Diffuse Sclerosis

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Background

Paul Schilder described a severe and fulminating syndrome of acute demyelinating disease in 1912.[1] The original case occurred in a 14-year-old girl who had been healthy prior to the development of papilledema, right hemiparesis, and elevated intracranial pressure. Her neurologic disease followed a course of 4.5 months of deterioration leading to death and ensuing pathological examination of her brain by Schilder. Schilder found 2 large lesions that manifested demyelination with axon sparing. The brain also contained other smaller lesions with a pathology typical for multiple sclerosis.

The exact nature of that child's illness remains controversial. Some have suggested that this child had either acute multiple sclerosis or, less likely, severe acute disseminated encephalomyelitis. The child possibly had some other illness, such as some form of acute fulminant angiopathic or vasculitic illness. The distribution of lesions in this index case (ie, bilateral but slightly asymmetrical large sharply demarcated areas of demyelination) and the resemblance of the pathology to multiple sclerosis (which in turn resembles the pathology of acute disseminated encephalomyelitis) became the hallmarks of the diagnosis of Schilder disease.

Subsequent reports by Schilder (1913 and 1924) included 2 additional patients, each with pathological changes that differed from the other and from the original case.[2, 3] As has been confirmed by reexamination of the pathological features several times in the 1950s, one of these additional patients likely had adrenoleukodystrophy and the other likely had subacute sclerosing panencephalitis. The disease mechanisms and the pathological features of these conditions were unknown at the time that Schilder published his reports.

The considerable controversy and confusion that has ensued has scarcely been dispelled. Although reports of more than 100 subsequent patients thought to be examples of this condition have accumulated in the medical literature in 9 decades, many of these cases may be examples of other illnesses.

In some of these cases, the diagnosis of Schilder disease was based on pathological analysis of the brains of patients who had died from brain degeneration. A smaller number of cases were identified on the basis of analysis of a brain biopsy specimen. The availability of pathological descriptions has permitted many cases to be carefully reconsidered with the benefit of subsequent knowledge of pathological entities unknown to Schilder and to many of the subsequent individuals who have published cases of suspected Schilder disease. This information has permitted the diagnosis of most of these cases to be reassigned to other diseases such as tumor, multiple sclerosis, adrenoleukodystrophy, encephalitis, or subacute sclerosing panencephalitis (SSPE).

Further confusion was generated with the development of CT and MRI technologies. Based upon the appearance of lesions in these imaging studies, a number of cases of supposed Schilder disease have been diagnosed in living individuals, without benefit of pathological analysis of the brain or a brain biopsy specimen. Diagnosis has been made in such cases because of the combination of clinical features and the presence of large white matter lesions on brain imaging.

Many of these individuals with radiographically diagnosed disease have survived much longer than has tended to be the case in individuals whose Schilder disease was diagnosed on the basis of postmortem pathological analysis. Some, indeed, appear to have gone into remission, often in a reduced state of function as compared to their premorbid state but without further exacerbations or progression. Whether such cases represent examples less fulminant forms of Schilder disease or whether postmortem pathological confirmation selects for the most fulminant and lethal forms of Schilder disease is unclear.

The fact that a large number of pathologically diagnosed cases have proven on reanalysis to be examples of diseases other than Schilder disease supports the view that many of these radiologically diagnosed cases are also something other than Schilder disease, such as encephalitis, acute disseminated encephalomyelitis, acute multiple sclerosis, leukodystrophy, SSPE, mitochondrial cytopathies, or other possibilities. A not inconsiderable portion of published reports of patients presumed to have Schilder disease contain too little clinical or pathological information to permit that diagnosis to be confirmed on the basis of modern criteria. Most reported cases have not had testing for adrenoleukodystrophy or SSPE.

Despite all of this confusion, a discrete pathological entity for which one of the various labels subsequently attached to the 1912 variety of Schilder disease may exist. Note that this still remains a pathological entity and that the diagnosis of Schilder disease should remain tentative until such time as it can be pathologically confirmed either by biopsy or postmortem brain analysis. Furthermore, as Charles Poser insisted in attempting to establish diagnostic criteria for Schilder disease, appropriate tests must be performed to exclude SSPE and adrenoleukodystrophy in every case thought to represent Schilder disease.[4]

The small number of cases that Poser or other authorities have been willing to accept as examples of Schilder disease remains a heterogenous collection, and as yet, no understanding of the pathophysiological basis for any of these cases exists. Even among the handful of cases Poser has accepted as examples of Schilder disease, not every case was monitored to postmortem analysis, rendering statements concerning the degenerative potential and lethality of disease tentative.

Although pathologically distinctive, the boundaries between Schilder disease, multiple sclerosis, acute multiple sclerosis, and acute disseminated encephalomyelitis remain unclear. Poser's careful pathologically confirmed 1957 series suggested that at least 70% of cases that have been reported as Schilder disease are examples of multiple sclerosis.[5] This figure was based upon those cases where pathological material remained or where clinical and pathological details were reported in adequate detail for meaningful reanalysis to be undertaken. To these cases he initially assigned the novel diagnosis of transitional sclerosis. He has subsequently chosen simply to describe such cases as multiple sclerosis.

Some of the cases that have been reported as examples of Schilder disease have had onset in the wake of an infection and a course of illness that included deterioration with subsequent improvement and no further recurrence. The sharp margin of demyelination in the large lesions of Schilder disease in some of these cases and the characteristic sparing of the subcortical rim would seem to weigh against acute disseminated encephalomyelitis as the source of these lesions.

However, large lesions may develop in cases of postinfectious or postvaccination acute disseminated encephalomyelitis, and in some instances, these lesions occur in subcortical locations. Furthermore, some of these cases respond quite dramatically to the administration of corticosteroids. These features suggest that the Schilder phenotype can be generated by acute disseminated encephalomyelitis, an entity whose pathological features closely resemble multiple sclerosis.

Diagnosis upon the basis of imaging studies without pathological confirmation increases the likelihood of etiological heterogeneity, including such entities as leukodystrophy, tumor, SSPE, various types of vasculitis, lymphangiomatosis, collagen vascular diseases, nutritional diseases, meningoencephalitis, and other entities in addition to multiple sclerosis and acute disseminated encephalomyelitis.

Poser's careful review of all reported cases has concluded that the medical literature contains no more than 9 definite cases of Schilder diffuse sclerosis of the 1912 type. In agreement with that conclusion, this discussion concentrates on the features of this exceedingly rare disease based upon the features in these 9 individuals. As has been noted, a discussion of the clinical and laboratory features of Schilder disease must perforce remain tentative because the available diagnostic criteria may in one or another respect fail to include or exclude cases appropriately and because the handful of cases that remain for consideration may therefore inadequately reflect the actual nature of this illness.

Indeed, whether this is a discrete illness remains uncertain. These serious uncertainties will not be completely resolved until the time that some specific test for Schilder disease becomes available or progress in the understanding of inflammatory diseases of the brain permits all cases to be parceled out to other diagnostic entities. In the discussion that follows, some consideration is given to 3 other diagnostic categories that overlap with Schilder disease: childhood multiple sclerosis, acute disseminated encephalomyelitis, and those infectious encephalitides for which no specific test exists. The inclusion of some remarks on these categories is necessary because the lack of specific tests make these still incompletely defined categories difficult to exclude and because the boundaries between them and Schilder disease remain incompletely defined.

Specific tests are available for adrenoleukodystrophy, SSPE, and progressive measles panencephalitis, and numerous highly detailed reviews of these diseases are available. Therefore, the reader is encouraged to consult those sources for information concerning the clinical course, laboratory features, and treatment of those important members of the differential diagnosis of Schilder disease.

Pathophysiology

The pathology of those cases that most closely resemble Schilder's original case is characteristic. Widespread demyelination of both cerebral hemispheres with varying degrees of axonal injury is found in autopsied cases. The lesions are usually somewhat asymmetrical, have sharp margins, and spare the immediate subcortical rim of white matter. Similar demyelinative changes are often found in the brainstem and cerebellum. The axonal injury, in the form of Wallerian degeneration, may occur throughout the nervous system, but changes are especially marked in the spinal cord. In severe cases, the pathology thus more closely resembles that of multiple sclerosis than acute disseminated encephalomyelitis.

Some authorities have described cases with characteristic bilateral lesions that are somewhat smaller than those in the foregoing group, lesions that are associated with additional multiple small plaques. The appearance of these plaques more typically resembles the usual multiple sclerosis plaque than typical acute disseminated encephalomyelitis lesions. These cases tend to manifest in adolescence or adulthood rather than childhood, and their clinical course is more variable than the acute severe and more widely disseminated cases.

Epidemiology

Frequency

United States

This disease is exceedingly rare. Excluding more than 100 reported cases as examples of other entities or because the case reports included too little information to be certain, just 9 cases remain in the world's literature. Two additional cases that have been reported since Poser's 1985 review may possibly be included, but neither of these cases fully satisfies the criteria established by Poser.

Mortality/Morbidity

Prior to MRI scanning, diagnosis was only made on postmortem analysis; hence, the cases were regarded as uniformly fatal. Further refinement of the understanding of morbidity and mortality will depend upon diagnostic criteria in the absence of a nonpathological diagnostic test. Death in the reported cases occurred within days to many months.

Race

No information concerning genetic or racial predilection exists.

Sex

Seven of the 9 cases of Schilder disease occurred in boys, all of whom were younger than 10 years. Two additional cases occurred in adolescent or adult women, the adolescent having been Schilder's index report.

Age

Strict definitions of Schilder disease (ie, bilateral large lesions without additional plaques or other findings) results in 7 patients, all boys, whose disease arose chiefly between 7 and 10 years of age. Two additional cases occurred in females older than 13 years.

History

The diagnostic criteria established by Poser in 1985 require 6 elements:[4]

  1. 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.
  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.

To Poser's criteria could be added the currently available diagnostic tests for early childhood leukodystrophies such as Krabbe or metachromatic leukodystrophies.

Based upon the 9 cases that have satisfied Poser's criteria, the following statements can be made concerning the history that precedes clinical presentation of Schilder disease.

Physical

Causes

The causes of Schilder disease, if it exists as an independent entity, are unknown. Although note evidence for a possible infectious illness at the onset of presumed Schilder disease, the significance of this observation remains unclear. In some reports, latency exists between this initial febrile illness and the subacute onset of Schilder disease. Some of these cases may be examples of acute disseminated encephalomyelitis. Other cases have a fulminant course without such clear distinction between prodrome and onset of the disease process thought to be Schilder disease. Many of these cases may be examples of encephalitis or some metabolic disorder.

Laboratory Studies

Imaging Studies

Other Tests

Procedures

Staging

No staging for Schilder disease has been proposed.

Medical Care

The underlying cause of Schilder disease remains unknown, particularly if limited to those cases that conform to the 1912 type. Implicit in that definition is inexorable disease progression. As has been noted, the definition then applies to approximately 9 of all reported cases. Whether the 1912 type cases are to be considered responsive to corticosteroid treatment and whether such treatment would have rendered moot the progressive nature of the illness that Schilder first defined is unknown.

If any wider definition is applied, particularly one based upon radiographic criteria, then a number of inflammatory illnesses are likely to be included, some of which are treatable. Even with radiographic diagnosis, adrenoleukodystrophy, SSPE, progressive rubella panencephalitis, and those forms of collagen vascular disease and encephalitis that can be excluded by CSF or other laboratory studies are presumably excluded from consideration as examples of diffuse sclerosis (Schilder 1912 type).

Based upon such radiologic diagnosis, the critical approach to treatment is to ascertain whether the lesion is responsive to the administration of high-dose intravenous corticosteroids.

General practice in such cases currently entails methylprednisolone administration of doses of 20-30 mg/kg each morning for each of 3-5 successive mornings, followed by a taper of oral corticosteroids. This treatment may be contraindicated by the possible presence of bacterial infections or the unexcluded possibility of herpetic encephalitis. Administration of corticosteroids should be accompanied by the administration of antacids or histamine (H2) receptor antagonists to reduce the risk for formation of Cushing ulcers. Patients should be monitored for such potential adverse effects as hypersensitivity, gastrointestinal bleeding, hypertension, hyperglycemia, hypokalemia, or opportunistic infection. These problems are seldom encountered.

Response to this form of therapy employing this or similar regimens has been documented in a number of single case reports provided over the past decade. Whether the effectiveness of such therapy is pertinent to consideration of strictly interpreted Schilder disease criteria is unclear. In many of these instances where no pathological information was obtained but response to therapy was beneficial, the underlying problem was likely acute disseminated encephalomyelitis or multiple sclerosis. Response to such therapy could also be noted in certain brain tumors (as has been the authors' experience) emulating Schilder disease and perhaps in other entities.

The addition of brain biopsy excludes such diagnoses as brain tumor, vasculitis, collagen vascular process, or encephalitis by the identification of specific pathological changes. In some instances, aspiration or surgical biopsy of large lesions suggesting Schilder disease has been accomplished, and several of these cases have also been reported during the past decade. In such cases, the pathological changes discerned often resemble either multiple sclerosis or acute disseminated encephalomyelitis; the pathological changes of these entities may be quite difficult if not impossible to distinguish on the basis of brain tissue biopsy.

Where such changes are found, the therapy described above, high doses of intravenous corticosteroids, is likely to prove beneficial, although lesions may recur. Some authorities (chiefly those accustomed to treating multiple sclerosis in adolescents and adults) are confident that recurrence of such lesions is diagnostic of multiple sclerosis. Other authorities, particularly those whose experience is largely limited to management of acute disseminated encephalomyelitis in prepubescent children, are confident that some of these cases may represent recurrent acute disseminated encephalomyelitis, an entity that the former group of authorities usually maintains does not exist.

This controversy is as yet unresolved, as are those controversies attendant upon the establishment of diagnostic boundaries for Schilder disease. However, several practical points can be made concerning treatment of those patients with radiographic findings suggesting Schilder disease (ie, large lesions of the type discussed above) and who have had all other pertinent differential considerations excluded (eg, vasculitic, tumor-related, collagen vascular, metabolic, other forms of illness).

Cases remaining that suggest the possible diagnosis of Schilder disease (diffuse sclerosis, Schilder disease of the 1912 type) or especially of transitional sclerosis (defined by the presence of small multiple sclerosis–like lesions in deep white matter in addition to large lesions) arising in postpubertal individuals should be considered to be multiple sclerosis until proven otherwise. The additional smaller lesions tend not to be found at the gray-white margin or in deep gray nuclei or thalamus. This diagnosis of multiple sclerosis can be supported in many cases by the fact that the CSF IgG index and oligoclonal band studies are frequently positive.

Many of these cases appear to respond favorably to intravenous steroid therapy, although their subsequent course is likely to be one of continued development of bouts of multiple sclerosis or the assumption of a progressive form of multiple sclerosis. In such cases, consideration must be given to treatment with immunomodulatory agents.[6] That form of treatment is beyond the scope of Schilder disease proper and is not further considered here. Details are available in Multiple Sclerosis.

Cases arising in prepubertal individuals with imaging findings suggestive of Schilder disease, for whom the alternative diagnoses noted above have been excluded (by specific tests), are likely to have an illness that falls within the family of acute disseminated encephalomyelitis. In some of these cases, smaller lesions are found in addition to the 1 or 2 large lesions that raise the possibility of a diagnosis of Schilder disease. In distinction to the group of adults just discussed, these additional lesions tend to be centripetal within the brain, some of them overlying the gray-white margin, and some may be found in deep gray nuclei or the thalamus.

The findings on CSF immune profile studies such as IgG index and oligoclonal bands are usually negative in these patients, although the myelin basic protein assay is frequently elevated. These patients tend to respond very well to a course of high-dose corticosteroids after the fashion discussed above. They may show resolution of illness, in some cases marked by the complete disappearance of large lesions, even those that appear to show central necrosis. Their subsequent course may include one or more recurrences, and in rare instances, the recurrence may be in the spinal cord (particularly the cervical spinal cord) rather than in the brain.

The best way to set either of the previously mentioned 2 groups apart from the largest number of alternative inflammatory, metabolic, or infectious diagnoses is brain biopsy. In some cases from either of the aforementioned groups, the opportunity for aspiration or biopsy is provided by attempts to reduce the volume of such lesions where they are thought to produce significant elevation of intracranial pressure. In a few such cases, intervention has been determined to be beneficial to the patient. In such cases, alternative diagnoses having been excluded, the pathology may be consistent with either multiple sclerosis or acute disseminated encephalomyelitis, entities that are in fact difficult to distinguish on the basis of a biopsy specimen from a single lesion.

In addition to cases that represent either multiple sclerosis or acute disseminated encephalomyelitis but are not found to have any of the alternative diagnoses noted above, the possibility remains that a very rare and small group of patients have a discrete disease that should be termed diffuse sclerosis (Schilder disease 1912 type). The efficacy of various treatment interventions and prognosis remains unclear.

In addition to treatment with corticosteroids, medical management entails support for breathing, circulation, nutrition, and attention to maintaining normal metabolic profiles during the acute phase of illness. Management includes in fulminant cases prevention of the development of skin breakdown or ulceration or of nosocomial infection from intravenous lines or other sources.

Surgical Care

Neurosurgical care may be required for obtaining a lesion biopsy. In some reported instances, neurosurgical aspiration of large lesions suggesting Schilder disease, particularly those with what appears to be central necrosis, has been judged valuable for both diagnostic purposes and alleviation of pressure.

Consultations

Consultations may be required from infectious disease specialists, rheumatologists, child neurologists, specialists in the diagnosis and management of multiple sclerosis, neurosurgeons, intensivists, and various therapists.

Diet

No specific diet is indicated for patients with Schilder disease. Those who appear to have Schilder disease but are found instead to have adrenoleukodystrophy have been treated with dietary modifications, the efficacy of which remains uncertain. Consideration of this topic is beyond the scope of this review.

Activity

No specific limitations to activity exist. Patients who are thought likely to have transitional sclerosis, and therefore are likely to have multiple sclerosis, may experience exacerbations of symptoms of illness because of exposure to heat, poor nutrition, or because they become overtired.

Medication Summary

The use of methylprednisolone, its indications, and its possible effects have been reviewed in Treatment. Other corticosteroids or intravenous gamma globulin (IVIG) possibly would also prove beneficial during the acute phase of presentation, but no information exists at present upon which to base any but the most general statements concerning these approaches. Whether intravenous corticosteroid therapy should be followed by an oral taper is unclear, although in most instances of recognized Schilderlike disease, such a taper is generally undertaken. No information exists concerning the appropriate length of such a taper or the influence of such a taper on outcome. No information exists concerning the efficacy of immunomodulatory therapy in Schilder disease as defined by the strict 1912-type criteria posed by CM Poser.

Methylprednisolone (Depo-Medrol, Solu-Medrol, Medrol)

Clinical Context:  The initial dose should be administered under close supervision because rare instances of anaphylaxis after initial dose have been reported.

Class Summary

Have anti-inflammatory properties and cause profound and varied metabolic effects. Corticosteroids modify the body's immune response to diverse stimuli.

Further Inpatient Care

The approach to inpatient management is as is indicated in Treatment.

Inpatient & Outpatient Medications

Deterrence/Prevention

No known method of prevention or deterrence exists.

Complications

Complications include cerebral herniation, inexorable progression of disease to death, development of pneumonia, sepsis, pulmonary embolization, skin breakdown and ulceration in individuals who are moribund, and the various complications due to corticosteroid administration noted above.

Prognosis

Author

Robert Stanley Rust Jr, MD, MA, Thomas E Worrell Jr Professor of Epileptology and Neurology, Co-Director of FE Dreifuss Child Neurology and Epilepsy Clinics, Director, Child Neurology, University of Virginia School of Medicine; Chair-Elect, Child Neurology Section, American Academy of Neurology

Disclosure: Nothing to disclose.

Specialty Editors

William J Nowack, MD, Associate Professor, Epilepsy Center, Department of Neurology, University of Kansas Medical Center

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Richard J Caselli, MD, Professor, Department of Neurology, Mayo Medical School, Rochester, MN; Chair, Department of Neurology, Mayo Clinic of Scottsdale

Disclosure: Nothing to disclose.

Selim R Benbadis, MD, Professor, Director of Comprehensive Epilepsy Program, Departments of Neurology and Neurosurgery, Tampa General Hospital, University of South Florida College of Medicine

Disclosure: UCB Pharma Honoraria Speaking, consulting; Lundbeck Honoraria Speaking, consulting; Cyberonics Honoraria Speaking, consulting; Glaxo Smith Kline Honoraria Speaking, consulting; Sleepmed/DigiTrace Honoraria Speaking, consulting; Sunovion Consulting fee None

Chief Editor

B Mark Keegan, MD, FRCPC, Associate Professor of Neurology, College of Medicine, Mayo Clinic; Master's Faculty, Mayo Graduate School; Consultant, Department of Neurology, Mayo Clinic, Rochester

Disclosure: Novartis Consulting fee Consulting; Bionest Consulting fee Consulting; Bristol Meyers Squibb Consulting fee Consulting; Caridian BCT Grant/research funds Other

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