Schilder's Disease

A rare progressive myelinoclastic  disorder of CNS affecting younger adulthood (between 7 and 12 years of age) and considered to be the variant of multiple sclerosis.

Introduction

A rare progressive myelinoclastic  disorder of CNS affecting younger adulthood (between 7 and 12 years of age) and considered to be the variant of multiple sclerosis.
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Diagnostic Criteria
  • Diagnostic criteria for Schilder’s disease was presented by Poster in 1985[5]
  • 1 to 2 cm large symmetrical plaques roughly greater than 2 cm in cerebral hemisphere mainly in centrum semiovale.
  • No adrenal gland dysfunction
  • No PNS Demyelination
  • No lesion on clinical, paraclinical, and imaging modalities.
  • Subacute and chronic myelinoclastic diffuse sclerosis
  • Serum VLCFA is normal that differentiates it from Adrenoleukodystrophy.

Etiology

Etiology is mainly unknown
  • Genetic abnormalities
  • Magnetic Resonance Spectroscopy has revealed metabolic abnormalities like
    • Increased lactate,
    • Increase choline to creatine ratio and
    • Decreased N-Acetyl aspartate to creatine ratio.
  • Viral Infections like Murine Virus (JHM)

Epidemiology

  • About 68 cases have been identified between 1960-2018.
  • Mainly affects the younger population between 5 -14 years of age.
  • Predominantly affects males.

Clinical Findings

Table 1: Features of Schilder’s Disease

History
Signs and Symptoms
Physical Findings
Which factors precipitated the disease? Have you experienced changes in bowel habits and urinary incontinence? Have you experienced psychiatric symptoms? Have you experienced headache and visual disturbances? Have you experienced intentional tremors and syncope? Have you experienced Dysarthria? Have you experienced weakness in your muscles on either side of the body?
Personality changes and loss of responsiveness, Changes in bowel and urinary symptoms, Papilledema and raised intracranial pressure, Dysarthria , Aphasia, Slowness of movement and Cerebellar changes
The most common symptoms encountered in Schilder’s disease include Pseudotumour symptoms, Babiniski sign positive, Deep tendon reflex positive, Aphasia, Flaccid paralysis, Optic neuritis/Atrophy Papillitis or stauungspapille, Bilateral optic neuritis, Demyelination in optic nerve and optic chiasm. Sensorineural hearing loss, Internuclear ophthalmoplegia, Raised intracranial pressure (Cushing Reflex Positive)

Differential Diagnosis

  • Multiple Sclerosis
    • Involves white matter
    • Has Oligoclonal bands in serum and CSF, unlike Schilder’s Disease.
  • Acute Multiple Sclerosis
  • Acute Disseminated Encephalomyelitis
  • Brain Abscess/Tumor
  • Neuromyelitis Optica/Balo concentric Sclerosis/Marburg MS
  • Astrocytoma/Glioblastoma multiforme
  • Adrenoleukodystrophy
  • Churg-Strauss syndrome
  • Granulomatosis with polyangiitis

Pathophysiology

  • Perivascular infiltration of CD45 positive T lymphocytes along with parenchymal  Astrocytes and macrophages along with myelinolysis.
  • Astrocytes are Glial Fibrillary acid positive and macrophages have foamy long  Fibrillary processes.
  • Microcytic degeneration and reactive gliosis is also observed.
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Areas most affected
  • Bifrontal lesions involving anterior Corpus Callosum and bilateral Parieto-occipital
  • Subcortical areas of genu and splenium of Corpus Callosum.

Pathognomic features

  • Large asymmetrical unmyelinated areas bilaterally along with alternation wavy pattern of preserved and unpreserved areas.
  • Both preserved and non preserved areas showed intact axons on neurofilament further strengthening the myelinoclastic and axon preserving nature of Schilder’s Disease.
  • These plaques usually spare U fibers on Luxol Fast Blue Stain and brain stem.

Table 2: Distinguishing features of Schilder’s disease from Multiple Sclerosis

Schilder’s disease
Multiple Sclerosis
Spinal cord involvement rarely occurs
Frequently affects the spinal cord in a primitive stage
Sparing of basal ganglia
Involvement of basal ganglia and thalamus
Cortex spared
Cortex involved
U-fibers spared
U-fiber lesion seen
Demyelination of optic chiasm
Optic chiasm spared
Source: Jarius S, Haas J, Paul F, Wildemann B.Myelinoclastic diffuse sclerosis (Schilder's disease) is immunologically distinct from multiple sclerosis: results from a retrospective analysis of 92 lumbar punctures .J Neuroinflammation. 2019;16(51):1-14
 

Investigations

MRI

  • 1 to 2 large demyelinating plaques in the cerebral hemisphere appear hyperintense on T2 weighted scan and hypointense on T1 weighted images and these lesions are greater than 2 cm.
  • MRI also shows Wallerian degeneration.
  • CNS Myelin Basic Protein in Schilder’s disease is greater than 207ng/dl.
  • Incomplete ring enhancement, hyperintensity of enhanced regions, absence of mass effects, and absence of cortical disease.
Technetium Scan and cerebral angiograms
  • 99 m Technetium pertechnetate brain imaging and flow, Cerebral angiograms, and Pneumoencephalogram.
Non-Contrast enhanced CT scan
  • Diagnostically more appropriate than an MRI scan.
CAT  Scan
  • It may show hypointense lesions

CSF Analysis

  • Positive Wassermann reaction is found in Schilder’s disease patient and their mother.
  • CSF, Nasal and Oropharangeal swabs for viral cultures like Bartonella, EB virus, Cytomegalovirus, herpes 1, 2, and 7.
Findings
  • Four CSF samples were taken in 3 months and WBCs and opening pressure are measured at LP.
  • CSF WBCs were elevated on day 15 day of the symptoms and negative on day 70.
  • CSF opening pressure was 200mmHg at second puncture and 350mmHg at 3 puncture.

FLAIR

  • Fluid attenuated inversion recovery sequences is a sort of brain imaging modality used to nullify the hyperintense shadow of CSF to diagnose periventricular lesions.
  • FLAIR shows increase images in the periphery and low signals in the center.

Ultrastructural Studies

  • Ultrastructural studies of the stained tissue reveal
    •  Myeloid bodies and
    • Zebra bodies

Perfusion weighted Scan

  • The lesion appears less perfused relative to areas of the brain not affected by myelinolysis.

Treatment

Palliative treatment
  • Palliative treatment like  Occupation, physical and nutritional therapy is effective in the later stages of Schilder’s disease.
  • Maintaining  Intravascular volume, ventilator support, electrolyte balance, and serial CBC to look for infection.
Pharmacological treatment
  • Methylprednisolone in a dose of 25-30mg/kg for 5 mornings followed by tapering steroid dose.
  • H2 receptor antagonists to deal with Cushing ulcers due to raised intracranial pressure.
  • Excellent response to steroids has been seen in patients with Schilder’s disease. Administration of steroids results in a decrease in size of lesions and improvement in the functionality   of affected organs
  • Human-derived immunoglobulins   are effective in Schilder’s disease.
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Fingolimod and Natalizumab should be avoided in tumefactive lesions of Schilder’s disease [19].
These drugs aggravate Neuromyelitis Optica.
  • Plasma exchange is also a rational treatment in patients nonresponsive to steroids.
  • Beta interferon and Rituximab has been used in the treatment of Schilder Disease.
Surgical Management
  • Surgical Decompression is effective in larger lesions to relieve the patient's symptoms.

Prognosis

  • Schilder’s disease is Monophasic in the majority of cases. Monophasic patterns may be progressive or static. However relapsing cases have been seen.
Factors affecting the prognosis
  • Degree of disease
  • Rate of Demyelination
  • <1 year: 40% cases
  • >10 years: 23% cases
  • Good prognosis in the prepubertal group when administered steroid intravenously and if the disease affects areas like deep gray nuclei or thalamus.

Complications

  • DIC
  • Pneumonia
  • Sepsis
  • Pulmonary embolism
  • Bed Sores due to chronic disease
  • Cerebral herniation

Further Reading

  • Garrido C, Levy-Gomes A, Teixeira J, Temudo T. Enfermedad de Schilder: dos nuevos casos y revision de la bibliografia[Schilder’s disease:two new cases and a review of the literature]. Rev Neurol.2004 Oct 16-31;39(8):734-8
  • Poser CM. Myelinoclastic diffuse sclerosis. In: Handbook of Clinical Neurology. V 3. New York, NY: American Elsevier; 1985:419-428.
  • Kraus D, Konen O, Straussberg R. Schilder’s disease:non-invasive diagnosisand successful treatment with human immunoglobulins.Europ J Paed Nurol. 2012;16(2):206-208.

Bibliography

  • Karussis The diagnosis of multiple sclerosis and the various related demyelinating syndromes: a critical review. J Autoimmun. 2014; 48-49:134-42.
  • Miyamoto N, Kagohashi M, Nishioka K, Fujishima K, Kitada T, Tomita Y,.Mori K, Maeda M, Wada R, Matsumoto M, Mori H, Mizuno Y, Okuma Y. An Autopsy Case of Schilder’s Variant of Multiple Sclerosis (Schilder’s Disease). Eur Neurol 2006;55:103–107.
  • De Groot CJ, Bergers E, Kamphorst W, Ravid R, Polman CH, Barkhof F, van der Valk P: Post-mortem MRI-guided sampling of multiple sclerosis brain lesions. Increased yield of active Demyelination and (p)reactive lesions.Brain 2001;124:1635-1645
  • Garrido C, Levy-Gomes A, Teixeira J, Temudo T. Enfermedad de Schilder: dos nuevos casos y revision de la bibliografia[Schilder’s disease:two new cases and a review of the literature]. Rev Neurol.2004 Oct 16-31;39(8):734-8
  • Poser CM. Myelinoclastic diffuse sclerosis. In: Handbook of Clinical Neurology. V 3. New York, NY: American Elsevier; 1985:419-428.
  • Nejat, F. and Eflekhar,B. Decompressive aspiration in myelinoclastic diffuse sclerosis or Schilder disease. Case report. Journal of Neurosurgery(2002),97(6),1447-1449
  • Kraus D, Konen O, Straussberg R, et al. Schilder's disease: non-invasive diagnosis and successful treatment with human immunoglobulins. Eur J Paediatr Neurol. 2012;16(2):206-8. PMID: 21925910.
  • 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.1998; 13(5):197–201
  • Kim DS, Na DG, Kim KH, Kim JH, Kim E, Yun BL, et al.Distinguishing tumefactive demyelinating lesions from glioma or central nervous system lymphoma: Added value of unenhanced CT compared with conventional contrast-enhanced MR imaging. Radiology. 2009;251:467-75.
  • Pretorius ML, Loock DB, Ravenscroft A, Schoeman JF. "Demyelinating disease of Schilder type in three young South African children: dramatic response to corticosteroids".  Child Neurol. 199813(5): 197–201.
  • Kurdi M, Ramsay D. Balo’s Concentric lesions with concurrent features of Schilder’s disease in relapsing multiple sclerosis: neuropathological findings. Autopsy Case Rep[Internet]2016;6(4):21-26
  • Kraus D, Konen O, Straussberg R. Schilder’s disease:non-invasive diagnosisand successful treatment with human immunoglobulins.Europ J Paed Nurol. 2012;16(2):206-208.
  • 15.  Kurul SH,  Çakmakçı H, Dirik E, Kovanlikaya A. Schilder's Disease: Case Study With Serial Neuroimaging. J Child Neurol. 2003;18:58-61.
  • Patricia H, Ellison, Barren KD. Clinical recovery from Schilder disease. 1979;29(2):244.
  • Jarius S, Haas J, Paul F, Wildemann B.Myelinoclastic diffuse sclerosis (Schilder's disease) is immunologically distinct from multiple sclerosis: results from retrospective analysis of 92 lumbar punctures.J Neuroinflammation. 2019;16(51):1-14
  • Lin Wei-Sheng, Kuo Meng-Fai, Peng S Shinn-Forng, Fan Pi-Chuan. Long-term Outcome of Schilder Disease Treated With Interferon-β. Pediatrics. 2019;144 (5): e20190505
  • Algahtani H, Shirah B, Alassiri A.Tumefactive demyelinating lesions:a comprehensive review. Mult Scler Relat Disord.2017;14:72-79