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A 72-year-old woman presents to an emergency department (ED) in Denver, with confusion and aphasia. She has been sent from a nursing home, where she is receiving treatment for an acute kidney injury, after suddenly losing her ability to communicate verbally and understand verbal instructions.

Assessment upon her arrival at the ED does not show a fever, and the following was noted:

• Pulse rate: 72 beats per minute

• Respiratory rate: 18 breaths per minute

• Blood pressure: 175/67 mm Hg

• Oxygen sat­uration: 97% breathing on 2 L/minute by nasal cannula

• Weight: 77.2 kg (170.2 lbs)

According to the nursing home report, it has been more than 4 hours since the patient was observed at her baseline. Laboratory tests performed prior to her arrival at the hospital show a blood glucose of 61 mg/dL; dextrose has not improved her mental status.

The patient is awake and able to move her arms and legs and open and move her eyes spontaneously, but she cannot speak or follow commands with any consistency.

Assessment reveals a Glasgow Coma Scale (GCS) score of 10 on admission (eye 4, verbal 2, motor 4). Her inability to follow commands interferes with some aspects of a neurologic examination, including assessment of motor strength, presence of pronator drift, and asterixis.

Clinicians make a diagnosis of receptive and expressive aphasia. The patient can respond and withdraw to painful stimuli in all extremities. Her reflexes are symmetric throughout, and there is no evidence of clonus or Babinski sign. Her pupils are equally reactive and there is no facial droop, convulsions, or myoclonic jerks. Cardiovascular and pulmonary examinations show normal results, as does examination of the abdomen, aside from numerous well-healed surgical scars.

The patient's recent medical history includes a stage IV sacral wound and osteomyelitis of the pelvis. She has insulin-dependent diabetes, and a chronic indwelling Foley catheter. Her medical history includes hypertension, Roux-en-Y gastric bypass, and coronary artery disease. She has no history of dementia. Prior to entering that facility for treatment of these conditions, she was living in her own residence without assistance.

At the nursing home, the patient was being treated with intravenous antibiotics for her wound and receiving rehabilitation for her osteomyelitis. Her medications included cefepime 2 grams intravenous every 8 hours and daptomy­cin 400 mg intravenous every 24 hours for ongoing treatment of pelvic osteomyelitis, insulin via an insulin pump, aspirin, prasugrel, pantoprazole, lisinopril, and metoprolol succinate.

Laboratory tests on arrival note elevated se­rum creatinine of 1.2 mg/dL with a blood urea nitrogen of 53 mg/dL when compared with baseline of 0.8 mg/dL. To account for the patient's weight, clinicians apply a modified Cockcroft-Gault equation and note a creatinine clearance of 45 mL/minute, although based on her recent kidney injury, the team suspects that her true glomerular filtration rate is likely lower.

Tests show that her levels of sodium, glucose, and other electrolytes are within normal limits. Complete blood count shows a normal white count of 7.2 k/μL, hemoglobin of 11.2 g/dL, and elevated platelets of 541 k/μL, suggesting chronic anemia.

Urinalysis identifies 3+ leukocytes. Liver function test results show aspartate aminotransfer­ase of 75 U/L and alanine aminotransferase of 90 U/L; the rest of the test results are normal.

The patient's thyroid function is normal, and a urine drug screen is negative. Although her presentation of acute aphasia suggests a possible left hemispheric transient ischemic attack or stroke, this concern is allayed when results of a computed tomography scan of the brain with angi­ography is normal. Similarly, follow-up magnetic resonance imag­ing shows no evidence of acute stroke or abnormalities in the left frontal or temporal lobes.

Clinicians were not able to assess the patient for infectious encephalitis with a lumbar puncture when she was admitted due to her inability to follow commands and the need to coordinate procedural sedation with anesthesia. The authors consider the patient to have acute delirium of unknown origin.

Diagnosis of Exclusion

Despite the abnormal findings on urinalysis, the absence of fever, the normal white blood cell count, and the patient's ongoing treatment with broad-spectrum antibiotics all eliminate acute infection as a probable cause. Clinicians also rule out the presence of meta­bolic abnormalities such as hypoglycemia and hyponatremia.

Likewise, the patient has no history of sedating medica­tions, toxic ingestions, or trauma to account for her condition. Clinicians obtain blood and urine cultures, and start the patient on broad-spectrum antibiot­ics and delirium precautions. After 24 hours, her condition has not improved, and she is not able to take any oral food or fluids; despite receiving intravenous fluids and supportive care, her serum creatinine increases to 1.9 mg/dL.

When the standard work-up yields no likely cause of the encephalopathy, clinicians broaden their line of inquiry. The patient's persistent aphasia and delirium 4 weeks after an acute kidney injury and initiation of treatment with cefepime prompt­ consideration of cefepime-induced neurotoxicity. Cefepime is discontinued, and an electroencephalogram (EEG) is ordered to evalu­ate for nonconvulsive status epilepticus (NCSE).

The pa­tient is placed on con­tinuous EEG monitoring and given two doses of 2 mg intravenous lorazepam and a 1,000 mg loading dose of intravenous levetiracetam. Within minutes of initial lorazepam administration, the NCSE resolves and clinicians subsequently note intermittent normalization of the EEG.

Based on the initial EEG finding, in addition to both the follow-up EEG findings and the patient's clinical improvement after anticonvulsant administration, the clinicians determine that the patient meets the Salzburg criteria for "definite NCSE."

Once the NCSE resolves, the patient has a GCS score of 15, and she is speak­ing in complete sentences and following commands, although she remains slightly confused and cannot recall how she arrived at the hospital. Repeat EEG performed the following morning shows bi-hemispheric slowing, but there is no further evidence of seizure activity. Following discontinuation of cefepime, NCSE and clinical seizures are resolved.

Discussion

Clinicians presenting this of cefepime-induced neurotoxicity note that it appears to be a unique report in the literature, in that the neurotoxicity began after 4 weeks of intravenous cefepime for pelvic osteomyelitis. Cefepime-induced neurotoxicity is more often reported in intensive care units (ICUs) and neuro-ICU settings, and tends to develop within 10 days of starting cefepime for management of severe infection and sepsis.

In this case, because the sepsis and critical illness caused by the infection had al­ready resolved, the patient's presentation of acute enceph­alopathy and aphasia led to an initial evaluation for stroke in the ED.

When results of those investigations were negative and a urinalysis was positive, the patient was admitted to the general medicine service for manage­ment of delirium and a suspected urinary tract infection.

These various misdiagnoses delayed recognition of this serious condition. The case authors note that their goal in reporting this case is to describe the characteristics of , and to alert clinicians to the clinical characteristics of NCSE as a potential indication of cefepime toxicity.

While broad-spectrum antibiotics are often used in the ED and critical care settings as initial treatments in patients with severe sepsis and septic shock, extended use can have serious consequences, including antimicrobial resistance, nosocomial infections, increased costs, and severe side effects.

And while antibiotic-related neurologic com­plications such as in this case are generally rare, they have been well document­ed, the case authors note.

Challenges can include the following:

• Distinguishing neurologic effects of antibiotic treatment from infection-related delirium

• Identifying metabolic abnormalities caused by the underly­ing illness, or by other medications started during hospitalization

In patients receiving a prolonged course of antibiotics, renal and liver function must be closely monitored, since these can af­fect drug pharmacokinetics and dosing. In addition, the authors urge clinicians to be aware of the rare and dangerous complications of the drugs being prescribed.

Cefepime-Induced Neurotoxicity

Cefepime-induced neurotoxicity was first reported in 1999, with symptoms typically beginning 1 to 10 days after the start of treatment. The most common presentation is delirium (80%). Other presenting neurologic symptoms include myoclonus (40%), NCSE (31%), seizures (11%), and aphasia (9%).

The most common risk factors for development of this disorder include renal dysfunction (87%), older age, critical illness, and dosing not adjusted for renal func­tion (50%).

While the pathophysiology has yet to be fully understood, it is theoretically related to concentration-dependent competitive gamma aminobutyric acid antagonism, triggered by accumulation of ce­fepime in the central nervous system (CNS).

Diagnostic criteria for cefepime-induced neurotoxicity are one of the following:

• Temporal association of compatible neurologic symptoms after cefepime administration

• Clinical or EEG improvements after discontinuation of cefepime that are otherwise unexplained

Prior reviews show that delays in diagnosis are common. In this patient's case, the authors note, it was likely due to anchoring on more commonly seen diagnoses on the gen­eral medicine service.

NCSE

is defined as a continuous state of seizures without convulsions, or multiple noncon­vulsive seizures for more than 30 minutes without interic­tal full recovery.

Symptoms of NCSE vary and are nonspecific; additional testing including an EEG should be performed in patients with acute onset of any of the following potential symptoms of NCSE: altered mental status (82%), lethargy or coma (22%), speech distur­bances (15%), myoclonus (13%), and hallucinations (6%).

Despite the nonspecific presentation of NCSE, the case authors advise additional testing, including an EEG, in patients who suddenly develop any of these symptoms without an alternative ex­planation. The authors cite a study of acute geriatric ward admissions, which found that eight patients admitted with altered mental status initially thought to be due to a UTI who did not recover their prior neurologic status were found to have NCSE on EEG.

In critically ill patients, nonconvulsive seizures can have a wide range of causes, including traumatic brain injury, CNS infection, anoxic brain injury, subarachnoid hemorrhage, toxic-metabolic disturbances, and sepsis. In this case, none of these etiologies were revealed in the history or physical, laborato­ry evaluation, or imaging studies.

NCSE generally requires additional anticon­vulsant treatment. For generalized convulsive status epi­lepticus, intravenous lorazepam is the first-line treatment. Phenytoin, valproic acid, and levetiracetam may be used as second-line agents, although there are more data to support their use in other forms of seizure and epilepsy than in NCSE. Some patients may require dialysis to reduce cefepime concentrations, the researchers note, adding that the concentrations at which cefepime causes toxicity are not well defined, nor has a diagnostic level been identified. Data suggest that trough levels greater than 20 mg/L or steady state levels greater than 35 mg/L should be avoided.

The case authors suggest that early recogni­tion of cefepime's possible contribution to progressive con­fusion and delirium, and prompt withdrawal of the drug, is not only central to successfully managing this adverse effect but has also been linked with improved prognosis and neurologic recovery. Most patients' symptoms improve an average of 2 days after the drug is discontinued.

Conclusions

The case authors conclude that in this patient with pelvic osteomyelitis treated with cefepime, who presented with an acute kidney injury and acute encephalop­athy with aphasia, the timing of her kidney injury dur­ing the fourth week of therapy suggests that injury was the likely precipitating factor that led to decreased renal clearance and incorrect cefepime dosing.

Knowing the various and sometimes subtle mani­festations of NCSE (i.e., altered mental status), along with the common usage of cefepime, make having an understand­ing of this drug's neurologic complications critical for the gen­eral internist. The team urges EEG evaluation and cefepime discontinuation in patients with unexplained progres­sive delirium, myoclonus, or speech disturbances.

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