University of Alabama at Birmingham

Gorgas Case 2017-10

Universidad Peruana Cayetano Heredia
The Gorgas Courses in Clinical Tropical Medicine are given at the Tropical Medicine Institute at Cayetano Heredia University in Lima, Perú. Each August we conduct one of our 2-week refresher courses for those with previous training in tropical medicine; currently in session is the Gorgas Advanced Course. For the past 16 years, we have been pleased to share interesting cases seen by the participants each week when our courses are in session; there will be one more case next week to complete the 2017 case series.

The following patient was seen in the Intensive Care Unit of the Children’s Hospital in Lima, Perú.

Eduardo Gotuzzo & German Henostroza
Course Directors
Image for Case 2017-10
History: An eight-year-old male patient, previously healthy, admitted with a two-month history of a painless, progressive, violaceous plaque on the left side of the nose, which was unresponsive to 10 days of antibiotics. Ten days before admission weakness of the left arm was followed by weakness in both lower extremities then both upper extremities as well as onset of rhinorrhea. Frontal and occipital headache, nausea, vomiting, began 1 week prior to admission. Progressive difficulty swallowing, somnolence, and altered mental status led to hospital admission and subsequent transfer to our hospital.

Previously healthy child, fully vaccinated. Trauma to the nose in the weeks prior included bumping into a wooden column, being hit with a plastic and being kicked in the nose (with no bleeding but with swelling that resolved spontaneously).

Epidemiology: Born and lives in Piura, north coastal desert of Peru. Contact with cats, dogs and chicken. No history of fresh-water exposure in lakes, ponds or rivers. No known TB contact. No relevant family history. Travel to a rural valley two weeks before admission for 15 days for treatment by a traditional healer.

Physical Examination: Febrile. Blood pressure: 140/90. Heart rate: 140. Respiratory rate: 60, O2 saturation: 89%. In obvious distress. Skin: Infiltrated violaceous plaque, with superficial desquamation, with defined edges in the left lateral region of the nose (Image A). No other lesions, discharge or abnormal findings in the oropharynx. Neurological exam, stuporous with a Glasgow coma scale of 10 (AO: 4 RV: 2 RM:4), hyper-reflexia and nuchal rigidity positive, but other meningeal signs negative, Babinski negative, normal ocular movements. No lymphadenopathy. The rest of the exam was normal.

Laboratory: Hematocrit: 36%, hemoglobin: 11.1 g/dL, platelets: 543,000. WBC 14,900 (85% neutrophils and 0.8% eosinophils); normal liver function tests, glucose, creatinine, urea, and electrolytes. CT scan is shown (Image B).

UPCH Case Editors: Carlos Seas, Clinical Course Coordinator / Karen  Luhmann, Associate Coordinator
UAB Case Editor: David O. Freedman, Course Director Emeritus / German Henostroza, Course Director
Diagnosis: Balamuthia mandrillaris (free-living amoeba).
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Discussion: A skin biopsy (Image C) revealed a flattened epidermis and diffuse infiltration of the reticular dermis by a lymphoplasmacytic infiltrate and multiple randomly distributed multinucleated giant cells. Some structures are observed inside apparent vacuoles that present a cytoplasm with bubbles and nuclei and nucleoli. The CT was read as severe edema, predominantly of the right hemisphere, multiple hypodense lesions, the largest located on the right of the midline with ring enhancement causing ventricular collapse and midline deviation. Based on our clinical experience with over 50 cases and the characteristic skin and brain lesions in concert, a diagnosis of Balamuthia mandrillaris was made. See cases 2007-10, 2004-2, 2015-6 for other patients with these same characteristic manifestations of this infection.

About 200 cases of B. Mandrillaris infection have been reported from all continents except from Africa. Most cases are reported in the western hemisphere, with the highest concentration in South America and the United States. The disease appears to occur more frequently among patients of Hispanic origin; possible explanations include genetic susceptibility or environmental exposure. Like most Latin American cases, the patient is not immunocompromised. Unlike Acanthamoeba and Naegleria species, which are more familiar to clinicians and known to occur in brackish ponds and creeks, an ecologic niche in nature has not been definitively found for Balamuthia. Our patients have come from throughout Peru, usually from desert areas and not always reporting a history of swimming in potentially contaminated fresh water. Entry of water into the nasal mucosa and the olfactory nerve endings is thought to occur with Acanthamoeba and Naegleria.

Naegleria infection causes an acute necrotizing and suppurative meningoencephalitis, an aggressive disease that is generally fatal in days. Acanthamoeba cause a sub-acute granulomatis encephalitis with a more prolonged but ultimately fatal course mainly seen in immunocompromised hosts. Occasionally, patients with Acanthamoeba have a skin lesion usually described as a chronic ulcer. Acanthamoeba, unlike Balamuthia, has been associated also with amoebic keratitis, a painful sight-threatening disease of the eye. In Balamuthia infection, the disease may follow a prolonged course, but most frequently has a fatal outcome. Almost all cases have an initial skin lesion, and this lesion precedes the inevitable CNS disease (granulomatous amebic encephalitis) by weeks or months. The CNS lesions generally appear distant or as metastases from the primary cutaneous lesion but uncommonly as in this there may be direct local extension to the brain. Patients have ranged from 3 to 65 years of age with 50% under age 15.

The typical skin lesion is a single painless plaque up to several centimeters in diameter; a few patients have had 2-3 lesions. Color may be skin tone, dark red, or slightly violaceous. Sensation is preserved. Location is usually on the central face with fewer than 10% with initial lesions on trunk or extremities. For facial lesions, the differential diagnosis may include tuberculosis, mucocutaneous leishmaniasis, leprosy, sporotrichosis, paracoccidioidomycosis, rhinoscleroma, or mucormycosis. Sarcoid, discoid lupus, and Wegeners can also be considered. Histologically, granulomatous inflammation with lymphocytes, histiocytes, plasma cells, as well as giant cells, is characteristic. Amoebic trophozoites are often scanty and multiple sections need to be examined. Some foci of vasculitis may be present.

CNS involvement most often manifests with headache, photophobia, seizures that progress to lethargy, sensori-motor deficit, coma and death. The CNS lesion is a progressive hemorrhagic necrosis with large numbers of amoebic trophozoites and cysts invading vascular sub-adventitial areas of arteries, veins, and capillaries, leading to perivasculitis and cerebral infarcts [Hum Pathol. 1999 Mar;30(3):269-73].

The mainstay of successful treatment depends on early diagnosis and therapy. Patients without brain lesion at diagnosis have better chances of recovery. Treatment with drug combinations for prolonged periods is warranted. This patient was started on fluconazole, albendazole, and miltefosine based on our experience with one patient [Clin Infect Dis. 2010;51(2):e7-11]. Our center has treated 11 patients with CNS involvement since that publication with the three drug combination, 7 survived with complete clearance of the lesions. This drug regimen is well tolerated; the most important side effects are nausea, stomach ache, and vomiting. The duration of treatment in most of these cases was from 6 to 18 months.

Miltefosine is known to have an in-vitro amebicidal effect against B. mandrillaris [J Eukaryot Microbiol. 2006 Mar-Apr;53(2):121-6] and crosses the blood-brain barrier. Although formal trials are lacking a number of case reports have shown good results when using miltefosine as part of a combination of drugs to treat free-living affections, including Naegleria sp. Acanthamoeba and B. mandrillaris and in the US miltefosine is FDA-approved and available but costly from a single commercial distributor. Albendazole and fluconazole are amebistatic effect; they interfere with the metabolism of ergosterol, one of the main components of the ameba wall. Fluconazole has good CNS penetration.

Other drugs with amebicidal effect are: pentamidine, antipsychotic agents’ phenothiazines and thioridazine. However, they are poorly tolerated. With IV amphotericin B or pentamidine, an initial and apparently favorable response or disappearance of cutaneous lesions still does not halt the eventual appearance of CNS disease. Similarly, in our hands, multi-drug combination therapy with agents such as albendazole, itraconazole, or fluconazole without miltefosine have still resulted in eventual appearance or progression of CNS disease.