Bad to the bone: A case of altered mental status

The case

A 5-year-old female with no significant past medical history presented to the emergency department (ED) in 2016 with altered mental status, decreased activity, fever, and decreased oral intake. Her mother reports that she was in her usual state of health until 1 week prior to presentation when she developed low grade fevers and abdominal pain with associated complaints of headaches, neck pain, and muscle aches. She was able to tolerate water but her overall oral intake was diminished with a marked decrease in urine output, worsening to once daily.

History and exam

The patient’s mother took her to a local hospital 4 days prior to her ED presentation with complaints of fever (maximum temperature 104°F), headache, and neck pain. She was discharged home when her influenza, streptococcal throat swab, chest x-ray, and urinalysis were all unremarkable. In the days following, she became increasingly too weak to get out of bed, was intermittently confused, refused to answer questions, and was more lethargic. The night before her ED presentation, her mother was extremely concerned when the patient could not remember her name or her parents’ names. Parents denied any rashes, vision changes, vomiting, or diarrhea.

The patient had no previous hospitalizations and was otherwise a healthy child. Her family history was reviewed and was non-contributory. She attended school and lived with her parents, aunt, and grandmother. The patient does not have any siblings. There were no reported sick contacts, allergies, recent travel, or new exposures. The patient’s immunizations were up to date.

On presentation to the ED, her vital signs were as follows: temperature 99.5°F; heart rate 135 beats/min; respiratory rate 24 breaths/min; blood pressure 71/52 mm Hg; oxygen saturation was 99% on room air; weight was 20.4 kg. On physical examination, she was awake, ill-appearing, but not toxic. She was not answering questions but would respond “ow” and “nothing is helping” to painful stimuli. Physical exam was otherwise significant for a normocephalic and atraumatic head, sunken eyes, and dry mucosal membranes. She was tachycardic with 2+ distal pulses bilaterally and a brisk capillary refill. Neurologically, she was altered and had positive Brudzinski and Kernig signs. Her Glasgow Coma Scale (GCS) was 13 (eyes 4, verbal 4, and motor 5).

Laboratory testing

Preliminary laboratory data in the ED revealed leukocytosis with a white blood cell count of 17,830/mm³, with 86% neutrophils, 6% lymphocytes and 6% monocytes. Her hemoglobin was low at 11.6 g/dL and she was thrombocytopenic with a platelet count of 22,000/mm³. A comprehensive metabolic panel revealed the following data: sodium 123 meq/L, potassium 5.0 meq/L, chloride 80 meq/L, carbon dioxide 13 meq/L, BUN 105 mg/dL, creatinine 2.5 mg/dL, glucose 105 mg/dL, calcium 8.2 mg/dL, total protein was 5.7 g/dL, and albumin were 2.8 g/dL. Her anion gap was elevated at 30 meq/L. All other metabolic panel results were unremarkable. Her C-reactive protein (CRP) was elevated at 20.8 mg/dL (normal range <0.5 mg/dL). Her lactic acid levels, PT and INR, and PTT were unremarkable. Due to her altered mental status, a computed tomography (CT) scan of her head was obtained and did not reveal any acute abnormalities.

Differential diagnosis

The most common cause of altered mental status in children is infection¹ which is consistent with this patient’s presentation of altered mental status in the setting of fever and found to have an elevated CRP and neutrophilia (Table 1). Given the patient’s positive Brudzinski and Kernig signs, bacterial, viral, fungal, and tubercular meningitides were possible sources of infection¹ that could not be excluded because the patient was not a candidate for LP given her significant thrombocytopenia. Encephalitis commonly presents with decreased consciousness² and could not be ruled out definitively without further infectious disease workup, including repeat head imaging. Other sources of infection included myocarditis, endocarditis, urinary tract infection, or pneumonia, but were less congruent with the patient’s presenting symptoms. Given the patients’ hypotension in the setting of infection, altered mental status secondary to sepsis should be considered. Sepsis-associated encephalopathy (SAE) is a term that refers to diffuse brain dysfunction resulting from cerebral hypoperfusion and/or alterations of the blood brain barrier due to systemic infection causing cognitive impairment.³ It is characterized by diffuse brain dysfunction elsewhere in the body without overt central nervous system infection.⁴ The source and etiology of infection are important factors in the development of SAE.⁴ The greatest risk of SAE is associated with biliary tract or intestinal infections followed by pulmonary infections. The most commonly implicated organisms are Staphylococcus Aureus, Enterococcus faecium, Acinebacter spp, Pseudomonas aeruginosa, and Stenotrophomonas maltophilia.^4,5 More severe brain dysfunction and higher mortality rates were observed in patients with SAE infected with multiple bacteria or Candida albicans.^4,6 Although not as well studied in children, SAE in adults presents with nonfocal neurologic manifestations and can present as a depressed state.⁷

Another potential cause of altered mental status could be toxic exposure. Exploratory ingestions are common in children aged younger than 6 years. (Table 1).⁸ The clinical presentation of occult ingestion varies depending on the ingested substance and occult toxic exposure should be considered in the differential diagnosis of a child who presents with acute onset multisystem dysfunction, unexplained metabolic acidosis, and altered mental status.⁹ However, the likelihood of a toxic ingestion underlying this patient’s presentation was low as the patient was not in the “at risk” age group of incidental ingestions (aged 1 to 4 years old), lacked a history of previous ingestions, and did not have exposure to commonly ingested agents such as cleaning products, analgesics, cough medications, topical agents, or pesticides. Additionally, the timeline of the onset of her presentation was inconsistent with an acute toxic ingestion.

Table 1

The patient’s basic metabolic panel was indicative of an anion gap metabolic acidosis and thus, metabolic disorders should be considered as a cause of her altered mental status (Table 1). Diabetic ketoacidosis could have been underlying her anion gap metabolic acidosis, but was less likely in the absence of polyuria, polydipsia, hyperglycemia, and a negative past medical history. Lactic acidosis in the setting of hypoperfusion due to sepsis could be considered, but her lactate levels were only mildly elevated suggesting that lactic acidosis was unlikely the underlying cause of her altered mental status. Other causes of anion gap metabolic acidosis include ingestion of toxic materials such as methanol, ethylene glycol, and salicylate poisoning. Her lack of exposure to these substances and more insidious onset of illness were inconsistent with toxic ingestion. Her presenting hypotension and elevated creatinine suggest that the most likely etiology of her anion gap metabolic acidosis was acute kidney injury (AKI) precipitated by severe dehydration. This may have contributed to her altered mental status, but would not account for the patient’s initial fever and lethargy that were more consistent with an infectious etiology.

Discussion

The patient’s hypotension, tachycardia, and leukocytosis raised concern for sepsis. The incidence of sepsis, characterized by immune dysregulation, has been steadily increasing in children since the mid-1990s¹⁰ with an estimated global incidence of pediatric and neonatal sepsis of 25.2 million in 2017.¹¹ Sepsis accounts for 4.4% of admissions to children’s hospitals with approximately 75,000 children hospitalized for severe sepsis each year.^10,12-14 Definitions of sepsis and organ dysfunction developed by the International Consensus Conference on Pediatric Sepsis help physicians identify sepsis, determine its severity, and monitor progression of a child’s illness.¹³ The consensus criteria also divide sepsis into categories based on the severity of presentation: severe inflammatory response (SIRS), severe sepsis, and septic shock, and multiple organ failure.¹³ The definition and clinical markers of sepsis differs in children compared to adults. In adults, elevated lactate is an important marker of sepsis and reduction of lactate levels is associated with improved adult survival.¹⁵ However, little evidence supports the use of lactate as a marker of clinical significance in children.¹⁵ Other inflammatory biomarkers, such as c-reactive protein (CRP) and procalcitonin may be useful in identifying infection, especially in patients with no apparent infection source¹⁶ or with neutropenia.¹⁷ C-reactive protein is also useful as a guide for de-escalation of antibiotics in patients without an identifiable source of infection.¹⁸ There has been some literature supporting the use of molecular methods to distinguish between bacterial and viral infections, including polymerase chain reaction (PCR) and detection of bacteria 16S (RNA) genes. Some evidence suggests that these methods have the potential to differentiate bacterial from viral infection in children with high accuracy,¹⁹ which has potential benefits regarding antibiotic stewardship.

Early identification of sepsis is important to ensure timely administration of broad-spectrum antibiotics and identification of an infection source to enable more targeted treatment. Although mortality in children due to severe sepsis is less than 10%,^10,13,20 morbidity is significant in pediatric patients with septic shock further emphasizing the importance of early identification and treatment of sepsis to prevent adverse outcomes. Because children can compensate for circulatory dysfunction, hypotension is a late finding and this can make early identification of sepsis difficult.²¹

Non-bacterial infections may cause a systemic inflammatory response that mimics sepsis, which should be taken into account when considering a clinical picture of sepsis. Epstein-Barr Virus-associated hemophagocytic syndrome (HPS) can present with signs of severe sepsis.²² Hemophagocytic syndrome is a condition in which T-cells, natural killer cells, and macrophages are abnormally activated causing hypercytokinemia leading to cell death and eventually multiorgan failure.^22–24 Epstein-Barr Virus is the most common infectious cause of HPS.^22,24,25 Hemophagocytic symdrome should be considered in the differential in patients presenting with prolonged fever, pancytopenia, and a sepsis-like picture that is unresponsive to antibiotics.²²

Patient course and management

In the ED, the patient was given intravenous (IV) ceftriaxone after blood cultures were drawn due to the high concern for meningitis and IV ketorolac for pain prior to the return of her laboratory results. The patient was not a candidate for LP given her thrombocytopenia. Vancomycin was held when her laboratory results revealed an AKI. She remained hypotensive after 3 normal saline boluses and was started on dopamine at 10 mcg/kg/min, titrated down to 5 mcg/kg/min for normotension. She was admitted to the pediatric intensive care unit for further management of her hypotension, which was thought to be due to septic shock and subsequently intubated due to concern for respiratory failure likely due to aggressive fluid resuscitation and infection (Figures 1a,b,c). Ceftriaxone was continued; vancomycin was started; and steroids were held given low likelihood of Streptococcus pneumoniae as the patient was up to date on her vaccinations. She was also started on acyclovir given concern for viral meningitis. An echocardiogram ruled out myocarditis and endocarditis as an infectious source. Her AKI was thought to be caused by volume depletion secondary to decreased fluid intake prior to admission and exacerbated by home ibuprofen use and ketorolac administration in the ED. Her renal function and hyponatremia noted on her initial labs resolved quickly with fluid resuscitation and without further renal sequelae.

Figure 1a-c

Given her altered mental status, a brain magnetic resonance imaging (MRI/MRA) was ordered and significant for a tiny focus of restricted diffusion in the white matter of the posterior left frontal lobe consistent with early subacute infarct (Figure 2a). On hospital day 5, she was extubated and found to have right-sided motor deficits. Repeat imaging revealed extensive skull base and cervical osteomyelitis and arteritis with complete occlusion of flow in the left carotid artery and limited flow in the right carotid artery with primary circulation through the posterior vessels (Figure 2b,c,d). The MRI also showed an extensive left side frontal lobe infarct (Figure 2b,c). The CT angiogram of her head and neck confirmed occlusion of the left internal carotid artery and marked narrowing of the right internal carotid artery. The CT was also significant for opacification of the sphenoid sinus and left mastoid air cells thought to be consistent with an infectious process. The following day, she had sphenoid abscess drainage via functional endoscopic sinus surgery and tympanostomy tubes placed by otolaryngology due to the extensive middle ear effusion noted on CT. She was treated with vancomycin, ceftriaxone, and clindamycin for 5 days, at which time the clindamycin was discontinued. Aerobic culture of sinuses was positive for coagulase positive Staphylococcus and anaerobic culture of sinuses was negative for growth. Cultures including blood cultures drawn in the ED and bacterial and viral CSF cultures were negative. The final diagnosis was skull base and cervical osteomyelitis caused by coagulase positive Staphylococcus. Origin of her osteomyelitis remained unclear.

Figure 2a-d

She was hospitalized for 6 weeks. Prior to discharge, she regained speech function; hemiparesis improved; renal function normal. She was treated with Lovenox for her infarcts. One month after discharge, she had no neurological deficits and returned to school. She has been seen in the ED for minor infections and injuries and is doing well without any sequelae from hospitalization.

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