Kiran P. Maski and Nicole J. Ullrich
Infections of the central nervous system (CNS) are less frequent than infections of other organ systems, because the brain is protected by both the anatomic barrier of the bony skull and blood-brain barrier. Nevertheless, CNS infections remain a significant cause of morbidity and mortality in children. Classic signs and symptoms of CNS infections are often not present or more subtle in young children, thereby making accurate diagnosis a challenge for the general pediatrician (Table 555-1). The outcome of CNS infection predominantly depends on the site of infection and etiologic organism in addition to host immune status. For full description of bacterial and viral CNS infections, see Chapters 231 and 232. In this chapter, we focus on the neurologic presentation of CNS infections and discuss the unique CNS involvement of purulent CNS infections, latent viral infections, and prion diseases.
SIGNS AND SYMPTOMS OF CNS INFECTIONS
The most common presentation of meningitis includes nonspecific signs and symptoms such as headache and nuchal rigidity. Meningismus refers to a condition in which the neck and back muscles tense as a reflex to avoid painful extension of the inflamed meninges. The physical findings of Kernig sign (passive extension of the knee from flexed thigh position elicits pain in the back) and Brudzinski sign (passive flexion of the neck elicits spontaneous flexion the lower extremities) are thought to reflect both the inflammation of the meninges and increased intracranial pressure. Nuchal rigidity is rare in neonates and uncommon in children ages 12 to 18 months. Other symptoms of meningitis vary depending on the etiology and location of the infection. The associated symptoms of fever, vomiting, lethargy, irritability, photophobia, anorexia, and dehydration all support the diagnosis.1 In neonates, a full fontanel may be present in addition to failure to thrive, irritability, apnea, seizures, opisthotonus, poor feeding, temperature instability, jaundice, and grey appearance.2
The anatomic boundaries between the meninges and brain parenchyma are indistinct. Many patients experience concurrent infections of the meninges and parenchyma, known as meningoencephalitis, often accompanied by signs of headache, generalized seizures, and mental status changes (delirium, agitation, somnolence, lethargy). Within the brain parenchyma, the inflammatory response is characterized by neutrophilic infiltrations and increased vascular permeability via alteration of the blood-brain barrier. Focal neurologic symptoms/signs may also be present including unilateral headache, paresis, cranial nerve palsy, or partial seizures. These findings may suggest a more localized involvement of brain parenchyma, or even focal infection, such as those caused by abscess or tuberculoma. Slowed blood flow secondary to infection within the parenchyma or meninges can result in acute vascular events such as venous infarction that then are also likely to produce more localizable neurologic signs. Patients who experience severely depressed consciousness, coma, vomiting, bulging fontanel, diastasis of sutures, or third or sixth cranial nerve palsy may have concurrent increased intracranial pressure secondary to inflammation from infection. These signs may also result from subdural effusions which develops in 10% to 30% cases of meningitis, particularly in infants.3Progression to decorticate/decerebrate posturing; papilledema; hyperventilation; and the triad of hypertension, bradycardia, and apnea suggests the development of dangerously high intracranial pressure and impending herniation. It is imperative to start antibiotic treatment first and then to consider neuroimaging if focal signs/symptoms and/or suspicion of increased intracranial pressure are present.
Meningitis is associated with seizure in up to 23% of children.4 In the younger child, it may be difficult to distinguish between a classic febrile seizure and a symptomatic seizure associated with fever resulting from underlying meningitis/encephalitis. Meningitis should be suspected if seizures occur 3 or more days after the onset of fever. Meningeal signs may be absent in children younger than 18 months of age who present with fever and seizure and there should be a low threshold to perform cerebrospinal fluid analysis. The American Academy of Pediatrics strongly urges physicians to consider lumbar puncture in infant less than 12 months who present with febrile seizure.7Careful attention should be made to changes in serum glucose, calcium and sodium (secondary to syndrome of inappropriate antidiuretic hormone [SIADH]) concentrations as seizure precipitants. Lumbar puncture results may also help to distinguish between viral, bacterial, parasitic, and fungal processes so that therapy can be tailored appropriately. Table 555-2 shows a comparison of cerebrospinal fluid (CSF) profiles associated with various CNS infectious agents. Specific agents causing bacterial and viral meningitis are listed in Tables 231-1 and 232-1.
Table 555-1. Signs and Symptoms of CNS Infection
Localized infections of the cerebellum can produce an acute cerebellar ataxia. Acute onset of gait difficulties, incoordination and nystagmus, slurred speech, and vomiting suggests either infectious or postinfectious cerebellitis. Fever is noted in nearly 75% of cases and latency of illness to onset of ataxia averages 9 days.8 The differential diagnosis of fever with cerebellar signs includes cerebellar abscess and acute labrynthitis. Rhomboencephalitis or brainstem encephalitis results from infection of the brainstem, specifically the pons and medulla. Symptoms/signs include meningismus, fever, and headache in addition to cerebellar dysfunction, hemi/quadriparesis, cranial nerve abnormalities (facial palsy, diplopia, dysphagia, dysautonomia), and opsoclonus. Cerebrospinal fluid (CSF) pleocytosis with increased protein and decreased glucose concentrations, and magnetic resonance imaging (MRI) that demonstrates increased signal in the pons/medulla, suggest the underlying diagnosis. In the pediatric population, Listeria,9 West Nile virus,10 enterovirus 71,11 and HHV612 infections have all been reported as etiologic agents of rhomboencephalitis.
Table 555-2. Cerebrospinal Fluid Profile in CNS Infections
Infection of the spinal cord or infectious myelitis can also be categorized into focal and diffuse pathology. Certain viruses, such as poliovirus, Epstein-Barr virus, enterovirus, echovirus, and coxsackie virus exhibit tropism for the anterior horn cell.13 Infection of anterior horn cells produces asymmetric motor weakness with or without fever, encephalopathy, and nausea/vomiting. Headache and mental status changes suggest a more widespread meningoencephalitis. Weakness that extends to the face and bulbar nuclei can result in autonomic, respiratory, and circulatory compromise. If the infection is limited to the anterior horn cell, sensory examination may remain normal. Acute transverse myelitis (ATM) (see Chapter 556) is defined as inflammation of gray and white matter in one or more adjacent spinal cord segments. Acute transverse myelitis is thought to result either from direct infection or postinfectious immune mediated processes, leading to diffuse involvement in the spinal cord and subsequent sensory and motor dysfunction.14 Early signs of spinal cord dysfunction include paresthesias, back pain in segmental distribution, bilateral weakness, bowel/bladder dysfunction, and sensory level with dysesthesia or hyperalgesia. Autonomic dysfunction may or may not be present. Symptoms typically develop over 4 hours to 21 days ultimately with progression to flaccid paralysis and then spasticity over weeks. In the setting of ATM, magnetic resonance imaging (MRI) of the spine typically demonstrates T2 hyperintense lesions that extend more than 2 vertebral body lengths, often with cord expansion and variable contrast enhancement.15 Cerebrospinal fluid analysis demonstrates increased protein content, suggestive of inflammation. The constellation of symptoms including fever, back pain, point tenderness of the spinous processes, motor weakness, and/or sphincter compromise may suggest spinal epidural abscess (EDA). There are no clear-cut clinical diagnostic criteria for EDA, and signs and symptoms commonly overlap with ATM. Immediate MRI with and without gadolinium and intravenous (IV) antibiotics are indicated if concern for epidural abscess exists.
DIAGNOSIS OF CNS INFECTION
Neurologic signs and symptoms, laboratory investigations and neuroimaging studies can all help facilitate the localization of disease processes and provide guidance for management. After history and physical examination are complete, the decision to perform lumbar puncture (LP) or neuroimaging should be made. A concern is that if intracranial pressure (ICP) is elevated LP may precipitate herniation of the hindbrain through the foramen. Raised ICP is common in children with uncomplicated acute bacterial meningitis. Careful measurement of opening pressure with legs extended can help identify elevated ICP. In one study, 33 of 35 infants and children with pyogenic meningitis had a significant elevation in CSF opening pressure at the time of evaluation.18 The vast majority of children presenting with suspected bacterial meningitis, however, have no clinical evidence of herniation; therefore routine computerized tomography (CT) scan of the brain is not indicated.19 A diagnostic LP should be done expeditiously and appropriate antibiotic therapy should be promptly initiated.
A computerized tomography (CT) scan of the brain should be considered prior to lumbar puncture if patient presents with symptoms or signs of ICP such as depressed mental status, posturing, papilledema, increase in blood pressure with slow pulse rate, or focal neurologic symptoms or signs.
Risk of herniation with lumbar puncture still exists even with normal head CT, and there is considerable variation in normal ventricular and cisternal size, making interpretation of a single scan unreliable.20Cerebral edema may produce CT abnormalities including slit-like lateral and third ventricles, generalized low attenuation of the white matter, and obliteration of the basilar and suprachiasmatic cisterns.21 If concern for herniation exists based on clinical judgment, the decision to perform an LP may need to be deferred. When the child’s condition has stabilized, the need for CSF evaluation can be reconsidered.
CEREBROSPINAL FLUID (CSF) INTERPRETATION
Evaluation of cerebrospinal fluid (CSF) can help determine the diagnosis of bacterial or viral meningitis or encephalitis (Table 555-2). Although CSF is considered an acellular space, 5 white blood cell (WBC) count and 5 red blood cell (RBC) count per μL are considered normal when CSF is sampled by lumbar puncture (LP); newborns, in contrast, may have up to 20 WBC/μL in the CSF.22 Pleocytosis is the rule in bacterial meningitis with CSF WBC counts in the range of 100 to 10,000/μL. Early in the disease, WBC in CSF may be normal. Polymorphonuclear cells predominate and usually account for more than 90% of the total. Very high WBC counts (> 50,000/μL) raise the possibility of intracranial abscess. CSF glucose is usually less than 50% of simultaneous serum glucose concentration, but low CSF glucose is also found in tuberculosis, fungal meningitis, subarachnoid hemorrhage, and carcinomatous meningitis. CSF protein concentration is usually elevated to 100 to 500 mg/dL in bacterial meningitis. The alteration in protein concentration reflects disruption of blood-brain barrier but is not in itself indicative of bacterial meningitis. Protein concentrations may be significantly elevated in patients with meningitis caused by Mycobacterium tuberculosis. Gram stain is positive in more than 90% of untreated meningitis and culture positive in 70% to 90% of patients with untreated meningitis.
NEUROLOGIC OUTCOME OF CNS INFECTION
The range of neurologic sequelae from central nervous system (CNS) infection largely depends on the etiologic agent, and duration and location of infection. CNS infections also vary in severity. Organisms with tropism to the brain can take years to demonstrate clinical disease, as with infections caused by transformed prions and slow viruses, or may produce rapid inflammation and neuronal destruction, as in some cases of meningococcal bacterial or herpes simplex virus (HSV) meningitis.
The neurologic complications after bacterial meningitis include bilateral severe or profound deafness, mental retardation, seizures, and spasticity and/or paresis.24 By contrast, most children with viral meningitis recover spontaneously, though persistent fatigue, sleep disturbances, behavior and concentration difficulties, and incoordination have been noted.25 Diseases attributed to chronic latent viruses and prion diseases are considered neurodegenerative diseases with uniformly poor outcome. Focal purulent collections in the brain and spine have shown dramatic improvement in mortality and reduction in neurologic sequelae as a result of advances in neuromaging and improved medical and neuro-surgical techniques. Future investigations into the role of selective immunomodulation and neuroprotective strategies may lead to significant advances in management and outcome of CNS infections.
Table 555-1 briefly reviews the clinical presentation and management of specific CNS infections; many of the bacterial and viral infections are discussed in Section 17. This chapter focus on CNS abscesses, chronic latent infections and prion diseases.
INTRACRANIAL AND SPINAL ABSCESSES
A brain or spinal abscess is a focal, intraparenchymal infection that begins as a localized cerebritis and becomes encapsulated.26 Brain and spinal abscesses are relatively uncommon in pediatric patients, but are potentially neurologically devastating and life threatening. In children, the most common sources of infection are related to underlying cyanotic congenital heart disease, meningitis, chronic otitis media, mastoiditis, sinusitis, cellulitis of scalp, face, orbit, dental infection, penetrating head injury, immunodeficient states, and intracranial foreign bodies. Early diagnosis and treatment of brain abscess can be life saving. The diagnosis and treatment of both spinal and brain abscesses are discussed in detail in Chapter 231.
Subdural empyema (SDE) refers to a collection of infected cerebrospinal fluid (CSF) or pus between the dura and arachnoid spaces and accounts for 15% to 20% of all localized intracranial infections.51Routine immunization for Haemophilus influenza has decreased the overall incidence because SDE was a common complication of H influenza meningitis.52 Now, the most common predisposing features are otorhinologic infections, especially paranasal sinus infections in children. Pathogens spread to the subdural space via valveless emissary veins in association with thrombophlebitis from infection of sinuses, mastoid, or middle ear or extension of osteomyelitis of the skull.53 Once infection reaches subdural space, it can easily spread over the convexities of the brain, extending to both hemispheres. Mastoiditis, untreated middle ear infection, skull trauma, neurosurgery, instrumentation of the ears or nose, and infection of preexisting subdural hematoma are known risk factors. In infants, SDE can result from poorly treated meningitis with infected subdural effusion, typically with the same hasorganism (Fig. 555-1).54 The causative agents of SDE represent those found in sinus and otic infections; aerobic and anaerobic streptococci are isolated in 44% to 60% of cases.55, 56 Postoperative and posttraumatic infections are often due to staphylococci and gram negative aerobic bacilli.
FIGURE 555-1. Subdural empyema. Fluid-attenuated inversion recovery sequence on brain MR of a six-week-old infant who presented with fever, lethargy, and irritability. He was diagnosed with Pasteurella multocidabacteremia, associated with cerebral spinal fluid/white blood cell (CSF/WBC) count of greater than 3000. He was later found to have a loculated subdural empyema, most evident on imaging as bilateral high signal intensity within the sulci of the temporal and parietal lobes.
Intracranial subdural empyema (SDE) can present with fever, headache, vomiting, altered mental status, and seizures. Meningismus may be present. Purulent material can spread widely in the subdural space causing focal or diffuse hemispheric signs. An enlarging head with spreading sutures in an infant who has or has had meningitis is probably caused by SDE or postmeningitic hydrocephalus. Diagnosis of SDE can be made by ultrasonography in infants. On computed tomography (CT) and magnetic resonance imaging (MRI), SDE may appear as a crescentic or elliptical area of hypodensity beneath the cranial vault or adjacent to the falx cerebri with or without loculations (Fig. 555-1). Subdural empyemas do not cross the midline, which distinguishes them from epidural abscess.53 Magnetic resonance imaging is the study of choice because of the ability to identify small subdural fluid collections, to delineate empyema at the base of the brain along the falx cerebri and posterior fossa, and to provide better anatomic delineation of infection.57 Lumbar puncture is contraindicated if SDE is suspected because of concern of increased intracranial pressure (ICP) and cerebral herniation; CSF gram stain and culture will be negative unless the course is complicated by bacterial meningitis.58
Subdural empyema (SDE) is a medical emergency and may require urgent medical, as well as neurosurgical, treatment. Choice of antibiotic should be tailored to the suspected route of infection. Cultures (aerobic and anaerobic) of purulent material are needed to guide specific antimicrobial agents and surgical decompression is useful for controlling intracranial pressure. Vancomycin is used if S aureus is suspected and can be changed to nafcillin (an agent that targets streptococci as well) once the organism is proven to be methicillin susceptible. Metronidazole is suggested if anaerobic infection is suspected. For infection of suspected gram-negative bacilli, empirical treatment with cefipime, ceftazidime, or meropenim is appropriate. There are no firm data regarding course of treatment, but a 3 to 4 week course of parental antibiotics is generally adopted.51 Neurosurgical evacuation of purulent material via burr hole or craniotomy diminishes mass effect, allows better antibiotic penetration, and permits identification of the causative organism. In infants, subdural taps through an open anterior fontanel can be considered. Once the aspirate reveals an organism, antibiotic therapy can be tailored appropriately. Antibiotic treatment alone has been used successfully in patients with minimal or no impairment of consciousness, no major neurologic deficit, limited extension of empyema without midline shift, and early improvement with antibiotics.51,59 All patients should be monitored with frequent imaging to document resolution of empyema. A course of oral antibiotics may also be considered after parental antibiotics are stopped. In the modern era, mortality rates of patients with cranial SDE are reported 0% to 12%.51,60 Despite improved survival rates compared to the pre-antibiotic era, 16% to 50% of surviving patients experience permanent neurologic deficits including motor weakness, seizures, and/or cognitive deficits.61
SPINAL SUBDURAL EMPYEMA
Spinal subdural empyema is rare and is thought to occur secondary to spread of infection from a distant site. Spinal empyema can present as radicular pain at multiple levels and with cord compression. The most frequent microbial isolates are Staphylococcus aureus and streptococci, coagulase negative staphylococci; gram negative bacilli are less frequent.51 Cases of spinal subdural empyema have been reported from hematogenous spread from skin lesions, systemic sepsis, direct spread from spinal osteomyelitis, complications of discography, and cervical acupuncture.62 Magnetic resonance imaging (MRI) is the diagnostic procedure of choice because it better defines the extent of the lesion compared to computerized tomography (CT).57 Laminectomy, in addition to parenteral antibiotics, may be necessary to drain the infection.
CRANIAL AND SPINAL EPIDURAL ABSCESSES
Epidural abscess (EDA) is a suppurative infection in the space between the cranium or vertebral column and dura. In contrast to infection in the subdural space, empyema in the epidural space will slowly progress because dura adheres tightly to the bone. As a result, the presentation of epidural empyema is more insidious and indolent than subdural infection. Symptoms may be present for weeks to months before diagnosis. Cranial EDA usually presents with localized tenderness and headache, but patients may otherwise feel well.53 If infection crosses to the cranial dura via emissary veins, signs and symptoms of subdural empyema will result. Infection can spread to overlying bone and cause osteomyelitis of the skull. A cranial EDA near the petrous bone can result in Gradenigo’s syndrome, characterized by involvement of cranial nerves V and VI with unilateral facial pain and weakness of the lateral rectus muscle. Cranial epidural abscesses may result from complications of head trauma, neurosurgical intervention, or spread of infection from contiguous structures such as nasal sinuses and middle ear. Cranial epidural abscess has been reported with fetal scalp monitoring and scalp venous catheter placement.63,64 The preferred imaging modality is MRI with gadolinium which will show characteristic finding of lenticular collection of fluid between bone and cerebral hemisphere with variable appearance and enhancement.39 Given the similar pathophysiology to subdural infection, management of cranial epidural abscess is identical to that of cranial subdural empyema discussed above. However, craniotomy or craniectomy may be necessary in treating epidural abscesses, as simple aspiration of purulent material through scalp or burr hole placement is rarely adequate.49, 65
Spinal EDA is a rare condition in children and usually results from hematogenous dissemination from foci elsewhere in body, from bacteremia or by extension of vertebral osteomyelitis.66 In adults, spinal SDA is associated with intravenous (IV) drug use, immunosuppression and recent spinal surgery.67 Spinal abscesses have been reported in children with leukemia and sickle cell disease but, overall, children are less likely to have underlying disease compared to adults. Spinal EDA is a rare complication of lumbar puncture.68 The predominant pathogen in spinal SDA is S aureus and methicillin-resistant S aureus(MRSA) infection is becoming more frequent.69 Other causes include aerobic and anaerobic streptococci, aerobic gram negative bacilli, Nocardia species, M tuberculosis, and fungi. The majority of children with spinal SDA presented with fever and back pain and had trouble walking. Nerve-root pain with radiculopathy; paresthesias; spinal cord dysfunction with motor, sensory, and sphincter dysfunction; and complete paralysis may also be noted. Emergency magnetic resonance imaging (MRI) with gadolinium is needed for diagnosis and lumbar puncture (LP) should be deferred. Blood cultures, elevated white blood cell (WBC) count, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) are also useful diagnostic tests. The standard management of spinal SDA is antibiotic therapy and surgical drainage. Empirical therapy may include vancomycin plus coverage for gram-negative bacilli (cefipime, ceftazidime, meropenem) especially if there is history of IV drug use or recent spinal procedure. Antibiotic treatment is generally provided for 6 to 8 weeks and duration of therapy is dictated by the clinical picture, normalization of ESR, CRP, and WBC, as well as radiographic improvement. Patients with neurologic dysfunction and spinal SDA may need emergency laminectomy with decompression and drainage or CT guided aspiration to minimize permanent sequelae.69 The main determinant of outcome for patient is neurologic status at the time of diagnosis. Neurologic sequelae in children with spinal SDA occurred in 18% in one study, with primarily motor weakness noted on follow-up examination69; death is unusual.
CHRONIC LATENT VIRUS INFECTIONS
Chronic latent viral infections are thought to result in several slowly progressing diseases of the human central nervous system such as subacute sclerosing panencephalitis, progressive rubella panencephalitis, and progressive multifocal leukoencephalopathy. Chronic latent viruses typically have a long incubation time of months to years, which results in the slow progression of disease and protracted onset and recognition of symptoms. Although extremely rare, these diseases may result in neurologic devastation and even death. The latent viral infections are distinguished from “slow infections” or spongiform encephalopathies, which result from infection with unconventional transmissible agents, now called prions.
SUBACUTE SCLEROSING PANENCEPHALITIS
Subacute sclerosing panencephalitis (SSPE) is a progressive, neurodegenerative disease primarily of childhood and early adolescence caused by persistent measles virus infection of the brain. SSPE affects children worldwide, with a reported annual incidence of 0.2 to 40 cases per million. Global initiatives for immunization against measles have produced a greater than 90% reduction in the incidence of SSPE from 1960 to 1975.72 In the most recent report of USA/World SSPE Registry, the age range of neurologic onset of SSPE symptoms varied between ages 3 and 24 years, with average age of onset of age 10 years, and a male:female ratio of 4:1.74 In the United States, a unique racial distribution emerged with patients of Hispanic origin being more commonly affected.
The incubation period for SSPE is typically 7 to 13 years after primary measles infection, but may be shorter in children with earlier age at infection; 50% of reported US cases occurred in patients with primary infection prior to age 2 and 75% were in children infected before age 4 years. Symptomatically, SSPE is a triphasic disease.75 The initial phase is manifested by subtle changes in behavior at home and school, with temper outbursts and irritability, cognitive decline and attention problems, and sleep disturbance. In the second clinical stage, massive myoclonus of the extremities, trunk, and head occurs, which is thought to reflect an inflammatory process in the basal ganglia. Generalized or focal seizures are also common. Approximately 50% of patients with SSPE have chorioretinitis and visual impairment. In the third stage, involuntary movements disappear as the primitive motor structures of the basal ganglia are destroyed. Extrapyramidal signs such as choreoathetosis, immobility, masked facies, dystonia, pill rolling tremor, and lead pipe rigidity then develop, followed by dementia, stupor, and coma. Loss of brainstem nuclei that support breathing, heart rate, and blood pressure inevitably leads to death.
The diagnosis of SSPE can be established with the presence of 3 of the 5 clinical criteria: (1) clinical course suggestive of SSPE with typical signs like myoclonus in addition to one of the other criteria; (2) electroencephalogram (EEG) showing periodic, stereotyped, high-voltage discharges; (3) elevated cerebrospinal fluid (CSF) gammaglobulin or oligoclonal band pattern; (4) elevated serum measles titer on enzyme-linked immunosorbent assay (ELISA) testing (≤ 1:256) and/or CSF (≤ 1:4); or (5) brain biopsy suggestive of panencephalitis.76 Brain biopsy is therefore not routinely needed to establish the diagnosis of SSPE. A simple and sensitive method for detecting measles virus DNA by PCR has been developed for CSF analysis, but is not routinely used in clinical practice.77 There are reports of neuroimaging changes in patients with SSPE, magnetic resonanc imaging (MRI) demonstrates T2 prolongation, subcortical and periventricular white matter, and subsequent cortical atrophy.78 No curative therapy is currently available for SSPE, although the antiviral agent, isoprinosine and riboviron, and interferon α, which augments the immune response and suppresses viral replication, have all shown modest benefit. Treatment is mostly supportive. Death occurs 1 to 3 years from onset of infection, although there are reports of prolonged spontaneous remission.79
PROGRESSIVE RUBELLA PANENCEPHALITIS
Progressive rubella panencephalitis (PRP) is an extremely rare neurodegenerative condition that can follow either congenital or postnatal rubella virus infection. There have been no reported cases in the literature in the past 30 years. The disease has affected children ages 8 to 19 years after primary rubella infection causing neurologic deterioration superimposed on existing deficits. The clinical syndrome mimics subacute sclerosing panencephalitis (SSPE), with decline in behavior and cognition resulting in dementia, clumsiness, and seizures (usually multifocal myoclonic type). Ataxia of gait, spasticity, dysarthria, dysphagia, and mutism may also ensue. Fundoscopic examination may demonstrate optic nerve atrophy. Diagnosis is based on elevated IgG concentrations and rubella antibody titers in the cerebrospinal fluid (CSF). In general, CSF analysis demonstrates a mild lymphocytosis with elevated protein. Radiologic studies later demonstrate severe cerebellar atrophy. Pathology consists of diffuse progressive subacute panencephalitis mainly affecting white matter. Neuronal loss, gliosis and severe demyelination, with focal cerebellar abnormalities are also noted.82 Treatment is supportive care and death occurs 2 to 5 years from symptom onset.
PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY
Progressive multifocal leukoencephalopathy (PML) is a rare and fatal John Cunningham (JC) virus infection affecting primarily the oligodendrocytes and leading to multifocal demyelination. This disease is caused by the JC virus, named after the initials of the patient in whom the virus was first isolated. JC virus is a polyoma-virus and member of the Papovaviridae family, which comprises small, nonenveloped viruses with circular, double-stranded DNA genome. JC virus is ubiquitous and thought to be acquired in childhood with seroprevalence reaching 51% positivity among children 9 to 11 years of age and 60% to 80% in adulthood.84 It lies dormant until a person becomes immunocompromised, permitting active replication.
Prior to the era of HIV/AIDS, PML was primarily seen in older adults with hematologic cancers or chronic immunosuppressive treatments. In the past 20 years, three-quarters of cases of PML have been in patients with AIDS and approximately 1% to 4% of patients with HIV infection will develop PML.85 Other important conditions associated with PML include chronic neoplastic disease (chronic lymphocytic leukemia, Hodgkin disease, lymphosarcoma, myeloproliferative disease), and, less commonly, nonneoplastic granulomatosis (tuberculosis, sarcoidosis). Patients receiving immunosuppressive treatments for renal cell disease, Crohn disease, and multiple sclerosis (MS) are also at risk. Most recently, cases were reported in patients receiving immunosuppressive therapy with natalizumab, a humanized monoclonal antibody designed to reduce migration of leukocytes from peripheral blood into tissue. PML is extremely rare among children; the majority of case reports are among children with AIDS.87
Clinical symptoms include personality changes, cognitive impairment, and hemiparesis, which evolve over days to weeks. Symptoms can progress to quadriparesis, visual changes, cranial nerve defects, cortical blindness, aphasia, ataxia, dysarthria, dementia, seizures, confusional state, and coma.88 Death occurs 3 to 6 months after the onset of neurologic symptoms and may be even more aggressive in AIDS patients untreated with highly active antiretroviral therapy.
The definitive diagnosis of PML is made by stereotactic brain biopsy. Pathologic features include areas of demyelination, accompanied by “ground glass” appearance of oligodendroglial nuclei, and bizarre astrocytes.89 Detection and amplification of JC virus DNA in cerebrospinal fluid (CSF) by polymerase chain reaction (PCR) provides a noninvasive test for PML, with a reported sensitivities range from 60% to 100%, reflective of patient population, clinical definition of PML, and PCR methodology.90 False negatives exist; therefore, clinical symptoms and signs must also be present to support the diagnosis of PML. Cerebrospinal fluid (CSF) may show mononu-clear pleocytosis and mild increase in protein content. Demyelination occurs predominantly in the cerebral hemispheres and subcortical regions but lesions in cerebellum, brain stem, and spinal cord have been reported. Lesions vary in size, ranging from microscopic areas of demyelination to massive multifocal plaques. Magnetic resonance imaging (MRI) is the more sensitive choice of neuroimaging and demonstrates patchy or confluent hyperintense lesions on T2-weighted and proton density images in the affected regions; overall, 5% to 10% of the lesions demonstrate contrast enhancement (Fig. 555-2).91 Electroencephalogram (EEG) may be normal or may demonstrate focal slowing.
Treatment for PML in patients without HIV is primarily supportive. There have been several reports of slowed disease progression with cytarabine, arabinoside, cidofovir, mirtazapine, interferon, idoxuridine, interleukin-2, and topotecan, but these failed to be reproduced in larger clinical trials of patients with PML with and without AIDS. In patients with AIDS, the use of protease inhibitors in addition to antiretroviral therapy has been shown to slow the progression of PML.
Transmissible spongiform encephalopathies (TSE), or prion diseases, represent a group of clinical syndromes characterized by slow progression of neurodegenerative disease affecting humans and animals. At least 5 diseases of prion etiology are recognized in humans: Kuru; Creutzfeldt-Jakob disease (CJD) with its variants including sporadic (sCJD), familial (fCJD), iatrogenic (iCJD), and new variant (nvCJD); Gert-mann-Straussler Scheinker syndrome; fatal familial insomnia; and sporadic familial insomnia. In the pediatric population, kuru and more recently nvCJD cases have been reported. Transmissible spongiform encephalopathies (TSEs) share many similar characteristics (see Table 555-3 for comparison).
FIGURE 555-2. Progressive multifocal leukoencephalopathy. Fluid attenuated inversion recovery magnetic resonance (MR) sequence of a 37-year-old man with HIV, who was noncompliant with antiretroviral therapy and subsequently presented with aphasia, gait changes, and visual difficulties. Diagnostic lumbar puncture demonstrated John Cunningham virus in the cerebrospinal fluid by polymerase chain reaction (PCR) testing. Magnetic resonance imaging (MRI) demonstrates patchy areas of subcortical white matter hyperintensity, which are characteristic of progressive multifocal leukoencephalopathy.
TSEs are all transmissible to humans by inoculation of tissues from affected patients. Incubation periods range from several months to decades and illness lasts month to years with invariable progression to death. There is no host response and all TSEs share a noninflammatory pathologic response to prion protein. Histopathologic changes are confined to the CNS with spongiform degeneration. Typical pathologic features include vacuolization, neuronal loss, and glial proliferation, mostly in cerebral cortex or cerebellum. Amyloid plaques are found in all patients with GSS and kuru and 10% to 15% of patients with sCJD.94 The clinical course includes features of dementia, incoordination, visual abnormalities, involuntary movements, and terminal akinetic mutism.
Table 555-3. Clinical and Pathologic Features of Spongiform Encephalopathies
Kuru is progressive neurodegenerative disease with predominant cerebellar features that first demonstrated the transmissibility of human TSE. Kuru (a Fore word for “trembling”) reached epidemic proportions among the Fore tribe in the 1950s, with nearly 1% of the population affected and was a significant cause of death.97 The disease was thought to be acquired through the preparation and ingestion of brains of dead relatives for ritualistic cannibalism. Clinical presentation begins with ataxia and progressive tremor of the trunk, extremities and head, and is then followed by choreiform movements months later. Intelligence is largely preserved though mood disturbances are reported. In most children, the disease is fatal 6 to 9 months from onset. Laboratory studies and CSF analysis are unremarkable. Incubation period may be lengthy, with up to several decades from time of inoculation.98
Creutzfeldt Jakob Disease
Creutzfeldt Jakob disease (CJD) has been recognized since the 1920s and is the most common human spongiform encephalopathy. Sporadic CJD (sCJD) comprises nearly 85% of CJD cases, at an annual rate of approximately 1 to 2 cases per million worldwide, with up to 100-fold higher rates reported in Slovakia and among Libyan-born Israelis, who have a high incidence of a mutation of the PRNP gene. The risk of CJD increases with age and in persons over age 50 years, for whom the annual rate is approximately 3.4 cases per million. Recently, the United States has reported fewer than 300 cases of CJD per year. Sporadic CJD is characterized by dementia, myoclonus, or, less commonly, other abnormal movements such as chorea, dystonia, cerebellar ataxia, and pyramidal and extrapyramidal tract signs.101 Late in the clinical course, patients experience akinetic mutism. Average survival is 1 year after onset of neurologic findings. Most laboratory studies are of little value in the diagnosis of CJD. Cerebrospinal fluid (CSF) analysis is often normal, but may reveal slight increase in protein levels. The 14-3-3 protein is a normal protein, not usually found in the CSF and its presence in the CSF may suggest CJD.102 The 14-3-3 protein has also been found in other neurologic diseases such as meningoencephalitis or stroke. The EEG shows generalized slowing early in the course and then progresses to periodic burst of biphasic or triphasic sharp wave complexes. Paroxysmal discharges may be precipitated by loud noises. Many patients have typical periodic suppression-burst complexes and high-voltage slow activity at some point on their EEG. At later stages of disease, CT reveals generalized atrophy and ventriculomegaly and MRI can reveal hyperintense signals in the basal ganglia on fluid attenuation inversion recovery (FLAIR) sequences. Brain biopsy for microscopic examination of brain tissue may be diagnostic but can only be recommended if a treatable disease is in the differential diagnosis, given risks to patients and transmissibility of disease. The demonstration of protease-resistant PrP proteins in brain extracts has been useful to confirm histopathologic diagnosis. Biopsy specimens of pharyngeal tonsil that show marked accumulation of PrP-res have also been valuable in diagnosis of CJD.103 No treatment has been proved to be effective.
Iatrogenic CJD (iCJD) presents similarly to sCJD, often with a shorter incubation period, ranging from 15 months to more than 20 years. There are links between iCJD and various medical and surgical interventions, including treatment with human pituitary growth and gonadotropin hormones derived from cadavers (hGH has been withdrawn from most countries since 1985), brain surgery with contaminated instruments and electrocorticographic electrodes, transplantation of infected corneas, and dura mater allografts. Epidemiologic studies have not suggested exposure to human blood or blood products as a cause of iCJD in humans, but low titers of TSE agents have been found in blood of experimentally infected animals.104 Secretions and excretions have not demonstrated transmissitivity. Only standard universal precautions are indicated in the management of patients with iCJD. The risk of transmission to family members and health care providers is low; however, caution should be used in obtaining CSF and handling tissues at autopsy. Iatrogenic CJD (iCJD) and, more rarely, sCJD have affected children and young adults.
New variant CJD (nvCJD) is a distinct clinical-pathologic entity, which is widely accepted to result from the same agent responsible for bovine spongiform encephalopathy. Since 1996, there have been 150 reports of nvCJD with striking prevalence in Britain. Several features of nvCJD distinguish it from sCJD, including younger age at diagnosis and longer duration of illness (13 months vs 4.5 months in sCJD).101 Neuropathology demonstrates specific florid or “daisy” plaques in 100% of the nvCJD cases. Psychiatric symptoms including depression and memory problems are common at disease onset. One third of patients develop persistent and often painful sensory symptoms or dysesthesias. After about 6 months, frank neurologic signs such as ataxia and involuntary movements (dystonia, myoclonus, chorea) occur in all cases with later development of akinetic mutism. Risk factors for nvCJD include young age, methionine homozygosity at codon 129 on the prion protein gene (PRNP), and residence in the UK. Patients with nvCJD lack the “typical” periodic electroencephalogram seen in sporadic CJD. Magnetic resonance imaging of the brain reveals increased signal intensity in the posterior thalamus in the majority of cases. Unlike the more classic forms of the disease, there is suggestion of increased infectivity outside the central nervous system. Four cases of transmitted infections of nvCJD have been reported, all in elderly patients who received transfusions of nonleukocyte reduced red cells from young patients who did not shows signs of nvCJD until years later.106 This raises concerns for the potential transmission of prion proteins via surgical procedures from individuals in the asymptomatic stage of the disease.
Other Prion Diseases
Familial forms of prion disease exist in Gertmann-Straussler Scheinker syndrome (GSS); fatal familial insomnia (FFI) and sporadic familial insomnia (SFI). Gertmann-Straussler Scheinker syndrome (GSS) is a rare, slowly progressive, autosomal dominant disease characterized by adult onset of memory loss, dementia, ataxia, and pathologic deposition of amyloidlike plaques in the brain. Cognitive decline begins in the thirties and forties, and the average disease duration is 7 years. Gertmann-Straussler Scheinker syndrome can be distinguished from CJD by earlier age at onset, longer disease duration, and prominent cerebellar ataxia.107 FFI is an autosomal dominant prion disease in which asparagine is substituted for aspartic acid at the 178 codon of the PrNP gene. The chief clinical features of FFI include a progressive insomnia, waking “sleep,” hallucinations, autonomic disturbances suggestive of sympathetic overdrive (tachycardia, hypertension, hyperhidrosis, hyperthermia), a rise in circulating catecholamine levels, cognitive changes (such as attentional disturbance and short-term memory deficits without a loss in general intelligence), motor system deficits (ataxia), and endocrine manifestations.108 Later cognitive changes involve a confusional state resembling dementia and, ultimately, death occurs. Mean age at onset is approximately 50 years, with most cases occurring between age 20 and 61 years. Rare SFI cases occur without PRNP mutation but have features similar to FFI. One case of fatal familial insomnia was reported in a 13-year-old child.109