Pediatrics

Schilder's disease

OVERVIEW: What every practioner needs to know.

Are you sure your patient has Schilder's disease? What are the typical findings for this disease?

  1. Hemiparesis

  2. Cognitive deterioration/aphasia

  3. Hemisensory loss

  4. Seizures

  5. Headaches

A note regarding Schilder's disease nomenclature

There are two diseases described by Paul Schilder that bear his name and are published as "Schilder's disease." The disease discussed in this article is a demyelinating disease also referred to as "myelinoclastic diffuse sclerosis" or merely "diffuse sclerosis." "Schilder's disease" is sometimes also used as a variant name for X-linked adrenoleukodystrophy, which is not the subject of this article.

What other disease/condition shares some of these symptoms?

Schilder's disease is a demyelinating disease, and as such, resembles the presentations of multiple sclerosis, neuromyelitis optica (Devic's disease), and acute disseminated encephalomyelitis (ADEM). Encephalitis, brain malignancy, granulomatous disease, cerebral vasculitis, and adrenaleukodystrophy can also mimic the presentation of Schilder's disease. Often, the mass lesions of Schilder's disease are mistaken for brain tumors; there are cases of surgical excision based on this erroneous assumption. The use of clinical criteria (i.e., the Poser criteria), severity of the presentation, and the diffuse nature of the lesions as seen on MRI can assist in differentiating Schilder's disease from these other conditions, although there is clinical and radiological overlap.

What caused this disease to develop at this time?

The precise trigger for Schilder's disease is unknown, but given its young age of onset, it could represent a more aggressive genetic or inborn metabolic error than other demyelinating diseases with adult onset. However, there are also theories that the younger age of onset reflects that an environmental influence might be predominant. In general, the onset of demyelinating diseases such as Schilder's disease is thought to represent a confluence of genetic predisposition and environmental exposures, although which factors are specific to Schilder's is unknown.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

The Poser criteria are typically used to define Schilder's disease. These six criteria are as follows:

  1. One or 2 roughly symmetrical large plaques are present, 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.

  2. No other lesions are demonstrable by clinical, paraclinical, or imaging data.

  3. No abnormalities of the peripheral nervous system are demonstrable.

  4. Results of adrenal function studies are normal.

  5. Serum very long chain fatty acids are normal.

  6. 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.

Unfortunately, there is no signature pathological hallmark of this disease on testing, but the following tests should be obtained in the evaluation of this condition:

  • Cerebrospinal fluid studies including glucose, protein, Gram stain, culture, oligoclonal bands, IgG index. These tests are typically normal in Schilder's disease, although elevated protein and oligoclonal bands have been reported in some cases. Abnormalities in these tests may prompt further testing for infectious causes.

  • Adrenal gland function testing (serum cortisol, 24-hour urine cortisol, ACTH baseline and stimulation test). The diagnosis of Schilder's disease requires the results ot these studies to be normal.

  • Very long chain fatty acids. The diagnosis of Schilder's disease requires that these studies be normal. An abnormality in this study would indicate an adrenaleukodystrophy.

  • Some investigators suggest that brain biopsy could differentiate Schilder's disease from similar conditions. If brain biopsy is performed, multiple reports suggest that the findings mimic those of brain malignancies such as astrocytoma and glioblastoma multiforme; therefore, care should be taken to confirm any pathological diagnosis.

    In Schilder's disease, there is inflammation confined to the white matter, with near total replacement by reactive astrocytes. Macrophages and lymphocytes may also be present with evidence of activity (i.e., foamy macrophages). Axons and U-fibers are spared; very little intact myelin will be present. There will be no tumor cells present. There should be no bacteria present on Gram, acid fast bacilli, nor silver stains.

Would imaging studies be helpful? If so, which ones?

  • An EEG can be helpful if seizures are suspected or are present. The EEG findings can correlate with visualized cerebral lesions in Schilder's disease. If seizures or altered mental status are not present, then the EEG has no diagnostic value.

  • The lesions in Schilder's disease can be visualized on computed tomography (CT) scan, and typically appear as hypodense lesions with ring enhancement and mass effect.

  • Magnetic resonance imaging (MRI) of the brain with and without contrast usually will demonstrate one or multiple hypointense lesions on T1 sequences; these lesions will be hyperintense on T2 sequences. The location of these lesions is almost always subcortical. Contrast enhancement of the rings may be present in acute disease states. Fluid attenuated inversion recovery (FLAIR) sequences will demonstrate hyperintense lesions.

  • Magnetic resonance spectroscopy (MRS) reliably shows a decreased N-acetylaspartate (NAA) peak, a reduced NAA to creatine (Cr) ratio, an increased choline (Cho) to creatine ratio, an elevated glutamate to glutamine peak, and an increased lactate peak in affected regions.

If you are able to confirm that the patient has Schilder's disease, what treatment should be initiated?

The mainstay of acute treatment of this disease, as for all demyelinating diseases in the initial phase or relapses, is immune suppression. The most common treatment to achieve adequate immunosuppression leading to symptomatic improvement is corticosteroids. 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 to 5 days. There is no empiric or reliable evidence for a course of 5 days being superior to a duration of 3 days in any metric of outcome , but generally if little to no clinical improvement is seen at 3 days, a 5-day course is advised. After high-dose methylprednisolone, one should taper over 3 to 6 weeks with oral corticosteroids. This same regimen is effective for recrudescence of the disease.

There are also case reports on the effectiveness of ACTH treatment, but typically the prohibitive cost and lack of availability of ACTH has markedly reduced the utility of this treatment option.

In a case of Schilder's disease refractory to corticosteroids, high-dose cyclophosphamide was used with a favorable outcome.

There are no reports of intravenous immunoglobulins, interferon therapies, or plasma exchange having any role in treating Schilder's disease.

In addition to corticosteroids, one must consider the state of the patient, because the brain lesions of Schilder's disease can result in severe short-term disability. Obviously, appropriate medical management of these patients includes ensuring that 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 is a report of a patient improving with surgical decompression of a large lesion; thus, neurosurgical consultation can be considered for extreme instances.

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. Thankfully, these side effects are uncommon and are not usually associated with a need for early termination of treatment. There is evidence for prevention of gastrointestinal ulceration while taking corticosteroids through the use of H2-antagonists and proton pump inhibitors.

Cyclophosphamide has many documented side effects in children, but among the most concerning is hemorrhagic cystitis, which is why mesna is given prophylactically with this medication to prevent this severe and sometimes fatal outcome. Other side effects include nausea/vomiting, alopecia, dyspepsia, fatigue, bone marrow suppression, and inhibition of wound healing.

What are the possible outcomes of Schilder's disease?

Schilder's disease is classically defined as a monophasic illness, occurring as a single isolated episode. The prognosis of this disease is directly related to the patient's response to treatment. In the majority of reported cases with clear clinical improvement following treatment, the described outcomes are near total recovery with little disability. However, there are exceptional cases of this disease in which patients have permanent significant physical and intellectual disabilities obviating functional independence. There are reported cases of fulminant disease.

Unfortunately, due to its rarity and controversy about diagnosis, there are no extant prospective or double-blinded studies in the literature to support any one treatment over another. The standard of care in any acute demyelinating disease is to treat with a goal of achieving significant immunosuppression. However, even this option is not supported by extensive evidence for changing the long-term outcomes in patients with this specific disease. The benefit of immunosuppression is inferred from the efficacy of this treatment in similar diseases (i.e., multiple sclerosis).

What causes this disease and how frequent is it?

  • Schilder's disease is exceedingly rare, with less than 50 cases in the reported medical literature meeting the full Poser criteria for diagnosis. Reported ages at presentation range in age from 4 to 69 years, with the majority of patients being older than age 7 years. There is no apparent trigger or identified predisposing factor for this disease. There are no published seasonal variations nor incidence data.

  • There are no studies to suggest a genetic linkage in Schilder's disease, although there are reasons to believe that a genetic linkage may be present (see below).

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. In response, the immune response transforms from eradication of the disease to destruction of healthy tissues.

In the case of Schilder's disease, the inappropriately targeted tissue is undiseased white matter. There are studies of other diseases like Schilder's disease that target white matter that suggest there may be gene mutations associated with an increased likelihood of this type of autoimmune disease. The specific sequence of events and universality of the genetic risk remain areas of active investigation.

Other clinical manifestations that might help with diagnosis and management

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, and 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 is the risk of inducing another malignancy, but, again, this small risk should be weighed against the significant consequences of not treating the condition.

There is no extant literature on long-term clinical outcomes from Schilder's disease. Most cases appear to remit, with patients becoming asymptomatic after successful initial treatment. However, extrapolating from what is known about similar diseases, one would expect that disability could include attention problems, weakness, sensory loss, gait changes, and/or intellectual decline.

Are additional laboratory studies available; even some that are not widely available?

How can Schilder's disease be prevented?

There is no known prevention nor suggested prophylaxis for Schilder's disease.

What is the evidence?

There are numerous case reports discussing the use of corticosteroids in the treatment of Schilder's disease. All of these reports are confined to Class 4-5 evidence because they represent individual expert opinions or summaries of conclusions derived from a case series. A bibliography of extant studies is as follows:

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. "A. 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. "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. "Presentation, management and follow-up of Schilder's disease". Pediatr Neurosurg. vol. 29. 1998. pp. 86-91.

Kiernan, MC, Vonau, M, Bullpitt, PR. "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, Köseolu, T, Turul, 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. "Childhood demyelinating diseases with a prolonged remitting course and their relation to Schilder's disease: report of two cases". J Neurol Neurosurg Psychiatry. vol. 66. 1999. pp. 407-8.

Miyamoto, N, Kagohashi, M, Nishioka, K. "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. "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. "Clinically definite multiple sclerosis after radiological Schilder-like onset". J Neurol. vol. 250. 2003. pp. 871-3.

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.

There is evidence for the use of corticosteroids and ACTH in the treatment of acute exacerbations of a disease similar to Schilder's disease, multiple sclerosis. The Cochrane Collaboration's Multiple Sclerosis Group, cited below, states that evidence is favorable for these treatments, but that further research is needed for long-term impact.

Filippini, G, Brusaferri, F, Sibley, WA. "Corticosteroids or ACTH for acute exacerbations in multiple sclerosis". Cochrane Database Syst Rev. 2000. pp. CD001331.

Ongoing controversies regarding etiology, diagnosis, treatment

The major controversy regarding Schilder's disease is defining it both in the acute and (rarely) recurrent states. There is debate about whether the findings in Schilder's disease represent a truly unique manifestation of autoimmune white matter disease or constitute merely a variant form of ADEM. Those who argue that Schilder's disease is a unique entity state that strict application of the Poser criteria to reported cases is needed, and that improvement in the quality of magnetic resonance imaging yields a viable means of differentiating the findings of Schilder's disease from other similar conditions. Others posit that true identification of Schilder's demands a definitive brain biopsy.

There is also a question regarding the nomenclature for a recurrence of Schilder's disease. The classical presentation of Schilder's disease is described as a single episode. There are isolated reports of children diagnosed with Schilder's disease who, after a period of remission, have new brain lesions and symptoms. Whether to term these individuals as still having "recurrent/relapsed Schilder's disease" or re-defining the entire disease history as "multiple sclerosis" is actively debated in the literature, and there is no clear consensus.

Given the rarity of Schilder's disease, and the vanishingly rare number of patients with two clinical episodes, it is unlikely these issues will be resolved in the near future. However, since the treatments for acute exacerbations of Schilder's disease, ADEM, multiple sclerosis, and similar demyelinating diseases are identical, a precise diagnosis is not currently necessary for initiation of therapy but may become so as treatments for these conditions are refined.

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