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June 2016

Fulminant Central Nervous System Nocardiosis in a Patient Treated With Alemtuzumab for Relapsing-Remitting Multiple Sclerosis

Author Affiliations
  • 1Department of Neurology, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
  • 2Division of Neuropathology, Institute of Pathology, Technische Universität München, Munich, Germany
  • 3Institute of Microbiology, Immunology, and Hygiene, Technische Universität München, Munich, Germany
  • 4Department of Neuroradiology, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
  • 5Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
JAMA Neurol. 2016;73(6):757-759. doi:10.1001/jamaneurol.2016.0146

A woman in her late 40s with relapsing-remitting multiple sclerosis (MS) was admitted because of reduced ambulation and personality change in the previous 3 weeks. Her diagnosis of MS was made in 2007, and she was initially treated with interferon beta-1a and switched to natalizumab because of ongoing disease activity. After 80 infusions, natalizumab was discontinued because of repeated relapses and seroconversion to positivity for JC virus. Her first cycle of alemtuzumab was given in February 2015 (Expanded Disability Status Scale score of 4.5), 18 weeks after the cessation of natalizumab treatment. Her medical history was remarkable for hypothyroidism, recurrent infections, and an anorectic disorder (body mass index [calculated as weight in kilograms divided by height in meters squared] on admission, 14).

On admission in June 2015, she had a tetraspastic syndrome and was wheelchair-bound. Her temperature was 37.2°C and her white blood cell count was 9100/μL (to convert to ×109/L, multiply by 0.001) with an essentially depleted mononuclear fraction (Table). Cerebrospinal fluid analysis showed 2 leukocytes per microliter. Magnetic resonance imaging showed multiple ring-enhancing lesions (Figure). Despite broad screening, no infectious agent was identified in the patient’s blood or cerebrospinal fluid (including Toxoplasma gondii, mycobacterial species, Pneumocystis jiroveci, fungi, or human immunodeficiency virus), and a search for infectious foci in the systemic compartment remained inconclusive.

Table.  Absolute Number of Leukocytes per Microliter of Patient’s Blood
Absolute Number of Leukocytes per Microliter of Patient’s Blood
Figure.  Sequential Magnetic Resonance Imaging Scans and Histologic Analysis of Intracerebral Biopsy
Sequential Magnetic Resonance Imaging Scans and Histologic Analysis of Intracerebral Biopsy

Coronal contrast enhanced T1-weighted images acquired 4 days before the patient’s admission to our multiple sclerosis center (A), on admission (B), and 8 weeks after first admission (C). Hematoxylin-eosin–stained brain biopsy specimens showing multiple abscess-like formations (D, original magnification ×100) localized in the vicinity of postcapillary venules (E, original magnification ×200).

Because the patient’s condition deteriorated within 2 days despite broad-spectrum antibiotic treatment, an intracranial biopsy specimen was obtained. Culture of intracranial abscess material resulted in identification of Nocardia farcinica (Figure). The patient’s antibiotic treatment was revised to imipenem, co-trimoxazole, and amikacin plus dexamethasone. She required transient noradrenaline infusion and was mechanically ventilated for 10 days before she improved and could be discharged for rehabilitation. On follow-up, she was ambulatory, her peripheral blood mononuclear cell count had partly recovered (Table), and number and size of Nocardia-associated intracerebral lesions were markedly reduced on the magnetic resonance image (Figure). Her intravenous antibiotic therapy was stopped after 8 weeks of treatment and oral administration of co-trimoxazole and amoxicillin-clavulanic acid was continued to maintain remission.


Alemtuzumab is a humanized monoclonal IgG1 antibody against CD52 and depletes circulating T cells, B cells, natural killer cells, and some monocytes.1 The pivotal trials of its use in patients with MS revealed no adverse effects except for secondary autoimmune phenomena and herpes virus infections. Here, we report a case of fulminant central nervous system nocardiosis at 5 months after initiation of alemtuzumab in a patient with MS. Notably, she received natalizumab before alemtuzumab. However, all mononuclear cell subsets in the patient’s peripheral blood showed no abnormalities before her treatment with alemtuzumab.

Cases of pulmonary and disseminated nocardiosis associated with alemtuzumab treatment have been reported only in patients with preexisting conditions that compromise immunity, including non-Hodgkin lymphoma, B-cell lymphocytic leukemia, and organ transplantation.2,3 In contrast, MS is not per se associated with decreased host defense. Although alemtuzumab eliminates crucial components of cellular immunity, only sporadic cases of moderate opportunistic infections were reported in patients with MS, including spirochetal gingivitis and Listeria meningitis.4Nocardia infects the lungs and spreads hematogenously, with potential damage to the central nervous system when intraepithelial and systemic cellular immunity fail.5

After 5 months of treatment with alemtuzumab, no signs of lymphocyte reconstitution were noticed in the patient, suggesting that she experienced prolonged immunodeficiency. In the present case, the regular dose of alemtuzumab (12 mg/d for 5 days) might have been excessive because of the patient’s preexisting anorectic condition. Thus, besides eliminating circulating mononuclear cell subsets, alemtuzumab might have depleted lymphocytes in compartments (eg, intraepithelial lymphocytes) that are normally spared. Furthermore, her low body mass index may have contributed to a preexisting immunodeficient state.6 At present, no pretreatment diagnostic test reliably identifies patients at risk for profound immunodeficiency with the administration of alemtuzumab. Thus, physicians should be cautious when considering alemtuzumab in patients with MS and suspected altered cellular immunity of any origin, including a low body mass index. Antibiotic treatment after nocardiosis of the central nervous system is recommended for 12 months and might be continued beyond this in our patient, depending on the reconstitution of her mononuclear cell compartment (Table).

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Article Information

Corresponding Author: Thomas Korn, MD, Department of Neurology, Klinikum rechts der Isar, Technische Universität München, Ismaninger Strasse 22, 81675 Munich, Germany (thomas.korn@tum.de).

Published Online: April 4, 2016. doi:10.1001/jamaneurol.2016.0146.

Conflict of Interest Disclosures: Dr Korn reported having received a research grant for preclinical research from Biogen Idec Inc and support from the German Research Council (grants TR 128 and SFB 1054) and the European Research Council. No other disclosures were reported.

Additional Contributions: The nocardiosis of the central nervous system in the alemtuzumab-treated patient described here was reported as a serious adverse event to the German authorities and to Genzyme, the manufacturer of Lemtrada (alemtuzumab). Verena Loleit, MD, Achim Berthele, MD, and Bernhard Hemmer, MD (Department of Neurology, Klinikum rechts der Isar, Technische Universitaet Muenchen); Claus Zimmer, MD (Department of Neuroradiology, Klinikum rechts der Isar, Technische Universitaet Muenchen); Tobias Lahmer, MD, and Wolfgang Huber, MD (II. Medizinische Klinik, Klinikum rechts der Isar, Technische Universitaet Muenchen); and Tania Kuempfel, MD (Institute of Clinical Neuroimmunology, Medical Campus Grosshadern, Ludwig-Maximilians-Universität München), critically read the manuscript and provided helpful discussions. None was compensated for this assistance. We would like to thank the patient for granting permission to publish this information.

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