Isolated Cerebral Nocardiosis Otitidiscaviarum in a Child with relapsed B-Lymphoblastic Leukemia: Diagnostic and Therapeutic Challenges Including Relevant Review of Literature

Sir,

Nocardia is responsible for 1.5% of cerebral abscess (CA) worldwide.[1] This ubiquitous bacteria have high mortality (33%) with variable presentations i.e., acute–chronic and isolated to disseminated.[2] Cerebral nocardiosis (CN) lacks classical signs on neuro-imaging and clinical and laboratory examination and is often diagnosed after surgical excision, which lends to a diagnostic delay and increased mortality. We describe a case of CN in a child with B-acute lymphoblastic leukemia (B-ALL), who had isolated cerebral localization, negative initial microbiological examination, and poor response to cotrimoxazole (CTX), which posed a diagnostic dilemma.

A 10-year-old male with precursor B-ALL presented with seizures during maintenance chemotherapy instituted as part of the Indian Collaborative Childhood Leukemia group (ICiCle) protocol.[3] No antecedent fever or focal neurological deficits were noted. Neuroimaging revealed a well-demarcated, multi-loculated lesion measuring 7.5 × 5.2 × 5.4 cm in the left temporoparietal lobe with peri-lesional edema Figure 1a. Decompressive craniotomy with excision was done on suspicion of leukemic infiltration. The tissue sent for histopathology evaluation (HPE) showed an abscess composed of fibro-collagenous tissue with scanty chronic inflammation and few hemosiderin-laden macrophages. Pus subjected for fungal and bacterial culture was sterile. After the completion of chemotherapy, he presented with bone marrow and testicular relapse. Subsequently, he developed facial nerve palsy, and neuroimaging showed residual lesion now in the left parieto-occipital region Figure 1b. Intravenous vancomycin and meropenem were administered for 4 weeks. Meanwhile, in view of raised intracranial pressure, pus drainage was done and sent for culture. The latter was sterile, and the real-time polymerase chain reaction (PCR) performed for Mycobacterium species was negative. The bits of the cyst wall sent for HPE revealed large central areas of liquefactive necrosis mixed with neutrophils and debris. The surrounding white matter exhibited reactive gliosis. No granulomas were seen, and histochemical stains done for fungus and acid-fast bacilli were negative. Modified (1%) Ziehl–Neelsen (ZN) stain showed numerous thin (<1 mm width) filamentous, beaded bacilli exhibiting branching patterns. Gram and Grocott's methenamine silver (GMS) stains were also consistent with Nocardia [Figure 2]. The bacilli were clinging to the cyst wall and were absent in the central necrotic areas, explaining the negativity of the culture and PCR. Following intravenous CTX × 2 weeks (@ 15 mg/kg/day in three divided doses), the oral CTX was supplemented with minocycline (50 mg twice a day). Repeat imaging showed an increase in the number of lesions involving the tempo-occipital region [Figure 1c]. Pus showed similar bacilli which were weakly Gram-positive and acid-fast on Kinyon's modified ZN stain. Samples inoculated onto sheep blood agar (5%–10%) showed whitish-dry cerebriform colonies after 3 days of incubation [Figure 2]. Furthermore, the isolate was identified as Nocardia otitidiscaviarum by matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) (Microflex LT Biotyper, Bruker Daltonics, Germany). Basic Local Alignment Search Tool (BLAST) analysis (https://blast.ncbi.nlm.nih.gov) of the sequence showed 99.83% identity with the sequence of Nocardia otitidiscaviarum strain (ATCC 14629I; Sequence ID AY756528). This patient developed bone marrow recurrence of ALL and was discharged on palliative therapy.

Figure 1.

(a) Axial view of Contrast-enhanced magnetic resonance imaging (CEMRI) Brain showing a relatively well-defined, mildly lobulated, multiseptated, smooth peripherally ring enhancing cystic lesion of size 7.5 × 5.2 × 5.4 cm in the left temporoparietal region with perilesional edema with midline shift. (b) Axial view of non-contrast computed tomography (NCCT) head showing a well-defined cystic lesion of size 7 × 6 × 4.5 cm in the left parieto-occipital region with extensive perilesional edema with mass effect. (c) Axial view of contrast-enhanced computed tomography (CECT) head showing recurrence of a ring-enhancing cystic lesion of size 8 × 6 × 5 cm in the left parieto-occipital region with two adjacent small daughter cystic lesions

Figure 2.

(a) Sections from the second sample submitted for histopathology, which showed fibrotic cyst wall with adherent central areas of liquefactive necrosis mixed with neutrophils and debris. (hematoxylin and eosin, 40 ×) Inset showing sheets of foamy macrophages and giant cells (hematoxylin and eosin, 400 ×). Numerous thin filamentous bacilli displaying a delicate branching highlighted on (b) Grocottmethenamine silver (GMS) stain (c) Grams stain (d) 1% Ziehl– Neelsen (ZN) stain [400 ×]. Sections from the third sample, after initiating antimicrobial therapy, showing (e) thick fibrotic wall with reactive gliosis (hematoxylin and eosin, 40 ×) (f).Immunohistochemistry for CD68 highlights the dense histiocytic population, whereas (g) glial fibrillary acidic protein (GFAP) highlights the gliotic wall. (DAB, 200 ×) (h) Kinyon's modified Ziehl–Neelsen stain showing thin filamentous weak acid-fast bacilli

Nocardia is a rare, life-threatening cause of cerebral abscess, which is acquired through inhalation or direct inoculation. Hence, pulmonary and cutaneous involvement are the commonest manifestations. This bacterium is highly neurotropic and up to 40% of cases with hematogenous dissemination have central nervous system (CNS) involvement.[4] Conversely, the isolated involvement of the CNS is uncommon, seen in 5% of cases.[5]

Anagnostou T et al.[6] analyzed 84 CN cases and documented neurologic abnormalities as the commonest (51% cases) presentation followed by headache, fever, distorted mental status, seizures (in 28%), vision abnormalities, ataxia, and personality changes. The index patient presented with non-localizing signs at first and developed focal deficit with disease progression. There was no history of fever or headache in our patient. As the patient was on follow-up for ALL, the appearance of intracranial mass lesions was thought to be leukemic infiltration. The diagnosis of CN was suggested on histological examination on the second biopsy as the initial biopsy yielded only a fibrous wall.Out of 17 cases of cerebral abscesses, this was the second case of Nocardial etiology.

Nocardia commonly infects those with hematological malignancies than solid malignancies. CN has been described in cases of myeloma, leukemias (lymphoblastic, myeloid, hairy cell, chronic lymphocytic leukemia), lymphomas such as diffuse large B-cell lymphoma (DLBCL), and Hodgkin lymphoma Table 1.[7,8,9] Majeed A. described CN in 3 of 10 patients with hematological neoplasms having a protracted clinical course similar to the index case. Older age and a longer duration of illness between leukemia diagnosis and infection were observed in the cases with fatal outcomes.[10]

Table 1.

Patterns of cerebral Nocardial infections in various hematological malignancies

Study	Hematological mamlignancy	Localization Of Nocardia	Species of Nocardia	Treatment regimen	Outcome
C. Cattaneo[11] (n=10, 3 with cerebral involvement)	Hairy cell leukemia (n=1), ITP + CLL (n=1), HES (n=1)	Lung involvement in all; additional bone involvement in one and disseminated nocardiosis in other two.	Nocardia asteroides (species identification was done only in one patient)		One died, two alive
Jacopo Monticelli[13] (n=1)	IgA Multiple myeloma	Multiple cerebral abscess	N. paucivorans		Alive
Lowell. S. Young et al.[14] (n=10, 3 with cerebral involvement)	Hodgkin’s disease (4) NHL (3), AML (1), CML (1), reticulum cell sarcoma (1)	Pulmonary involvement in all; cerebral abscess in three	N. asteroides by Benkes criteria	sulfonamide therapy	One alive, two died
Peter Berkey et al. (n=5; one with cerebral involvement)[7]	Hodgkin’s disease (3), malignant lymphoma (1), and ALL (1).	Isolated meningitis in case of ALL (n=1); rest lung involvement	N. asteroids		Alive
A Majeed et al.[10] (n=1)	AML, post-allogenic-HCT	Pulmonary; orbital and cerebral abscess	Nocardia mexicana		Alive
Yutaro Hino et al.[15] (n=1)	AML with myelodysplasia-related changes; post BMT HLA-matched unrelated donor	Disseminated; pulmonary, liver, cerebral, and subcutaneous abscess	Nocardia abscessus	oral TMP/SMX	Alive (30 months)
Marina A Eisenberg[16] (n=1)	AML, post BMT	Disseminated, involvement of skin, eyes (subretinal abscess), lungs, and brain.	N. asteroides	Intravitreal amikacin and vancomycin + systemic vancomycin, TMP/SMX, and meropenem	Died
Katsushi Tajima[17] (n=1)	DLBCL	Pulmonary and cerebral (meningitis)	N. otitidiscaviarum	TMP/SMX
Present case (n=1)	precursor B-ALL	Isolated cerebral	Nocardia otitidiscaviarum	co-trimoxazole + oral minocycline	Alive (.)

Idiopathic thrombocytopenic purpura (ITP), chronic lymphocytic leukemia (CLL), hypereosinophilic syndrome (HES), human leukocyte antigen (HLA), ALL, Acute myeloid leukemia (AML), Bone marrow transplant (BMT), Hemopoietic stem cell transplant (HCT), Diffuse large B-cell lymphoma (DLBCL)

Species-wise, N.asteroides was the most common species before the molecular era. With the advent ofgene sequencing, several less common species such as N. farcinica, N. cyriacigeorgica in <5% cases, and N. transvalensis, N. brasilensis, and N. otitidiscaviarum have been reported in CA in <2% cases.[11] Species identification is indispensable in modern medicine, which focuses on personalized therapy. For e.g., the index case responded poorly to CTX and minocycline and was found to be resistant to sensitivity testing. However, it was sensitive to gentamycin, amikacin, and imipenem. This led to a delay of 3 months in starting the appropriate therapy from the time of firstseizure. Other reasons for the chronic intractable course [Figure 3] and suboptimal response could be due to the thickened fibrotic wall, which could have impeded the delivery of the antibiotics.

Figure 3.

Flowchart showing sequence of events in the index case

A high index of suspicion for Nocardial etiology should be reserved for cases harboring prolonged lymphocyte dysfunction even if there is no pulmonary lesion. As Nocardia is difficult to detect on smears, and culture combination of histopathology with species identification by molecular techniques is essential for the timely initiation of sensitive antibiotics, treatment (and prophylaxis) for Nocardial brain abscess using a combination of a carbapenem and CTX should be initiated in such cases.

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Conflicts of interest

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