Cerebral mucormycosis: proton MR spectroscopy and MR imaging

Magnetic Resonance Imaging 18 (2000) 915–920

Case report

Cerebral mucormycosis: proton MR spectroscopy and MR imaging Justin A. Siegala, Edwin D. Cacayorinb,*, A. Sami Nassifb, Donna Rizkc, Csaba Galambosd, Beth Levyd, Donald Kennedyc, J. Viscontic, William Permanb a

Saint Louis University School of Medicine, St Louis University Hospital, St. Louis, MO 63110-0250, USA b Department of Radiology, St Louis University Hospital, St. Louis, MO 63110-0250, USA c Department of Internal Medicine, St Louis University Hospital, St. Louis, MO 63110-0250, USA d Department of Pathology, St Louis University Hospital, St. Louis, MO 63110-0250, USA Received 11 May 2000; accepted 8 July 2000

Abstract Proton magnetic resonance spectroscopy (MRS) was integrated with magnetic resonance imaging (MRI) in the evaluation of a case of cerebral mucormycosis. MRS showed markedly elevated lactate, depleted N-acetyl aspartate and metabolite resonances attributable to succinate and acetate. The spectroscopy profile is essentially similar to that of bacterial abscess but without the commonly seen resonances of the amino acids valine, leucine and isoleucine. Our extensive literature review did not yield any reports of MRS findings on cerebral mucormycosis. MRS prospectively limited the differential diagnoses given the otherwise nonspecific and complex MR imaging findings in our immunosuppressed patient. © 2000 Elsevier Science Inc. All rights reserved. Keywords: Magnetic resonance spectroscopy (MRS); Fungus; Mucormycosis; Immunosuppression

1. Introduction Central nervous system (CNS) lesions in immunosuppressed patients often exhibit complex clinical and radiologic findings and frequently need prompt recognition and treatment to avoid irreversible and fatal neurologic injuries [1–7]. Magnetic resonance spectroscopy (MRS) provides graphic depiction of metabolic information and reflects the degree of secondary neuronal loss/dysfunction [8 –13]. Magnetic resonance imaging (MRI) is a sensitive and noninvasive diagnostic modality for brain parenchymal abnormalities, but the changes depicted are often nonspecific. The integration of MRS provides biochemical information that may appropriately limit the differential diagnosis [14 –17]. MRS is gaining wide acceptance as a noninvasive adjunct to MRI in the detection, evaluation and prognostication of disease processes affecting the central nervous system. Investigators have described spectral patterns of brain abscesses [18 –23], but we failed to uncover any reports of MRS on cerebral mucormycosis. In this case report, we describe the MRS and imaging findings in a patient with

* Corresponding author. Tel.: ⫹1-314-268-5783; fax: ⫹10314-2685116.

autopsy proven CNS mucormycosis involving the basal ganglia, thalamus, corpus callosum and midbrain.

2. Case report A 32-year-old man with a past medical history of chronic myelogenous leukemia and bone marrow transplant presented with increasing left hemiparesis. Two weeks prior, he presented with bilateral lower extremity numbness and urine and stool retention and was hospitalized with a diagnosis of transverse myelitis involving the upper cervical and thoracic spinal cord. He responded favorably to steroid therapy. The etiology of the myelitis remained indeterminate; the patient did not have a recent history of a viral exanthema or immunization. The MRI of the brain on the first admission was normal. After his initial discharge, the patient was able to walk but experienced urinary difficulties. Three days prior to the current admission, the patient began to drag his left leg, experienced right face and eye pain and had one episode of objective fever. By the day prior to admission, the patient developed bilateral lower extremity weakness and was unable to walk. The admission physical examination was remarkable for diminished strength in both lower extremities (3– 4/5), hyperactive lower extremity re-

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flexes, and loss of position sense in the lower extremities and in the left upper extremity. No visual deficits were noted and the patient was afebrile. Laboratory evaluation revealed thrombocytopenia (71,000 platelets/microliter) anemia (hemoglobin 8.4 g/dL, hematocrit 23.8%), and an elevated leukocyte count of 13,200 cells/microliter (neutrophils 96%; lymphocytes 2.1%; myelocytes 1.3%; and eosinophils 0.2%). CSF studies showed an elevated protein (89 mg/dL), although the glucose concentration and leukocyte count were within normal limits. CSF protein electrophoresis did not reveal oligoclonal banding. MR imaging of the brain on admission showed parenchymal abnormalities of the right basal ganglia, right thalamus and subjacent midbrain. The confluent lesions were essentially hypointense in signal intensity on all imaging sequences acquired [T1-weighted, T2-weighted, diffusionweighted, and fluid attenuated inversion recovery (FLAIR) images] and exhibited peripheral enhancement on the post gadolinium enhanced images. There was moderate surrounding vasogenic edema of the adjacent portions of the centrum semiovale and splenium of the corpus callosum. There was secondary effacement of the adjacent portions of the right lateral ventricle and a slight left sided transfalcine shift of the septum pellucidum (Fig. 1). The changes were considered nonspecific for a particular disease process. The pattern suggested existence of a necrotizing and/or hemorrhagic process, and since the changes were not evident on the MRI obtained 2 weeks prior, the differential diagnostic considerations primarily included abscess (bacterial or fungal) or septic infarct, lymphoma, toxoplasmosis and an acute (inflammatory) demyelinating process. The patient was treated with antifungal, antiviral and antibacterial agents. His neurologic deficits remained unchanged. Two days after admission, proton MRS was obtained in conjunction with another MRI scan. There had been progressive enlargement of the lesions and development of more extensive surrounding vasogenic anemia and also hydrocephalus. The MRS acquired with 1.2 ⫻ 1.5 ⫻ 1.5 cm voxel size placed and centered over a “cystic/necrotic/hemorrhagic” lesion of the right basal ganglia, and using a spin echo time of 135 msec, showed a distinct spectrum of markedly elevated lactate (inverted lactate doublet), imperceptible N-acetyl aspartate (NAA), and identifiable resonances that could be attributed to succinate, and acetate. The choline peak was slightly elevated and creatine and myo-inositol levels were reduced. Amino acid resonances particularly corresponding to valine, leucine/isoleucine were not observed although an alanine peak and an unassignable resonance at 3.8 ppm could be delineated (Fig. 2). The spectroscopy pattern favored the diagnosis of abscess with lymphoma remaining as the alternative choice because of the elevation of choline. The patient had a ventriculostomy placed and underwent stereotactic biopsy of the right basal ganglia. The biopsy

revealed hemorrhagic necrosis, mixed acute and granulomatous inflammation, and numerous fungal hyphae morphologically consistent with mucormycosis. There were numerous fungal emboli associated with angioinvasive growth and vascular necrosis. Intravenous Amphotericin B was continued. A chest radiograph showed multiple bilateral lesions, some with central cavitations. The patient was initially stable postoperatively. However, the following afternoon, he developed severe respiratory failure, and a significant elevation in intracranial pressure leading to rapid neurologic deterioration. The patient expired on postoperative day two. Postmortem evaluation revealed disseminated mucormycosis. There was extensive primary pulmonary involvement, with dissemination to the liver, spleen, thyroid and brain. In the brain, there was extensive hemorrhage of the right basal ganglia, thalamus, and adjacent centrum semiovale with minimal peripheral involvement of the midbrain and corpus callosum (Fig. 3). Microscopic evaluation showed changes identical to those of the prior brain biopsy, namely, hemorrhagic tissue necrosis and angioinvasive fungal hyphae morphologically consistent with Rhizopus. The spinal cord showed multiple microscopic foci of subacute demyelination involving the dorsolateral white matter; no fungal myelitis was present.

3. Discussion The clinical differential diagnosis for rapidly progressing CNS lesions in this immunosuppressed patient with a history of steroid therapy for transverse myelitis included opportunistic bacterial and/or fungal infections, encephalitidis, and malignant neoplasms. MRI showed confluent peripherally enhancing hypointense lesions primarily localizing in the regions of the basal ganglia, thalamus and midbrain. The MRI findings are nonspecific for a particular disease process, but fungal abscesses, toxoplasmosis and lymphoma can all present with centrally necrotizing and peripherally enhancing lesions and a propensity to involve the lentiform nuclei [7,24 –31]. The lesions in our patient were essentially hypointense in signal intensity on the T1- and T2-weighted images, a feature that could relate to coagulative necrosis, and increased accumulation of hemorrhagic by products and paramagnetic materials such as iron, magnesium and manganese [6,7,24,25,32]. Infarction was considered contributory to the rapid evolution of the MRI findings. Integration of the MRS, MRI and clinical data prospectively limited our diagnostic considerations to angioinvasive bacterial or fungal cerebritis/abscess (infectious vascuolopathy) and lymphoma, partly endovascular. Proton MRS supplements the morphological findings of MRI of the brain with chemical information inherent to structural changes of normal and abnormal tissues and reflective of the preponderant molecular elements and end products of the various ongoing metabolic processes [8 –10,

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Fig. 1. (a) (T2-weighted 2300/104), (b) (FLAIR-10002/165), (c) (Post gadolinium enhanced T1-weighted) demonstrating peripherally enhancing hypointense confluent lesions of the right basal ganglia and thalamus with surrounding edema. The features exhibited would be consistent with necrotizing and or hemorrhagic lesions. (d) (Diffusion weighted image) shows limited hyperintense zones correlating to areas of infarction and necrosis.

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Fig. 2. MR Spectroscopy with voxel placed over the right basal ganglia lesions (⫹Fig. 1c) and acquired at TE 135 msec, showing markedly elevated lactate (Lac, inverted doublet), and identifiable resonances of succinate (S), acetate (Ac), and alanine (Al), lipid (L) and an unidentifiable (U) resonance at 3.8 ppm. N-acetyl aspartate (NAA) is depleted; myoinositol (ml) and creatine (Cr) are reduced in levels. The spectroscopy profile is similar to that of a pyogenic abscess but without the commonly observed resonances of the amino acids valine, leucine and isoleucine. Choline is elevated which appropriately correlated to histologically confirme acute and granulomatous inflammatory changes.

12–15,17,33,34]. Currently, MRS identifies basic resonances that are primarily attributable to N-acetyl aspartate (NAA), choline (Cho), creatine (Cr), myo-inositol (ml), and lactate. N-acetyl aspartate is considered a neuronal and axonal marker and a decrease in level is reflective of neuronal loss/dysfunction [8,9,12,34]. Choline is a constituent metabolite of cell membrane and myelin; elevation of the Cho peak is observed in disease processes attended by rapid cell membrane destruction/synthesis and catabolism of myelin [10,34 –36]. The higher levels of choline are more frequently encountered with hypercellular high grade/anaplastic neoplasms [11,12,33,34] and with active or inflammatory demyelinating disease [37– 41]. Myo-inositol, a precursor for the second messenger systems and a brain osmolyte [42,43], and creatine, a cellular energetic metabolite [34,44], constitute the other metabolites identified with MRS. Overall, depletion of these fundamental metabolites implicates the existence of a destructive process of the CNS [12,19,22,34]. Lactate is an end product of anaerobic glycolysis and is considered a marker of hypoxia [10,34,42,45]. Its elevation is nonspecific, but the large lactate peaks have been commonly identified in necrotizing high-grade neoplasms including lymphomas, and in pyogenic abscesses including toxoplasmosis [12,13,15,18 –21,29]. Lower increases in lactate levels have also been observed in infarcts, demyelinat-

Fig. 3. Gross photograph of the hemorrhagic lesions (A) and corresponding photomicrograph (B) demonstrating necrosis and an acute inflammatory infiltrate containing several large non-septate hyphae. Note fungal embolus and destruction of the blood vessel wall (arrow) (40⫻ magnification).

ing disease, encephalitis and in cystic gliomas [12,14,17, 39 – 41,46,47]. Lipid resonance, which can be elevated with malignant neoplasm and in cryptococcosis, may overlap lactate in MRS acquired at certain spin echo times; the use of a spin echo time of 135 msec permits the delineation of reversed J coupled peak that is specific for lactate [19,22, 29,34], and as depicted in this case report. In our patient, the MRS with the single voxel centered over the necrotic/hemorrhagic lesion(s) of the basal ganglia, distinctly showed markedly elevated lactate peak and resonances assignable to the succinate (2.4 ppm), acetate (1.9 ppm) and alanine (1.5 ppm), along with depletion of NAA and decreased levels of creatine and myo-inositol. Overall, the spectroscopy profile closely resembles that expected of a bacterial abscess but without amino acid resonances that are particularly attributable to valine and isoleucine (0.9 ppm) and leucine (3.6 ppm). Investigators have consistently observed in pyogenic abscesses the combined spectra of markedly elevated lactate, and resonances of succinate, acetate and amino acids [19,22,23,48,49]. Succinate and acetate are considered to be the end products of homolactic and heterolactic fermentation and are considered key markers of bacterial infection [19,48,49]. The amino acids valine, leucine and isoleucine are believed to result from enzymatic

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proteolysis in pus [50,51]. Necrotic neoplasms have not been observed to show elevated levels of succinate and amino acids on MRS [19,22]. As would be additionally applicable to the other differential diagnosis in our immunocompromised patient, NAA depletion and lactate elevation would similarly be pronounced with toxoplasmosis; less pronounced with lymphoma and multiple sclerosis, lesions that also manifest concomitant elevation of choline [16,17,38,39]. Choline was elevated in our case. This appropriately correlated to the histologically evident acute and granulomatous inflammatory changes but may also relate to partial volume averaging (voxel placement related) of the non-uniform consistency of the infectious vascuolopathy as has been observed by other investigators as well [16,17,23, 32]. An exhaustive review of the literature failed to reveal a previous report on the application of MRS to non-cryptococcal fungal infection. We have described the pathoradiologic and MRS findings on an autopsy confirmed case of cerebral mucormycosis. Elevated levels of acetate and succinate in conjunction with resonances attributable to amino acids have been consistently observed with bacterial abscesses. Perhaps, as observed in this case report, CNS mucormycosis during its evolution, presents a similar spectroscopy profile but without distinct resonances attributable to the amino acids valine, leucine and isoleucine. Further studies are needed to confirm the validity of this hypothesis. Mucormycosis and Aspergillosis are aggressive opportunistic infections, which must be rapidly diagnosed to have hope of successful treatment. Cerebral aspergillosis and mucormycosis have a propensity for endovascular invasion; hemorrhagic infarction frequently predating the development of fungal cerebritis and abscess as temporally depicted in this case. Integration of MRS with MRI may non-invasively expedite and enhance the diagnosis of cerebral fungal infections.

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