Catastrophic Neurologic Disorders in the Emergency Department , 2nd Edition

Chapter 7. Confused and Febrile

Fever and confusion are common presenting problems in the emergency department and thus are combined here. Fever in sick, dazed patients is often tied to an acute neurologic illness. It matters in which emergency department, in which place in the world the patient has recently traveled,1 whether patients present in summer and fall, and whether the patient is immunocompromised.2,3 Infection of the central nervous system (CNS) is readily considered, and decisions may have to be made quickly on a few clinical clues. The mortality and morbidity from the ravages of infection as a result of procrastination are very high. Also, evidence of an infection outside the CNS may not be immediately obvious and a great number of diagnostic possibilities are present. Fever and confusion can be caused by bacteremia, focal bacterial infection (upper respiratory tract, skin, and soft tissue infection), and nonbacterial illness such as viremia, drug fever, or malignant neuroleptic syndrome, malignancy, connective tissue disease, and thromboembolism. One should pity the physician (mostly the neurologist) who must make sense out of a perplexed, irritable, impulsive, desultory, markedly uncooperative febrile patient making smutty remarks. This chapter provides methodological diagnostic steps in organizing the evaluation of these patients. More specific disorders are discussed in Chapters 17 and 18.

Clinical Assessment

The diagnostic possibilities remain beyond measure if not narrowed down by additional distinctive symptoms. The most useful inquiries in the histories are shown in Table 7.1. For example, neurologic examination could indicate that confusion means aphasia, a postictal state, or nonconvulsive status epilepticus. Unusual signs may need attention and certainly could have a nonneurologic, infectious explanation. These are muscle rigidity (strychnine in illicit drugs, rabies, tetanus), myoclonus (Salmonella typhi), and trismus (tetanus). Fever and confusion can be associated with marked rigidity and tremors in the face and arms and should suggest an acute autonomic storm (neuroleptic malignant syndrome, lethal catatonia, or serotonin syndrome; see Chapter 5).4

The major domains of neurologic examination of a confused and febrile patient should include a serious attempt to assess demeanor and orientation, followed by thought content, attention, language, memory, and visuospatial skills. Each of these cognitive spheres may be judged in only a hurried cursory manner when agitation or delirium is prominent (Box 7.1).5 First, it is important to observe the patient's poise. Uneasiness and restlessness may also indicate a medical disorder (e.g., hyperthyroidism, hypoglycemia, severe hypoxemia) or drug intoxication (e.g., theophylline, lidocaine). Impulsivity and emotional outburst and their opposite manifestation, abulia, are largely due to acute frontal lesions. Second, orientation is addressed and requires simple questions such as “How did you get here?” or “Where are you?” or “What is the month and year?” or “Why are you here?” However, the content of the answers may be disturbed with perseveration (continuation of thoughts) and intrusions (words from prior context, often due to aphasia). Attention tests include spelling words backward, reciting the days of the week in reverse order, or other spelling tests. Language should at least include assessment of fluency, inflection and melody, rate, volume, articulation, and comprehension. Memory testing is challenging in confused febrile patients, but remote memory (significant life events in the family) or recent breaking news can be assessed. Visuospatial orientation may be briefly assessed by the patient localizing body parts or clock drawing and filling in the numbers. All of these manifestations may be stable, progressing, or fluctuating.

Table 7.1. Critical Observations and Clues in the Confused Febrile Patient

·  Debilitated, wasted, underfed (drug abuse, alcoholism, cancer)

·  Prior transplantation or AIDS (Toxaplasma encephalitis or aspergillus)

·  Beginning of endemic encephalitis (arboviruses)

·  Exposure to wilderness, tropics, animal bite (rabies)

·  Exposure to excessive heat (heatstroke)

·  Recent travel or immigration from developing country (neurocysticercosis, fungal meningitis)

·  Recent vaccination (ADEM)

ADEM, acute demyelinating encephalomyelitis; AIDS, acquired immunodeficiency syndrome.

Confusional behavior may be due to mass lesions, which often produce language disorders. Masses in the frontal lobe that are located on the right (in right-handed persons) may enlarge to impressive tumors that may not be detected by even the most meticulous neurologic examination. A left frontal lobe mass, particularly if the lesion extends posteriorly, is manifested by Broca's aphasia. Its characteristics are distinct; the patient is constantly unable to repeat an exact sentence, speaks in short phrases and with revisions, and makes major grammatical errors together with loss of cohesion in lengthier narratives. Frontal lobe syndrome has been well recognized and appears in many guises, such as loss of vitality and notable slow thinking. It may be manifested by weird behavior, sexual harassment, cynically inappropriate remarks in an attempt to be humorous, or intense irritability. Any executive function requiring planning ahead or some type of organization and planning is disturbed but may be covered up by euphoria, platitudes in speech, or “robot-like” behavior, in many with preservation of social graces.

Masses in the temporal lobe may also generate changes in behavior and therefore may remain unnoticed or be delayed in recognition. Left-sided masses may change a normal personality into one of depression and apathy. More posterior localization in the temporal lobe may produce Wernicke's aphasia. This classic type of aphasia is recognized by continuously “empty” speech, often with syllables, words, or phrases at the end of sentences and characteristically with incomprehensible content (e.g., one of our patients, asked to define island, responded “place where petos… no trees… united presip thing” and to define motor, responded “thing that makes the drive thing”). Involvement of the nondominant temporal lobe may be manifested by an upper quadrant hemianopia and nonverbal auditory agnosia (inability to recognize daily familiar sounds, such as a loud clap or tearing of paper).

Parietal lobe masses also produce effects that depend on localization. Right parietal lesions usually cause neglect of the paralyzed right limb up to entire unawareness but also cause marked inertia and aloofness. A dominant (left in right-handed persons) parietal lobe impairs normal arithmetical skills, ability to copy three-dimensional constructions (e.g., making interlocking rings with the index finger and thumb), recognition of fingers, and rightleft orientation. A non-fluent aphasia may occur as well.

Occipital lobe masses produce hemianopia. When only the inferior occipital cortex is involved, achromatopsia (loss of color vision in a hemianopic field) or abnormal color naming (“What is the color of the sky, an apple, a tomato”) may result. Extension into the subcortical area from edema might produce alexia without agraphia, but all in a left occipital lesion.

Systemic signs can provide a clue to the infectious agent. Obviously, an illness beginning with a cough suggests a primary respiratory infection, but there is a broad differential diagnosis. Community-acquired respiratory infection, a proclivity for systemic manifestations include influenza A and B, adenoviral infection, Mycoplasma pneumoniae, Legionella pneumophila, and reactivation of tuberculosis. All of these disorders could have neurologic manifestations. An illness with a prominent rash, fever, and confusion could be due to viral, bacterial, and fungal agents with a possibility of seeding in the CNS (Table 7.2).

The multisystem involvement (myocarditis, pneumonia, lymphadenopathy, or hepatorenal dysfunction) associated with encephalopathy could indicate a certain infectious agent. Diagnostic considerations should include Q fever6 (periventricular or focal edema on magnetic resonance imaging [MRI]), pneumonia, lymphocytic pleocytosis caused by zoonotic agent Coxiella burnetii, leptospirosis (meningitis, hepatic dysfunction, muscle pain, conjunctivitis), tularemia (ulceroglandular disease, conjunctivitis, and lymphadenopathy), Mycoplasma pneumoniae (pneumonia, transverse myelitis, conjunctivitis), and cat-scratch disease (lymphadenopathy, vasculitis caused by Bartonella henselae).7

Box 7.1. DSM-IV Diagnostic Criteria for Delirium due to Multiple Etiologies

A. Disturbance of consciousness (i.e., reduced clarity of awareness of the environment), with reduced ability to focus, sustain, or shift attention.

B. A change in cognition (e.g., memory deficit, disorientation, language disturbance) or the development of a perceptual disturbance that is not better accounted for by a prescription-existing, established, or evolving dementia.

C. The disturbance develops over a short period of time (usually hours to days) and tends to fluctuate during the course of the day.

D. There is evidence from the history, physical examination, or laboratory findings that the delirium has more than one etiology (e.g., more than one etiologic general medical condition, a general medical condition plus substance intoxication, or medication side effect).

Coding note: Use multiple codes reflecting specific delirium and specific etiologies (e.g., delirium due to viral encephalitis, alcohol withdrawal delirium).

With permission from American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 4th ed. Washington DC: American Psychiatric Association, 1994.

Table 7.2. Clinical Signs Indicating Central Nervous System Disease in Confused Febrile Patients



Skin rash

·  Rickettsial diseases

·  Vasculitis

·  Aspergillosis


·  Thrombocytopenic purpura

·  Meningococcemia

·  Endocarditis

·  Drug eruption from intoxication

·  Leukemia


·  Toxoplasmosis

·  Tuberculosis

·  Sepsis

·  Human immunodeficiency virus infection

·  Lymphoma

Pulmonary infiltrates

·  Legionella species

·  Fungi

·  Tuberculosis

·  Mycoplasma

·  Pneumonia

·  Q fever

·  Tick-borne diseases

In any patient, it is important to consider an immunocompromised state, which raises an entirely different set of possibilities.2 Acute HIV infections can be present in a young adult with fever, confusion, lymphadenopathy, pharyngitis, and rash. One may consider questioning patients about sexual practice or intravenous drug abuse.

It would be inappropriate to have a too narrow scope in analyzing causes of febrile confusion, linking it only to meningoencephalitis. Specialization may in fact be a disadvantage when interpreting clinical signs in patients with such a broad presentation. Many systemic illnesses may produce a confusional state and agitation, and the major considerations are shown in Table 7.3.6

Febrile neutropenia is a common finding in patients with recently treated malignancies, particularly with aggressive myelosuppressive drugs. Infections become frequent and severe, with neutrophil counts less than 100 cells/mL. Remission induction therapy for acute leukemia is commonly followed by a prolonged period of virtually absent neutrophils. The most common pathogens in patients with neutropenia are Staphylococcus epidermidis, Streptococcus spp., Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa. Many yeasts or fungi can be implicated. In hematologic malignancies, Listeria monocytogenes, Cryptococcus neoformans, Toxoplasma gondii, and Nocardia are common CNS infections when patients present with febrile neutropenia. When an Ommaya reservoir is in situ for chemotherapeutic delivery in leptomeningeal disease, coagulase-negative staphylococci and other skin inhabitants can be implicated. Patients seen in the emergency department with neutropenia, prior induction therapy or bone marrow transplant, pneumonia, or other documented infection as well as a major comorbid condition should be admitted using empirical broad-spectrum antibiotics and aggressive evaluation of its source.

Table 7.3. Systemic Illnesses Producing Fever and Confusion

·  Septic shock

·  Thyrotoxicosis

·  Anticholinergic drug intoxication

·  Streptococcal shock syndrome

·  Heat stroke

·  Lobar pneumonia

·  Acute osteomyelitis

·  Abdominal suppuration

·  Endocarditis

·  Erysipelas

·  Measles

·  Psittacosis

·  Influenza

·  Yellow fever

·  Typhoid fever

·  Cholera

Line of Action

It is virtually impossible to approach these patients from every conceivable angle. Clearly, primary disorders of the CNS need rapid assessment because therapeutic options are limited and time-locked. Encephalitis (particularly arboviruses),8,9 meningitis, vasculitis, parainfectious encephalopathy, or a postictal state from epilepsy should be considered.

Studies with the highest yield and in the shortest period of time are needed and should be prioritized. To bring some clarity in patients who present with multiple converging problems, steps are shown in Figure 7.1. When the suspicion of intracranial disease is high, it is quite justifiable to temporarily sedate the patient (e.g., propofol), intubate, administer antibiotic agents and acyclovir, and obtain MRIs while obtaining cerebrospinal fluid (CSF).

The most reasonable sequence of evaluation is first to obtain laboratory data that could suggest a possible systemic infection. The chance of a bacterial infection increases with age (>50 years), erythrocyte sedimentation rate (>30), white blood cell count (>15,000), bands (>1500), and comorbid illness.10,11Laboratory tests should include a toxicology screen and drug levels, if needed, in addition to routine chemistry and hematology markers. Initially, an electroencephalogram should have some priority but may be artifactually abnormal or show a medication effect when sedative drugs are needed to control agitation. If no obvious or clearly defined abnormalities are present, one should proceed with a computed tomographic scan or MRI when encephalitis is present. MRI will, early in the disease, document characteristic findings of herpes simplex (temporal lobe subinsular region), mosquito-borne encephalitis (cortical spotted lesions and basal ganglia), hyperintensities, or enhancing meninges (fungal or bacterial meningitis).12 Almost simultaneously, CSF analysis should be sent for multiple polymerase chain reactions (PCRs), and failure to do so is a lost opportunity to diagnose the underlying organism.13 PCRs are robust in documenting the presence of herpes simplex, Epstein-Barr virus, and varicella-zoster DNA and may detect organisms that do not grow in culture.14 Fungal meningoencephalitis is very uncommon, but cryptococcosis, coccidioidomycosis, Histoplasma capsulatum, and Blastomyces dermatitidis are more endemic.12 Detection by growth in CSF or of specific antibody is possible, but multiple CSF specimens are needed to detect a positive culture.

Figure 7.1 Critical steps in the evaluation of the febrile confused patient. CT, computed tomography; MR, magnetic resonance; FLAIR, fluid attenuation inversion recovery; GAD, glutamic acid decarboxylase; CBC, complete blood count; CSF, cerebrospinal fluid; PCR, polymerase chain reaction; IGM, immunoglobulin M; DWI, diffusion-weighted imaging.

Table 7.4. Etiologies of Central Nervous System Disease and Their Detection by Laboratory Methods



Diagnostic Tests Recommended


Viral (with or without accompanying meningitis)

Herpes simplex virus-1

Polymerase chain reaction (PCR) and cell culture of cerebrospinal fluid (CSF) and tissue

Varicella-zoster virus (VZV)

PCR and cell culture of CSF and tissue


PCR in cell fluid CSF and tissue

Epstein-Barr virus

Antibody (serum), PCR of tissue


Immunoglobulin M (IgM) and IgG antibody (serum and CSF), antigen detection and PCR (brain tissue) available for some viruses

West Nile virus

PCR testing of CSF, IgM antibody (CSF and serum)

Colorado tick fever virus

Antibody (serum)

Human immunodeficiency virus

Laboratory testing not specific for central nervous system (CNS) involvement

JC polyoma virus (agent of progressive multifocal leukoencephalopathy)

PCR testing of CSF, PCR or in situ hybridization of brain tissue


Antigen testing of skin biopsy (hair follicles), conjunctival smear or brain tissue, PCR testing of tissue

Herpes B virus

Cell culture or PCR of lesion (special biocontainment laboratory required)


Document recent infection at primary site outside CNS


Bacterial causes

Rickettsia rickettsii (Rocky Mountain spotted fever)

Antibody (serum)

Borrelia burgdorferi

Antibody (serum and CSF), PCR testing of CSF

Treponema pallidum

Antibody (serum and CSF)

Mycoplasma pneumoniae

Antibody (serum), culture

Fungal causes


Fungal culture for all

Blastomyces dermatitidis

Fungal stain of CSF recommended

Coccidioides immitis

Antibody (serum and CSF)

Cryptococcus neoformans

Cryptococcal antigen (CSF and serum)

Parasitic causes

Naegleria species

Histopadiology, direct microscopic examination for ameba

Plasmodium falciparum

Examination of thick and thin smears made with finger-stick blood

Toxoplasma gondii

Histopathology, antibody (serum)


Acute (neutrophilic pleocytosis)

Streptococcus pneumoniae

Gram stain and aerobic culture for all except amebas and anaerobes

Neisseria meningitidis

Bacterial antigen testing rarely useful

Listeria monocytogenes

Bacterial antigen testing rarely useful

Streptococcus agalactiae

Bacterial antigen testing rarely useful

Haemophilus influenzae

Bacterial antigen testing rarely useful

Streptococcus aureus

Gram-negative bacilli*

Anaerobic bacteria

Anaerobic transport and culture

Ameba (Naegleria and Acanthamoeba species)

Microscopic examination of CSF and coculture with Escherichia coli or Stenotrophomonas maltophilia

Chronic (predominantly lymphocytic pleocytosis)


Bacterial causes

Nocardia asteroides complex

Modified acid-fast stain, aerobic bacterial or fungal culture

Brucella species

Aerobic bacterial cultures, hold agar plates 14 days, inoculate aerobic blood culture bottle with additional fluid

Leptospira interrogans

CSF dark-field examination and culture, antibody tests (serum)

Mycobacterium tuberculosis

CSF acid-fast culture and PCR where available

Treponema pallidum

Antibody tests (serum and CSF)

Borrelia burgdorferi

Antibody tests (serum and CSF)

Fungal causes

CSF fungal culture for all

Cryptococcus neoformans

Cryptococcal antigen test (CSF)

Candida species

Gram stain for fungi (CSF) useful with shunt infections

Coccidioides immitis

Antibody tests (CSF and serum)

Histoplasma capsulatum

Histoplasma antigen testing (CSF and urine)

Blastomyces dermatitidis

Gram stain for fungi (CSF) may be useful

Other opportunistic filamentous

Gram stain for fungi (CSF) may be useful fungi

Parasitic causes

Taenia soleum (cysticercosis)

Microscopic examination of aspiration material or biopsy, antibody (serum by immunoblot)

Echinococcus granulosis (echinococcosis)

Examination of removed cyst or cyst fluid for scolices

Toxoplasma gondii

PCR testing of CSF

Trichinella spiralis

Microscopic examination of muscle for larvae, antibody testing (serum)

Angiostrongylus species

Eosinophilic meningitis

Baylisascaris (raccoon ascarid)

Eosinophilic meningoencephalitis

Viral “aseptic” (initially neutrophilic, then mononuclear pleocytosis)



PCR testing of CSF, cell culture of lesion, antibody (serum) occasionally useful

Mumps virus

CSF, cell culture IgM and IgG antibody (serum)

Herpes simplex viruses 1 and 2

PCR testing of CSF

Lymphocytic choriomeningitis virus

antibody (serum)

Varicella-zoster virus

PCR testing of CSF


PCR testing of CSF

Epstein-Barr virus

PCR testing of CSF

*Includes common arboviruses in North America, such as St. Louis encephalitis, LaCrosse encephalitis, and eastern and western equine encephalitis viruses.
Postinfectious encephalitis caused by measles virus, VZV, influenza virus, and vaccinia (pox) virus.
Source: Thomson RB Jr, Bertram H: Laboratory diagnosis of central nervous system infections. Infect Dis Clin North Am 15 (no. 4):1047, 2001. By permission of Elsevier.

CSF in herpes simplex encephalitis will show a characteristic formula of normal or raised pressure at 10–200 cells (lymphocytes)/mm3, normal glucose, and increased protein but can be normal in 5% of presenting cases.15,16 CSF and serum antibodies (immunoglobulins M and G) should be obtained specific to any mosquito-borne viral encephalitis and repeated after 1 week. Indirect immunofluorescent assays are useful if Rocky Mountain spotted fever or ehrlichiosis is considered.16,17

When CSF is suggestive of an infection, it would be prudent to start with a multipronged approach directed against possible resistant bacteria (fourth-generation cephalosporin), herpes simplex (acyclovir and vancomycin), and ticks (doxycycline), while awaiting test results. The importance of dexamethasone is discussed in Chapter 17. The current laboratory methods assisting in diagnosis of meningitis or encephalitis are shown in Table 7.4. The interpretation of MRI and CSF is not considered further but is described in Chapters 16 and 17.


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