisol, 24-hour urine cortisol, ACTH baseline and stimulation test) is required to exclude the possibility of weakness or sensory changes being attributable to adrenaleukodsytrophy. The diagnosis of Schilder’s disease requires these studies be normal.
Very long chain fatty acids. The diagnosis of Schilder’s disease requires these studies be normal. An abnormality in this study would indicate an adrenaleukodystrophy.
Would imaging studies be helpful? If so, which ones?
Magnetic resonance imaging (MRI) with and without contrast of brain usually will demonstrate one or multiple hypointense lesions on T1 sequences; these lesions will be hyperintense on T2 sequences. It is helpful to acquire sequences using a specific protocol for multiple sclerosis if available at the time of imaging. Contrast enhancement of the lesions’ rings may be present in acute disease states. Fluid attenuated inversion recover (FLAIR) sequences will demonstrate hyperintense lesions. Leptomeningeal enhancement is not typical in demyelinating diseases and suggests presence of a malignancy or a vasculitis.
Magnetic resonance spectroscopy (MRS) can show lactate peaks and evidence of axonal injury/loss in severe cases of acute demyelination. There are not specific markers for particular demyelinating diseases as yet.
The lesions in demyelinating diseases can be visualized on computed tomography (CT) scan and typically appear as hypodense lesions with ring enhancement and mass effect. The lesions of Marburg variant MS are typically within the deeper white matter of the brain. Balo’s concentric sclerosis typically features concentrically arranged ringed lesions.
Optical coherence tomography (OCT) is a new investigative technique which allows direct non-invasive measurement of a cross-sectional thickness of the retinal nerve fiber layer. This measurement can be used serially to assess thinning of that layer which would be a finding consistent with an acute optic neuritis and, if progressive, confirm a demyelinating disease such as multiple sclerosis. If it is available, it would be helpful to obtain for longitudinal follow-up.
Visual evoked responses (VER) examination, in which the latency between a visual stimulus and a sensory response in the occipital lobe is measured, can be used to confirm mild optic neuritis in cases where the clinical and neurological examinations are inconclusive and other modalities such as OCT (see above) are unavailable.
If there is any historical or physical examination evidence to suggest that sarcoidosis is in the differential diagnosis, a chest CT scan with contrast is needed to assess for evidence of sarcoidosis.
Confirming the diagnosis
The following algorithm is suggested by Yeh et al. (2009) as a diagnostic framework for the diagnosis of demyelinating diseases. See Figure 1.
The McDonald (Modified) Criteria for Diagnosis of Multiple Sclerosis are as followed from Polman et al. (2011) See Figure 2.
The Poser criteria are typically used to define Schilder’s Disease. These six criteria are as follows:
One or 2 roughly symmetrical large plaques are manifest, and if more than 1 is present, 1 should be in each brain hemisphere, chiefly in the centrum semiovale. Plaques are greater than 2 cm in 2 of 3 dimensions.
No other lesions are demonstrable by clinical, paraclinical, or imaging data.
No abnormalities of the peripheral nervous system are demonstrable.
Results of adrenal function studies are normal.
Serum very long chain fatty acids are normal.
Pathological analysis by autopsy or biopsy demonstrates histologic changes consistent with subacute or chronic myelinoclastic diffuse sclerosis, changes which in essence cannot be distinguished from those of multiple sclerosis.
There are no definitive nor widely utilized diagnostic criteria for transverse myelitis. The distinction of MS variants is described above but there are no definitive established criteria.
If you are able to confirm that the patient has demyelinating disease, what treatment should be initiated?
The mainstay of acute treatment of all demyelinating diseases in the initial phase or during relapses, is immune suppression. The most common treatment to achieve adequate immunosuppression leading to symptomatic improvement is corticosteroids which are prescribed for all acute presentations or exacerbations of demyelinating diseases including ADEM.
In the hospital setting, intravenous methylprednisolone (20-30 mg/kg per day or a maximum dose of 1000 mg daily) is the usual treatment for 3-5 days. There is no empiric or reliable evidence for a course of 5 days being superior in any metric of outcome to a duration of 3 days, but generally if little to no clinical improvement is seen at 3 days a 5-day course is advised. In ADEM treatment, a 3-day course is usually sufficient.
After high dose methylprednisolone is completed, oral corticosteroids should be given to for 4-6 weeks of treatment following completion of IV therapy. Shorter durations of oral corticosteroid tapers have been associated with higher relapse risk in optic neuritis. Initial starting dose of oral steroids is recommended at 1 mg/kg/day and can be administered either as prednisolone suspension or as prednisone tablets or a maximum starting dose of 60 mg daily. There is no established taper protocol, but a reduction of 5 mg every 3 days from the initial 60 mg dose would achieve the desired goal duration of treatment in a safe manner.
This same regimen (3-5 days IV methylprednisolone followed by 28 or more days of oral steroids is advised for recrudescence of optic neuritis even in the presence of other treatments for primary causes.
There are case reports for effectiveness of ACTH and dexamethasone, but typically the prohibitive cost and lack of availability of ACTH has markedly reduced the utility of this treatment option and methylprednisolone has a more favorable side effect profile than dexamethasone.
As a primary treatment, there are limited data that suggest plasma exchange can ameleriorate some disability in severe demyelinating disease exacerbations. However, many more retrospective studies have established plasma exchange is an appropriate secondary treatment option in cases of demyelination refractory to initial treatment with steroids. Therefore, plasma exchange is proposed as a “rescue” option that improves outcomes acutely and long-term in several studies of adult patients.
There is no definitive guideline to direct practitioners regarding when to consider plasma exchange. Plasma exchange appears to yield improvements in patients without evidence of clinical response to several doses of steroids, with worsening of symptoms despite several doses of steroids administered, or when elevated titers of auto-antibodies are thought to be causal.
This treatment should be initiated as soon as possible and could be considered as early as 3 days into steroid treatment. There is no established exchange volume (1:1), frequency (daily versus every 2 days), or total number of exchanges though typically 2-5 total exchanges of at least 1:1 volume on an alternating day basis are effective. Multiple studies have confirmed that unlike steroid treatment, a single course of plasma exchange does not prevent future relapses. Therefore, steroid treatment can and likely should continue concurrently while plasma exchange occurs.
Intravenous immunoglobulin (IVIG) is reported to be an effective alternative option in the treatment of MS in children, specifically steroid-refractory or malignant (Marburg variant) forms or when patients are unable to tolerate steroid or plasma exchange treatments. Intravenous immunoglobulin (400-500 mg/kg) is an option for steroid refractory cases of neuroimmunological diseases in which plasma exchange is contraindicated by renal insufficiency or is simply not available.
Duration of IVIG therapy reported to be effective for ADEM is 5 consecutive days, and generally a 5-day treatment course is employed for any neuroimmunological disease entity. It may also have particular effectiveness when combined with steroids in atypical ADEM with a predominant involvement of the peripheral nervous system. IVIG is not an effective treatment of optic neuritis in children. There are no published reports of IVIG treatment of Schilder’s disease, Marburg variant MS, or opticospinal MS in children; there are isolated case reports of IVIG use in NMO and pediatric MS.
In addition to corticosteroids, one must consider the state of the patient as the brain lesions of any demyelinating disease can result in severe short-term disability. Obviously, appropriate medical management of these patients includes ensuring adequate ventilation capability is and remains present, maintaining euvolemia and vascular tone, providing adequate nutrition, whether by oral or parenteral routes, monitoring for electrolyte status, and surveillance for infection. There are reports of the need for surgical decompression in cases of ADEM, multiple sclerosis, and Schilder’s disease due to brain edema; thus, neurosurgical consultation can be considered for extreme instances.
Seizures are infrequent sequelae of neuroimmunological diseases. Appropriate treatment for acute onset of seizures in the inpatient setting would include intravenous preparations of phenobarbital (in infants and children less than 2 years of age), fos-phenytoin (in children > 12 months of age,) valproate (in children > 2 years of age.) Levetiracetam, which is available in intravenous and oral preparations, is also often used for seizure management in children owing to its favorable side effect profile and lack of known interactions with other medications, but rarely can cause agitation or even psychosis and thus should be used cautiously in the setting of encephalopathy.
Long-term treatment of demyelinating diseases can include so-called disease modifying drugs for which there are only case reports of efficacy in children. These medications work by modifying the ability of the immune residents of the central nervous system to mount all immune responses but particularly the autoimmunity at the root cause of these diseases.
The first line therapies for chronic demyelinating diseases that have published data to support their usage in children are interferon preparations and glatiramer acetate. These medications are injectable (intramuscular or subcutaneous) and vary from daily to weekly administration. The doses and treatment frequencies are as follows: interferon beta-1a IM (30 mcg IM weekly), interferon beta-1a SC (44 mcg 3 times/week), interferon beta-1b SC (0.25 mcg every other day), and glatiramer acetate SC (20 mg daily).
Second line therapies for pediatric multiple sclerosis include azathioprine, mitoxantrone, and cyclophosphamide. These immunosuppressive treatments are supported by Class IV evidence and individual case reports in most cases. Two monoclonal antibodies, rituximab and natalizumab, are used in refractory adult MS and effectively by depleting B-cell populations throughout the body and within the CSF compartment, respectively. All of these therapies are reserved for refractory disease and should be initiated only by practitioners with experience in their use and side effects. These medications are not approved for usage in children for demyelinating diseases.
What are the adverse effects associated with each treatment option?
The side effects of corticosteroids and ACTH are well-documented and include hyperglycemia, hypertension, psychosis/mood changes, gastrointestinal ulceration/bleeding, hypokalemia, insomnia, and opportunistic infections. These side effects are thankfully uncommon and are not typically serious enough to cause a need for early termination of treatment. There is evidence for prevention of gastrointestinal ulceration while taking corticosteroids through the use H2-antagnosists and proton pump inhibitors.
Plasma exchange is generally a safe and well-tolerated procedure in children. It requires surgical implantation of a catheter suitable for exchange, which has the usual surgical risks of bleeding, infection. Long-term the catheter is a potential infectious and embolic source. There are patients in whom plasma exchange is contraindicated. Hemodynamically unstable patients, or patients with cardiovascular compromise as a result of myocardial infarction, arrhythmias, or coronary artery disease are contraindicated from exchange. Severe, uncorrectable coagulopathies are also a contraindication. Patients with severe hepatic failure and renal failure are also not appropriate for plasma exchange therapy.
During therapy, there are multiple complications reported, but most are easily corrected through readily available means. Hypotension and bradycardia are frequently encountered and may require fluid support. Hypocalcemia and other electrolyte abnormalities can also require intervention and electrolytes should be monitored. Coagulopathy, anemia, and deep vein thrombosis/pulmonary embolism are also serious, potentially mortal, complications in rare instances.
The most common adverse effects associated with interferons are flu-like symptoms such as myalgias and fatigue. These symptoms may be more pronounced in children. A transaminitis can occur, and after initiation of treatment these should be monitored at least once within the first 3 months of therapy.
Glatiramer acetate is typically well-tolerated with local site injection reactions and allergic reaction being the most commonly reported issues.
Natalizumab and rituximab are not approved for use in children for demyelinating diseases, and there are few anecdotal reports of efficacy. There is no published safety data for natalizumab in children.
Azathioprine, mitoxantrone, and cyclophosphamide all share common risk of immune suppression leading to opportunistic infection risk. They can also suppress other bone marrow derived cell lines leading to complications related to anemia and thrombocytopenia. Cyclophosphamide can acutely cause hemorrhagic cystitis if administered without proper precautions. There is also a small risk of causing a secondary malignancy associated with long-term use of these medications.
What are the possible outcomes of demyelinating diseases?
The overwhelming majority of pediatric multiple sclerosis cases conform to a relapsing-remitting pattern of relapses, meaning they will have periods of relative stability interspersed with acute relapses. There is considerable variability in progression in pediatric patients and no reliable marker for outcomes. In general, there is a lag of approximately 10 years from diagnosis to some measurable disability. Given recent treatments however this timetable may be in the process of elongating. However, it is still the reality that children diagnosed with multiple sclerosis will certainly accrue disabilities over time except in exceptional cases.
ADEM is considered a monophasic illness with, at worst, a 40% risk of evolution into a relapsing disease.
Schilder’s Disease is also associated with relatively benign outcomes.
Acute pediatric transverse myelitis can cause serious lifelong disability in up to 50% of cases surveyed at follow-up. Generally cases with worse clinical appearance at presentation (larger/longer spinal cord lesion, back pain, need for ventilatory support) have worse outcomes. It can recur in up to 25% of cases and rarely evolves into multiple sclerosis.
Pediatric NMO studies reveal variable outcomes reported in longitudinal studies. While severe NMO can cause blindness and paralysis, there are also reports of benign outcomes with no or minimal disability. Clinical course is the best determinant of outcome and initial presentation is not prognostic unless yielding a very severe disability refractory to treatment.
Acutely, treatment of relapses with steroids is the standard of care and the benefit in terms of improving short-term disability is without debate. Obviously frequent usage of steroids should be a signal to pursue disease modifying therapies and improvement of baseline disease treatments.
When considering treatment of refractory demyelinating diseases, the chemotherapeutics are certainly a very risky option with regard to toxicity during treatment and long-term risk of malignancy induction. These decisions require careful thought and fully informed consent. There is scant data regarding ultimately if these are truly beneficial when weighed against their multiplicity risks.
The immune modulator therapies are generally benign and devoid of long-term side effects, but they are not as well tolerated in pediatric patients as adults.
What causes this disease and how frequent is it?
Pediatric multiple sclerosis cases are rare, comprising 2-10% of all cases of multiple sclerosis worldwide. There are no reliable genetic and no known seasonal associations.
Unlike adult demyelinating diseases, it appears that environmental, not genetic, factors predominantly influence the manifestation of demyelinating diseases in early life. Specifically, while in adults longer distance from the equator and a European ethnic background appear to be positively correlated with disease, these same factors do not correlate with disease in children. There are case reports of familial NMO with multiple family members with aquaporin-4 autoimmunity. There may also be mitochondrial DNA polymorphisms that increase likelihood of manifesting optic neuritis.
Unlike other manifestations of demyelinating disease, there is no consistent report of immune-related genetic spans such as the Human Leukocyte Antigen (HLA) regions conferring increased risk of isolated optic neuritis as well as multiple sclerosis, but larger studies are not available to confirm a distinct genetic predisposition.
Schilder’s disease, Marburg variant, and Balo’s concentric sclerosis are exceedingly rare in pediatric multiple sclerosis on the order of less than total fifty published cases of each type in the extant pediatric literature.
Acute transverse myelitis is estimated at an incidence of 1 to 30 per million cases.
NMO is very rare in children and estimated to have an incidence of less than 1 per million.
How do these pathogens/genes/exposures cause the disease?
In theory, autoimmune diseases occur as a result of an environmental exposure, usually an illness, causing a cascade of immune responses that, in turn, cause an inappropriate recognition of excluded “self” antigens in the host. The immune response transforms from eradication of the disease to destruction of healthy tissues, in demyelinating diseases, the inappropriately targeted tissue is mainly white matter.
What is thought to occur in ADEM and other acute demyelinating diseases is a combination of autoimmunity and loss of regulation of the native immune response. In the majority of ADEM cases, what is believed to occur is a form of “molecular mimicry” in which the preceding infection has antigens that resemble self-derived epitopes, which in turns leads to inappropriate immune activation against both invading and native structures. Preceding infection can also disrupt the normal process of prevention of self-immunity by removing regulatory cells that would otherwise have prevented inappropriate autoimmune responses.
Finally, some viruses have been shown to directly damage or even inhabit myelin and therefore lead to identification of myelin as an appropriate immune target.
What complications might you expect from the disease or treatment of the disease?
Short-term complications of treatment are discussed above. Corticosteroids can cause long-term weight gain, a potential risk of developing diabetes mellitus type II in already at risk individuals, but these risks should not affect any decision to treat. The most concerning long-term effect of a chemotherapy medication such as cyclophosphamide would be the possible risk of inducing another malignancy, but, again, this small risk should be weighed against the significant consideration of the consequences of not treating the condition.
Long term data on disease modifying agents in multiple sclerosis are not known in the pediatric population.
Are additional laboratory studies available; even some that are not widely available?
Optical coherence tomography (OCT) is a new investigative technique using near infra-red spectrum light which allows direct non-invasive measurement of a cross-sectional thickness of the retinal nerve fiber layer. This measurement can be used serially to assess thinning of that layer which would be a finding consistent with an acute optic neuritis and, if progressive, confirm a demyelinating disease such as multiple sclerosis. If it is available, it would be helpful to obtain for longitudinal follow-up.
Visual evoked response (VER) examinations, in which the latency between a visual stimulus and a sensory response in the occipital lobe is measured, can be used to confirm mild optic neuritis in cases where the clinical and neurological examinations are inconclusive and other modalities such as OCT (see above) are unavailable.
How can demyelinating diseases be prevented?
Presently, there are no known or available prophylactic treatments for demyelinating diseases. There are no certain genetic predispositions that would mandate genetic counseling prior to or after birth of an affected child.
There is a historical and recently reinvigorated interest in Vitamin D intake and its relationship to multiple sclerosis with individuals having low vitamin D being at increased risk of diagnosis with MS.
Cigarette smoke exposure is also a possible pathogenic trigger.
What is the evidence?
Banwell, B, Bar-Or, A, Giovannoni, G, Dale, RC, Tardieu, M. “Therapies for multiple sclerosis: considerations in the pediatric patient”. Nat Rev Neurol. vol. 7. 2011. pp. 109-22.
Borchers, AT, Gershwin, ME. “Transverse myelitis”. Autoimmun Rev. vol. 11. 2012. pp. 231-48.
Collongues, N, Marignier, R, Zéphir, H, Papeix, C, Fontaine, B, Blanc, F. “Long-term follow-up of neuromyelitis optica with a pediatric onset”. Neurology. vol. 75. 2010. pp. 1084-8.
Dale, RC, Brilot, F, Banwell, B. “Pediatric central nervous system inflammatory demyelination: acute disseminated encephalomyelitis, clinically isolated syndromes, neuromyelitis optica, and multiple sclerosis”. Curr Opin Neurol. vol. 22. 2009. pp. 233-40.
Huppke, P, Gärtner, J. “A practical guide to pediatric multiple sclerosis”. Neuropediatrics. vol. 41. 2010. pp. 157-62.
Karussis, D. “The diagnosis of multiple sclerosis and the various related demyelinating syndromes: a critical review”. J Autoimmun. 2014. pp. 48-49.
Kuntz, NL, Chabas, D, Weinstock-Guttman, B, Chitnis, T, Yeh, EA, Krupp, L. “Network of US Pediatric Multiple Sclerosis Centers. Treatment of multiple sclerosis in children and adolescents”. Expert Opin Pharmacother. vol. 11. 2010. pp. 505-20.
O’Mahony, J, Shroff, M, Banwell, B. “Mimics and rare presentations of pediatric demyelination”. Neuroimaging Clin N Am. vol. 23. 2013. pp. 321-36.
Peña, JA, Ravelo, ME, Mora-La Cruz, E, Montiel-Nava, C. “NMO in pediatric patients: brain involvement and clinical expression”. Arq Neuropsiquiatr. vol. 69. 2011. pp. 34-8.
Venkateswaran, S, Banwell, B. “Pediatric multiple sclerosis”. Neurologist. vol. 16. 2010. pp. 92-105.
Yeh, EA, Chitnis, T, Krupp, L, Ness, J, Chabas, D, Kuntz, N, Waubant, E. “US Network of Pediatric Multiple Sclerosis Centers of Excellence. Pediatric multiple sclerosis”. Nat Rev Neurol. vol. 5. 2009. pp. 621-31.
Filippini, G, Brusaferri, F, Sibley, WA, Citterio, A, Ciucci, G, Midgard, R, Candelise, L. “Corticosteroids or ACTH for acute exacerbations in multiple sclerosis”. Cochrane Database of Systematic Reviews 2000.
Afifi, AK, Bell, WE, Menezes, AH, Moore, SA. “Myelinoclastic diffuse sclerosis (Schilder’s disease): report of a case and review of the literature”. J Child Neurol. vol. 9. 1994. pp. 398-403.
Bacigaluppi, S, Polonara, G, Zavanone, ML, Campanella, R, Branca, V, Gaini, SM. “Schilder’s disease: non-invasive diagnosis?: A case report and review”. Neurol Sci. vol. 30. 2009. pp. 421-30.
Censori, B, Agostinis, C, Partziguian, T, Gazzaniga, G, Biroli, F, Mamoli, A. “Large demyelinating brain lesion mimicking a herniating tumor”. Neurol Sci. vol. 22. 2001. pp. 325-9.
Fitzgerald, MJ, Coleman, LT. “Recurrent myelinoclastic diffuse sclerosis: a case report of a child with Schilder’s variant of multiple sclerosis”. Pediatr Radiol. vol. 30. 2000. pp. 861-5.
Garell, PC, Menezes, AH, Baumbach, G, Moore, SA, Nelson, G, Mathews, K, Afifi, AK. “Presentation, management and follow-up of Schilder’s disease”. Pediatr Neurosurg. vol. 29. 1998. pp. 86-91.
Kiernan, MC, Vonau, M, Bullpitt, PR, Tohver, E, Milder, DG. “Butterfly lesion of the corpus callosum due to Schilder’s disease”. J Clin Neurosci. vol. 8. 2001. pp. 367-9.
Konkol, RJ, Bousounis, D, Kuban, KC. “Schilder’s disease: additional aspects and a therapeutic option”. Neuropediatrics. vol. 18. 1987. pp. 149-52.
Kotil, K, Kalayci, M, KöseoÄŸlu, T, TuÄŸrul, A. “Myelinoclastic diffuse sclerosis (Schilder’s disease): report of a case and review of the literature”. Br J Neurosurg. vol. 16. 2002. pp. 516-9.
Kurul, S, Cakmakçi, H, Dirik, E, Kovanlikaya, A. “Schilder’s disease: case study with serial neuroimaging”. J Child Neurol. vol. 18. 2003. pp. 58-61.
Leuzzi, V, Lyon, G, Cilio, MR, Pedespan, JM, Fontan, D, Chateil, JF, Vital, A. “Childhood demyelinating diseases with a prolonged remitting course and their relation to Schilder’s disease: report of two cases”. J NeurolNeurosurg Psychiatry. vol. 66. 1999. pp. 407-8.
Miyamoto, N, Kagohashi, M, Nishioka, K, Fujishima, K, Kitada, T, Tomita, Y. “An autopsy case of Schilder’s variant of multiple sclerosis (Schilder’s disease)”. Eur Neurol. vol. 55. 2006. pp. 103-7.
Morales, Y, Parisi, JE, Lucchinetti, CF. “The pathology of multiple sclerosis: evidence for heterogeneity”. Adv Neurol. vol. 98. 2006. pp. 27-45.
Nejat, F, Eftekhar, B. “Decompressive aspiration in myelinoclastic diffuse sclerosis or Schilder disease. Case report”. J Neurosurg. vol. 97. 2002. pp. 1447-9.
Obara, S, Takeshima, H, Awa, R, Yonezawa, H, Oyoshi, T, Nagayama, T. “Tumefactive myelinoclastic diffuse sclerosis-case report”. Neurol Med Chir (Tokyo). vol. 43. 2003. pp. 563-6.
Pretorius, ML, Loock, DB, Ravenscroft, A, Schoeman, JF. “Demyelinating disease of Schilder type in three young South African children: dramatic response to corticosteroids”. J Child Neurol. vol. 13. 1998. pp. 197-201.
Sastre-Garriga, J, Rovira, A, Río, J, Tintoré, M, Grivé, E, Montalban, X. “Clinically definite multiple sclerosis after radiological Schilder-like onset”. J Neurol. vol. 250. 2003. pp. 871-3.
Simon, JH, Kleinschmidt-DeMasters, BK. “Variants of multiple sclerosis”. Neuroimaging Clin N Am. vol. 18. 2008. pp. 703-16.
Yilmaz, Y, Kocaman, C, Karabagli, H, Ozek, M. “Is the brain biopsy obligatory or not for the diagnosis of Schilder’s disease? Review of the literature”. Childs Nerv Syst. vol. 24. 2008. pp. 3-6.
Ongoing controversies regarding etiology, diagnosis, treatment
The diagnosis, treatment, and outcomes of demyelinating diseases in children remains an area of active investigation. The application of adult diagnostic criteria and adult pathogenesis models remains problematic. As more cases accumulate in larger data bases, our learning will expand, but these diseases fortunately remain rare and thus the standards of care are derived from adult treatments and outcome analyses.
Copyright © 2017, 2013 Decision Support in Medicine, LLC. All rights reserved.
No sponsor or advertiser has participated in, approved or paid for the content provided by Decision Support in Medicine LLC. The Licensed Content is the property of and copyrighted by DSM.
- OVERVIEW: What every practitioner needs to know
- Are you sure your patient has demyelinating disease? What are the typical findings for this disease?
- What other disease/condition shares some of these symptoms?
- What caused this disease to develop at this time?
- What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?
- Would imaging studies be helpful? If so, which ones?
- Confirming the diagnosis
- If you are able to confirm that the patient has demyelinating disease, what treatment should be initiated?
- What are the adverse effects associated with each treatment option?
- What are the possible outcomes of demyelinating diseases?
- What causes this disease and how frequent is it?
- How do these pathogens/genes/exposures cause the disease?
- What complications might you expect from the disease or treatment of the disease?
- Are additional laboratory studies available; even some that are not widely available?
- How can demyelinating diseases be prevented?
- What is the evidence?
- Ongoing controversies regarding etiology, diagnosis, treatment