For those of you trying to document your diagnosis, or trying to prove disability, the article below may be helpful to you. It is from a 2002 Psychiatry textbook, written by Dr. Brian Fallon of Columbia University Medical Center. It also highlights other infectious diseases that may cause psychiatric symptoms, often misdiagnosed as a psychiatric disorder rather than the function of a disease process.
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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