CLINICAL CASE

PRESENTATION OF CASE

A 70 year-old woman with a history of migraines was admitted to this hospital in the fall because fever,
headache and progressive encephalopathy.

The patient had been in her usual state of health until 12 days before this admission, with temperatures as
high as 39.7 developed, along chills, fatigue, weakness,and headache. The patient also had nausea and
intermitent episodes of vomiting. She took acetaminophen and sumatriptan, but the symptoms persisted.
On the six day of illness, she was seen by her primary care physician. A rapid influenza test was negative, and
the results of urinalysis were reportedly normal; a blood sample was sent to the laboratory for testing for
Borrelia burgdorferi antibodies.

The following day, the patient was seen in the emergency department at another hospital for further
evaluation. On examination, she was febrile and appeared ill. The platelet count, prothrombin-time
international normalized radio, anion gap and blood levels of electrolytes, and lactate were normal, as were
the results of renal-function tests and urinalysis; other laboratory test results are shown in Table 1. Blood
and urine specimens were sent for culture. A chest radio-graph was normal. A lumbar puncture was
performed; the results of cerebrospinal fluid (CSF) analysis are shown in Table 1. Vancomycin and
piperacillin-tazobactam were administered intravenously, and admission to the hospital was recommended.
The patient declined admission and was discharged home with a prescription for oral doxycycline.

During the next 2 days, fevers persisted, and the patient became progressively less interactive. She got out
of bed infrequently; she had an unsteady gait and needed assistance to walk. Oral intake decreased
frequency of urination increased, and tremulousness of the arms and jaw developed. On the ninth day of
illness (4 days before this admission), the patient´s family again took her to the emergency department at
the other hospital.

On examination, the patient appeared uncomfortable and ill and was trembling. She was alert and oriented,
followed commands, and responded to questions with single-word answers. The temperature was 39.4 C;
the other vital signs were normal. The oral mucous membranes appeared dry. The platelet count, anion gap,
venous blood gas measurements, and blood levels of electrolytes, lactate, and ammonia were normal, as
were the results of renal-function tests, liver-function tests, and urinalysis; other laboratory test results are
shown in Table 1. The test for B. burgdorferi antibodies (for which a sample had been sent 3 days earlier)
was negative, as were the blood and urine cultures (for which samples had been sent 2 days earlier). Blood
specimens were obtained, and imaging studies were performed.

Results of computed tomography (CT) of the head, performed after the intravenous administration of
contrast material, were normal. CT of the abdomen and pelvis, performed after the intravenous
administration of contrast material, revealed trace bilateral pleural effusions, four indeterminate lesions (8
to 20mm in diameter) in the liver, a nonobstructive calculus (2mm in diameter) in the lower pole of the left
kidneys, trace free fluid in the pelvis, diffuse atherosclerotic calcifications in the aorta, and its visualized
branches, colonic diverticula and degenerative changes of the bony skeleton.

A bolus of normal saline was administered intravenously, and the patient was admitted to the other
hospital. Aciclovir, ceftriaxone, vancomycin, ampicillin, paracetamol and intravenous fluids were
administered. During the next 3 days, intermittent fevers with temperatures like high until 38.4 ° C
continued, and the patient became disoriented and then mut. She was no longer able to follow comands.
Urinary retention, lead-pipe muscular rigidity in the arms and legs, increased deep tendon reflexes, and
nuchal rigidity with passive flexion developed.Polymerase chain reaction (PCR) assays for herpes simplex
virus DNA and Enterovirus RNA, performed on the CSF sample obtained during the first emergency
department visit, were negative. The erythrocyte sedimentation rate and blood levels of C3, C4, thyrotropin,
folate and vitamin B12 were normal, and blood tests for human immunodeficiency virus antibodies,
Treponema pallidum antibodies, Cryptococcal antigen, Anaplasma phagocytophilum DNA, babesia DNA
species, antinuclear antibodies, and the β2-glycoprotein antibodies were negative. An electrocardiogram
and a transthoracic echocardiogram were normal.

Magnetic resonance imaging (MRI) of the head, performed after the intravenous administration of contrast
material, reportedly revealed diffuse abnormal meningeal enhancement that was most notable in the
cerebellum. Acyclovir was discontinued.

On the fourth hospital day, the patient had a 2-minute episode during which the eyes rolled upward and the
arms and legs stiffened. Lorazepam and levetiracetam were administered. Electroencephalography that was
performed after the event revealed generalized slowing. The patient was transferred to this hospital for
further treatment.

On admission, additional history was obtained from the patient’s family. The patient had had mild cognitive
decline during the past year, and her son had begun assisting with management of her finances.
Approximately 3 weeks before the onset of illness, the patient had noticed a dime-sized erythematous lesion
on the right shoulder and thought it might have resulted from an insect bite. During the week before the
onset of illness, she had been seen by a dentist for an unspecified treatment and had taken clindamycin for
2 days. She had a history of migraines, fibromyalgia, depression, and anxiety, and in the remote past she had
undergone cholecystectomy, hysterectomy, and treatment for Lyme disease. Her medications included
citalopram and sumatriptan; she had no known allergies. She lived with her husband, two adult children,
and pet dogs and cats near a horse farm in a wooded area of northern New England. She enjoyed spending
time outdoors and frequently removed ticks from her pets. She did not smoke tobacco or use illicit drugs,
and she drank alcohol rarely. There was a family history of Alzheimer’s disease and stroke.

On examination, the vital signs were normal. The patient was somnolent, nonverbal, and unable to follow
commands. She intermittently opened her eyes in response to a loud voice and tracked the examiner with
conjugate gaze. There was no movement of the arms after application of pressure to the beds of the
fingernails; triple flexion occurred after application of pressure to the beds of the toenails. Deep-tendon
reflexes in the arms and legs were brisk. Nuchal rigidity was present. There was a systolic ejection murmur
(grade 2/6) at the left sternal border. The remainder of the general physical examination was normal. The
red-cell indexes, platelet count, prothrombin time, partial thromboplastin time, anion gap, and blood levels
of electrolytes were normal, as were the results of renal-function and liver-function tests; other laboratory
test results are shown in Table 1. A lumbar puncture was performed, with an opening pressure of 18 cm of
water; the results of CSF analysis are shown in Table 1.

Dr. R. Gilberto Gonzalez: MRI of the head (Fig. 1) revealed findings consistent with progressive
meningoencephalitis. The findings were most prominent in the cerebellar hemispheres and were more
severe on the left side than on the right side. There was associated edema in the cerebellar hemispheres. As
compared with the previous MRI study, this study showed an increase in effacement involving the fourth
ventricle and an increase in the size of the lateral and third ventricles, findings suggestive of early
obstructive hydrocephalus. Results of magnetic resonance angiography of the head and neck were normal.
Dr. Hogan: A diagnostic test was performed.

DIFFERENTIAL DIAGNOSIS

Dr. Kimon C. Zachary: This 70 year-old woman was, to the best of our knowledge, immunocompetent aside
from her age. She presented in autumn with an acute febrile illness, with headache and progressive
neurologic signs and symptoms, including depressed sensorium, nuchal rigidity, gait ataxia,parkinsonism,
hyperreflexia, and a possible seizure. The information provided suggests that she has a syndrome of acute
meningoencephalitis, with inflammation of the meninges and brain parenchyma. The differential diagnosis is
quite expansive, including noninfectious entities and many infectious diseases.
Noninfectious Causes

Although this patient was not known to have a malignant tumor, paraneoplastic encephalitis merits
consideration. Patients with paraneoplastic encephalitis usually have involvement of the limbic system or
brain stem or present with a more generalized encephalomyelitis; this patient’s illness did not fit any of
these patterns. Given the prominent involvement of the cerebellum, paraneoplastic cerebellar degeneration
should be considered, but this disorder would not cause an acute febrile illness with meningitis and evidence
of encephalitis outside the cerebellum. Autoimmune encephalitis is rare; the most common and best
characterized type is anti–Nmethyl- d-aspartate (NMDA) receptor encephalitis. This entity appears almost
exclusively in young adults and children and is very rare in persons older than 50 years of age.

Bacterial Infections

Pyogenic bacterial meningitis from Streptococcus pneumoniae, Neisseria meningitidis, or Haemophilus

influenzae can be ruled out in this patient, given the pace of the illness, the CSF profile, and the presence of
multifocal encephalitis. In contrast, central nervous system (CNS) infection with Listeria monocytogenes is a
strong consideration. Listeria meningitis occurs primarily in immunocompromised hosts or persons older
than 50 years of age, can develop in a less-than-fulminant manner, and can be associated with a CSF white-
cell count of less than 1000 per cubic millimeter; these features are compatible with this patient’s
presentation. Encephalitis due to listeria infection usually has brain-stem involvement (rhombencephalitis),
which was not present in this patient.

Given the patient’s environmental exposures, tickborne bacterial infections should also be considered.
Rocky Mountain spotted fever, which is due to Rickettsia rickettsii, is uncommon in New England. Rocky
Mountain spotted fever causes an acute febrile illness, usually with a prominent headache, and also causes
an endothelial vasculitis, which can lead to brain disease. Early treatment with doxycycline greatly lowers
morbidity and mortality. Rash is often absent in the first 3 or 4 days of the illness but would have been
present by the time this patient presented to this hospital, on day 13 of her illness.

Anaplasmosis, which is due to A. phagocytophilum, is common in New England and is transmitted by Ixodes
scapularis, the black-legged deer tick. Patients with anaplasmosis typically present with an acute febrile
illness, often with a headache. This patient had a negative PCR assay for this infection, although this result
does not rule out the diagnosis. However, encephalitis is rare in patients with anaplasmosis, and the
hallmark laboratory abnormalities namely: leukopenia, thrombocytopenia, and elevated aminotransferase
levels were not seen in this case.

Lyme disease, which is due to B. burgdorferi, is a well-known cause of aseptic meningitis and of cranial and
radicular neuritis, manifestations that occur in the early disseminated stage of infection. However,
encephalitis is rare in patients with neuroborreliosis, and testing for Lyme antibodies, which is usually
positive in the context of neuroinvasive disease, was negative in this case.

Infection with B. miyamotoi, a spirochete that is more closely related to B. hermsii (an agent of relapsing
fever) than to B. burgdorferi, is an emerging cause of human disease in the northeastern United States. The
most common clinical presentation resembles that of anaplasmosis, including similar laboratory
abnormalities, which were absent in this case. An association between B. miyamotoi infection and
meningoencephalitis has been described, albeit in immunocompromised persons.

This patient’s frequent exposure to animals raises the possibility of leptospirosis, which is transmitted by
means of exposure to contaminated animal urine. Aseptic meningitis is a common feature of this illness, but
encephalitis is rare, and the patient’s normal renal and hepatic laboratory values argue against this infection.
Bartonella henselae infection, which is transmitted by cats or their fleas, can be associated with
encephalopathy or encephalitis, although well documented cases of CNS invasion are very rare.
Respiratory tract infection with Mycoplasma pneumoniae can be complicated by CNS disease. However,
most cases occur in children and young adults, and no antecedent respiratory illness was reported in this
patient. Mycobacterium tuberculosis infection can cause a gradual onset of meningitis, which is usually most
prominent at the skull base, and can also cause tubercular abscesses of the brain. The findings in this patient
would be highly atypical of tuberculosis, and no epidemiologic risk factors for this disease were reported.

Fungal Infections

Cryptococcus neoformans infection is a well-known and widely distributed cause of meningoencephalitis

that usually occurs in patients with compromised cell-mediated immunity; the occurrence of C. neoformans
infection in immunocompetent persons has been well described but is rare. In comparison, C. gattii infection
is more likely to develop in immunocompetent persons, but it is not known to occur in New England.
Furthermore, cryptococcal antigen was not detected in the patient’s blood. Histoplasma capsulatum
infection is uncommon in New England and rarely causes meningoencephalitis. This patient did not have any
epidemiologic risk factors for other geographically restricted endemic mycoses, such as Coccidioides immitis
infection, a well-known cause of CNS disease.

Protozoa Infections

On rare occasion, certain free-living amebas can cause meningoencephalitis. Naegleria fowleri is found in
bodies of fresh water, typically in climates warmer than that of northern New England. This ameba can
invade the meninges and brain by means of nasal inoculation while the host is submerged in contaminated
water, thereby causing a fulminant infection with a dismal prognosis. This patient did not have a plausible
exposure, so this disease is unlikely. Acanthamoeba and balamuthia species are protozoa that are present
ubiquitously in the environment. These organisms can cause a gradual onset of meningoencephalitis that is
known as granulomatous amebic encephalitis, but the disease occurs primarily in immunocompromised
persons and therefore is unlikely in this case.

Viruses Infections

As a group, viruses are the most commonly identified cause of acute encephalitis and meningoencephalitis.
Herpes simplex virus is the most commonly identified cause of viral encephalitis in the United States.
Because early treatment with intravenous acyclovir lowers morbidity and mortality, prompt consideration of
herpes simplex virus is of critical importance. In herpes simplex encephalitis, a temporal lobe is typically
involved, which was not the case in this patient, and concomitant meningitis is unusual. The CSF PCR assay
for herpes simplex virus DNA is highly sensitive and specific.The test can be negative very early in the course
of illness but should be positive by day 7; this patient had a negative test on day 7 of her illness.

Reactivation of varicella–zoster virus can cause CNS vasculopathy, which results in a strokelike syndrome.
This often occurs after a typical eruption of herpes zoster, particularly herpes zoster ophthalmicus. A more
diffuse reactivation that involves multiple small intracerebral arteries can develop, but it usually occurs in
immunocompromised persons. This patient’s imaging studies were not suggestive of vasculitis.

Rabies should be considered in a case of encephalitis of unknown origin. A relevant animal exposure was not
described in this case, although it could have been occult, particularly if bats were present in the patient’s
rural home. However, her clinical presentation did not include the hydrophobia, pharyngeal spasms, or
agitation that are seen in encephalitic (“furious”) rabies or the ascending paralysis that is seen in paralytic
(“dumb”) rabies.

Given the patient’s home environment, exposure to the excreta of mice is also possible and would confer a
predisposition to infection with lymphocytic choriomeningitis virus. This viral infection often causes
leukopenia and thrombocytopenia, which were absent in this case, and rarely causes encephalitis. In the
summer and autumn, enteroviruses are common causes of aseptic meningitis and occasionally cause
encephalitis. In this patient, a CSF PCR assay was negative for enterovirus RNA.
Arthropod-Borne Viruses (Arboviruses)

Eastern equine encephalitis virus and West Nile virus are both present in New England; these viruses are
amplified in birds and transmitted by mosquitoes. Eastern equine encephalitis virus has been a sporadic
cause of human encephalitis in states along the Atlantic coast, with cases reported in the mid-to-late
summer in New England. Although this viral infection is still rare, with 5 to 15 cases reported to the Centers
for Disease Control and Prevention (CDC) annually, more cases have been reported in northern states in
recent years, including 9 cases in northern New England from 2007 to 2016. Eastern equine encephalitis
virus infection is typically associated with leukocytosis in peripheral blood and pleocytosis in CSF, with a
white-cell count ranging from 500 to 2000 per cubic millimeter, a higher count than that seen in this case.
Involvement of the basal ganglia and thalamus is common.

West Nile virus has been by far the most common neuroinvasive arbovirus in the United States, with
approximately 1300 cases reported to the CDC in 2016 and again in 2017. However, relatively few cases
have been reported in northern New England (7 cases from 2013 to 2016). Mild leukocytosis in peripheral
blood is sometimes present, and pleocytosis in CSF is associated with a white-cell count of less than 500 per
cubic millimeter. Parkinsonism and evidence of basal ganglia involvement are common.

Similar to West Nile virus, Powassan virus is a flavivirus, but it is transmitted by the I.scapularis tick and
maintained in a rodent reservoir. Until recent years, this viral infection was very rare in New England, with
no cases reported to the CDC in most years. However, 5 cases in northern New England and 13 cases in
Massachusetts were reported from 2013 to 2016.The clinical spectrum associated with Powassan virus
encephalitis is similar to that associated with eastern equine encephalitis virus infection and West Nile virus
infection. Results of routine laboratory studies are typically normal, and the CSF white-cell count is usually
less than 1000 per cubic millimeter. Parkinsonism and involvement of the basal ganglia and thalamus are
common.

This patient has a clinical syndrome that is compatible with infection with eastern equine encephalitis virus,
West Nile virus, or Powassan virus. The normal white-cell count in peripheral blood and relatively modest
pleocytosis in CSF argue against eastern equine encephalitis virus.

The incubation period for West Nile Virus neuroinvasive disease is approximately 2 to 14 days; we know that
the patient became ill during autumn and that mosquito activity declines with cooler weather, usually
ending after a hard frost.

However, ticks remain active well into autumn, even in northern New England. Therefore, the patient’s
infection was more likely to have been transmitted by a tick than by a mosquito, which makes Powassan
virus infection the most likely diagnosis in this case. To establish the diagnosis, I would perform a CSF test for
Powassan virus IgM antibodies.

Pathological Discussion

Dr. John A. Branda: Several tests for vectorborne agents of viral encephalitis were performed. Serum tests
for West Nile virus IgM and IgG antibodies were negative, as was a CSF PCR assay for West Nile virus RNA.
CSF tests for IgM antibodies to West Nile virus, St. Louis encephalitis virus, and eastern equine encephalitis
virus were also negative. However, a CSF test for Powassan virus IgM antibodies was positive, as was the
more specific plaque reduction neutralization test, at a CSF titer of 1:4. In the context of the clinical findings,
these results establish the diagnosis of Powassan virus encephalitis.

Powassan virus can be challenging to diagnose, because direct detection of the virus in blood or CSF with
PCR assays or culture techniques is typically possible only during the prodromal phase of illness. During this
phase, patients may not seek clinical attention, and if they do, there may be no reason to suspect Powassan
virus infection. Once the illness enters the encephalitic phase, viremia is often undetectable and the
diagnosis usually relies on antibody testing. In the first days or weeks of encephalitis, it is usually possible to
detect only an IgM antibody response. This presents a challenge, because first-line tests for Powassan virus
IgM antibodies, such as enzyme-linked immunosorbent assays or similar immunoassays, are more likely to
produce false positive results than tests for Powassan virus IgG antibodies. The false positive results are
mainly caused by cross-reactivity with antibodies directed against other flaviviruses. A positive serum or CSF
test for Powassan virus IgM antibodies should be confirmed with a test for neutralizing antibodies, such as
the plaque reduction neutralization test or a similar assay. When Powassan virus infection is suspected,
consultation with a public health laboratory is recommended for assistance with choosing the appropriate
diagnostic tests.

A variety of factors influence the epidemiology of tickborne illnesses. Human behaviors such as land use,
cultural habits, and health care reporting are important determinants, as is population-level immunity.
Weather also affects the distribution and seasonality of tickborne illnesses. Models show that the
geographic and annual variation in the timing of human Lyme disease can be predicted by temperature,
precipitation, and humidity.

There is widespread scientific consensus that human activities are changing the world climate, resulting in
more variable weather, heat waves, heavy precipitation events, and more intense storms. In a 2016 report,
the U.S. Global Change Research Program predicted that climate change would interact with other factors to
result in an overall increase in tickborne illnesses, by means of altered geographic distribution, earlier
seasonal tick activity, and the emergence or reemergence of pathogens. In fact, the number of cases of
tickborne bacterial and protozoan diseases reported to the CDC increased from approximately 22,000 in
2004 to more than 48,000 in 2016.

Consequently, clinicians are on the front line in responding to the effect of climate change on the health of
individual patients and communities, and they should be prepared to counsel patients about steps to
mitigate risk. For example, patients can lower their risk of tickborne illnesses by using insect repellents,
wearing longsleeved shirts and pants, avoiding bushy and wooded areas, and performing thorough tick
checks after spending time outdoors.

Dr. Hogan: This patient had a monthlong hospital course, which was complicated by delirium, clinically
significant parkinsonism, and poor oral intake, which led to placement of a gastrostomy tube. Over the
course of several weeks, her mental status gradually improved. She regained the ability to walk and was
ultimately transferred to a rehabilitation hospital. Over time, her motor skills and overall state of health
continued to improve, and the abnormal findings on imaging studies diminished.

Fourteen months after discharge, at the most recent follow-up appointment, the patient still had a shuffling
gait and some parkinsonism. She had a mild sensation of disequilibrium and some mild cognitive deficits, but
her overall condition has continued to slowly improve with supportive care.

Final Diagnosis

Powassan virus encephalitis.

This case was presented at the Harvard Medical School postgraduate course, “Infectious Diseases in Adults
2018”