Acta Neuropathol (1991) 81:467 - 470


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Case reports Brain lesions in chronic granulomatous disease* M. G. Hadfield 1, N. R. Ghatak 1, E J. Laine 2, E. C. Myel ~, E S. Massie 4, and W. M. Kramer 4 Departments of Pathologyl, Radiology 2 and Neurology 3, Medical College of Virginia/Virginia Commonwealth University, Box 17, MCV Station, Richmond, VA 23298, USA 4St. Mary's Hospital, Richmond,Virginia Received September 24, 1990/Revised, accepted October 22, 1990

Summary. In chronic granulomatous disease ( C G D ) enzyme-deficient neutrophils and mononuclear cells lack the respiratory brust required for biocidal activity. Recurrent infections lead to granulomas in various organs but brain lesions are rare. In the present case, a 23-year-old male with numerous infections since early childhood died of overwhelming pulmonary aspergillosis. H e first began to experience neurological deficits at the age of 17. Computerized tomography and magnetic resonance imaging revealed fleeting white matter lesions that were interpreted as multiple sclerosis (MS). A t post mort em, three types of brain lesions were found: (1) Pigmented macrophages in perivascular spaces and the leptomeninges similar to those reported previously. T h e y contained fine, golden-brown, lipofuscin-like material whose chemical composition included a sulfur peak by X-ray analysis. (2) Focal, well-demarcated, "burnt out" white m a t t e r lesions with loss of both myelin and axons and intense sclerosis. (3) Diffuse areas of mild pallor in the centrum ovale which spared the U fibers. The pigmented macrophages are characteristic of those seen in the periphery in CGD. The origin of the discrete, destructive white matter lesions is unclear. T h e y may have resulted from: (i) earlier activity by C G D macrophages; (ii) previous infections due to sepsis or embolism; or (iii) possibly post-infectious encephalomyelitis. The more diffuse, mild, white matter lesions are attributed to edema. Evidence for MS, progressive multifocal leukoencephalopathy, or human immunodeficiency virus encephalitis was lacking. This case is presented to alert us to look more carefully for brain lesions in CGD, characterize them and to help determine their cause.

Key words: Chronic granulomatous disease - White matter lesions - Pigmented macrophages - Lipofuscin Sulfur * This case was presented at the American Association of Neuropathologists' Annual Meeting, San Francisco, CA, June 13-17, 1990 (abstract no. 199) Offprint requests to: M. G. Hadfield (address see above)

Chronic granulomatous disease ( C G D ) is a rare disorder. It is seen in patients who have congenital enzyme deficiencies of phagocytes [14]. This leads to repeated infections and, usually, an early death. The abnormal granulocytes and monocytes are capable of ingesting viable organisms but they lack the "respiratory burst" required to kill them [16]. Such defective cells are in turn removed by the reticuloendothelial system. Over a period of time, they accumulate as granulomas in various organs of the body [13]. Although meningitis-like signs may be present in over 15 % of cases [11, 19], granulomas of the brain or other brain lesions are rarely reported in C G D [3, 22]. Recently, however, Riggs et al. [15] highlighted the presence of meningeal and perivascular collections of pigmented macrophages in CGD. In the present case,we report similar golden-hued macrophages in the brain and two types of demyelinating lesions.

Case report The patient was a product of an uncomplicated term pregnancy. At 3 months of age he began to have recurrent otitis media and repeated respiratory tract infections. A mastoidectomy was required at 1 year of age. Over the next several years, he continued to suffer from repeated bouts of infection, including multiple episodes of E. coli and aspergillus pneumonia, chronic lung disease, osteomyelitis, granulomatous lesions of the skin, mucous membranes and intestines, adenitis and fevers without an obvious source of infection. Multiple nitro-blue tetrazolium reduction tests with neutrophils were invariably negative, thus confirming a diagnosis of CGD. At the age of 17 years, he developed his first neurological symptoms, complaining of double vision, clumsiness and ataxia. His examination was consistent with a right medial longitudinal fasciculus lesion. Head computerized tomography (CT) scan showed an enhancing lesion in the periventricular region of the left parietal lobe. Brain stem evoked potential (BSEP) was abnormal on the right. Subsequently, up to 19 years of age, he had several episodes of neurological symptoms and deficits with multiple hospitalizations, including: headaches and numbness of the left hand and side of the face, numbness of the right side of the body, pain in the lower back, numbness of the lower extremities and weakness of the left lower extremity, numbness and paresthe-



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b Fig. la,b. Discrete "burnt out" demyelinating lesions in the: a cerebellum and b centrum ovale. Note the loss of gray matter in the dentate nucleus (a). In b, most of the dark spherical objects seen in perivascular spaces represent pigmented macrophages. Luxol fast blue/PAS; a • 40; b • 132,50 Fig. 2. Pigmented macrophages: a surrounding a vessel in the basal ganglia and h in the leptomeninges. The pigment is fine, granular and golden-brown in color, a x 185,50; b x 132,50

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Fig. 3. a A perivascular macrophage showing light and dark lipofuscin-like granular material within lysosomes. This material corresponds to the pigment inclusions seen by light microscopy; X 10,780. b Energy-dispersive X-ray analysis (EDAX) of the lipofuscin demonstrating sulfur content. The other elements are extraneous ones present in the metal stains, the embedding media, the copper grids and the electron microscope column, including pole pieces, etc

469 sias of the left side of the body, neck stiffness and pain with radiation to the shoulder and back. During the subsequent 4 years, he had no neurological complaints; but at age 23, he developed neck pain and numbness and tingling of the right side of his body and his left upper extremity. Magnetic resonance imaging (MRI) of the head showed multiple lesions involving the white matter of both cerebral hemispheres and along white matter tracts in the brain stem and peduncles. Five months later, he was admitted terminally with a severe, bilateral aspergillus pneumonia and expired 11 days later.

Autopsy findings General A tracheostomy, a recent incision of the right chest and drain tubes were seen externally. Both pleural cavities were totally obliterated by dense fibrous adhesions. There was extensive consolidation of both lungs, which were studded with numerous microabscesses. Histologically, the abscesses contained neutrophils in their centers, often with included aspergillus hyphae. The surrounding granulomatous reaction also contained occasional aspergillus organisms. Between the microabscesses, the lungs showed extensive consolidation, with fibrin exudation, and in many instances, organizing pneumonia with fibrosis of the alveoli. The liver and spleen were enlarged and the kidneys were swollen and pale, though without frank tubular necrosis. In the liver, spleen, bone marrow and one lymph node, there were clusters of histiocytes which contained abundant, golden-brown lipofuscin-like pigment which exhibited autofluorescence.

Gross brain At initial brain cutting, no frank lesions were noted. Specifically, there were no multiple sclerosis (MS) plaques in the centrum ovale or brain stem, nor were there other white matter lesions, except for questionable areas of discoloration. The brain was subsequently recut, using the CT and MRI scans as a guide. When the sites of greatest intensity changes were sectioned, a few small loci of unequivocal dark discoloration were noted in the white matter - in the subcortical regions of the right parieto-occipital lobe, in juxtaposition to the basal ganglia and near the occipital poles of the lateral ventricles. They measured but a few millimeters in diameter. The spinal cord was not available for examination.

Light microscopy of brain The areas of dark discoloration corresponded to small patches of demyelinated, gliotic parenchyma that were essentially devoid of inflammatory cells (Fig. la,b). These lesions involved predominantly white matter but also spilled over into the adjacent cortex and deeper nuclear centers. Where white matter was involved, there was marked demyelination (luxol fast blue stain) but the axons (Bielschowski silver stain) were also missing. Where gray matter was involved, the neurons were missing, in some instances (H&E stain), but in other areas they were preserved. Sclerosis was marked in these lesions (Holzer stain). A more subtle change was mild rarefaction of myelin in the cores of several gyri, with sparing of the U fibers. In perivascular spaces, particularly in the basal ganglia (Fig. 2a), and also in the leptomeninges (Fig. 2b), collections of foamy, refractile macrophages (H&E stain) were encountered. They contained a distinctive, fine, golden-brown pigment that resembled lipofuscin and exhibited autofluorescence. They were not associated with other inflammatory cells except for rare monocytes. They stained negatively for iron and were not PAS positive.

No organisms could be seen with the aid of other special stains for bacteria, tubercle bacilli, fungi and parasites.

Electron microscopy of brain The pigmented mononuclear cells seen with the light microscope contained nuclei with smooth, unindented nuclear membranes and densely clumped chromatin, In the cytosol, there were numerous, spheroidal, membrane-bound vesicles or lysosomes of various sizes. They contained electron-dense granular material that was consistent with lipofuscin (Fig. 3a). This material consisted of both pale and dark areas. Using energy-dispersive X-ray analysis (EDAX), sulfur was identified as a constituent (Fig. 3b). Other organelles were poorly preserved. No microorganisms, myelin or lipid debris were encountered in these cells. Astrocytic processes were prominent and contained numerous, thin 800-nm filaments. The white matter lesions could not be satisfactorily evaluated because the myelin lamellae were poorly preserved at the ultrastructural level in this formalin-fixed, deparaffinized autopsy tissue.

Electron microscopy of spleen Pigmented macrophages in the spleen contained lipofuscin-like material [2] identical to that described above in the brain. Again, sulfur was demonstrated in this material by EDAX.

Discussion P i g m e n t e d m a c r o p h a g e s e m e r g e as the h a l l m a r k feature o f this case. T h e y are identical to those classically r e p o r t e d in C G D in b o t h peripheral organs [2, 9, 10, 18] and, m o r e recently the brain [15]. I n the CNS, t h e y are largely restricted to perivascular spaces and the leptomeninges. H o w e v e r , we saw occasional ones in the " b u r n t o u t " d e m y e l i n a t i n g lesions described above. T h e p i g m e n t inclusions, in b o t h central and peripheral m a c r o p h a g e s , b e a r the light and electron microscopic features o f lipofuscin. This view is s u p p o r t e d by the d e m o n s t r a t i o n of a u t o f l u o r e s c e n c e . A p p a r e n t l y , the diminished oxidative capacity of these defective cells must in s o m e w a y a c c o u n t for an a b n o r m a l l y rapid a c c u m u l a t i o n of lipofuscin. T h e sulfur d e t e c t e d in this material b y X-ray analysis m a y represent an accumulation o f sulfated a m i n o acids in lysosomes deficient in sulfatase. H o w e v e r , U l s h a f e r et al. [20] r e p o r t small a m o u n t s of sulfur in lipofuscin of n o r m a l retinal p i g m e n t epithelia by E D A X . It is possible t h a t the p i g m e n t e d m a c r o p h a g e s seen in C G D m a y be derived f r o m circulating m o n o c y t e s . H o w e v e r , Riggs et al [15] postulate that in C G D , the reticulo-endothelial system of the brain and its investments m a y well r e s p o n d like t h o s e of the liver, spleen and l y m p h n o d e s , etc. T h e origin o f the discrete, focal, " b u r n t o u t " white m a t t e r lesions is difficult to d e t e r m i n e . It is possible that (1) t h e y m a y represent p r i m a r y C G D lesions that were f o r m e r l y m o r e active; (2) s o m e of t h e m m a y represent earlier sites of infection resulting f r o m septicemia or fungemia. I f t h e y are the result of infected emboli, the lesions m a y in part be due to s u p e r i m p o s e d ischemic d a m a g e ; or (3) t h e y m a y represent post-infectious

470 encephalomyelitis (PIE). However, the demyelinating lesions involved m o r e than just perivenous loci and often spilled over into gray matter. T h e r e was also a significant loss of axons in the lesions and the m a c r o p h a g e s did not contain lipid debris. Based on the axonal loss and the absence of gross plaques, MS was ruled out. T h e r e were no stigmata of progressive multifocal leukoencephalitis. Focal white m a t t e r lesions m a y also occur in h u m a n immunodeficiency virus encephalitis [17] but no multinucleated giant cells or other signs of active inflammation were present and the clinical presentation was not compatible with AIDS. We attribute the m o r e diffuse and subtle rarefactive white m a t t e r lesions (with sparing of the U fibers) to the pressure effects of edema. T h e e d e m a m a y have resulted f r o m a previous episode of infection and/or inflammation. In cases of C G D , infectious complications, including meningitis and meningoencephalitis have occurred, either in the setting of generalized sepsis or as isolated events and brain abscess has b e e n described [5]. In young subjects without a predisposing cause, a candida meningitis [7] or tardive streptococcal meningitis [8] m a y lead one to suspect C G D as the underlying state. Varicella-Zoster infection has also occurred in C G D [12]. Rarely, the g r a n u l o m a t a have b e e n k n o w n to involve the v e r t e b r a e and spinal canal and to compress the spinal cord [6, 21]. In conclusion, we have r e p o r t e d this case because C G D is an u n c o m m o n disorder in which brain lesions are rarely reported. Moreover, the survival of the present patient was unusually long [1, 4] and the neurological history and the presence of white m a t t e r lesions on CT and M R I warranted a careful clinico-pathological correlation. We have confirmed the presence of p i g m e n t e d m a c r o p h a g e s [15]. T h e addition of demyelinating lesions in the present case, w h e t h e r they be p r i m a r y or secondary, should further alert us to examine the brain m o r e carefully in cases of C G D .

References 1. Balfour HH, Shehan JJ, Speicher CE, Kauder E (1971) Chronic granulomatous disease of childhood in a 23-year-old man. JAMA 217:960-961 2. Bartman J, Van de Velde RL, Friedman F (1967) Pigmented lipid histiocytosis and susceptibility to infection: ultrastructure of splenic histiocytes. Pediatrics 1967: 40:1000-1002 3. Bridges RA, Berendes H, Good RA (1959) A fatal granulomatous disease of childhood. The clinical, pathological and laboratory features of a new syndrome. J Dis Child 97: 387-408 4. Dilworth JA, Mardel GL (1967) Adults with chronic granulomatous disease of "childhood" Clin Res 24: 452A

5. Donowitz GR, Mandell GL (1983) Clinical presentation and unusual infections in chronic granulomatous disease. In: Gallen JI, Fauci AS (eds) Advances in Host Defense Mechanisms, vol 3. Raven Press, New York, pp 656. Evans HE, Edgcomb JH (1962) Unexplained granulomatosis in childhood: a clinicopathological dilemma. Arch Pathol 74: 360-366 7. Fleischmann J, Church JA, Lehrer RI (1986) Primary candida meningitis and chronic granulomatous disease. Am J Med Sci 29:334-341 8. Garel D, Devictor D, Tchernia G, Pham T, Dommergues JP (1989) Streptococcus group B tardive meningitis revealing chronic septic granulomatosis. Ann Pediatr 36:35-37 9. Harada T, Sugihara H, Tsuchiyama H, Noda H (1977) Histochemical and ultrastructural observation of the pigment in pigmented lipid histiocytes of chronic granulomatous disease. Acta Histochem Cytochem 10:500-507 10. Hotchi M, Fujiwara M, NasuT (1980) Chronic granulomatous disease associated with peculiar aspergillus lesions, pathoanatomical report based on two autopsy cases and a brief review of all autopsy cases reported in Japan. Virchows Arch [A] 387: 1-15 11. Johnston RB, Newman SL (1977) Chronic granulomatous disease. Pediatr Clin North Am 24:365-376 12. Kobayashi S, Ichinohe S, Okabe N, Tatsuzawa O (1988) Varicella-zoster virus infection in chronic granulomatous disease. Pediatr Infect Dis J 7:809-810 13. Landing BH, Shirkey HS (1957) A syndrome of recurrent infection and infiltration of viscera by pigmented lipid histiocytes. Pediatrics 20:431-438 14. Quie PG, White JG, Holmes B, Good RA (1967) In vitro bactericidal capacity of human polymorphonuclear leukocytes: diminished activity in chronic granulomatous disease of childhood. J Clin Invest 46:668-679 15. Riggs JE, Quaglieri FC, Schochet SS Jr, Dove DJ (1989) Pigmented, lipid-laden histiocytes in the central nervous system in chronic granulomatous disease of childhood. J Child Neurol 4:61-63 16. Segal AW (1985) Variations on the theme of chronic granulomatous disease. Lancet I: 1378-1383 17. SmithTW, DeGirolami U, Henin D, Bolgert F, Hauw J-J (1990) Human immunodeficiency virus (HIV) leukoencephalopathy and the Microcirculation. J Neuropathol Exp Neurol 649: 357-370 18. Tanaka T, Takahashi K, Morita H, (19 ) Chronic granulomatous disease of childhood and sea-blue histiocytosis, a pathologic study of an autopsy case. Acta Pathol Jpn 34: 1385-1401 19. Tauber AI, Borregaard N, Simons E,Wright J (1983) Chronic granulomatous disease: a syndrome of phagocyte oxidase deficiencies. Medicine 61:286-309 20. Ulshafer RJ, Allen CB, Rubin ML (1990) Distributions of elements in the human retinal pigment epithelium. Arch Ophthalmol 108:113-117 21. Vichi GF, Jenuso R, de Martino M,Vierucci A (1986) Unusual evolution of chronic granulomatous disease with mediastinum localization and diffusion into vertebrae, ribs and vertebral canal. ROFO 145:109-111 22. Walker DH, Okiye G (1957) Chronic granulomatous disease involving the central nervous system. Pediatr Pathol 1: 159-167

Brain lesions in chronic granulomatous disease.

In chronic granulomatous disease (CGD) enzyme-deficient neutrophils and mononuclear cells lack the respiratory burst required for biocidal activity. R...
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