Fallon_2_Neuroborreliosis_Review
Fallon,
Nields, Lyme disease: A Neuropsychiatric Illness
NEILDS_YALE
The following
chapter was given to James Phillips
in April 2002. Think he read it? No. It's not a
penis matter,
and Phillips has no other topics.
Shadock’s 2002
Comprehensive Textbook of Psychiatry
CHAPTER 2.
NEUROPSYCHIATRY AND BEHAVIORAL NEUROLOGY 2.9
NEUROPSYCHIATRIC ASPECTS OF OTHER INFECTIOUS DISEASES BRIAN
ANTHONY FALLON, M.D., M.P.H.
http://www.columbia-lyme.org
Spirochetal Diseases
Non-HIV Viral Infections
of the Central Nervous System
Subacute Spongiform
Encephalopathies
Other Infectious Causes of
Neuropsychiatric Disorders
Emerging Areas of
Investigation
Suggested Cross-References
Ever since the link
between severe neuropsychiatric disorders and infectious disease was
established in the early 1900s by the identification of the cause of
syphilis, questions have been asked about the role of other infectious
organisms in the etiology of neuropsychiatric disorders. At times the link
between an infectious agent and a neuropsychiatric disorder is obvious, as
in the case of neurosyphilis, the viral influenza outbreak of the 1920s, and
the current human immunodeficiency virus (HIV) and Lyme disease epidemics.
At other times the link is less clear but strongly suspected, as has been
true for chronic fatigue syndrome or in the search for bacterial or viral
etiologies of obsessive-compulsive and psychotic disorders. Psychopathology
may emerge as a result of direct invasion of the central nervous system
(CNS) by neurotropic agents or by an indirect host-determined cellular,
humoral, or cytokine immune response to infectious organisms that
inadvertently damages host tissue. In its effort to protect, the immune
response may thereby provoke neuropsychiatric disorders.
This section focuses on
selected infectious diseases other than HIV disease that invade the CNS and
that have been directly associated with neuropsychiatric syndromes.
Particular attention will be paid to the neuropsychiatric aspects of Lyme
disease because it has spread rapidly since the 1970s in various parts of
the world and has been associated with a plethora of neuropsychological and
neurobehavioral problems in both children and adults. In addition, the
concluding portion of this section will briefly address a few areas of
recent investigation on the overlap of infectious disease and
neuropsychiatry.
SPIROCHETAL DISEASES
Under the umbrella of the
order of spirochetes are three agents that are known to invade the CNS.
These include borrelia, treponema, and leptospira. Borrelia, which require
an arthropod vector and a mammalian or bird reservoir, are commonly known to
cause relapsing fever and Lyme disease. Treponema, which are spread
person to person and do not use an arthropod vector, are the spirochetes
responsible for syphilis. Leptospira, which are spread by contaminated
water, are the agents of Weil’s disease, which can have CNS manifestations.
Lyme Disease Lyme disease
(Lyme borreliosis), transmitted by the bite of an infected Ixodes tick, can
cause a vast array of neuropsychiatric disorders, ranging from mild mood
changes to psychosis and severe memory loss. Lyme disease has been reported
throughout the United States and in many countries throughout the world. The
causative agent of Lyme disease, Borrelia burgdorferi, is initially
inoculated into the skin by an infected tick, typically inducing a local
rash, known as erythema migrans, which is reported by approximately two
thirds of infected patients. Rapidly disseminated by the bloodstream through
the body, B. burgdorferi has been found in the CNS as soon as 3 weeks after
initial skin infection. Known to be neurotropic, B. burgdorferi may reside
in the cerebrospinal fluid (CSF) or adhere to glial cells or other brain
tissue. Like its spirochetal counterpart, Treponema pallidum, B. burgdorferi
may remain latent, causing illness months to years later. Partly because of
this latency in disease expression, patients may be unable to recall the
initial tick bite or rash. Antigenic variability, which refers to the
ability to express different surface antigens and to thus evade the immune
response, is a feature of borrelial organisms that B. burgdorferi shares.
Diagnosis The
epidemiological surveillance criteria for the diagnosis of Lyme disease in
the United States require a history of exposure to an area endemic for Lyme
disease and either a physician-diagnosed erythema migrans rash or
serological evidence of exposure to B. burgdorferi and at least one of the
following three clinical features: (1) arthritis; (2) neurologic symptoms
(cranial or peripheral neuropathy, meningitis, encephalomyelitis, or
encephalitis with evidence of intrathecal antibody production); or (3)
cardiac conduction defects. Although useful for epidemiological monitoring,
these criteria are unduly restrictive and should not be used for clinical
purposes, because these criteria exclude patients who might have Lyme
disease, such as seropositive patients who have diffuse arthralgias but not
frank arthritis or patients who have encephalopathy without objective CSF
abnormalities. Further complicating the diagnosis is the unreliability of
the serologic tests. False-positive results might result because of
cross-reactivity with other spirochetal organisms.
False-negative results may
occur because the patient is tested too soon after infection and before an
appropriate antibody response is mounted or because the patient’s immune
response has been abrogated as can occur when a patient is given antibiotic
shortly after initial infection. It is not uncommon for a patient with Lyme
disease to have negative or equivocal test results in one laboratory, but
positive ones in another or for a patient to have negative test results
initially but positive ones several months later after antibiotic treatment
has been initiated. For these reasons a rational approach to the diagnosis
of Lyme disease must be based upon the primary clinical presentation,
followed by the supportive evidence of laboratory test results. Laboratory
tests that can be helpful include indirect tests such as the enzyme-linked
immunosorbent assay (ELISA) and Western blot analysis and direct tests such
as the polymerase chain reaction (PCR) assay for borrelial deoxyribonucleic
acid (DNA) or antigen detection assay. When Lyme disease is suspected, the
clinician should order both an ELISA and a Western blot, as some patients
may have a negative ELISA result but a positive Western blot result.
Bands of particular
significance on the Western blot include the ones identified by the Centers
for Disease Control as being most frequent and specific, as well as the 31kD
(OspA) and 34 kD (OspB) bands. Although highly specific for B. burgdorferi
DNA, the PCR assay has low sensitivity. Although laboratory testing is a
valuable component of the diagnostic assessment, negative test results
cannot be used to exclude Lyme disease in a patient with typical clinical
features and a history of exposure to a Lyme disease endemic area.
Clinical Features
The erythema migrans rash is the hallmark feature of early Lyme disease;
antibiotic treatment at this stage often results in cure. Although typically
the rash has a bull’s eye, rounded appearance, it may also have a
triangular, elongated, or other shape. Because patients may not recall
seeing the rash, the flu-like symptoms that often occur shortly after the
rash may be ignored, only to be followed several months to years later by
the emergence of a multisystem disease affecting the joints, the heart, the
eyes, and the peripheral or central nervous system; 15 to 40 percent of
patients may have neurologic signs as their presenting feature. Headaches
may be followed by meningitis, cranial neuritis, motor or sensory
radiculitis, or an encephalitis characterized by mood lability and
disturbances of memory or sleep. Although suggestive of Lyme disease, Bell’s
palsy may occur in only 5 to 10 percent of a sample of patients with
neurologic Lyme disease. Symptoms of radiculoneuropathy or peripheral nerve
involvement include sharp stabbing or deep boring pains that may radiate
from the spine into an extremity of the trunk; areas of numbness, burning,
or tingling; weakness; and fasciculations. In later stages of Lyme disease a
minority of patients may develop a chronic meningoencephalomyelitis
characterized by somnolence, confusion, poor concentration, impaired memory,
myoclonus, apraxia, ataxia, paraparesis, dysarthria, dysphasia, seizures, or
bladder abnormalities. Some of these patients may be misdiagnosed as having
multiple sclerosis because of a relapsing and remitting course and the
concurrence of spinal motor signs, ataxia, bladder dysfunction, and, less
often, optic neuritis.
The profile of
neuropsychiatric Lyme disease typically includes disturbances of cognition
and mood. On formal neuropsychological testing, more than 50 percent of
patients with chronic neurologic Lyme disease will show impairment in
short-term memory, processing speed, or attention. This cognitive
impairment, although worsened by marked pain or mood disorders, exists
independently of the physical symptoms or the severity of concurrent
depression. Typical cognitive symptoms include word-finding problems,
word-substitutions, new-onset dyslexia, transient episodes of geographic
disorientation, marked inattention and distractibility, difficulty with
organization, and the sensation that one’s brain is in a fog. Less commonly,
the severity of the cognitive disturbance causes a global impairment,
suggestive of a new-onset dementia.
Although the full
spectrum of psychiatric disorders has been associated with B. burgdorferi
infection, by far the most frequent are disturbances of mood, characterized
by irritability, mood swings, and sleep loss. The majority of controlled
studies in which patients with Lyme disease are compared to healthy controls
or to patients with other illnesses reveal that depression occurs more
frequently in the group with Lyme disease. Children with neurological Lyme
disease typically present with complaints of headaches as the most common
symptom, followed by behavioral, cognitive, or mood disturbance as the next
most prevalent symptom. Behavioral problems include falling asleep in class,
agitation, and poor school performance; common cognitive problems include
attentional and short-term memory and visospatial deficits; common mood
problems include irritability and new-onset anxiety. Other less common
neuropsychiatric aspects associated with Lyme disease in adults and children
include panic attacks, transient paranoia, illusions or hallucinations
(visual, olfactory, auditory), anorexia, depersonalization, violent
outbursts, obsessive-compulsive disorder, agitated mania, hyperacute
sensitivity to light or sound, and what appears to be personality change.
Because of the multisystem involvement in Lyme disease and the frequent
concurrence of anxiety and depression, patients may be mistakenly diagnosed
as having a primary psychiatric or a somatoform disorder before Lyme disease
is even considered. If Lyme disease is considered but serological tests are
equivocal despite the presence of a clinical profile typical of Lyme
disease, the somatoform label may once again be mistakenly applied.
A 22-year-old
previously healthy college graduate in his first few months of law school
developed joint and muscle pains. A medical workup was
negative, but the symptoms persisted and worsened,
accompanied by fatigue so severe that he was unable to go to class or to
study. Referral to a psychiatrist resulted in
treatment with a selective serotonin reuptake inhibitor (SSRI) for possible
depression without much benefit. Further medical workup revealed a positive
result for Lyme disease ELISA with an equivocal Western
blot analysis result. The diagnosis of probable Lyme disease was made and
the patient was given a 6-week course of oral antibiotics, with a marked
improvement in symptoms. Over the following 4 months his prior symptoms
returned accompanied by headaches, word-finding problems, paresthesias,
shooting and stabbing pains, and hypersensitivity to light and sound.
Several consulting doctors gave conflicting opinions, with some firmly
stating that this could not be persistent Lyme disease as it had been
adequately treated and others stating that persistent infection was indeed
possible and that additional treatment with antibiotics was warranted. The
Lyme tests remained equivocal and a brain magnetic resonance imaging (MRI)
revealed no abnormalities. Three additional months of oral antibiotics
resulted in some improvement of arthritic symptoms, but the fatigue and
cognitive problems remained. Several months later, the patient developed
paranoid delusions followed by a manic episode for which he was
hospitalized. Without further testing such as a spinal tap or
electroencephalogram (EEG), his doctors dismissed Lyme disease as a possible
cause for his new-onset mania. The patient was discharged on antipsychotic
agents and lithium, with only a partial improvement in his mood lability. An
outpatient internist then checked the patient’s spinal fluid, which showed
white blood count of 7 × 109 per liter 7 (white blood count [WBC]) and
evidence of B. burgdorferi antibodies in both his serum and cerebral spinal
fluid (CSF). The diagnosis of neuroborreliosis was made and the patient was
placed on a 3-month course of intravenous antibiotics. Although the mood
lability, mania, and cognitive problems dramatically resolved with long-term
antibiotic treatment, 3 years later the patient had not yet returned to
school because of problems with persistent fatigue. At that point, because a
PCR assay of his plasma was positive for Lyme disease and a brain single
photon emission computed tomography (SPECT) scan revealed global
heterogeneous hypoperfusion, the patient was once again treated
with antibiotics.
This case highlights the
diagnostic difficulties of Lyme disease: the confusion triggered by
equivocal results on serological tests, the need to consider B. burgdorferi
as the cause for new-onset mania, the inadequate response to standard
psychiatric medications, the initially robust but subsequently partial
response to antibiotic regimens, and the persistence of the DNA of the
organism despite aggressive antibiotic therapy.
Tests for CNS Lyme
Disease Examination of the CSF is crucial to rule out other possible causes
of CNS disease and to identify the presence of Lyme meningitis or
encephalitis. In early neurologic Lyme disease, a spinal tap may reveal
lymphocytic pleocytosis, mildly increased protein, and, in some cases, an
elevated immunoglobulin G (IgG) index or the presence of oligoclonal bands.
In later-stage neurological Lyme disease, however, the CSF may appear
normal. MRI studies may reveal punctate white matter lesions on T2-weighted
images, suggestive of a demyelinating disorder such as multiple sclerosis.
EEG studies are generally normal, although diffuse slowing or epileptiform
discharges may be seen. SPECT and positron emission tomography (PET) studies
may be particularly helpful in late-stage Lyme disease. Recent reports
indicate that many patients with Lyme encephalopathy have a pattern of
either global or heterogeneous hypoperfusion, which in some cases improves
after antibiotic treatment (Fig. 2.9-1). Given the difficulties facing the
clinician attempting to determine whether the fatigue, mood lability, and
cognitive tracking problems are caused by primary depression or by an
underlying systemic disease, functional imaging studies are a valuable tool
to assist in the differential diagnosis.
FIGURE 2.9-1 Transverse views obtained with Technetium-99m HMPAO SPECT. The
two views on the left are of the brain of an adolescent with Lyme
encephalopathy and demonstrate moderate heterogeneous hypoperfusion.
The views on the right are of the brain of an adolescent without
encephalopathy and demonstrate a normally perfused scan. The color spectrum
scale, from purple to white, represents low to normal perfusion. (See color
Plate 2.)
Differential Diagnosis
In considering the diagnosis of Lyme disease, it is important to ask the
patient about exposure to a Lyme disease-endemic area, history of a tick
bite or unusual rash, and the presence of multisystemic involvement. Called
the “new great imitator” (after the original great imitator, syphilis), the
broad spectrum of atypical neurological manifestations of Lyme disease
include strokes, Guillain-Barré syndrome, cerebellar syndromes, seizures,
pseudotumor-like syndrome in children, spastic paraparesis,
multiple–sclerosis–like illnesses, and progressive dementias. Similarly,
other diseases that may look like neuropsychiatric Lyme disease need to be
excluded, such as major depression with somatic preoccupation, panic
disorder, systemic lupus erythematosus or other connective tissue diseases,
chronic fatigue syndrome, endocrinological disorders, vitamin deficiencies,
other infectious illnesses, vascular dementias, and other neurodegenerative
disorders.
Treatment For
early Lyme disease without CNS involvement, 3 to 4 weeks of oral doxycycline
(Vibramycin) (100 mg twice a day), amoxicillin (Amoxil) (500 mg three times
a day), or cefuroxime (Ceftin) (500 mg twice a day) is recommended. For Lyme
disease with CNS involvement, an initial course of 4 to 6 weeks of
intravenous ceftriaxone (Rocephin) (2 grams/day) or cefotaxime (Claforan) (2
grams/8 hours) is recommended. Symptoms may worsen during the first week of
antibiotic treatment, much like the Jarisch-Herxheimer reaction during the
treatment of syphilis. For patients who relapse, longer and repeated courses
of antibiotics are often helpful. Failure to treat Lyme disease early in its
course or for a sufficiently long duration may lead to a chronic illness
characterized by persistent waxing and waning neuropsychiatric disturbances,
arthralgias, myalgias, sensory-hyperacuities, and severe fatigue. In some
patients these symptoms reflect the effects of persistent infection while in
others the symptoms may reflect a residual postinfectious syndrome. Because
the laboratory tests for chronic Lyme disease are not sufficiently reliable
to document the presence or absence of persistent infection, decisions
regarding treatment should be based primarily upon the physician’s clinical
judgment. Given the emerging literature that indicates that B. burgdorferi
is capable of remarkable persistence in the human host despite standard
courses of antibiotic treatment and clinical reports documenting improvement
in chronic Lyme disease among some patients treated with long courses of
antibiotics, many community physicians are now willing to treat such
patients more aggressively. Other physicians, wary of the risks associated
with long-term antibiotic treatment, choose not to treat these patients.
Until well-controlled studies are conducted of patients with chronic
symptoms, the debate on the proper antibiotic treatment for chronic Lyme
disease will continue. A vaccine for Lyme disease was introduced in 1999;
however, it is only effective in about 50 to 75 percent of cases.
Neurosyphilis The
cause of syphilis, Treponema pallidum, was identified in 1905. Because of
the cognitive loss and neuropsychiatric disturbances associated with
tertiary neurosyphilis, these patients accounted for 5 to 15 percent of
psychiatric hospital admissions and were diagnosed as having general
paresis, general paralysis of the insane, or dementia paralytica. With
penicillin treatment of primary and secondary syphilis, neurosyphilis is now
an uncommon cause of hospital admissions.
Primary syphilis is
manifest by a syphilitic ulcer, the chancre, at the site of inoculation.
Secondary syphilis, a result of hematogenous dissemination of the
spirochete, is characterized by flu-like symptoms followed by a skin rash,
generalized lymphadenopathy, and mucosal lesions. Left untreated, both
primary and secondary syphilis resolve on their own, after which the patient
enters a latent period during which infection is present but clinical
symptoms are not manifest. After months to years, about one third of
patients with untreated latent syphilis develop tertiary syphilis that
affects the brain or heart.
As in neuroborreliosis,
invasion of the CNS by Treponema pallidum occurs early in the disease and
may be asymptomatic for months to years prior to clinical expression.
Clinical neurosyphilis
can be divided into four types: syphilitic meningitis, meningovascular
syphilis, parenchymatous neurosyphilis, and gummatous neurosyphilis.
Syphilitic meningitis, the result of direct meningeal inflammation, rarely
has focal findings. Meningovascular syphilis results from the ischemic
changes caused by proliferative endarteritis, resulting in permanent CNS
damage. In parenchymatous neurosyphilis (general paresis or tabes dorsalis),
which generally starts 10 to 20 years after infection, there is direct
neural destruction resulting in diminished neuron concentration,
demyelination, and gliosis (Fig. 2.9-2). In gummatous neurosyphilis, the
mass effect causes neurological symptoms.
FIGURE 2.9-2 Tabes dorsalis. Degeneration of the posterior column in the
sacral and thoracic cord (myelin sheath stain). Reprinted with permission
from Merritt HH, Adams RD, Solomon
HC: Neurosyphilis. Oxford University Press, New York, 1946.)
General paresis
often starts with subtle cognitive and emotional changes, such as problems
with concentration and irritability; if untreated, it can lead to memory
loss, confabulation, anomia, apraxia, or pseudobulbar palsy. The disease may
mimic any other psychiatric disorders as well. Half of the patients with
neurosyphilis will manifest dementia of whom one quarter will have prominent
psychiatric manifestations such as depression, paranoia, psychosis, or
mania. A worsening of symptoms during the first 24 hours after the
initiation of antibiotic treatment has been termed the Jarisch-Herxheimer
reaction; in rare cases, psychosis may emerge shortly after antibiotics are
started. With disease progression there is loss of muscle tone and fine
motor control and seizures, spasticity, and eventually paralysis and death
occur. Focal neurological findings are rare, consistent with the generalized
pathophysiology. Tabes dorsalis on the other hand develops somewhat later
than general paresis, 15 to 20 years after infection, and causes a more
characteristic clinical picture of lancinating pains, attacks of abdominal
pain, and paresthesias. Because of progressive loss of proprioception and
sensation, patients compensate by walking with a broad-based, shuffling
gait. Unlike patients with general paresis, not all patients with tabes will
have CSF abnormalities.
Tests T. pallidum is
difficult to demonstrate in the CSF and difficult to culture. Although PCR
techniques are being developed to detect the genetic material of the
spirochete, this method is currently only available in research
laboratories. Clinicians must rely upon serological tests in the context of
a careful history and physical examination. Serological tests for syphilis
include the nontreponemal Veneral Disease Research Laboratory (VDRI) and
rapid plasma reagin (RPR) tests and, for confirmatory purposes, the
fluorescent treponemal antibody-absorption (FTA-ABS) test. CSF studies are
useful to confirm the diagnosis of neurosyphilis if clinical findings are
suggestive, to diagnose asymptomatic involvement so that treatment can be
started, and to follow treatment efficacy. These CSF studies are limited by
the low specificity of the typical abnormalities of elevated protein,
g-globulin, and leukocyte count and the low sensitivity (but high
specificity) of the VDRL test. The CSF FTA-ABS test on the other hand is
thought to have excellent sensitivity but less specificity than the CSF VDRL
test.
Neuroradiological studies
of neurosyphilis report the presence of cortical atrophy, most commonly
affecting the frontal and temporal lobes.
Treatment The goal
in clinical neurosyphilis is to reverse the manifestations or arrest the
disease progression, although in some patients antibiotic therapy may not be
able to achieve these goals. Standard courses consist of intravenous aqueous
penicillin G, 12 to 24 million units daily in divided doses at 4-hour
intervals for 2 weeks, or intramuscular weekly injections of 2.4 to 4.8
million units of penicillin G benzathine for 3 weeks or intramuscular
injections of 2.4 million units of penicillin G procaine four times daily
for 2 weeks. The likelihood of marked improvement for patients with general
paresis is less than that for patients with syphilitic meningitis or
meningovascular syphilis, reflecting the pathological process, which in the
former is irreversible neuron damage and in the latter is CNS inflammation.
During the first year after treatment, the serum and CSF should be regularly
monitored for the reemergence of reactivity so that treatment can be
reinitiated if necessary. Certain conditions, such as comorbid HIV
infection, may place patients at greater risk for persistence of treponemal
infection after antibiotic treatment. However, most neurosyphilis patients,
when treated, will show improvement in the cognitive, psychiatric, and
functional domains.
NON-HIV VIRAL INFECTIONS
OF THE CENTRAL NERVOUS SYSTEM
Numerous viruses are
invasive and neurotropic, with the extent of consequent neuronal dysfunction
varying widely depending upon the virulence of the virus and the
immunological response of the host. This section will focus upon agents
known to cause striking neuropsychiatric diseases: herpes simplex, rabies,
measles, and subacute sclerosing panencephalitis; Table 2.9-1 presents other
infectious causes of neuropsychiatric disorders.
Table 2.9-1 Selected Infectious Causes of Neuropsychiatric Disorders
Herpes Viruses Included
under the spectrum of herpesviruses are human herpesvirus 1 (HHV-1), that
is, herpes simplex virus 1; HHV-2, that is, herpes simplex virus 2,
varicella-zoster virus, Epstein-Barr virus (EBV), cytomegalovirus (CMV),
HHV-6, HHV-7, and Kaposi’s sarcoma herpesvirus.
Herpes Simplex Herpes
simplex encephalitis is a dramatic disorder, characterized by the abrupt
onset of fever, personality change, and headaches, followed by cognitive
changes and focal neurological signs, such as aphasia, visual field
deficits, hemiparesis, or partial seizures. Although focality is an
important feature of herpes simplex encephalitis, other viruses, such as the
LaCrosse virus or the nonpolio enteroviruses, may also cause focal signs.
Neurobehavioral aspects of herpes simplex encephalitis such as
hallucinations, memory loss, or behavioral disturbances may be the primary
clinical feature, a consequence of the predilection of the virus for the
temporal lobes. Although the course of illness is typically rapidly
progressive, resulting in refractory seizures, coma, and death within 2
weeks, occasionally the progression may be slower with varied
neuropsychiatric features.
HSV-1 is usually
transmitted orally entering the CNS through sensory nerves, particularly the
trigeminal ganglia. HSV-2 is transmitted genitally and may seed the sacral
ganglia or disseminate hematogenously. Herpes simplex viruses typically
produce a lytic infection with neuronal necrosis and tissue destruction, and
intranuclear inclusion bodies in the neurons and glia. Patients who survive
herpes simplex encephalitis may exhibit postencephalitic symptoms, such as
amnesia, aphasia, and less commonly, the Klüver-Bucy syndrome or dementia.
Routine serological
studies are of little value in suspected herpes simplex encephalitis. The
CSF usually demonstrates leukocytosis (approximately 100 cells/mm3), a
moderate protein elevation, and a normal or depressed glucose content. PCR
analysis of the CSF to detect HSV DNA is at present the diagnostic procedure
of choice because the PCR assay has high sensitivity and specificity. Recent
studies indicate that approximately 80 percent of patients with
biopsy-proven herpes simplex encephalitis will have focal EEG abnormalities
consisting of slowing or repetitive epileptiform discharges in the
frontotemporal area. MRI studies in early stages of herpes simplex
encephalitis may reveal T2 prolongation in the insular cortex and cingulate
gyrus. SPECT or PET imaging may show reduced blood flow in the orbitofrontal
and temporal regions. Brain biopsy can be helpful in cases that are
difficult to diagnose, although the complication rate is approximately 3
percent.
If untreated, 40 to 70
percent of patients with herpes simplex encephalitis will die. Antiviral
therapies include acyclovir (zovirax) and vidarbine (Vira-A); however, even
with acyclovir treatment fewer than 40 percent of patients survive with
minimal or no sequelae (Fig. 2.9-3).
FIGURE 2.9-3 Herpes encephalitis. A, Contrast-enhanced axial CT scan shows
diffuse
decreased density of the left temporal lobe with minimal hypodensity of the
medial right
temporal lobe. An abnormal CT scan is usually not seen until day 6 to 7
after the onset of
manifestations.
Eventually, a majority of scans show gyral enhancement in the sylvian
fissure area.
These findings should
raise the suspicion of an underlying infectious lesion such as herpes, early
infarction from emboli or
vasculitis, or metastatic tumors. B, T2-weighted axial MRI scan shows
diffuse
increased signal intensity
along the left temporal lobe cortex as well as the posteromedial left
temporal
lobe. Both medial frontal
lobes are involved as well. An abnormal MRI scan is usually seen by day 1 or
2
after the onset of
manifestations. The patient was treated for herpes encephalitis and
responded to
acyclovir therapy.
(Reprinted with permission from Jubelt B, Miller JR: Viral infections. In
Meritt’s
Textbook of Neurology, ed
9, LP Rowland, editor. Williams & Wilkins, Baltimore, 1995.)
Epstein-Barr Virus Most
adults have evidence of past exposure to EBV, with approximately 50 percent
seropositivity among
children over age 5. Infection in childhood is generally mild, whereas in
adolescence and young
adulthood it may result in infectious mononucleosis or, rarely, a fulminant
life-threatening disease.
EBV enters the body by infecting oral mucosal epithelial cells. The clinical
symptoms of infectious
mononucleosis of sore throat, headache, malaise, and fatigue are largely a
result of the vigorous
cellular immune response to EBV infection rather than direct cytotoxic
effects.
Significant neurological
complications of EBV infection are rare, occurring in less than 0.5 percent
of
cases of infectious
mononucleosis.
EBV encephalitis occurs
usually within 1 to 3 weeks after the onset of clinical infectious
mononucleosis. Patients
with EBV encephalitis may present with cerebellar ataxia, personality
changes, psychosis,
transient global amnesia, perceptual distortions of size and space, focal
neurological findings,
seizures, or coma. EEG usually reveals generalized slowing with occasional
sharp-wave activity. The
diagnosis of an EBV neuropsychiatric syndrome requires an appropriate
clinical
history in the setting of
serological evidence of acute or, rarely, chronic active infection. In cases
of EBV
encephalitis commonly
there is a lymphocytic pleocytosis (atypical lymphocytes are particularly
suggestive) with elevated
protein. In most cases EBV encephalitis is self-limited, with recovery
occurring
within weeks to months;
rarely, acute EBV infection may result in a relapsing or chronic
encephalitis.
Treatment is generally
supportive.
Other Herpes Viruses With
herpes zoster, neuropsychiatric complications occur most frequently in
immunocompromised patients, resulting in encephalitis, myelitis, or
leukoencephalitis. With CMV infection, encephalitis may also occur because
CMV is tropic for the CNS; however, only in rare exceptions has CMV
encephalitis occurred in non–HIV-infected immunocompromised individuals.
Rabies Although most cases
of human rabies occur after animal bites, other sources of rabies infection
include aerosols (risk for spelunkers) and person-to-person transmission
following corneal transplants. The virus replicates locally at the site of
inoculation and subsequently spreads to the CNS by retrograde axonal
transport, infecting the lower areas of the brain most prominently,
particularly the limbic system, hippocampus, brainstem, and cerebellum.
Limbic system involvement may result in aberrant sexual behavior and
behavioral dyscontrol, whereas brainstem involvement typically results in
alterations of body temperature and respiratory control. The site and amount
of inoculation is associated with morbidity. For example, multiple dog bites
to the face may result in a 60 percent mortality rate without prophylactic
intervention whereas multiple bites to the hand are associated with lower
mortality rates of about 15 percent. The incubation period prior to
symptomatic expression ranges from a few days to several years. Once
symptoms emerge, the course is rapidly fatal. Most patients get the furious
form characterized by agitation, hallucinations, odd behaviors, extreme
excitability, and in some cases, hydrophobia. Diagnosis is based on the
history of an animal bite in a patient with unexplained encephalitis that
has been confirmed by the demonstration of rabies antigen on a skin biopsy
of the patient or from a putatively infected animal. There is no treatment
for rabies virus infection. Disease prevention is critical, aided by
preexposure vaccination in high-risk individuals and postexposure
prophylaxis with rabies immunoglobulin and rabies vaccine (Fig. 2.9-4).
FIGURE 2.9-4 Rabies. Inclusion bodies (Negri bodies) in cytoplasm of
ganglion cell of cerebral cortex. (Reprinted with permission from Jubelt B,
Miller JR: Viral infections. In Merritt’s Textbook of Neurology, ed 9,
LP Rowland, editor. Williams & Wilkins, Baltimore, 1995.)
Subacute Sclerosing
Panencephalitis Subacute sclerosing panencephalitis is a very rare slow
infection with measles virus that causes progressive inflammation and
sclerosis of the brain. Primarily affecting children and young adults, the
rate of subacute sclerosing panencephalitis decreased markedly after 1960 as
a result of widespread measles vaccination, with a current rate in the
United States of only 1 per 100 million people per year. The onset generally
occurs 7 to 12 years after measles and is subtle, characterized by gradual
changes in behavior and school performance. Neuropsychological testing may
demonstrate reduced overall intelligence and problems with reading, writing,
and visuospatial processing. Neuropsychiatric symptoms may include
hallucinations, apraxia, agnosia, and Balint’s syndrome (optic ataxia,
simultanagnosia, and sticky fixation). Repetitive myoclonic jerks are
common, at times accompanied by movement disorders and cerebellar ataxia. In
advanced stages, dementia, mutism, cortical blindness, optic atrophy,
stupor, coma, and death occur.
The usual course of the
illness is 1 to 3 years, with rare patients surviving up to 10 years.
Serological testing may
reveal unusually high titers of antibodies to measles virus. CSF studies
typically show high measles antibody titers and a greatly elevated gamma
globulin fraction with oligoclonal bands in a CSF with slightly elevated
protein concentrations. EEG studies are essential, particularly in the
myoclonic stage, when they reveal high-amplitude bilateral and stereotyped
complexes that repeat every 3 to 5 seconds. MRI studies may reveal enlarged
ventricles and diffuse brain atrophy, with multifocal low-density white
matter lesions and lucent areas in the basal ganglia. PET and SPECT studies
may reveal early subcortical hypermetabolism followed by global cortical and
subcortical hypometabolism.
No treatments are known to
reverse the disease, although slightly prolonged survival has been reported
with isoprinosine (Inosiplex) and with intraventricular or intrathecal
injections of interferon-a.
Progressive Multifocal
Leukoencephalopathy This disease affects immunocompromised subjects and is a
progressive infection of oligodendroglial cells with the JC papovavirus.
Typically the onset is abrupt with focal neurological or neuropsychological
signs and the course is almost invariably fatal within 2 to 4 months.
Definitive diagnosis requires a brain biopsy. Neuroimaging studies reveal
multifocal areas of high signal intensity in the white matter. Functional
imaging with PET or SPECT may reveal a heterogeneous pattern of reduced
metabolic activity and perfusion.
SUBACUTE SPONGIFORM
ENCEPHALOPATHIES
Included in this group are
Creutzfeldt-Jakob disease; kuru, a dementing disease of three New Guinea
tribes that is most likely spread by ritual cannibalism;
Gerstmann-Straüssler syndrome, a familial disorder characterized by dementia
and ataxia; and fatal familial insomnia, a disorder causing disturbances of
sleep and of motor, autonomic, and endocrine function. These disorders are
all slow infections caused by a transmissible agent not yet clearly
described that may be a prion, a virino or an atypical virus. Prions are
proteinaceous agents devoid of nucleic acid that are crucial in the
pathogenesis of the spongiform encephalopathies. A virino is a small
molecule (probably a nucleic acid) associated with a host protein.
Characteristic of the neuropathology of these disorders is the neuronal
vacuolation that leads to spongy degeneration of the cerebral cortical gray
matter.
Creutzfeldt-Jakob Disease
Invariably fatal, this transmissible, rapidly progressive disorder occurs
mainly in middle age or older and is manifest early on by fatigue, flu-like
symptoms, and mild cognitive impairment or focal findings such as aphasia or
apraxia. Subsequent psychiatric manifestations include mood lability,
anxiety, euphoria, depression, delusions, hallucinations, or marked
personality changes. Progression of disease occurs over months leading
to dementia, akinetic mutism, coma, and death. Other common neurological
findings are generalized startle myoclonus, cortical blindness, and
extrapyramidal and cerebellar signs.
The rates of
Creutzfeldt-Jakob disease range from 0.25 to 2 cases per million persons a
year worldwide. The infectious agent self-replicates and can be transmitted
to humans by inoculation with infected tissues and sometimes by ingestion in
food. Iatrogenic transmission has been reported via transplantation of
contaminated cornea or to children via contaminated supplies of human growth
hormone. Household contacts are not at greater risk than the general
population, unless there is direct inoculation. Because of an epidemic of a
newly recognized prion disease, bovine spongiform encephalopathy (mad cow
disease), among cattle in the United Kingdom and because of the unexpected
recent emergence of cases of an atypical form of Creutzfeldt-Jakob disease
among teenagers in the United Kingdom, fears exist that transmission to
humans may have occurred as a result of eating infected meat (Fig. 2.9-5).
FIGURE 2.9-5 Creutzfeldt-Jakob disease. Section from cortex showing status
spongiosis of the neuropil, loss of neurons, and prominent astrocytosis. (PTAH
stain × 120). (Reprinted with permission from Jubelt B, Miller JR: Viral
infections. In Merritt’s Textbook of Neurology, ed 9, LP Rowland, editor.
Williams & Wilkins, Baltimore, 1995.)
Diagnosis requires
pathological examination of the cortex, which reveals the classic triad of
spongiform vacuolation, loss of neurons, and glial cell proliferation.
Genetic susceptibility is a factor in disease risk, indicated by a common
polymorphism of the human prion protein. An immunoassay for
Creutzfeldt-Jakob disease in the CSF is currently under development, showing
promise in supporting the diagnosis of Creutzfeldt-Jakob disease in patients
with dementia. EEG abnormalities, although not specific for
Creutzfeldt-Jakob disease, are present in nearly all patients: a slow and
irregular background rhythm with periodic complex discharges. Computed
tomography (CT) and MRI studies may reveal cortical atrophy later in the
course of disease; SPECT and PET reveal heterogeneously decreased uptake
throughout the cortex. There is no known treatment for Creutzfeldt-Jakob
disease.
OTHER INFECTIOUS CAUSES OF
NEUROPSYCHIATRIC DISORDERS
A variety of
bacterial, mycoplasmal, fungal, and parasitic infections can cause
neuropsychiatric disturbances as a result of a chronic meningitis or
sequelae from an acute infection (Table 2.9-1).
EMERGING AREAS OF
INVESTIGATION
Chronic Fatigue Syndrome
Chronic fatigue syndrome, more commonly referred to as myalgic
encephalomyelitis in the United Kingdom and Canada, is a multisystem
syndrome characterized by 6 months or more of severe, debilitating fatigue,
often accompanied by myalgia, headaches, pharyngitis, low-grade fever,
cognitive complaints, gastrointestinal symptoms, and tender lymph nodes. The
search for an infectious cause of chronic fatigue syndrome has been active
because of the high percentage of patients who report abrupt onset after a
severe flu-like illness. In the mid-1980s chronic fatigue syndrome was
linked to infection with Epstein-Barr virus. After EBV was shown in
controlled studies to have no specific role in the etiology of chronic
fatigue syndrome, reports have linked chronic fatigue syndrome to a variety
of other agents, including enteroviruses, retroviruses, and new lymphotropic
herpesviruses but these reports have not been consistently replicated in
well-designed studies. Certain organisms, however, such as B. burgdorferi
(which causes Lyme disease), can result in a chronic fatigue syndrome-like
picture; however, most cases of CFS are not linked to Lyme disease. Evidence
of immune dysregulation has been frequently reported among patients
with chronic fatigue syndrome, but the data are not consistent across
studies nor are they reflective of illness severity. Various studies have
found high rates (15 to 54 percent) of depressive disorders among patients
with chronic fatigue syndrome. In addition, recent research has shown that
patients who are most likely to be plagued by persistent fatigue after an
acute viral illness are patients with preexisting or comorbid psychiatric
problems. However, other research has shown that the cognitive impairment in
chronic fatigue syndrome exists even in the absence of preexisting or
comorbid psychiatric disorders, thus leading to the conclusion that
psychiatric disorders alone cannot account for chronic fatigue syndrome. At
present, chronic fatigue syndrome is best conceptualized as a heterogeneous
syndrome of uncertain etiology, most likely involving an interplay of
psychiatric, infectious, neuroendocrine, and immunological factors.
Group A b-Hemolytic
Streptococci Poststreptococcal autoimmunity has been postulated to be a
cause of certain types of childhood-onset obsessive-compulsive disorders and
Tourette’s disorder based on the observation that children who develop
Sydenham’s chorea are often observed to have tics or obsessive-compulsive
symptoms prior to the onset of the chorea. These pediatric autoimmune
neuropsychiatric disorders are characterized by abrupt and dramatic symptom
exacerbations that are temporally related to group A b-hemolytic
streptococcal infections. Recent research has identified a genetic marker in
pediatric autoimmune neuropsychiatric disorders that has previously been
shown to be both highly specific and sensitive in identifying individuals
with rheumatic fever. In one study 85 percent of children who developed
streptococcal-related obsessive-compulsive disorder or tics and 89 percent
of children with Sydenham’s chorea carried the D8/17 monoclonal antibody
marker on DR+ cells in the peripheral circulation, whereas only 17 percent
of healthy controls carried this marker. Investigations are currently
underway to determine whether treatments that modulate the immune response
(e.g., intravenous g-globulin or plasmapheresis) are effective in
eliminating obsessive-compulsive disorder and tic disorders among children
with pediatric autoimmune neuropsychiatric disorders.
Borna Disease Virus Borna
disease virus (BDV) is a small neurotropic ribonucleic acid (RNA) virus that
infects various domestic animal species, causing disturbances in behavior
and cognition and, rarely, death. Researchers have found that BDV targets
cells of the limbic system in animals and compromises their neuronal
function without causing direct damage. BDV has recently been linked to a
wide array of neuropsychiatric disorders in humans. Evidence suggestive of
BDV infection in humans has been accumulating from several research centers.
One research group recently identified serum antibodies to BDV in 9.6
percent of 416 people with schizophrenia, major depressive disorders,
bipolar I disorder, and other neuropsychiatric disease whereas these serum
antibodies were found in only 1.5 percent of 203 healthy controls. Reverse
transcriptase-PCR identified BDV RNA sequences in 13 of a subset of 26
psychiatric patients but in none of 23 healthy controls. Other reports have
identified BDV antibodies in 6.8 percent of patients with psychiatric
illnesses versus 3 percent of surgical controls. These studies represent
provocative preliminary findings that suggest a possible role for BDV in a
subset of human neuropsychiatric diseases; well-controlled microbiological
and epidemiological studies are needed to determine the significance of
these reports.
SUGGESTED
CROSS-REFERENCES
Acquired immune
deficiency syndrome is discussed in Section 2.8; interactions of the immune
system and the CNS are discussed in Section 1.12; neuropsychological testing
is discussed in Section 7.4; and neuroimaging is discussed in Section 2.13.
Obsessive-compulsive disorder and schizophrenia are discussed in Chapter 15
and Chapter 12, respectively.
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Books@Ovid
Copyright © 2000 Lippincott Williams & Wilkins
Harold I. Kaplan, M.D, Benjamin J. Sadock, M.D and Virginia A. Sadock, M.D.
Kaplan & Sadock’s Comprehensive Textbook of Psychiatry