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73-Year-Old Woman With Fever and Mental Status Changes

      A 73-year-old right-handed woman from Wisconsin presented to her local hospital in early March with sharp central chest pain, epigastric discomfort, and painful swallowing. Findings on a work-up for intra-abdominal pathology and cardiac ischemia (including extensive blood work, serial electrocardiograms, and a computed tomographic [CT] scan of the abdomen and pelvis were unremarkable, and the patient was given a presumptive diagnosis of gastroesophageal reflux disease. Before discharge, however, the patient developed recurrent fevers ranging as high as 39.4°C and had difficulty with speaking. Over the next day, her mental status and speech continued to worsen, prompting transfer to Mayo Clinic in Rochester, Minn.
      The patient's medical history was notable for nonischemic dilated cardiomyopathy with frequent ventricular ectopy, polymyalgia, and hypothyroidism. Her surgical history included excision of 2 parathyroid glands for hyperparathyroidism. She had traveled only within the upper Midwest. Her medications were all oral and included 81 mg/d of aspirin, 12.5 mg of carvedilol twice daily, 50 mg/d of losartan, 40 mg/d of furosemide, 400 mg/d of amiodarone, 20 mg/d of prednisone (as part of a slow taper after an initial dosage of 30 mg/d started 4 months earlier), and 125 μg/d of levothyroxine.
      On physical examination, the patient had a temperature of 38.4°C, a heart rate of 92 beats/min, a regular blood pressure of 140/60 mm Hg, a respiratory rate of 24/min, and an oxygen saturation rate of 94% while breathing room air. Her mucous membranes were dry, and 2 shallow bleeding ulcers were noted on her upper palate and tongue. Findings on examination of the lungs, abdomen, extremities, and skin were normal. However, cardiac examination revealed a grade 2/6 systolic ejection murmur.
      Neurologic examination revealed that the patient was somnolent, opening her eyes and maintaining arousal only when verbally stimulated. She was unable to follow even simple 1-step commands and answered “yes” to most questions. Her speech was otherwise unintelligible. The patient was able to track with her eyes and blinked to threat bilaterally. Her optic discs were flat, and her face was symmetric. She had strong spontaneous movements of the upper and lower extremities and localized to pain throughout. Reflexes on the right were slightly stronger than those on the left. The right plantar response was extensor, whereas the left was flexor. No nuchal rigidity was observed.
      • 1.
        On the basis of available clinical information, which one of the following diagnoses is most likely in this patient?
        • a.
          Delirium
        • b.
          Urosepsis
        • c.
          Encephalitis
        • d.
          Thyroid storm
        • e.
          Ischemic stroke
      Although delirium can cause a sudden change in mental status in an acutely ill elderly patient, it is not the best single diagnosis in this case because the patient's mental status was progressively declining rather than fluctuating. Furthermore, delirium alone does not explain her fever or the focal findings on neurologic examination. Urosepsis could explain her fever but fails to explain the focal findings on neurologic examination. Encephalitis is the most likely diagnosis because inflammation of the brain parenchyma commonly causes mental status changes with focal neurologic deficits (such as the mixed expressive and receptive aphasia and right-sided hyperreflexia seen in this patient). Bacterial meningitis could also present in this manner, and headache and nuchal rigidity are not always present in elderly or immunosuppressed patients. Thyroid storm can cause high fevers and mental status changes, but other characteristic features such as tachycardia and tremor were notably absent. Although the patient had recently begun treatment with amiodarone, it would be unlikely to cause thyrotoxicosis in a patient with antecedent hypothyroidism. Finally, a low ejection fraction can predispose to cardioembolic stroke. However, the neurologic deficits caused by stroke are usually maximal at onset, unlike this patient's speech difficulty, which progressed over several hours.
      Thus, encephalitis is the most likely diagnosis. To further delineate the cause of the encephalitis, we performed additional tests. The patient had an elevated white blood cell count at 14.8 × 109/L (reference ranges shown parenthetically) (3.5-10.5 × 109/L) with neutrophilia. A noncontrast head CT scan was negative. Lumbar puncture revealed an opening cerebrospinal fluid (CSF) pressure of 130 mm H2O (60-200 mm H2O), a glucose level of 63 mg/dL, a protein level of 59 mg/dL (14-45 mg/dL), and 117 nucleated cells per μL (0-5 cells per μL). Of the nucleated cells, 24% were neutrophils, 19% lymphocytes, and 56% monocytes. There were 75 red blood cells per μL (0 cells per μL), and xanthrochromia was present. The serum glucose level was 90 mg/dL (70-100 mg/dL), making the CSF-to-serum glucose ratio 0.7 (normal ratio in nondiabetic patients is approximately 0.6). Gram stain of the CSF was negative.
      • 2.
        The above CSF findings are most consistent with which one of the following types of infection?
        • a.
          Bacterial
        • b.
          Viral
        • c.
          Granulomatous
        • d.
          Fungal
        • e.
          Parasitic
      Bacterial infections of the central nervous system (CNS) result in a low CSF glucose concentration (CSF-to-serum ratio <0.4), primarily because of impaired functioning of the glucose transporter system across the blood-brain barrier. Bacterial infections also elevate protein levels (often to >100 mg/dL) and cell (especially neutrophil) counts (often to >500 per μL). No such results were observed for this patient. In contrast, viral infections of the CNS typically do not alter the CSF glucose concentration, elevate protein levels more modestly, and result in a lymphocytic pleocytosis (although neutrophils can be seen early in the course of infection). The findings obtained through CSF examination of this patient were thus most consistent with a viral etiology. Like viral infections, granulomatous disease and fungal infections of the CNS cause moderate elevation of protein levels and a lymphocytic pleocytosis; unlike viral infections, however, they both lower the CSF glucose concentration. Parasitic infections such as cysticercosis are classically associated with an eosinophilic pleocytosis.
      Further testing included an electroencephalogram (EEG), which showed left frontotemporal periodic lateralized epileptiform discharges (PLEDs).
      • 3.
        Given this patient's presentation, which one of the following is the most likely infectious etiology?
        • a.
          West Nile virus
        • b.
          LaCrosse (California) encephalitis virus
        • c.
          Varicella zoster virus (VZV)
        • d.
          Lyme neuroborreliosis
        • e.
          Herpes simplex virus (HSV)
      West Nile virus and LaCrosse (California) encephalitis virus, both of which are arthropod-borne viruses (Arboviruses), produce epidemics of encephalitis during the summer months. As this patient presented in early March, she is unlikely to have either of these infections. Varicella zoster virus meningoencephalitis is more common in immunocompromised hosts and often (although not always) occurs as a complication of cutaneous zoster, which this patient did not have. Although VZV can cause the moderate elevations of protein and the lymphocytic pleocytosis seen in this patient's CSF, it does not account for the presence of red blood cells and xanthrochromia. Lyme disease typically causes meningitis associated with cranial neuropathies, which were not present in this patient. It is also caused by the spirochete Borrelia burgdorferi, which is a bacterium not a virus.
      Herpes simplex virus encephalitis, a necrotizing CNS infection with evidence of vascular invasion on pathologic study, causes xanthrochromia or increased numbers of red blood cells in the CSF of 84% of infected patients.
      • Whitley RJ
      • Soong SJ
      • Linneman Jr, C
      • Liu C
      • Pazin G
      • Alford CA
      Herpes simplex encephalitis: clinical assessment.
      Because this patient had both red blood cells and xanthrochromia in her CSF, HSV encephalitis is the most likely infectious etiology. Another clue to this diagnosis is the patient's initial complaint of painful swallowing and the presence of shallow oral ulcers on examination; however, neither of these findings is typical of HSV. The patient's mixed expressive-receptive aphasia and right-sided hyperreflexia reflect the predilection of HSV for the inferofrontal and temporal lobes. The presence of left frontotemporal PLEDs on her EEG was indicative of acute underlying injury and neurologic dysfunction. Intravenous (IV) acyclovir therapy was initiated for a presumptive diagnosis of HSV encephalitis.
      • 4.
        Which one of the following methods is the best way to confirm this diagnosis?
        • a.
          Analysis of serum antibody levels
        • b.
          Analysis of CSF antibody levels
        • c.
          Viral culture of CSF
        • d.
          Polymerase chain reaction (PCR) of CSF
        • e.
          Brain biopsy
      Although serum antibody levels may help distinguish primary from reactivated HSV infection, they are of no use in the diagnosis of acute HSV encephalitis. Cerebrospinal fluid antibody levels may help make a retrospective diagnosis of HSV encephalitis but are not recommended in the acute setting. Viral culture of CSF for HSV is less than 10% sensitive, making it a poor diagnostic test. Polymerase chain reaction of the CSF, which is rapid and has a high sensitivity and specificity for HSV encephalitis, is thus the diagnostic method of choice. Cell culture or immunohistochemical staining of brain biopsy specimens can identify HSV with even higher sensitivity and specificity, but these tests can only be obtained through invasive procedures and take days to yield results. Polymerase chain reaction of the patient's CSF eventually came back positive for HSV type 1.
      Several hours later, the patient's mental status declined, and she had a witnessed generalized tonic-clonic seizure. The seizure was quickly aborted with IV lorazepam, and a loading dose of fosphenytoin was given. After her seizure, the patient was noted to be less responsive, unable to follow commands, and essentially mute. She continued to open her eyes and track moving objects, but had new jerking eye movements to the right. She remained able to move all extremities and had no tonicclonic limb movements.
      • 5.
        Which one of the following tests would be the least helpful to investigate the patient's sudden change in mental status?
        • a.
          Head CT
        • b.
          Repeated lumbar puncture
        • c.
          Total and free serum phenytoin levels
        • d.
          Repeated EEG
        • e.
          Serum creatinine level
      Head CT is essential because the necrotizing nature of HSV encephalitis could lead to intracranial hemorrhage. Repeated lumbar puncture is of little use in this situation and could increase the risk of brain herniation if an intracranial hemorrhage were present. Total and free phenytoin levels are important as supratherapeutic levels can cause confusion and nystagmus. Repeated EEG is indicated as status epilepticus can occur despite therapeutic antiepileptic drug levels. Also, EEG is useful in differentiating ongoing seizure activity from a prolonged postictal state or medication effect. Cognitive decline and clonic eye movements in a patient with HSV encephalitis are highly suggestive of ongoing seizure activity, and treatment should not be delayed. Finally, serum creatinine level should be measured because the dose of acyclovir needs to be adjusted for renal function. When given at inappropriate dosages, acyclovir can cause confusion and somnolence.
      Repeated head CT showed only the expected evolution of HSV encephalitis without hemorrhage. Total and free serum phenytoin levels were 13.1 μg/mL (10-20 μg/mL) and 1.3 μg/mL (1.0-2.0 μg/mL), respectively. The serum creatinine level was 1.1 mg/dL (0.7-1.2 mg/dL). Repeated EEG showed frequent electrographic seizures consistent with nonconvulsive status epilepticus.
      The patient was transferred to an intensive care unit where she was placed on continuous EEG monitoring. She received additional doses of IV lorazepam and fosphenytoin until a high therapeutic level of phenytoin was achieved. With these measures, her seizures were controlled. She completed a 3-week course of acyclovir and received maintenance daily oral phenytoin. Her mental status normalized before discharge, but she had serious cognitive difficulties (primarily affecting short-term memory and judgment) that precluded her from living independently or returning to work. Her mixed expressive and receptive aphasia also persisted, although she did make some progress with speech therapy.

      DISCUSSION

      Herpes simplex virus encephalitis is the most common form of sporadic encephalitis in children older than 6 months and in adults, accounting for 10% to 20% of all cases of viral encephalitis per year (before the occurrence of West Nile Virus encephalitis).
      • Corey L
      • Spear P
      Infections with herpes simplex viruses (2).
      The age distribution of HSV encephalitis is bimodal, with one third of cases affecting children and adolescents and one half of cases affecting adults aged 50 years and older.
      • Whitley RJ
      • Soong SJ
      • Linneman Jr, C
      • Liu C
      • Pazin G
      • Alford CA
      Herpes simplex encephalitis: clinical assessment.
      Unlike other causes of viral encephalitis, HSV encephalitis has no seasonal variation.
      In immunocompetent adults, more than 90% of cases are caused by HSV type 1, which is usually due to reactivation of latent infection. Latent HSV type 1 is detectable in the trigeminal ganglia of nearly all seropositive persons.
      • Tyler KL
      Herpes simplex virus infections of the central nervous system: encephalitis and meningitis, including Mollaret's.
      Reactivation is thought to lead to viral spread via the trigeminal nerve to the face or lips (causing herpes labialis) or, less commonly, via tentorial nerves to the anterior and medial cranial fossa (causing HSV encephalitis). The virus can also spread to the temporal lobes via the olfactory tracts.
      • Tyler KL
      Herpes simplex virus infections of the central nervous system: encephalitis and meningitis, including Mollaret's.
      Counterintuitively, HSV encephalitis does not appear to be more common in immunocompromised patients.
      • Whitley RJ
      • Soong SJ
      • Linneman Jr, C
      • Liu C
      • Pazin G
      • Alford CA
      Herpes simplex encephalitis: clinical assessment.
      Such patients may, however, be more likely to develop HSV type 2 encephalitis, which is usually due to primary infection rather than reactivation.
      • Schiff D
      • Rosenblum MK
      Herpes simplex encephalitis (HSE) and the immunocompromised: a clinical and autopsy study of HSE in the settings of cancer and human immunodeficiency virus-type 1 infection.
      Herpes simplex virus encephalitis should be clinically suspected in patients presenting with acute-onset fever, headache, and altered sensorium with or without focal neurologic signs. Focal neurologic signs commonly seen in HSV encephalitis include hemiparesis, ataxia, dysphagia, aphasia, or seizures. More than 90% of patients with HSV encephalitis will have one of these signs together with fever.
      • Whitley RJ
      • Soong SJ
      • Linneman Jr, C
      • Liu C
      • Pazin G
      • Alford CA
      Herpes simplex encephalitis: clinical assessment.
      Conversely, HSV encephalitis has been identified as the causal pathogen in 52% of patients with encephalitis who presented with focal neurologic findings.
      • Domingues RB
      • Tsanaclis AM
      • Pannuti CS
      • Mayo MS
      • Lakeman FD
      Evaluation of the range of clinical presentations of herpes simplex encephalitis by using polymerase chain reaction assay of cerebrospinal fluid samples.
      Early diagnosis is important because antiviral therapy substantially decreases the morbidity and mortality due to HSV encephalitis. Polymerase chain reaction of the CSF, with a sensitivity of 98% and a specificity of 94%, is the diagnostic method of choice.
      • Lakeman FD
      • Whitley RJ
      • National Institute of Allergy and Infectious Disease Collaborative Antiviral Study Group
      Diagnosis of herpes simplex encephalitis: application of polymerase chain reaction to cerebrospinal fluid from brain-biopsied patients and correlation with disease.
      Although uncommon, false negatives can occur when CSF PCR testing is done less than 72 hours after symptom onset. Thus, if pretest clinical suspicion is high, antiviral therapy should be continued until an alternative diagnosis is established or CSF PCR is repeated at least 72 hours after symptom onset.
      • Tyler KL
      Herpes simplex virus infections of the central nervous system: encephalitis and meningitis, including Mollaret's.
      Other tests such as head imaging and EEG can provide diagnostic clues for HSV encephalitis. Brain CT scans have only 50% sensitivity early in the course of the disease.
      • Levitz RE
      Herpes simplex encephalitis: a review.
      In contrast, magnetic resonance imaging shows temporal lobe abnormalities in approximately 90% of patients with HSV encephalitis.
      • Tyler KL
      Herpes simplex virus infections of the central nervous system: encephalitis and meningitis, including Mollaret's.
      Extratemporal abnormalities can also be present.
      • Tyler KL
      Herpes simplex virus infections of the central nervous system: encephalitis and meningitis, including Mollaret's.
      The typical finding is one of unilateral hyperintensity on T2-weighted imaging with associated mass effect.
      • Levitz RE
      Herpes simplex encephalitis: a review.
      Moreover, HSV encephalitis can cause changes on diffusion-weighted imaging. However, these changes are not limited to a single vascular territory, as they are after ischemic stroke. Focal EEG findings are found in more than 80% of cases but are often nonspecific. For example, the presence of PLEDs is suggestive of HSV encephalitis, but their absence does not exclude or significantly reduce the likelihood of HSV infection.
      • Misra UK
      • Kalita J
      Neurophysiological studies in herpes simplex encephalitis.
      Likewise, resolution of EEG abnormalities does not correlate well with clinical recovery.
      • Lai CW
      • Gragasin ME
      Electroencephalography in herpes simplex encephalitis.
      Seizures occur in approximately 50% of patients with HSV encephalitis and can present as status epilepticus (5 minutes of continuous seizure activity or a series of seizures without return to full consciousness).
      • Whitley RJ
      • Soong SJ
      • Linneman Jr, C
      • Liu C
      • Pazin G
      • Alford CA
      Herpes simplex encephalitis: clinical assessment.
      Nonconvulsive status epilepticus, characterized by few or no motor manifestations of seizure, accounts for nearly 25% of all cases.
      • Cascino GD
      Nonconvulsive status epilepticus in adults and children.
      Although patients with nonconvulsive status epilepticus do not have obvious motor manifestations, they do have cognitive and behavioral changes that should prompt consideration of the diagnosis. Early recognition of nonconvulsive status epilepticus is important because delaying therapy decreases the likelihood of successfully aborting the seizures. Prophylactic antiepileptics are not commonly used in HSV encephalitis, but seizures should be managed aggressively if they occur because up to 25% of patients with HSV encephalitis will eventually develop epilepsy.
      • McGrath N
      • Anderson NE
      • Croxson MC
      • Powell KF
      Herpes simplex encephalitis treated with acyclovir: diagnosis and long term outcome.
      The current recommendation for treatment of HSV encephalitis is IV acyclovir at 10 mg/kg every 8 hours for 2 to 3 weeks.
      • Tyler KL
      Herpes simplex virus infections of the central nervous system: encephalitis and meningitis, including Mollaret's.
      This duration of therapy is based on reports of relapse after only 10 days of therapy. Dose adjustments are necessary in patients with renal impairment.
      If left untreated, mortality from HSV encephalitis exceeds 70%.
      • Tyler KL
      Herpes simplex virus infections of the central nervous system: encephalitis and meningitis, including Mollaret's.
      Treatment with acyclovir halts viral replication and reduces 6-month mortality rates to around 15%.
      • Raschilas F
      • Wolff M
      • Delatour F
      • et al.
      Outcome of and prognostic factors for herpes simplex encephalitis in adult patients: results of a multicenter study.
      Prognostic factors in HSV encephalitis include age, level of consciousness at the time of presentation, and duration of infection before treatment initiation.
      • Raschilas F
      • Wolff M
      • Delatour F
      • et al.
      Outcome of and prognostic factors for herpes simplex encephalitis in adult patients: results of a multicenter study.
      Even with early administration of acyclovir, however, only 14% of patients completely recover, and nearly two thirds of survivors have serious neurologic deficits.
      • Raschilas F
      • Wolff M
      • Delatour F
      • et al.
      Outcome of and prognostic factors for herpes simplex encephalitis in adult patients: results of a multicenter study.

      REFERENCES

        • Whitley RJ
        • Soong SJ
        • Linneman Jr, C
        • Liu C
        • Pazin G
        • Alford CA
        Herpes simplex encephalitis: clinical assessment.
        JAMA. 1982; 247: 317-320
        • Corey L
        • Spear P
        Infections with herpes simplex viruses (2).
        N Engl J Med. 1986; 314: 749-757
        • Tyler KL
        Herpes simplex virus infections of the central nervous system: encephalitis and meningitis, including Mollaret's.
        Herpes. 2004; 11: 57A-64A
        • Schiff D
        • Rosenblum MK
        Herpes simplex encephalitis (HSE) and the immunocompromised: a clinical and autopsy study of HSE in the settings of cancer and human immunodeficiency virus-type 1 infection.
        Hum Pathol. 1998; 29: 215-222
        • Domingues RB
        • Tsanaclis AM
        • Pannuti CS
        • Mayo MS
        • Lakeman FD
        Evaluation of the range of clinical presentations of herpes simplex encephalitis by using polymerase chain reaction assay of cerebrospinal fluid samples.
        Clin Infect Dis. 1997; 25: 86-91
        • Lakeman FD
        • Whitley RJ
        • National Institute of Allergy and Infectious Disease Collaborative Antiviral Study Group
        Diagnosis of herpes simplex encephalitis: application of polymerase chain reaction to cerebrospinal fluid from brain-biopsied patients and correlation with disease.
        J Infect Dis. 1995; 171: 857-863
        • Levitz RE
        Herpes simplex encephalitis: a review.
        Heart Lung. 1998; 27: 209-212
        • Misra UK
        • Kalita J
        Neurophysiological studies in herpes simplex encephalitis.
        Electromyogr Clin Neurophysiol. 1998; 38: 177-182
        • Lai CW
        • Gragasin ME
        Electroencephalography in herpes simplex encephalitis.
        J Clin Neurophysiol. 1998; 5: 87-103
        • Cascino GD
        Nonconvulsive status epilepticus in adults and children.
        Epilepsia. 1993; 34: S21-S28
        • McGrath N
        • Anderson NE
        • Croxson MC
        • Powell KF
        Herpes simplex encephalitis treated with acyclovir: diagnosis and long term outcome.
        J Neurol Neurosurg Psychiatry. 1997; 63: 321-326
        • Raschilas F
        • Wolff M
        • Delatour F
        • et al.
        Outcome of and prognostic factors for herpes simplex encephalitis in adult patients: results of a multicenter study.
        Clin Infect Dis. 2002 Aug 1; 35 (Epub 2002 Jul 10.): 254-260