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44-Year-Old Man With Headache and Neurological Symptoms

      A 44-year-old male construction worker presented to the emergency department with a 1-week history of occipital headache associated with blurry vision, disequilibrium, and gait instability. His symptoms began with vision changes and headache and had progression to gait instability several days before presentation. The headache was rated as 7 out of 10 in severity, worsened with neck extension, and slightly relieved by neck flexion. He did not have any significant medical history and did not take any medications regularly. On review of systems, he endorsed new night sweats for 2 months. All other review of systems was negative. He denied any drug use or smoking history. He endorsed occasional alcohol use and denied any recent travel.
      On physical examination, he appeared comfortable and in no acute distress. His temperature was 36.6°C and blood pressure 127/87 mm Hg with a regular pulse of 79 beats/min. He was breathing at 99% oxygen saturation on room air at 16 breaths/min. He had no lymphadenopathy. Cardiac examination revealed regular rhythm with no rubs or gallops. His lungs were clear to auscultation bilaterally. His abdomen was soft and nontender. His neurological examination revealed no focal weakness or cranial nerve abnormality with normal strength and tone. His speech was fluent but slightly slowed. Finger to nose and heel to shin were slightly impaired on the left side. He had difficulty with rapid movements in the left upper and lower extremities and slight difficulty with gait.
      Initial laboratory testing revealed the following (references ranges provided parenthetically): hemoglobin level, 16.2 g/dL (13.2 to 16.9 g/dL); leukocyte count, 9.9×109/L ((3.4 to 9.6)×109/L); platelet count, 216×109/L (135 to 317×109/L). His electrolyte panel revealed a sodium level of 138 mmol/L (135 to 145 mmol/L), potassium level 4.1 mmol/L (3.6 to 5.2 mmol/L), chloride level 96 mmol/L (98 to 107 mmol/L), bicarbonate level 30 mmol/L (22 to 29 mmol/L), and creatinine level 1.0 mg/dL (0.74 to 1.35 mg/dL). The patient was found to be HIV negative. Computed tomography of the head with and without intravenous (IV) contrast revealed a 2.8 cm×1.8 cm ring-enhancing mass in the cerebellar hemisphere. Magnetic resonance imaging of the brain revealed 3.1 cm×1.9 cm×1.8 cm bilobulated, ring-enhancing lesion.
      • 1.
        Which one of the following is the most appropriate next step for this patient?
        • a.
          Repeat imaging in 6 months
        • b.
          Biopsy
        • c.
          Administration of antifungal medications
        • d.
          Methylprednisolone
        • e.
          Surgical resection
      Given the acuity of the patient’s illness, it would not be appropriate to delay intervention and repeat imaging in 6 months. In this patient with neurological findings and recent ring-enhancing lesion seen on imaging, biopsy should be performed to determine the etiology. The differential diagnosis of cerebral ring-enhancing lesion can be divided into 3 broad categories: infectious, inflammatory/demyelinating, and neoplastic. Infectious etiologies include neurocysticercosis and tuberculosis (more common in developing countries), along with toxoplasmosis, fungal infections including histoplasmosis and cryptococcosis, and abscess formation. Inflammatory/demyelinating disorders include multiple sclerosis, sarcoidosis, and vasculitis. Brain metastases are the most common intracranial neoplasms followed by primary brain tumors.
      • Sharma V.
      • Prabhash K.
      • Noronha V.
      • Tandon N.
      • Joshi A.
      A systematic approach to diagnosis of cystic brain lesions.
      With a wide range of etiologies for this patient’s cerebral lesion, tissue sampling and culture are the most appropriate next step to narrow the differential. Given the lack of medical history, this patient has no obvious risk factors for being immunocompromised. It would not be appropriate to initiate antifungal medications without appropriate biopsy and culture. Methylprednisolone could be considered with symptomatic brain compression or cerebral edema, but this was not the case in our patient. His neurological findings are more focal and not consistent with diffuse edema; therefore, cortico steroids would not be indicated. Surgical excision would not be appropriate without first determining the etiology of the lesion by biopsy.
      The patient received a suboccipital craniotomy with biopsy of the lesion. Specimens were obtained and subjected to aerobic, anaerobic, fungal, and acid fast bacilli culture. The obtained aerobic cultures revealed narrow (∼1 μm in diameter) branching filaments.
      • 2.
        Which one of the following diagnosis is most likely consistent with aerobic cultures obtained from the central nervous system (CNS) lesion in this patient?
        • a.
          Actinomyces spp.
        • b.
          Nocardia spp.
        • c.
          Candida spp.
        • d.
          Aspergillus spp.
        • e.
          Taenia solium
      Actinomyces spp. are Gram-positive, branching, filamentous bacteria that can cause CNS infection. However, Actinomyces is anaerobic, not aerobic and would not be the most likely pathogen in this case. The most likely diagnosis in this immunocompetent patient is infections caused by Nocardia spp., which are aerobic Gram-positive bacilli that form branching filaments. Candida spp. are yeast found normally on the skin and mucous membranes that can cause candidiasis. Candida spp. are described as round to oval budding yeasts depending on the species hyphae and pseudohyphae, which is not consistent with the culture results of this patient. Aspergillus spp. are fungi that primarily affect immunocompromised patients and contain spores and hyphae, which is not consistent with our patient’s culture results. Taenia solium tapeworm infection can cause neurocysticercosis, the most common parasitic infection of the brain. Computed tomography of the head usually exhibits multiple thin-walled cysts with a bright “dot” in the center (scolex). Our patient’s computed tomography of the head did not have these findings, and he lacks any significant exposures for neurocysticercosis, making this an unlikely diagnosis.
      Following the biopsy results, the patient had received a diagnosis of CNS nocardiosis. After thorough examination, no skin manifestations were found on the patient’s body. Computed tomography of the chest revealed left upper lobe irregular pulmonary opacity with mediastinal extension and mediastinal lymphadenopathy. His CNS nocardiosis was determined to be from hematogenous spread from an initial pulmonary infection via inhalation despite his lack of pulmonary symptoms on initial presentation.
      • 3.
        Which one of the following antibiotics is the most appropriate initial treatment of CNS nocardiosis in this patient?
        • a.
          Imipenem and sulfamethoxazole/trimethoprim
        • b.
          Meropenem
        • c.
          Ertapenem and sulfamethoxazole/trimethoprim
        • d.
          Ceftriaxone and metronidazole
        • e.
          Vancomycin
      In this patient with pulmonary and CNS disease, the most appropriate therapy includes imipenem and sulfamethoxazole/trimethoprim, which was initiated after confirming the diagnosis. For the past 50 years, sulfonamides have been the antimicrobials of choice. Patients with sulfa allergies should undergo desensitization to sulfamethoxazole/trimethoprim when possible as studies have found increased survival in patients treated with sulfonamide-containing regimens. Because of increased resistance, imipenem should be added to sulfamethoxazole/trimethoprim for increased activity against Nocardia sp. for empirical treatment—rather than meropenem or ertapenem. Ceftriaxone can be used for patients with nocardiosis, but only in combination with amikacin rather than metronidazole. Amikacin can be discontinued after clinical improvement and after Nocardia susceptibilities are obtained. For patients with sulfonamide allergies, minocycline can be used as an alternative oral agent.
      • Wilson J.W.
      Nocardiosis: updates and clinical overview.
      Although it has good Gram-positive coverage, IV vancomycin would not be indicated in this infection.
      The patient was prescribed imipenem and amikacin for 6 weeks and sulfamethoxazole/trimethoprim for 12 months.
      • 4.
        Of the following different forms of nocardiosis, which one is the most common type of involvement in an immunocompetent individual like this patient?
        • a.
          Primary cutaneous and soft tissue nocardiosis
        • b.
          Primary CNS nocardiosis
        • c.
          Nocardia bacteremia
        • d.
          Pulmonary nocardiosis
        • e.
          Infective endocarditis caused by Nocardia sp.
      One-third of cases of nocardiosis occur in immunocompetent patients. Primary cutaneous and soft tissue nocardiosis is the most common form of nocardiosis in the immunocompetent host and can result from traumatic injury to the skin with inoculation from soil with subsequent abscess formation.
      • Wilson J.W.
      Nocardiosis: updates and clinical overview.
      Isolated CNS nocardiosis is usually not seen in immunocompetent individuals and is also most often associated with concurrent pulmonary infection. Although hematogenous spread is common in nocardiosis, Nocardia bacteremia is exceedingly rare. Because inhalation is the primary route of bacterial exposure, pulmonary nocardiosis is the most common presentation out of all infections caused by Nocardia spp. Our patient was most likely exposed to Nocardia spp. via inhalation as he worked in construction and was often exposed to dirt and dust. He likely had the pulmonary infection first and then had neurological symptoms after spread to the CNS. Although there are reports of infective endocarditis caused by Nocardia spp., these are rare and usually seen in patients with a history of prosthetic valve, unlike this patient.
      • 5.
        Which one of the following is most likely true in our immunocompetent patient with CNS nocardiosis?
        • a.
          Recurrence rate is rare
        • b.
          The patient’s sex is a risk factor
        • c.
          Treatment duration should be 2 months
        • d.
          He is at high risk for Nocardia bacteremia
        • e.
          He will require minimal follow-up after treatment
      Nocardiosis has a high rate of recurrence; therefore, prolonged antibiotic treatment is recommended. Patients with CNS nocardiosis can have a relapse rate of up to 13.6% even with appropriate therapy.
      • Krueger E.G.
      • Norsa L.
      • Kenney M.
      • Price P.A.
      Nocardiosis of the central nervous system.
      Nocardia spp. infection has a male predominance, so his sex is a risk factor for infection. Patients should be treated for a minimum of 3 months and up to 12 months for immunocompromised patients. Although he is at risk for further hematogenous spread, the incidence of Nocardia bacteremia in all patient populations is low. Timely and consistent follow-up (up to several years after the completion of treatment) is necessary to monitor for recurrence.
      The patient was followed closely in the infectious disease clinic and underwent follow-up computed tomography of the chest and head after 6 months of therapy, which revealed interval decrease in size of the left-sided lung opacity and complete resolution of the ring-enhancing lesion in the brain. Repeat imaging at his 12-month follow-up was normal, and antibiotic therapy was discontinued.

      Discussion

      Nocardiosis is an infection due to bacteria belonging to the genus Nocardia. Patients with immunosuppressive conditions are most often infected, but up to one-third of patients presenting with nocardiosis are immunocompetent. Patients with an especially high risk of infection caused by Nocardia spp. are those with depressed cell–mediated immunity. These would include patients with underlying malignant tumors malignancies, concurrent HIV infection, those receiving long-term cortico steroids, and solid-organ or hematopoietic stem cell transplantation.
      • Wilson J.W.
      Nocardiosis: updates and clinical overview.
      Nocardia spp. are aerobic Gram-positive bacilli that form branching filaments. The species of the genus Nocardia belong to the family Nocardiaceae in the suborder Corynebacteriaceae of the order Actinomycetales. Differentiating between species is difficult because of a lack of distinguishing phenotypic characteristics, and identification requires a laboratory with molecular capabilities. Previously, Nocardia abscessus was thought to be the most prevalent species affecting humans. Because of newer molecular technology including polymerase chain reaction restriction enzyme analysis and 16S ribosomal RNA sequencing, it is now known that there are more than 30 known species of Nocardia of clinical significance, with the most common pathogenic species being N nova complex, N abscessus, N transvalensis complex, N asteroides, N farcinica, and N brasiliensis.
      • Brown-Elliott B.A.
      • Brown J.M.
      • Conville P.S.
      • Wallace Jr., R.J.
      Clinical and laboratory features of the Nocardia spp. based on current molecular taxonomy.
      ,
      • Conville P.S.
      • Witebsky F.G.
      The complexity of Nocardia taxonomy: implications for the clinical microbiology laboratory.
      Nocardiosis can occur in pulmonary, cutaneous, or disseminated forms. The main port of entry for Nocardia spp. is inhalation, as the bacteria are found in soil, water, and on decaying plant matter. Unsurprisingly, pulmonary nocardiosis is the most common clinical presentation of the infection overall. There is large variability on the chest radiograph, which can exhibit consolidation, nodular opacities, cavitary lesions, pleural effusions, or scattered infiltrates.
      • Wilson J.W.
      Nocardiosis: updates and clinical overview.
      Symptoms can include progressive fatigue, fever, night sweats, chronic cough (productive or nonproductive), hemoptysis, chest pain, or shortness of breath. The second main route of transmission is inoculation of the bacteria into the soft tissue via a cut or abrasion. This can cause cutaneous or subcutaneous nocardiosis, which is more common in the immunocompetent host (including primary cutaneous, lymphocutaneous, cutaneous involvement from a disseminated focus, and mycetoma).
      • Kandi V.
      Human Nocardia infections: a review of pulmonary nocardiosis.
      After inoculation, abscesses or cellulitis can develop and can resemble other forms of bacterial skin infections. Systemic nocardiosis (defined as lesions found in ≥2 locations in the body) occurs via hematogenous or contiguous spread and can affect virtually any organ. Presentation and symptoms depend on the area or organs affected. Central nervous system involvement is the most common extrapulmonary form of nocardiosis and accounts for up to 22.6% of infections. Additionally, in 1 study of 1050 cases of nocardiosis, 38.2% of CNS infections were noted in individuals without evidence of infection elsewhere and were regarded as primary CNS infections.
      • Beaman B.L.
      • Beaman L.
      Nocardia species: host-parasite relationships.
      Central nervous system nocardiosis involves formation of a parenchymal abscess and presenting symptoms include fever, headache, meningismus, seizures, and/or focal deficits. Bacteremia with Nocardia spp. is relatively rare. Two characteristics that separate nocardiosis from other bacterial infections are the high rate of relapse and the ability to spread to virtually any organ. Because of this, it is important to know the extent of disease for appropriate antibiotic therapy duration. Patients should receive a thorough skin examination, along with imaging of the chest and head to determine pulmonary and CNS involvement.
      Because of the variable in vitro antimicrobial susceptibility of Nocardia spp., treatment of infections should be individualized. Isolated Nocardia sp. should undergo antimicrobial susceptibility testing, and treatments should be adjusted accordingly. Because of a lack of prospective controlled trials, definitive therapy recommendations are somewhat vague. For many years, sulfonamides were considered standard of therapy. This consensus among experts, despite the bacteriostatic activity, is based largely on a few retrospective reviews in which there was increased survival in patients with nocardiosis with the use of sulfonamides. Currently, empirical therapy with trimethoprim-sulfamethoxazole is the treatment of choice by most clinicians.
      • Sharma V.
      • Prabhash K.
      • Noronha V.
      • Tandon N.
      • Joshi A.
      A systematic approach to diagnosis of cystic brain lesions.
      ,
      • Wilson J.W.
      Nocardiosis: updates and clinical overview.
      Treatment regimen for nonsevere infection (including isolated cutaneous and mild-to-moderate pulmonary disease) includes sulfamethoxazole/trimethoprim administered orally. Severe pulmonary or disseminated disease without CNS involvement should include IV therapy with sulfamethoxazole/trimethoprim plus amikacin. Alternative therapy includes imipenem IV plus amikacin IV. Isolated CNS disease includes treatment with both sulfamethoxazole/trimethoprim IV and imipenem IV. Central nervous system disease with multiorgan involvement should include therapy with all 3: sulfamethoxazole/trimethoprim IV plus amikacin IV plus imipenem IV.
      • Wilson J.W.
      Nocardiosis: updates and clinical overview.
      ,
      • McNeil M.M.
      • Brown J.M.
      • Hutwagner L.C.
      • Schiff T.A.
      Evaluation of therapy for Nocardia asteroides complex infections.
      ,
      • Smego R.A.
      • Moeller M.B.
      • Gallis H.A.
      Trimethoprim-sulfamethoxazole therapy for Nocardia infections.
      Because of the relapsing nature of nocardiosis, extended treatment duration is recommended. Immunocompetent patients should receive appropriate antibiotic therapy for 3 to 6 months and patients who are immunocompromised and/or have CNS involvement should be treated for at least 12 months.
      • Wilson J.W.
      Nocardiosis: updates and clinical overview.
      Patients should be monitored at regular monthly intervals after the initiation of treatment to monitor response and assess drug toxicity. Patients should also be evaluated radiographically at 6 and 12 months during treatment to monitor response. Given the high rate of recurrence, the patient should have the imaging repeated 6 and 12 months after the completion of treatment.

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        • Joshi A.
        A systematic approach to diagnosis of cystic brain lesions.
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        Nocardiosis: updates and clinical overview.
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        Nocardiosis of the central nervous system.
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        Clinical and laboratory features of the Nocardia spp. based on current molecular taxonomy.
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        The complexity of Nocardia taxonomy: implications for the clinical microbiology laboratory.
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        Human Nocardia infections: a review of pulmonary nocardiosis.
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