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Show Journal of Clinical Neuro- ophthalmology 9( 4): 236- 240, 1989. Schilder's Myelinoclastic Diffuse Sclerosis Marco A. Lana- Peixoto, M. D., and Eustaquio C. dos Santos, M. D. © 1989 Raven Press, Ltd., New York We report here a case of Schilder's myelinoclastic diffuse sclerosis in a 14- year- old girl with sudden bilateral visual loss. Computed tomographic scan showed two large symmetrical lesions in the oCcipital lobes and a smaller hypodense area in the frontal lobe. Cerebrospinal fluid examination revealed increased immunoglobulin G fraction with the presence of oligoclonal bands. Ultrastructural study of a biopsy specimen disclosed a demyelinating disorder with no cytoplasmic inclusions. Steroid treatment was followed by a dramatic response, with almost complete visual recovery and shrinkage of the lesions. Key Words: Schilder's myelinoclastic sclerosisDemyelinating diseases--- Adrenoleukodystrophy. From the Department of Neurology, Federal University of Minas Gerais Medical School, Belo Horizonte, Brazil. Address correspondence and reprint requests to Dr. M. A. Lana- Peixoto, Departmento de Neurologia, Instituto Hilton Rocha, Av. Anel da Serra 1355, Belo Horizonte, MG, 30210 ;:_",.. .. , i 236 Few well- documented cases of Schilder's myelinoclastic diffuse sclerosis 1912 type have been reported in the literature. However, the eponym " Schilder's disease" has been widely used to designate several distinct clinical and pathological disorders of the central nervous system. Myelinoclastic diffuse sclerosis, as described by Schilder in his 1912 case, is a very rare condition that needs to be differentiated from other myelin diseases, particularly adrenoleukodystrophy by specific biochemical and/ or ultrastructural studies ( 1,2). The following case fulfills the criteria for the diagnosis of Schilder's myelinoclastic diffuse sclerosis, 1912 type, as established by Poser et al. ( 2), and demonstrates its clinical and imaging dramatic response to steroid treatment. CASE REPORT A 14- year- old dark- skinned, right- handed girl was admitted to the hospital with a I- month history of sudden bilateral blindness and parietooccipital headache. It had been 1.5 years since an episode of left hemiplegia with partial loss of sensation on her left side, which resolved almost completely after 19 days. At that time she also had a partial motor seizure involving the left side of her face. There was no history of preceding infection or vaccination. Previous medical history or family history for neurologic and visual disorders were negative. Physical examination on admission disclosed visual acuity was hand movements bilaterally. Ophthalmoscopic exam was normal and the pupils were 3 mm in diameter and fully reactive to light. There was a mild left hemiparesis, but no brisk or pathologic reflex could be elicited. Pinprick, light touch, vibration, and position sense were normal, as was the remainder of the neurologic examination. Routine laboratory studies including complete blood cell count, erythrocyte sedimentation rate, serum protein electrophoresis, glucose, urea nitrogen, creatinine, electrolytes, SCHILDER'S DISEASE 237 cholesterol, lipoproteins, liver function tests, and VORL were all normal. Urinalysis, and skull and chest roentgenograms were also negative. Lumbar puncture revealed cerebrospinal fluid with an opening pressure of 120 mm H20. Analysis of the fluid showed 2 lymphocytes/ mm3 , a glucose level of 64 mg/ dL, and a protein level of 71 mg/ dL with 14% "(- globulin and an immunoglobulin G level of 5.2 mg/ dL. Oligoclonal bands were also noted. An electroencephalogram ( EEG) revealed slowing of the background activity with bursts of 3-- 4 cycles/ s polymorphic waves on the right frontal and central areas. The computed tomographic ( CT) scan ( Fig. 1) revealed two roughly symmetrical hypodense lesions, with a dense ring of contrast enhancement in the ocdpitallobes and a smaller irregular hypodense area in the right frontal region. The right lateral ventricle was slightly increased. The presumptive diagnosis of a demyelinating disorder or a leukodystrophy was made and the patient's adrenocortical function was evaluated. Determination of serum cortisol and urinary 17- ketosteroids and 17- hydroxysteroids showed normal values. Adrenocorticotropic hormone ( ACTH) stimulation test was performed and revealed no evidence of adrenocortical failure. Conduction studies of the median, ulnar, and peroneal nerves showed normal values. A right occipital brain biopsy was then carried out. The histologic examination by LuxolFast Blue and silver staining techniques disclosed . FIG. 1. Initial computed tomographic scan shows lo~ density lesions with a ring of contrast enhancement In both occipital lobes and in right frontal lobe. confluent areas of myelin disintegration. In some areas the U- fibers were also involved. The axons were less intensively affected and the cortical neurons were completely spared. Perivascular cuffs with lymphocytes and phagocytes were prominent and a large number of reactive giant astrocytes, some of them multinucleated, were found within the lesions. Small scattered areas of frank tissue necrosis and cavitation were seen. Electronmicroscopy failed to reveal any evidence of the characteristic cytoplasmic membrane- like inclusions, as were found in adrenoleukodystrophy. The patient was treated with intravenous dexamethasone, 16 mg daily, for 1 month and then with oral prednisone in tapering doses for 3 weeks. She responded well to treatment and 30 days after starting steroid therapy she could count fingers at 50 em from both eyes. On Goldmann perimetry there was a marked constriction of the visual fields ( Fig. 2). Serial CT scans 1.5, 3, and 8 months later showed progressive reduction of the size of the demyelinating lesions and disappearance of contrast enhancement ( Fig. 3). Visual acuity recovered to 20/ 20 bilaterally and Goldmann perimetry showed a remarkable expansion of the visual fields, remaining only a binasal inferior defect ( Fig. 4). No change in the intensity of the left hemiparesis was observed. DISCUSSION In 1912, 1913, and 1924, Schilder described three different nosological entities ( 3- 5) under the term " encephalitis periaxialis diffusa." Since then a great number of articles have been published under the title " Schilder's disease" to report cases of many other distinct disorders of the nervous system. In 1912, Schilder originally reported a case of a 14- year- old girl with mental signs and increased intracranial pressure. His clinical diagnosis was that of a posterior fossa expanding lesion that developed over a period of about 4.5 months. Surprisingly, Schilder found at autopsy two welldemarcated areas of demyelination, with almost complete sparing of the axons and the subcortical U- fibers. He considered this case a new disease of myelin that should be differentiated from brain tumors and multiple sclerosis. The following year, Schilder ( 4) published a postmortem study of the brain of a patient previously described by Haberfeld and Spieler ( 6) in 1910. He considered it a variant of encephalitis periaxialis diffusa and did not attach importance to the fact that a sibling of the patient had died of a similar disease. In 1924, Schilder reported the last of his three cases ( 5) con- / Clill Neuro- ophthalmol. Vol, 9. No, 4, 1989 238 M. A. LANA- PEIXOTO AND E. C. DOS SANTOS FIG. 2. Marked constriction of the visual fields on Goldmann perimetry. cerning a 37- year- old woman with a neurological disease that developed after a bout of influenza. Postmortem examination of her brain disclosed areas of diffuse demyelination and intense perivascular lymphocytic infiltrates, as well as capillary proliferation. He concluded that this case was a diffuse subacute encephalitis and included it in the group of periaxial encephalitides. Subsequent studies on Schilder's original cases have characterized them as three different entities. His first case is now called diffuse myelinoclastic sclerosis or true Schilder's disease 1912 type ( 1, 7). FIG. 3. Computed tomographic scan after treatment shows impressive shrinkage of the lesions with no contrast enhancement. JClin Neuro- uphtlwlmvl, Vol. 9, No. 1, 1989 His 1913 case has been identified as adrenoleukodystrophy ( 8,9), whereas his 1924 report concerns what is presently known as subacute sclerosing penencephalitis ( 10). Much of the confusion regarding the nomenclature on Schilder's disease comes from the misuse of the terms Schilder's disease and Schilder's diffuse sclerosis to name a host of unrelated and heterogeneous conditions that have become recognized as belonging to entirely distinct categories. As a matter of fact, Schilder himself unwittingly initiated such an enormous confusion that, most unfortunately, lasts to this day. Attempts to clarify this situation soon appeared in the medical literature. In 1934, Bouman ( 11) reviewed 100 cases reported as Schilder's disease or Schilder's diffuse sclerosis and found only 17 cases that were in accordance with Schilder's 1912 criteria. Other disorders were harboured under these terms, such as leukodystrophies, perinatal encephalopathies, subacute sclerosing encephalitides, postinfectious perivenous encephalopathies, transitional sclerosis, and glioblastomatosis. However, it is probable that most of the 17 cases selected by Bouman as Schilder's disease 1912 type may actually represent instances of adrenoleukodystrophy ( 1). Poser ( 1,7) and Poser et a1. ( 2) have more recently clarified the terminology and established specific criteria for the diagnosis of Schilder's myelinoclastic diffuse sclerosis 1912 type. Reviewing the literature, Poser ( 1) and Poser et a1. ( 2) listed only nine published cases that can be considered as probable instances of Schilder's myelinoclastic diffuse sclerosis ( 12- 20). They added two cases of their own that represent unquestionable Schilder's myelinoclastic diffuse sclerosis, as the diagnosis was established by biochem- SCHILDER'S DISEASE 239 FIG. 4. Goldmann perimetry after treatment. ical and electron- microscopic examination. They concluded that most of the patients with presumed Schilder's disease reported in the literature would be better placed under the diagnoses of adrenoleukodystrophy, transitional or multiple sclerosis, or acute disseminated encephalomyelitis. Schilder's disease is a subacute or chronic myelinoclastic disorder resulting in the formation of large bilateral plaques affecting the centrum semiovale of the cerebral hemispheres. Adrenocortical function must be normal and there must be no involvement of the peripheral nerves. It may affect both children and adults of both sexes, although most of the probable and definite cases have occurred in male children. It is a diagnosis of exclusion that cannot be established exclusively on clinical grounds, neither by CT scan nor by light microscopic examination of a brain biopsy specimen. Other myelin, as well as inflammatory disorders, must be definitively ruled out. Special attention has to be paid to rule out adrenoleukodystrophy, as it may even affect girls- probably representing symptomatic carriers- and may simulate Schilder's myelinoclastic diffuse sclerosis on CT imaging and histologic preparations. Actually, in some cases of adrenoleukodystrophy there are sharply demarcated areas of myelin breakdown, with anisomorphic gliosis and intense perivascular inflammatory reaction simulating a myelinoclastic disorder. Further confusing the differentiation is the normalcy of the adrenocortical function tests in many cases of adrenoleukodystrophy. It can only be ruled out by means of analysis of the fatty- acid components of serum or brain cholesterol esters, or by the absence of the characteristic cytoplasmic inclusions on electron- microscopic study of brain or adrenal cortex. Since these criteria for definite diagnosis of Schilder's myelinoclastic diffuse sclerosis were established, a new biopsy- proven case was reported by Sedwick et a1. ( 21) in a 51- year- old woman with mental confusion, headache, and bilateral blindness. The present case fulfills the criteria for the diagnosis of true Schilder's myelinoclastic diffuse sclerosis 1912 type, as has been proposed by Poser ( 1) and Poser et a1. ( 2). Careful electron- microscopic examination of a brain biopsy specimen failed to reveal any cytoplasmic inclusions that would suggest adrenoleukodystrophy. In addition, oligoclonal bands were noted in the cerebrospinal fluid immunoglobulin G fraction, which was also increased. This finding has never been reported in adrenoleukodystrophy ( 22). A unique feature of this case was the presence of three hypodense lesions in the brain. A right frontal lobe lesion with no contrast enhancement was observed, in addition to two roughly symmetrical large hypodense areas with contrast enhancement at their edges in the occipital lobes. It is possible that the frontal lesion represented an old plaque and the occipital ones had developed more recently. This explains the left hemiparesis and the partial motor seizure that occurred 18 months preceding the visual symptoms. Steroid treatment was followed by a dramatic response both clinically and on CT imaging. The patient's vision improved from perception of hand movements to 20/ 20 bilaterally, with a mild binasal inferior defect on the visual fields examination. There was a progressive shrinkage of the occipital lesions to a point of almost complete disappearance, as was documented by serial CT scans. Corticosteroid therapy was followed by J Clin Neuro- ophthalmol, Vol. 9, No. 4, 1989 240 M. A. LANA- PEIXOTO AND E. C. DOS SANTOS m, Hk~' d impwvement of the clinical condition in ,\ IW ~' rl) b, 1ble ( 2Ll) and in two other proven cases \ 1.2) but (\) uld nl) t change the complete bilateral blindne~ s in the case reported by Sedwick et al. \ 21 ). Reduction of the size of the lesion has been ,1bl) 11llted in two previous cases ( 1,2). Althou~ h it is an extremely rare condition, true Schilder's myelinoclastic diffuse sclerosis 1912 type must be included in the differential diagnosis of acute neurological deficits, particularly when visual loss occurs and bilateral large hypodense lesions are observed on CT scan. Appropriate workup may establish the correct diagnosis. REFERENCES Poser C~ I ~ lvelinoclastic diffuse sclerosis. In: Vinken PJ and Bruvn G'vV. eds. Handbook of Cli> ll( al Neurology. Vol 47. Amsterdam: Else\' ier Science Publishers, 1985: 419- 28. ~ Poser CM. Goutieres F, Carpentier AM, Aicardi J. Schilder's mwlinoclastic diffuse sclerosis. Pt'diatrl( s 1986; 77: 107- 12 . 3. Schilder P. Zur Kenntnis der sogennanten diffusen SkJerose. Z Gt'samlc' Neurol PSl/ chiatr 1912; 10: 1-- 60. 4. Schilder P Zur Frage der ' Encephalitis periaxialis diffusa. Z Gesamte SeuTOI PSl/ chiatr 1913; 15: 359- 76. 5. Schilder P. 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