Diffuse Sclerosis

Paul Schilder described a severe and fulminating syndrome of acute demyelinating disease in 1912. ^{[1, 2]} 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. ^[3]

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. ^{[4, 5]} 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. ^[6]

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. ^[7] 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.

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.

Frequency

Less than 20 sporadic cases (predominantly males) have been reported to date. ^[8]

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.

Demographics

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.

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.

Prognosis depends upon definition of illness. In the current state of knowledge, determining the duration of disease, rate of progression, and outcome from the strictly defined category of diffuse sclerosis (Schilder disease 1912 type) that includes approximately 9 cases is impossible. This is also true because potentially valuable therapies such as intravenous high-dose corticosteroids have not been subjected to carefully designed trials in these cases.

In those individuals who have been reported as having Schilder disease but whom Poser has placed into the category of transitional sclerosis, the outlook derived from 70 cases Poser reported in 1957 demonstrated mean duration of survival to be 6.2 years after onset (range 3 d to 45 y). Disease duration was less than 1 year in as many as 40% of cases, but survival times of at least 10 years were experienced in more than 23%. These cases are in all likelihood examples of an often aggressive form of multiple sclerosis, hence the survival of these individuals tends on average to be shorter than that experienced by most individuals with multiple sclerosis.

In those prepubertal cases with a good response to intravenous corticosteroids, and particularly those who are found to have smaller lesions in locations typical for acute disseminated encephalomyelitis (eg, cortical ribbon, deep gray nuclei, thalamus), a better prognosis may be found in some cases. Information concerning this group and the potential of corticosteroids for remediation of illness is limited. The authors have encountered a small number of patients with large lesions who have had recurrent bouts of illness that have proven difficult to prevent and for whom, despite survival times for as long as 5 years without many cumulative deficits, the prognosis remains guarded.