The Journal of Emergency Medicine, Vol. -, No. -, pp. 1–5, 2015 Copyright Ó 2015 Elsevier Inc. Printed in the USA. All rights reserved 0736-4679/$ - see front matter
Case Presentations of the Harvard Emergency Medicine Residencies
ALTERED MENTAL STATUS AND FEVER Lauren M. Allister, MD,*† Megan L. Schultz, MD, MA,‡§ David F. M. Brown, MD,*† and Emily S. Miller, MD*† *Department of Emergency Medicine, Harvard Medical School, Boston, Massachusetts, †Department of Emergency Medicine, Massachusetts General Hospital, Boston, Massachusetts, ‡Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, and §Department of Pediatrics, Massachusetts General Hospital, Boston, Massachusetts Reprint Address: Emily S. Miller, MD, Department of Emergency Medicine, Massachusetts General Hospital, Harvard Medical School, Zero Emerson Place, Suite 3B, Boston, MA 02114
a presumed diagnosis of urinary tract infection vs. another unspecified bacterial process. The day after this visit the monospot test resulted as positive; the family was informed of a presumed diagnosis of mononucleosis and told to continue antibiotics. The patient transiently improved, but in the 3 days prior to ED presentation, she began to complain of headache and developed neck pain, fever to 39 C, progressive anorexia, decreased oral intake, and increasing fatigue. On the morning of presentation to the ED, her mother found her difficult to arouse from sleep, febrile, and confused. Review of symptoms was negative for vomiting, diarrhea, abdominal pain, chest pain, cough, abnormal movements, joint swelling, and rash. Her mother reported that the patient may have collided with another girl during a soccer game 1 week prior, but stated she had not lost consciousness or had worsening symptoms after that event. The patient had a past medical history notable for mild asthma and multiple food allergies and was taking the recently prescribed amoxicillin/clavulanic acid along with her regular medications: montelukast, mometasone furoate, and fluticasone proprionate nasal sprays, as well as an albuterol inhaler as needed. The patient had been prescribed atovaquone/proguanil, but neither she nor her other family members took any chemoprophylaxis during the trip, as they had frequently visited family in Ghana and had
Dr. Lauren Allister: Today’s case is that of an 8-year-old girl who presented to the Emergency Department (ED) with fever and altered mental status. The patient was reportedly well until 2 weeks prior to her ED visit when she presented to her pediatrician with headache and sore throat. Multiple family members had similar symptoms at that time. The family had recently returned from a multiple-week visit to Ghana but had not had any sick contacts while abroad. At the initial pediatrician visit, the patient was well appearing and, on examination, was found to have an erythematous, exudative posterior oropharynx with associated cervical lymphadenopathy. A rapid antigen test for Group A Streptococcus was performed at this visit and was negative. The patient was discharged home with a presumed viral infection. The patient continued to feel increasingly unwell with persistent fever, and returned to the pediatrician 3 days later. At the second visit the patient was more ill appearing, was febrile to 38.7 C, and had a persistently erythematous and exudative oropharynx. She appeared tired but had a nonfocal neurological examination. Given these persistent and progressive symptoms, laboratory studies were performed. The white blood cell count was 17,200 cells/mm3, urinalysis revealed mild pyuria (11 white blood cells/high power field), and a monospot test (heterophile antibody test) was sent. The patient was discharged home on oral amoxicillin/clavulanic acid with
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never previously contracted any travel-borne illnesses. She had no recent new food or environmental exposures. She had no significant infectious history. She had no known drug allergies. Dr. Nicholas Maldonado: Can you describe her physical examination upon presentation to the ED? Dr. Allister: The patient was intermittently responsive, with a waxing and waning mental status; she was occasionally awake and answering questions, but was then agitated and confused, and subsequently was somnolent. Vital signs were notable for a temperature of 37 C (98.6 F) after having recently been medicated with acetaminophen, heart rate of 130 beats/min, blood pressure of 91/48 mm Hg, respiratory rate of 20 breaths/min, and an oxygen saturation of 100% on 2 L of supplemental oxygen via nasal cannula placed on arrival. The head was normocephalic and atraumatic. Pupils were equally round and reactive to light with intact extraocular movements; however, horizontal nystagmus, scleral icterus, and conjunctival pallor were appreciated. The oropharynx was clear. The neck was supple with full range of motion. The chest examination was clear bilaterally without crackles, retractions, or increased work of breathing. Cardiac examination was notable for tachycardia without rubs, gallops, or murmurs. The abdomen was soft, nontender to palpation, and without appreciable hepatosplenomegaly. She was moving all extremities equally. The skin was notable for brisk capillary refill and there were no petechiae, purpura, or other rashes or lesions. Neurologic examination was notable for waxing and waning mental status and gross hypertonia without abnormal movements or weakness; however, she was unable to follow most commands. Dr. Maldonado: Before you began your initial evaluation, what diagnoses were you considering in this patient? Dr. Allister: The first diagnostic considerations were infectious etiologies related to the recent trip to Ghana with her family. Malaria, yellow fever, typhoid, and meningitis (Neisseria meningitidis) are infections endemic to this region of Africa (1). We also considered non-travelborne illnesses including viral, bacterial, or Lyme meningitis or encephalitis, or an evolving sepsis picture. Given the positive heterophile testing at the primary care physician’s office, as well as documented pyuria, progressive mononucleosis or a progressive urinary tract infection could also have been possible etiologies for the worsening clinical picture. We discussed whether her altered mental status could be secondary to a mixed infectious/ toxidrome picture, such as acetaminophen toxicity from overuse of acetaminophen as an antipyretic or Reye syndrome (rapidly progressive encephalopathy with hepatic failure) if salicylates had been used for antipyresis. There was an incidental report of a head strike a week prior to
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presentation, so an evolving traumatic intracranial injury mixed with a febrile illness was also a consideration. Dr. Maldonado: What were your initial steps in the stabilization and evaluation of this patient? Dr. Megan Schultz: Initial stabilization involved assessing this patient’s airway, breathing, and circulation. She was maintaining her airway, and oxygen saturation on 2 L of nasal cannula oxygen was 100%. She was hemodynamically stable with brisk capillary refill. A peripheral intravenous (i.v.) line was placed. Laboratory studies were sent, including a complete metabolic panel, complete blood count with differential, Lyme titer, comprehensive serum toxicology panel, urinalysis, blood and urine cultures, and a thick and thin blood smear for malaria. A head computed tomography (CT) scan was performed to assess for traumatic findings or abnormalities suggestive of central nervous system infection or changes in intracranial pressure. Dr. Maldonado: What were the results of these initial tests and how did they influence your differential diagnosis? Dr. Schultz: The initial laboratory testing was significant for anemia (hematocrit 14.7%), thrombocytopenia (platelets 33,000/mm3), mild electrolyte dysfunction (bicarbonate of 21.8 mmol/L, calcium 7.8 mg/dL, phosphorus 3.0 mg/dL), and abnormal liver function tests (protein 5 g/dL, albumin 2.6 g/dL, aspartate aminotransferase 67 U/L, direct bilirubin 2.1 mg/dl, total bilirubin 4.2 mg/dL). The lactate was elevated at 3.8 mmol/L. The white blood cell count, other electrolytes, and coagulation profiles were normal. The initial glucose measurement was 102 mg/dL. Toxicology screening was normal and an initial Lyme antibody test was negative. The head CT scan did not show any evidence of hemorrhage or mass lesion. Less than 1 h into her evaluation we received the critical result of the thick and thin smear for malaria, which showed 32% parasitemia with preliminary forms consistent with Plasmodium falciparum (Figure 1). Our working diagnosis from that point forward was malaria, with which the other labs were consistent, and more specifically, cerebral malaria. Dr. Maldonado: Can you discuss how you made the diagnosis of cerebral malaria? How does this categorization differ from other presentations of malaria? Dr. Schultz: Several large studies have shown that malaria is the most common cause of fever in travelers returning from a tropical country, and our patient had further malaria risk factors in being an American-born nonimmune child of immigrants, staying with family while in Ghana, and not being chemoprophylaxed (2–4). The severity of malaria is typically classified by the degree of peripheral parasitemia as well as clinical and laboratory findings. Although the correlation between parasitemia and prognosis varies by the level of malaria
Altered Mental Status and Fever
Figure 1. Peripheral blood smear demonstrating intraerythrocytic Plasmodium falciparum (arrows indicate three of the many infected cells present on the slide).
transmission in a specific area, malaria mortality first begins to rise with parasite densities >100,000/mm3, or 2.5% parasitemia (5). The clinical findings of severe malaria include altered mental status, weakness, seizures, respiratory distress, renal failure, disseminated intravascular coagulopathy, jaundice, and shock (6). The laboratory findings include anemia (hemoglobin < 5 g/dL), hypoglycemia (glucose < 40 mg/dL), metabolic acidosis (bicarbonate < 15 mmol/L), hemoglobinuria, increased lactate (lactate > 5 mmol/L), and increased creatinine (>3 mg/dL) (5). Severe malaria is diagnosed when a patient has confirmed parasitemia and any one of the above clinical or laboratory findings. Our patient met criteria for severe malaria by virtue of her parasitemia, altered mental status, weakness, jaundice, and anemia. Cerebral malaria is the most severe manifestation of malaria and is strictly defined as coma with parasitemia on peripheral blood smear (6). In practice, the definition of cerebral malaria can be broadened to include impaired consciousness or abnormal neurological findings, or both, such as seizures, abnormal respiratory patterns, abnormal pupillary and eye movements, increased tone, posturing, abnormal reflexes, and retinopathy (7). Cerebral malaria can be challenging to diagnose because its neurological features are nonspecific. For example, seizures can be seen with profound hypoglycemia and fever, both of which are features of severe malaria. In addition, patients in malaria-endemic areas can have incidental parasitemia found on peripheral smear that is wholly unrelated to their neurological findings (8). This potential ambiguity requires that, to accurately diagnose cerebral malaria, all other causes of encephalopathy must first be excluded or corrected (e.g., correction of hypoglycemia, cultures of cerebrospinal fluid to look for bacterial meningitis). The inclusion of ‘‘malaria retinopathy’’ (retinal whitening and vessel
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color changes, both specific to malaria) as part of the definition for cerebral malaria has been proposed to help more clearly define the diagnosis and its central nervous system manifestations (9,10). Our patient had a significantly altered mental status. Her head CT scan was normal, her electrolytes were only mildly altered, and her blood glucose was normal. She was too clinically unstable and thrombocytopenic for us to safely perform a lumbar puncture in the ED, but we felt that the likelihood of concomitant viral, Lyme, or bacterial meningitis was unlikely. Therefore, given her tenuous mental status that was evolving toward potential coma, her other manifestations of severe malaria, and the significant peripheral parasitemia, we felt that she met the criteria for the diagnosis of cerebral malaria. Dr. Maldonado: What causes cerebral malaria? What were you most concerned about acutely in the ED? Dr. Schultz: The exact pathophysiology of cerebral malaria remains unclear, with multiple postulated mechanisms for the central nervous system effects. One theory hypothesizes that central nervous system symptoms are mediated through sequestration of parasitized red blood cells (pRBCs) in cerebral microvasculature (8). This is caused by adherence of the pRBCs to endothelial lining, pRBC auto-agglutination, platelet-mediated clumping, and rosette formation between pRBCs and nonparasitized erythrocytes (8). Dysfunction of the blood–brain barrier and inflammatory cytokines such as tumor necrosis factor and quinolinic acid may also play a role. Together, these mechanisms result in reduced cerebral blood flow, hypoxia, hypoglycemia, and intracranial hypertension (7,8). For pediatric patients, whose developing brains are potentially more susceptible to traumatic, ischemic, toxic, and inflammatory insults, the clinical presentation of cerebral malaria can differ from their adult counterparts (7,11). Seizures, neurological sequelae at the time of hospital discharge, abnormal brainstem reflexes, and longer-term neurocognitive deficits are more frequently reported in pediatric patients with cerebral malaria (6,11,12). Other features of cerebral malaria such as retinopathy, cerebral edema, and elevated cerebrospinal fluid pressures are reported with equal frequency in pediatric and adult patients (11). The overall mortality rate is generally lower in children compared to adults (11). For our patient, we were concerned about evolving multisystem end organ damage and rapid progression of central nervous system disease. It was essential for us to quickly initiate antimalarial treatment as well as neuroprotection. Dr. Maldonado: What therapy did you initiate for this patient in the ED, and how was she treated over her hospital course?
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Dr. Schultz: In the ED, we initiated treatment for her malaria as well as symptomatic care. She received intravenous fluids and electrolyte repletion with serial bedside glucose monitoring. Ceftriaxone and vancomycin were administered to cover for common bacterial pathogens in the pediatric population (Streptococcus pneumoniae, Haemophilus influenzae, Neisseria meningitidis, Escherichia coli, methicillin-resistant Staphylococcus aureus), as 5–8% of children with cerebral malaria have concurrent bacterial infections (13). Whereas patients with uncomplicated falciparum malaria can be treated with oral quinine plus doxycycline or clindamycin, severe malaria is typically treated with parenteral quinidine (14,15). These agents were included in her therapeutic regimen, but our infectious disease consultants also recommended that we initiate treatment with i.v. artesunate. Dr. Maldonado: Can you discuss artesunate as an antimalarial agent? What does it offer over standard therapies and why it was selected for use in this patient? Dr. Schultz: Artesunate is a newer antimalarial agent that has been shown to decrease mortality in severe malaria compared to i.v. quinidine (16). Artesunate is a prodrug for its active metabolite, dihydroartemisinin, and has been shown to treat fever and clear parasitemia faster than other antimalarials (17,18). In addition, it has fewer side effects than quinine and quinidine, which can cause nausea, vomiting, dizziness, tinnitus, hearing loss, hypoglycemia, and cardiotoxicity (19). Although its mechanism of action is not well understood, it is thought to involve the inhibition of a key parasite ATPase or the production of free radicals in the parasite food vacuole. One meta-analysis of six randomized trials comparing artesunate with quinine recommended artesunate as the drug of choice for adults with severe malaria after finding that artesunate significantly reduced mortality, parasite clearance time, and hypoglycemia (16,17,19). Artesunate is not approved by the Food and Drug Administration, but can be used via an Investigational New Drug (IND) application from the Centers for Disease Control and Prevention (CDC). Patients are eligible to receive artesunate if they have >5% parasitemia or signs of severe malaria (e.g., altered mental status, jaundice, anemia). The IND protocol recommends artesunate be administered at 2.4 mg/kg/day divided into four equal doses, for 3 days total (19). After 3 days, patients should be transitioned to a longer-acting antimalarial such as doxycycline, clindamycin, or atovaquone/proguanil (17). Our patient qualified for artesunate due to her high parasite load and signs of severe malaria. Its benign side-effect profile and rapid onset of action were further benefits in this child with cerebral malaria, where the long-term effects of reduced cerebral blood flow and hypoxia can be devastating.
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Dr. Maldonado: After the patient’s blood smear showed significant parasitemia, the diagnosis of malaria seemed clear. Assuming she had been infected with malaria at her initial presentation to her pediatrician’s office, what do you make of her positive heterophile (Monospot) test at that time? Dr. Schultz: Heterophile antibody tests are rapid, inexpensive, and commonly used to diagnose Epstein-Barr virus (EBV) infection. However, heterophile antibodies are nonspecific and can be identified in a number of conditions with abnormal structure or function of erythrocytes (20,21). As a result, falsely positive Monospot tests have been reported in malaria, sickle cell disease, toxoplasmosis, cytomegalovirus, hepatitis, human immunodeficiency virus, brucellosis, Lyme disease, syphilis, Dengue fever, babesiosis, and drug reactions (21–24). Several studies have focused on the associations between malaria, EBV, and heterophile antibody testing. One study examined heterophile antibody activity in the sera of patients in malarious and nonmalarious areas of Tanzania and found elevated levels of the antibody in sera of both groups. The comparable presence of heterophile antibody suggests that the antibody may not be in reaction to malaria itself but to RBC deformities: either long-standing, as with sickle cell disease, or acquired, as during the replication phase of active malarial infection (21). Postulated, although unproven, is that the generation of heterophile antibodies during malarial replication may be a protective immune reaction to the deformation of host RBCs in efforts to remove these cells from host circulation (21). Although co-infection with malaria and EBV was possible for this patient, she was not formally tested for EBV titers during her hospital course. The clinical assumption was that the positive heterophile test was likely a false-positive test and secondary to the underlying malaria. Dr. Maldonado: What are the long-term effects of cerebral malaria? What was the patient’s hospital course and long-term outcome? Dr. Schultz: Up to 25% of children with cerebral malaria have some level of long-term neurocognitive impairment. Reported sequelae include spasticity, cranial palsies, aphasia, seizure disorders, attention deficits, and impairments in executive function and memory (8). Patients with hypoglycemia, seizures, prolonged coma, and hyporeflexia have a greater risk of long-term cognitive impairment (6,8). Rapid treatment of the underlying malaria with attention to neurologic status and associated manifestations of severe parasitemia are essential to optimal care. Our patient was treated with 3 days of intravenous artesunate, with discontinuation of clindamycin and quinidine once artesunate was initiated. Peripheral blood
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smears were monitored, and the parasitemia decreased from 32% on the day of her admission to 1.7% the following day, to undetectable levels by her third hospital day. In addition to the multidrug regimen above, our patient also received an exchange transfusion, often performed in cerebral or severe malaria, or if there is >10% parasitemia. She was then transitioned to oral atovaquone/proguanil for a 3-day course, as per the CDC artesunate protocol guidelines. The patient continued on ceftriaxone and vancomycin for 48 h until blood and urine cultures were found to be negative. An electroencephalogram was performed and showed generalized delta slowing without focal features or epileptiform activity. A brain magnetic resonance imaging study did not reveal any signs of meningitis, encephalitis, or vasculitis. After receiving a fosphenytoin load for seizure prophylaxis, she was transitioned to twice daily fosphenytoin for 3 days. This was changed to twice daily levetiracetam, which was continued as an outpatient for 1 month and then gradually weaned off over a 2-week period. The patient followed up in the Pediatric Neurology clinic 1 month after discharge. At that time, she had made a full recovery and had no residual hyperreflexia, weakness, or headaches. Her mother reported normal baseline activity at home and in school. Her neurological examination in the office was completely normal. Dr. Maldonado: What are the major take-home points for this case? Dr. Schultz: In terms of disease recognition, it is vital to consider malaria in the returning traveler for any febrile patient who has been abroad, even if other diagnoses (as in this case, with possible mononucleosis) have been made. Malaria can present with a spectrum of clinical signs and symptoms; understanding both the direct and indirect clinical manifestations of parasitemia is crucial for time-sensitive critical care of ill patients and reducing the risk of long-term sequelae. Artesunate is a valuable agent in the treatment of severe and cerebral malaria; knowing the standard treatment protocols and evolving treatment options available for care at the local and national level can improve overall treatment and outcomes for severely ill patients presenting with malaria. REFERENCES 1. Centers for Disease Control and Prevention (CDC). Health information for travelers to Ghana. Available at: http://wwwnc.cdc.gov/ travel/destinations/traveler/none/GHANA#travel-notices. Accessed April 24, 2014.
5 2. Wilson ME, Freedman DO. Etiology of travel-related fever. Curr Opin Infect Dis 2007;20:449–53. 3. Hill DR. The burden of illness in international travelers. N Engl J Med 2006;354:115–7. 4. Speil C, Mushtaq A, Adamski A, Khardori N. Fever of unknown origin in the returning traveler. Infect Dis Clin North Am 2007; 21:1091–113. , x. 5. World Health Organization. Management of severe malaria: a practical handbook. 3rd edn. Geneva, Switzerland: World Health Organization; 2013. Available at: www.who.int/malaria/publications/ atoz/9789241548526/en/. Accessed April 24, 2014. 6. Idro R, Jenkins NE, Newton CR. Pathogenesis, clinical features, and neurological outcome of cerebral malaria. Lancet Neurol 2005;4: 827–40. 7. Phillips RE, Solomon T. Cerebral malaria in children. Lancet 1990; 336:1355–60. 8. Idro R, Marsh K, John CC, et al. Cerebral malaria: mechanisms of brain injury and strategies for improved neurocognitive outcome. Pediatr Res 2010;68:267–74. 9. Beare NA, Lewallen S, Taylor TE, et al. Redefining cerebral malaria by including malaria retinopathy. Future Microbiol 2011;6:349–55. 10. Beare NA, Taylor TE, Harding SP, et al. Malarial retinopathy: a newly established diagnostic sign in severe malaria. Am J Trop Med Hyg 2006;75:790–7. 11. Hawkes M, Elphinstone RE, Conroy AL, et al. Contrasting pediatric and adult cerebral malaria: the role of the endothelial barrier. Virulence 2013;4:543–55. 12. John CC, Bangirana P, Byarugaba J, et al. Cerebral malaria in children is associated with long-term cognitive impairment. Pediatrics 2008;122:e92–9. 13. Berkley J, Mwarumba S, Bramham K, et al. Bacteraemia complicating severe malaria in children. Trans R Soc Trop Med Hyg 1999;93:283–6. 14. White NJ. The treatment of malaria. N Engl J Med 1996;335: 800–6. 15. Fraser IP, Cserti CM, Dzik WH. Case records of the Massachusetts General Hospital. Case 32-2006. A 3-year-old girl with fever after a visit to Africa. N Engl J Med 2006;355:1715–22. 16. Sinclair D, Donegan S, Isba R, et al. Artesunate versus quinine for treating severe malaria. Cochrane Database Syst Rev 2012;6: CD005967. 17. Jones KL, Donegan S, Lalloo DG. Artesunate versus quinine for treating severe malaria. Cochrane Database Syst Rev 2007;(4): CD005967. 18. Kyu HH, Fernandez E. Artemisinin derivatives versus quinine for cerebral malaria in African children: a systematic review. Bull World Health Organ 2009;87:896–904. 19. Rosenthal PJ. Artesunate for the treatment of severe falciparum malaria. N Engl J Med 2008;358:1829–36. 20. Meuwissen JH, Leeuwenberg AD, Molenkamp GE. Studies on various aspects of the indirect haemagglutination test for malaria. Bull World Health Organ 1972;46:771–82. 21. Houba V, Faulk WP, Matola YG. Heterophilic antibodies in relation to malarial infection: population and experimental studies. Clin Exp Immunol 1974;18:89–93. 22. Cahill JD. Malaria with a positive ‘monospot’ test. J R Soc Med 2000;93:336. 23. Cunha BA, Mickail N, Laguerre M. Babesiosis mimicking Epstein Barr Virus (EBV) infectious mononucleosis: another cause of false positive monospot tests. J Infect 2012;64:531–2. 24. Cunha BA, Munoz-Gomez S. Dengue fever in a returning traveller from El Salvador: another cause of a false positive Monospot test. Travel Med Infect Dis 2014;12:293–5.
Case Presentations of the Harvard Emergency Medicine Residencies
ALTERED MENTAL STATUS AND FEVER Lauren M. Allister, MD,*† Megan L. Schultz, MD, MA,‡§ David F. M. Brown, MD,*† and Emily S. Miller, MD*† *Department of Emergency Medicine, Harvard Medical School, Boston, Massachusetts, †Department of Emergency Medicine, Massachusetts General Hospital, Boston, Massachusetts, ‡Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, and §Department of Pediatrics, Massachusetts General Hospital, Boston, Massachusetts Reprint Address: Emily S. Miller, MD, Department of Emergency Medicine, Massachusetts General Hospital, Harvard Medical School, Zero Emerson Place, Suite 3B, Boston, MA 02114
a presumed diagnosis of urinary tract infection vs. another unspecified bacterial process. The day after this visit the monospot test resulted as positive; the family was informed of a presumed diagnosis of mononucleosis and told to continue antibiotics. The patient transiently improved, but in the 3 days prior to ED presentation, she began to complain of headache and developed neck pain, fever to 39 C, progressive anorexia, decreased oral intake, and increasing fatigue. On the morning of presentation to the ED, her mother found her difficult to arouse from sleep, febrile, and confused. Review of symptoms was negative for vomiting, diarrhea, abdominal pain, chest pain, cough, abnormal movements, joint swelling, and rash. Her mother reported that the patient may have collided with another girl during a soccer game 1 week prior, but stated she had not lost consciousness or had worsening symptoms after that event. The patient had a past medical history notable for mild asthma and multiple food allergies and was taking the recently prescribed amoxicillin/clavulanic acid along with her regular medications: montelukast, mometasone furoate, and fluticasone proprionate nasal sprays, as well as an albuterol inhaler as needed. The patient had been prescribed atovaquone/proguanil, but neither she nor her other family members took any chemoprophylaxis during the trip, as they had frequently visited family in Ghana and had
Dr. Lauren Allister: Today’s case is that of an 8-year-old girl who presented to the Emergency Department (ED) with fever and altered mental status. The patient was reportedly well until 2 weeks prior to her ED visit when she presented to her pediatrician with headache and sore throat. Multiple family members had similar symptoms at that time. The family had recently returned from a multiple-week visit to Ghana but had not had any sick contacts while abroad. At the initial pediatrician visit, the patient was well appearing and, on examination, was found to have an erythematous, exudative posterior oropharynx with associated cervical lymphadenopathy. A rapid antigen test for Group A Streptococcus was performed at this visit and was negative. The patient was discharged home with a presumed viral infection. The patient continued to feel increasingly unwell with persistent fever, and returned to the pediatrician 3 days later. At the second visit the patient was more ill appearing, was febrile to 38.7 C, and had a persistently erythematous and exudative oropharynx. She appeared tired but had a nonfocal neurological examination. Given these persistent and progressive symptoms, laboratory studies were performed. The white blood cell count was 17,200 cells/mm3, urinalysis revealed mild pyuria (11 white blood cells/high power field), and a monospot test (heterophile antibody test) was sent. The patient was discharged home on oral amoxicillin/clavulanic acid with
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never previously contracted any travel-borne illnesses. She had no recent new food or environmental exposures. She had no significant infectious history. She had no known drug allergies. Dr. Nicholas Maldonado: Can you describe her physical examination upon presentation to the ED? Dr. Allister: The patient was intermittently responsive, with a waxing and waning mental status; she was occasionally awake and answering questions, but was then agitated and confused, and subsequently was somnolent. Vital signs were notable for a temperature of 37 C (98.6 F) after having recently been medicated with acetaminophen, heart rate of 130 beats/min, blood pressure of 91/48 mm Hg, respiratory rate of 20 breaths/min, and an oxygen saturation of 100% on 2 L of supplemental oxygen via nasal cannula placed on arrival. The head was normocephalic and atraumatic. Pupils were equally round and reactive to light with intact extraocular movements; however, horizontal nystagmus, scleral icterus, and conjunctival pallor were appreciated. The oropharynx was clear. The neck was supple with full range of motion. The chest examination was clear bilaterally without crackles, retractions, or increased work of breathing. Cardiac examination was notable for tachycardia without rubs, gallops, or murmurs. The abdomen was soft, nontender to palpation, and without appreciable hepatosplenomegaly. She was moving all extremities equally. The skin was notable for brisk capillary refill and there were no petechiae, purpura, or other rashes or lesions. Neurologic examination was notable for waxing and waning mental status and gross hypertonia without abnormal movements or weakness; however, she was unable to follow most commands. Dr. Maldonado: Before you began your initial evaluation, what diagnoses were you considering in this patient? Dr. Allister: The first diagnostic considerations were infectious etiologies related to the recent trip to Ghana with her family. Malaria, yellow fever, typhoid, and meningitis (Neisseria meningitidis) are infections endemic to this region of Africa (1). We also considered non-travelborne illnesses including viral, bacterial, or Lyme meningitis or encephalitis, or an evolving sepsis picture. Given the positive heterophile testing at the primary care physician’s office, as well as documented pyuria, progressive mononucleosis or a progressive urinary tract infection could also have been possible etiologies for the worsening clinical picture. We discussed whether her altered mental status could be secondary to a mixed infectious/ toxidrome picture, such as acetaminophen toxicity from overuse of acetaminophen as an antipyretic or Reye syndrome (rapidly progressive encephalopathy with hepatic failure) if salicylates had been used for antipyresis. There was an incidental report of a head strike a week prior to
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presentation, so an evolving traumatic intracranial injury mixed with a febrile illness was also a consideration. Dr. Maldonado: What were your initial steps in the stabilization and evaluation of this patient? Dr. Megan Schultz: Initial stabilization involved assessing this patient’s airway, breathing, and circulation. She was maintaining her airway, and oxygen saturation on 2 L of nasal cannula oxygen was 100%. She was hemodynamically stable with brisk capillary refill. A peripheral intravenous (i.v.) line was placed. Laboratory studies were sent, including a complete metabolic panel, complete blood count with differential, Lyme titer, comprehensive serum toxicology panel, urinalysis, blood and urine cultures, and a thick and thin blood smear for malaria. A head computed tomography (CT) scan was performed to assess for traumatic findings or abnormalities suggestive of central nervous system infection or changes in intracranial pressure. Dr. Maldonado: What were the results of these initial tests and how did they influence your differential diagnosis? Dr. Schultz: The initial laboratory testing was significant for anemia (hematocrit 14.7%), thrombocytopenia (platelets 33,000/mm3), mild electrolyte dysfunction (bicarbonate of 21.8 mmol/L, calcium 7.8 mg/dL, phosphorus 3.0 mg/dL), and abnormal liver function tests (protein 5 g/dL, albumin 2.6 g/dL, aspartate aminotransferase 67 U/L, direct bilirubin 2.1 mg/dl, total bilirubin 4.2 mg/dL). The lactate was elevated at 3.8 mmol/L. The white blood cell count, other electrolytes, and coagulation profiles were normal. The initial glucose measurement was 102 mg/dL. Toxicology screening was normal and an initial Lyme antibody test was negative. The head CT scan did not show any evidence of hemorrhage or mass lesion. Less than 1 h into her evaluation we received the critical result of the thick and thin smear for malaria, which showed 32% parasitemia with preliminary forms consistent with Plasmodium falciparum (Figure 1). Our working diagnosis from that point forward was malaria, with which the other labs were consistent, and more specifically, cerebral malaria. Dr. Maldonado: Can you discuss how you made the diagnosis of cerebral malaria? How does this categorization differ from other presentations of malaria? Dr. Schultz: Several large studies have shown that malaria is the most common cause of fever in travelers returning from a tropical country, and our patient had further malaria risk factors in being an American-born nonimmune child of immigrants, staying with family while in Ghana, and not being chemoprophylaxed (2–4). The severity of malaria is typically classified by the degree of peripheral parasitemia as well as clinical and laboratory findings. Although the correlation between parasitemia and prognosis varies by the level of malaria
Altered Mental Status and Fever
Figure 1. Peripheral blood smear demonstrating intraerythrocytic Plasmodium falciparum (arrows indicate three of the many infected cells present on the slide).
transmission in a specific area, malaria mortality first begins to rise with parasite densities >100,000/mm3, or 2.5% parasitemia (5). The clinical findings of severe malaria include altered mental status, weakness, seizures, respiratory distress, renal failure, disseminated intravascular coagulopathy, jaundice, and shock (6). The laboratory findings include anemia (hemoglobin < 5 g/dL), hypoglycemia (glucose < 40 mg/dL), metabolic acidosis (bicarbonate < 15 mmol/L), hemoglobinuria, increased lactate (lactate > 5 mmol/L), and increased creatinine (>3 mg/dL) (5). Severe malaria is diagnosed when a patient has confirmed parasitemia and any one of the above clinical or laboratory findings. Our patient met criteria for severe malaria by virtue of her parasitemia, altered mental status, weakness, jaundice, and anemia. Cerebral malaria is the most severe manifestation of malaria and is strictly defined as coma with parasitemia on peripheral blood smear (6). In practice, the definition of cerebral malaria can be broadened to include impaired consciousness or abnormal neurological findings, or both, such as seizures, abnormal respiratory patterns, abnormal pupillary and eye movements, increased tone, posturing, abnormal reflexes, and retinopathy (7). Cerebral malaria can be challenging to diagnose because its neurological features are nonspecific. For example, seizures can be seen with profound hypoglycemia and fever, both of which are features of severe malaria. In addition, patients in malaria-endemic areas can have incidental parasitemia found on peripheral smear that is wholly unrelated to their neurological findings (8). This potential ambiguity requires that, to accurately diagnose cerebral malaria, all other causes of encephalopathy must first be excluded or corrected (e.g., correction of hypoglycemia, cultures of cerebrospinal fluid to look for bacterial meningitis). The inclusion of ‘‘malaria retinopathy’’ (retinal whitening and vessel
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color changes, both specific to malaria) as part of the definition for cerebral malaria has been proposed to help more clearly define the diagnosis and its central nervous system manifestations (9,10). Our patient had a significantly altered mental status. Her head CT scan was normal, her electrolytes were only mildly altered, and her blood glucose was normal. She was too clinically unstable and thrombocytopenic for us to safely perform a lumbar puncture in the ED, but we felt that the likelihood of concomitant viral, Lyme, or bacterial meningitis was unlikely. Therefore, given her tenuous mental status that was evolving toward potential coma, her other manifestations of severe malaria, and the significant peripheral parasitemia, we felt that she met the criteria for the diagnosis of cerebral malaria. Dr. Maldonado: What causes cerebral malaria? What were you most concerned about acutely in the ED? Dr. Schultz: The exact pathophysiology of cerebral malaria remains unclear, with multiple postulated mechanisms for the central nervous system effects. One theory hypothesizes that central nervous system symptoms are mediated through sequestration of parasitized red blood cells (pRBCs) in cerebral microvasculature (8). This is caused by adherence of the pRBCs to endothelial lining, pRBC auto-agglutination, platelet-mediated clumping, and rosette formation between pRBCs and nonparasitized erythrocytes (8). Dysfunction of the blood–brain barrier and inflammatory cytokines such as tumor necrosis factor and quinolinic acid may also play a role. Together, these mechanisms result in reduced cerebral blood flow, hypoxia, hypoglycemia, and intracranial hypertension (7,8). For pediatric patients, whose developing brains are potentially more susceptible to traumatic, ischemic, toxic, and inflammatory insults, the clinical presentation of cerebral malaria can differ from their adult counterparts (7,11). Seizures, neurological sequelae at the time of hospital discharge, abnormal brainstem reflexes, and longer-term neurocognitive deficits are more frequently reported in pediatric patients with cerebral malaria (6,11,12). Other features of cerebral malaria such as retinopathy, cerebral edema, and elevated cerebrospinal fluid pressures are reported with equal frequency in pediatric and adult patients (11). The overall mortality rate is generally lower in children compared to adults (11). For our patient, we were concerned about evolving multisystem end organ damage and rapid progression of central nervous system disease. It was essential for us to quickly initiate antimalarial treatment as well as neuroprotection. Dr. Maldonado: What therapy did you initiate for this patient in the ED, and how was she treated over her hospital course?
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Dr. Schultz: In the ED, we initiated treatment for her malaria as well as symptomatic care. She received intravenous fluids and electrolyte repletion with serial bedside glucose monitoring. Ceftriaxone and vancomycin were administered to cover for common bacterial pathogens in the pediatric population (Streptococcus pneumoniae, Haemophilus influenzae, Neisseria meningitidis, Escherichia coli, methicillin-resistant Staphylococcus aureus), as 5–8% of children with cerebral malaria have concurrent bacterial infections (13). Whereas patients with uncomplicated falciparum malaria can be treated with oral quinine plus doxycycline or clindamycin, severe malaria is typically treated with parenteral quinidine (14,15). These agents were included in her therapeutic regimen, but our infectious disease consultants also recommended that we initiate treatment with i.v. artesunate. Dr. Maldonado: Can you discuss artesunate as an antimalarial agent? What does it offer over standard therapies and why it was selected for use in this patient? Dr. Schultz: Artesunate is a newer antimalarial agent that has been shown to decrease mortality in severe malaria compared to i.v. quinidine (16). Artesunate is a prodrug for its active metabolite, dihydroartemisinin, and has been shown to treat fever and clear parasitemia faster than other antimalarials (17,18). In addition, it has fewer side effects than quinine and quinidine, which can cause nausea, vomiting, dizziness, tinnitus, hearing loss, hypoglycemia, and cardiotoxicity (19). Although its mechanism of action is not well understood, it is thought to involve the inhibition of a key parasite ATPase or the production of free radicals in the parasite food vacuole. One meta-analysis of six randomized trials comparing artesunate with quinine recommended artesunate as the drug of choice for adults with severe malaria after finding that artesunate significantly reduced mortality, parasite clearance time, and hypoglycemia (16,17,19). Artesunate is not approved by the Food and Drug Administration, but can be used via an Investigational New Drug (IND) application from the Centers for Disease Control and Prevention (CDC). Patients are eligible to receive artesunate if they have >5% parasitemia or signs of severe malaria (e.g., altered mental status, jaundice, anemia). The IND protocol recommends artesunate be administered at 2.4 mg/kg/day divided into four equal doses, for 3 days total (19). After 3 days, patients should be transitioned to a longer-acting antimalarial such as doxycycline, clindamycin, or atovaquone/proguanil (17). Our patient qualified for artesunate due to her high parasite load and signs of severe malaria. Its benign side-effect profile and rapid onset of action were further benefits in this child with cerebral malaria, where the long-term effects of reduced cerebral blood flow and hypoxia can be devastating.
L. M. Allister et al.
Dr. Maldonado: After the patient’s blood smear showed significant parasitemia, the diagnosis of malaria seemed clear. Assuming she had been infected with malaria at her initial presentation to her pediatrician’s office, what do you make of her positive heterophile (Monospot) test at that time? Dr. Schultz: Heterophile antibody tests are rapid, inexpensive, and commonly used to diagnose Epstein-Barr virus (EBV) infection. However, heterophile antibodies are nonspecific and can be identified in a number of conditions with abnormal structure or function of erythrocytes (20,21). As a result, falsely positive Monospot tests have been reported in malaria, sickle cell disease, toxoplasmosis, cytomegalovirus, hepatitis, human immunodeficiency virus, brucellosis, Lyme disease, syphilis, Dengue fever, babesiosis, and drug reactions (21–24). Several studies have focused on the associations between malaria, EBV, and heterophile antibody testing. One study examined heterophile antibody activity in the sera of patients in malarious and nonmalarious areas of Tanzania and found elevated levels of the antibody in sera of both groups. The comparable presence of heterophile antibody suggests that the antibody may not be in reaction to malaria itself but to RBC deformities: either long-standing, as with sickle cell disease, or acquired, as during the replication phase of active malarial infection (21). Postulated, although unproven, is that the generation of heterophile antibodies during malarial replication may be a protective immune reaction to the deformation of host RBCs in efforts to remove these cells from host circulation (21). Although co-infection with malaria and EBV was possible for this patient, she was not formally tested for EBV titers during her hospital course. The clinical assumption was that the positive heterophile test was likely a false-positive test and secondary to the underlying malaria. Dr. Maldonado: What are the long-term effects of cerebral malaria? What was the patient’s hospital course and long-term outcome? Dr. Schultz: Up to 25% of children with cerebral malaria have some level of long-term neurocognitive impairment. Reported sequelae include spasticity, cranial palsies, aphasia, seizure disorders, attention deficits, and impairments in executive function and memory (8). Patients with hypoglycemia, seizures, prolonged coma, and hyporeflexia have a greater risk of long-term cognitive impairment (6,8). Rapid treatment of the underlying malaria with attention to neurologic status and associated manifestations of severe parasitemia are essential to optimal care. Our patient was treated with 3 days of intravenous artesunate, with discontinuation of clindamycin and quinidine once artesunate was initiated. Peripheral blood
Altered Mental Status and Fever
smears were monitored, and the parasitemia decreased from 32% on the day of her admission to 1.7% the following day, to undetectable levels by her third hospital day. In addition to the multidrug regimen above, our patient also received an exchange transfusion, often performed in cerebral or severe malaria, or if there is >10% parasitemia. She was then transitioned to oral atovaquone/proguanil for a 3-day course, as per the CDC artesunate protocol guidelines. The patient continued on ceftriaxone and vancomycin for 48 h until blood and urine cultures were found to be negative. An electroencephalogram was performed and showed generalized delta slowing without focal features or epileptiform activity. A brain magnetic resonance imaging study did not reveal any signs of meningitis, encephalitis, or vasculitis. After receiving a fosphenytoin load for seizure prophylaxis, she was transitioned to twice daily fosphenytoin for 3 days. This was changed to twice daily levetiracetam, which was continued as an outpatient for 1 month and then gradually weaned off over a 2-week period. The patient followed up in the Pediatric Neurology clinic 1 month after discharge. At that time, she had made a full recovery and had no residual hyperreflexia, weakness, or headaches. Her mother reported normal baseline activity at home and in school. Her neurological examination in the office was completely normal. Dr. Maldonado: What are the major take-home points for this case? Dr. Schultz: In terms of disease recognition, it is vital to consider malaria in the returning traveler for any febrile patient who has been abroad, even if other diagnoses (as in this case, with possible mononucleosis) have been made. Malaria can present with a spectrum of clinical signs and symptoms; understanding both the direct and indirect clinical manifestations of parasitemia is crucial for time-sensitive critical care of ill patients and reducing the risk of long-term sequelae. Artesunate is a valuable agent in the treatment of severe and cerebral malaria; knowing the standard treatment protocols and evolving treatment options available for care at the local and national level can improve overall treatment and outcomes for severely ill patients presenting with malaria. REFERENCES 1. Centers for Disease Control and Prevention (CDC). Health information for travelers to Ghana. Available at: http://wwwnc.cdc.gov/ travel/destinations/traveler/none/GHANA#travel-notices. Accessed April 24, 2014.
5 2. Wilson ME, Freedman DO. Etiology of travel-related fever. Curr Opin Infect Dis 2007;20:449–53. 3. Hill DR. The burden of illness in international travelers. N Engl J Med 2006;354:115–7. 4. Speil C, Mushtaq A, Adamski A, Khardori N. Fever of unknown origin in the returning traveler. Infect Dis Clin North Am 2007; 21:1091–113. , x. 5. World Health Organization. Management of severe malaria: a practical handbook. 3rd edn. Geneva, Switzerland: World Health Organization; 2013. Available at: www.who.int/malaria/publications/ atoz/9789241548526/en/. Accessed April 24, 2014. 6. Idro R, Jenkins NE, Newton CR. Pathogenesis, clinical features, and neurological outcome of cerebral malaria. Lancet Neurol 2005;4: 827–40. 7. Phillips RE, Solomon T. Cerebral malaria in children. Lancet 1990; 336:1355–60. 8. Idro R, Marsh K, John CC, et al. Cerebral malaria: mechanisms of brain injury and strategies for improved neurocognitive outcome. Pediatr Res 2010;68:267–74. 9. Beare NA, Lewallen S, Taylor TE, et al. Redefining cerebral malaria by including malaria retinopathy. Future Microbiol 2011;6:349–55. 10. Beare NA, Taylor TE, Harding SP, et al. Malarial retinopathy: a newly established diagnostic sign in severe malaria. Am J Trop Med Hyg 2006;75:790–7. 11. Hawkes M, Elphinstone RE, Conroy AL, et al. Contrasting pediatric and adult cerebral malaria: the role of the endothelial barrier. Virulence 2013;4:543–55. 12. John CC, Bangirana P, Byarugaba J, et al. Cerebral malaria in children is associated with long-term cognitive impairment. Pediatrics 2008;122:e92–9. 13. Berkley J, Mwarumba S, Bramham K, et al. Bacteraemia complicating severe malaria in children. Trans R Soc Trop Med Hyg 1999;93:283–6. 14. White NJ. The treatment of malaria. N Engl J Med 1996;335: 800–6. 15. Fraser IP, Cserti CM, Dzik WH. Case records of the Massachusetts General Hospital. Case 32-2006. A 3-year-old girl with fever after a visit to Africa. N Engl J Med 2006;355:1715–22. 16. Sinclair D, Donegan S, Isba R, et al. Artesunate versus quinine for treating severe malaria. Cochrane Database Syst Rev 2012;6: CD005967. 17. Jones KL, Donegan S, Lalloo DG. Artesunate versus quinine for treating severe malaria. Cochrane Database Syst Rev 2007;(4): CD005967. 18. Kyu HH, Fernandez E. Artemisinin derivatives versus quinine for cerebral malaria in African children: a systematic review. Bull World Health Organ 2009;87:896–904. 19. Rosenthal PJ. Artesunate for the treatment of severe falciparum malaria. N Engl J Med 2008;358:1829–36. 20. Meuwissen JH, Leeuwenberg AD, Molenkamp GE. Studies on various aspects of the indirect haemagglutination test for malaria. Bull World Health Organ 1972;46:771–82. 21. Houba V, Faulk WP, Matola YG. Heterophilic antibodies in relation to malarial infection: population and experimental studies. Clin Exp Immunol 1974;18:89–93. 22. Cahill JD. Malaria with a positive ‘monospot’ test. J R Soc Med 2000;93:336. 23. Cunha BA, Mickail N, Laguerre M. Babesiosis mimicking Epstein Barr Virus (EBV) infectious mononucleosis: another cause of false positive monospot tests. J Infect 2012;64:531–2. 24. Cunha BA, Munoz-Gomez S. Dengue fever in a returning traveller from El Salvador: another cause of a false positive Monospot test. Travel Med Infect Dis 2014;12:293–5.
