13.1 Pathogens Responsible for Bacterial Infections
The epidemiology of bacterial meningitis has changed significantly, primarily because of widespread immunization with the conjugated Haemophilus influenzae vaccine (HIB) in 1990 and the Streptococcus pneumoniae vaccine in 2000. Before the introduction of these vaccines, H. influenzae accounted for nearly half of all bacterial meningitis cases (45%), followed by S. pneumoniae (18%) and then Neisseria meningitides (14%). After the introduction of the HIB vaccine, the most common pathogens were S. pneumoniae (47%), N. meningitides (25%), group B streptococcus (12%), and Listeria monocytogenes (8%) (refer to the following tables). It is likely that the most recent addition of the S. pneumoniae vaccine will change the specific epidemiology of bacterial meningitis again. Indeed, the widespread use of the pneumococcal vaccine beginning in infancy has decreased the incidence of invasive disease by S. pneumoniae by more than 90%.
Before introduction of Haemophilus influenzae type B vaccines | |||
Othersa | |||
aStaphylococcus aureus, S. epidermidis, Streptococcus group B, Escherichia coli, Proteus mirabilis, Pseudomonas aeruginosa, Mycobacterium tuberculosis, Acinetobacter species. | |||
The incidence of bacterial meningitis is 4–10 cases per 100,000 persons per year in the United States. The causative agents vary with the age of the patients. Mortality rates for all causes of meningitis were approximately 20%, except H. influenzae meningitis in which it is less than 3%.
13.1.1 Signs and symptoms of meningitis
In adults the symptoms include fever, headaches, stiff neck, confusion or altered mental status, lethargy, photophobia, seizures, vomiting, profuse sweating, myalgia, and generalized malaise. The classic triad is fever, neck stiffness, and altered mental status. Only 44% of adults in the community had the classic triad. Ninety-five percent of the patients had at least two of the three symptoms. Positive signs of Kerning and Brudzinski are hallmarks of meningitis yet present in only about 50% of adults. Confusion and fever suggest possible meningitis, particularly associated with a seizure. Seizures occur in 5–28% of adults with meningitis. Seizures are the presenting symptom in one-third of children, and occur more frequently with S. pneumoniae and H. influenzae, than with meningococcal meningitis. Cranial nerve palsies (CNs III, IV, VI, and VII) occur in 10–20% of patients. Focal neurologic deficits (i.e., dysphasia, hemiparesis) due to ischemia and infarction adjacent to the subarachnoid space are less frequent. A petechial rash is common with meningococcemia (up to 50% of cases) and less frequently with Staphylococcus aureus, Acinetobacter species, and Rickettsia species. Patients may develop signs of raised intracranial pressure with papilledema, temporal lobe herniation, and coma.
In very young infants with meningitis, the chief complaint is often nonspecific and include: irritability, lethargy, poor feeding, fever, seizures, apnea, a rash, or a bulging fontanelle.
In geriatric patients, frequently the presenting sign of meningitis is confusion or an altered mental status.
The onset of presentation differs depending on many variables including age, underlying comorbidity, immunocompetence, mental competence, ability to communicate, prior antibiotic therapy, and the specific bacterial pathogens.
The differential diagnosis of viral meningitis includes the other causes of aseptic meningitis, such as partially treated bacterial meningitis, nonpolio enteroviruses, mumps (the most common cause of aseptic meningitis) tuberculous meningitis, spirochetal infections (leptospirosis, borreliosis, Lyme disease, and syphilis), and fungal, amoebic, neoplastic, sarcoidosis, chemical meningitis/drugs (azathioprine, NSAIDs, antimicrobial trimethoprim/sulfamethoxazole [TMP/SMX], ranitidine, carbamazepine), cranial hypotension, postsurgical state, granulomatous, and idiopathic meningitides.
Mace SE. Acute bacterial meningitis. Emerg Med Clin North Am 2008;26(2):281–317, viii
Bareja R, Pottathi S, Shah RK, et al. Trends in Bacterial etiology amongst cases of Meningitis. J Acad Indus Res 2013;1(12):761–765
Bacterial Meningitis in Canada. Bacterial meningitis in Canada: hospitalizations (1994–2001). Can Commun Dis Rep 2005;31(23):241–247
Katz JT, Ellerin TB, Tunkel AR. Acute bacterial meningitis. Hospital Physician Board Review Manual. Infect Dis 2004;9(4):1–12
van de Beek D, de Gans J, Spanjaard L, Weisfelt M, Reitsma JB, Vermeulen M. Clinical features and prognostic factors in adults with bacterial meningitis. N Engl J Med 2004;351(18):1849–1859
Durand ML, Calderwood SB, Weber DJ, et al. Acute bacterial meningitis in adults. A review of 493 episodes. N Engl J Med 1993;328(1):21–28
Kim KS, Harwood-Nass A. Acute bacterial meningitis in infants and children. Lancet Infect Dis 2010;10(1): 32–42
Riordan FA, Thomson AP, Sills JA, Hart CA. Bacterial meningitis in the first three months of life. Postgrad Med J 1995;71(831):36–38
Chávez-Bueno S, McCracken GH, Jr. Bacterial meningitis in children. Pediatr Clin North Am 2005;52(3): 795–810, vii
13.2 Viral Infections
In the central nervous system (CNS), demyelination, degenerative disorders, and neoplastic disease are all more common than infections, yet the prompt and accurate diagnosis of CNS infections is perhaps more important than any of these diseases because of the profound effect accurate diagnosis of infection has on patient treatment and outcome. Prompt institution of appropriate antibacterial and/or antiviral therapy is critical.
Viruses can cause meningitis or encephalitis, and the clinical presentation may overlap, with the latter having more significant alterations in the level of consciousness and possibly new psychiatric symptoms, cognitive defects, seizures, or focal neurologic deficits. The presentation of viral CNS infections is usually of a sudden onset of illness with fever, headache, nuchal rigidity, focal neurological signs, cerebrospinal fluid (CSF) pleocytosis, and focal abnormalities may be seen on EEG, CT, and/or MRI. The diagnosis of meningitis or encephalitis is based upon which feature predominates in the illness although meningoencephalitis is also a common term that recognizes the overlap. Distinguishing between encephalitis and meningitis is important because the likely etiology and subsequent management of each is different.
A detailed history can provide clues for an etiologic diagnosis. Occurrence during summer suggests arbovirus (e.g., West Nile virus) or enterovirus infection, while winter disease suggests other infections (e.g., influenza). The travel history can reveal clues to geographically restricted viruses, such as those predominantly found in Asia (Japanese encephalitis). Other points include taking a history of sexual contacts (e.g., HIV), insect contact (e.g., mosquitos harboring Western and Eastern equine viruses, West Nile virus), animal contact (e.g., rabies virus, lymphocytic choriomeningitis virus [LCMV]), recent vaccination or viral illness (e.g., acute demyelinating meningoencephalitis); and immunosuppression (e.g., human herpes virus 6, varicella zoster virus [VZV], cytomegalovirus [CMV], or JC virus).
Mortality and morbidity vary according to cause, but are high, e.g., mortality 10–40% in Japanese encephalitis, with neurological sequelae in 5–75% of survivors.
On physical examination, patients often have fever and may have signs of meningeal irritation but clear sensorium (i.e., meningitis), or altered mental status (i.e., encephalitis). The skin examination provides additional information, such as a petechial rash suggests meningococcal meningitis; a maculopapular rash can occur with West Nile virus meningoencephalitis; and a group of vesicles in a dermatomal pattern suggests VZV. Some manifestations suggest temporal lobe features in herpes simplex encephalitis; hydrophobia in rabies; parkinsonian and extrapyramidal features in Japanese encephalitis.
A lumbar puncture is important. Interpreting the results can be difficult, as there is overlap between the CSF findings in bacterial and viral infections; however, broad general differences can be stated. In acute bacterial meningitis, CSF white cell counts are usually high (hundreds or thousands per mL), with neutrophilic predominance, accompanied by elevated proteins and hypoglycorrhachia; while in viral meningitis, CSF shows a mild pleocytosis and lymphocytic predominance (though in early phase it can be neutrophilic), slightly elevated protein, and normal glucose (except LCMV when glucose is low). CSF analysis remains the best test for the diagnosis of meningeal diseases.
Knowledge of the possibilities and limitations of diagnostic methods for specific viral CNS infections is vital. A positive CSF polymerase chain reaction (PCR) finding is usually reliable for etiological diagnosis. The demonstration of intrathecal antibody synthesis is useful for confirming the etiology in a later stage of disease, hitherto sufficiently evaluated in herpes simplex encephalitis and tick-borne encephalitis.
Nucleic acid amplification methods have improved the detection of common (herpes simplex virus [HSV], enterovirus, and VZV) and uncommon viral pathogens. The results of these tests are available more quickly and are more sensitive than viral cultures. Other viral causes of meningoencephalitis, such as arboviruses (including West Nile virus), can be identified by detection of IgM and IgG antibodies in CSF. Despite improved virological and differential diagnostic methods, etiology remains unknown in about half (50%) of the cases with suspected viral encephalitis.
Imaging with CT scans alone can be done in uncomplicated cases of meningitis, but MRI is the single most important diagnostic test for parenchymal infections. The MRI signal intensity, and spatial distribution patterns in the CNS help differentiate important infections from other diseases. This shall include bacterial cerebritis and abscess, tuberculoma, and tuberculous meningitis; various forms of viral encephalitis, such as herpes simplex, herpes zoster, CMV and West Nile; viral leukoencephalopathies, such as progressive multifocal leukoencephalopathy (PML); and the transmissible spongiform encephalopathies, especially Creutzfeldt–Jakob disease (CJD). Differential include comparisons to the most common parasitic diseases, especially cysticercosis and toxoplasmosis, and to unusual manifestations of neoplastic, demyelinating, and metabolic diseases.
The differential diagnosis of viral encephalitis includes meningitis, Behcet’s disease, systemic lupus erythematosus, multiple sclerosis, secondary syphilis, leukemia, lymphoma, other infective encephalopathies (bacterial, fungal, protozoal, and parasitic), intracranial abscesses and neoplasms, toxic and metabolic encephalopathies, and heat stroke. The diagnosis of “viral encephalitis” should not be made too hastily, because it may condemn the patient with concealed cerebral malaria or some other curable encephalopathy to delayed treatment or even death.
Kenedy PGE. Viral encephalitis: causes, differential diagnosis, and management. J Neurol Neurosurg Psychiatry 2004;75:110–115
Whitley RJ, Gnann JW. Viral encephalitis: familiar infections and emerging pathogens. Lancet 2002;359(9305):507–513
Baringer JR. Herpes simplex virus encephalitis. In: Davis LE, Kennedy PGE, eds. Infectious diseases of the nervous system 1st ed. Butterworth-Heinemann; 2002:135–164
Johnson RT. Viral infections of the nervous system. 2nd ed. Philadelphia: Lippincott-Raven; 1998
Ziai WC, Lewin JJ, III. Update in the diagnosis and management of central nervous system infections. Neurol Clin 2008;26(2):427–468, viii
Tunkel AR, Glasser CA, Bloch KC, et al. Infectious Society of America. The management of encephalitis: clinical practice guidelines by the infectious Disease Society of America. Clin Infect Dis 2008;47:303–327
13.2.1 RNA Viruses
Enteroviruses (polioviruses, coxsackie viruses A, B, echoviruses, and enteroviruses)
The CNS is the most commonly involved organ system during the spread of human enteroviruses from the alimentary tract. A number of neurologic syndromes are recognized, and each can be caused by a number of different types of enteroviruses, i.e., aseptic meningitis, encephalitis, lower motor neuron paralysis, acute cerebellar ataxia, cranial nerve palsies, chronic persistent infections. Enteroviruses are responsible for 80–90% and mumps for 10–20% of diagnosed cases of viral meningitis, with many other viruses sometimes incriminated with considerable geographical and seasonal variation.
Differential diagnosis of paralytic poliomyelitis: postinfectious and other immunopathic polyneuroradiculopathies, such as Guillain–Bare syndrome and Landry’s ascending paralysis; metabolic neuropathies such as acute porphyria; paralytic rabies; neoplastic polyradiculopathies; and rarities, such as tick paralysis and herpesvirus simiae (B virus) infection. The lack of objective sensory loss in poliomyelitis usually distinguishes it from these other entities.
Out of the 450 RNA viruses transmitted by arthropods, the two most common families causing encephalitis are: (a) the Togaviridae (i.e., Western equine encephalitis, Eastern equine encephalitis, St. Louis encephalitis) and (b) the Bunyaviridae (i.e., California encephalitis viruses). Japanese encephalitis is the most common encephalitis in Asia. Encephalitides caused by arthropod-borne viruses accounts for about 10% of all reported cases annually. An arbovirus may produce a fulminating encephalitis or an aseptic meningitis. Neither the clinical picture not the laboratory abnormalities distinguish one arbovirus infection from another. In fact, the arboviral encephalitis cannot be differentiated from any of the other causes of encephalitis clinically. Similarly, the pathological findings in the brains are also nonspecific for arboviral infection. The diagnosis of arboviral infections is made serologically (i.e., hemagglutinating inhibition, neutralizing antibodies, and late in disease the complement fixation)
Encephalitis occurs in about 0.5–1 of every 1,000 measles cases. The clinical picture is characterized by a recurrence of the fever and the development of headache, lethargy, irritability, confusion, and seizures in up to 56% cases. The majority of patients return to normal within 48–72 hours, but about 30% of them progress to a persisting coma. Approximately 15% of patients with measles encephalitis will die, and in addition, 25% will develop severe brain damage and neurologic deficits such as mental retardation, seizures, deafness, hemiplegia, severe behavioral disorders. Subacute sclerosing panencephalitis, caused by measles virus, typically presents with very gradual onset of altered behavior, mild intellectual deterioration, and loss of energy. After that periodic involuntary movements appear; further progression is marked by intellectual deterioration, rigidity, spasticity, and increasing helplessness; 40% of patients die within a year.
The CNS involvement as a complication of mumps is approximately in 15% of the patients. Meningitis is far more common than is encephalitis. The neurological features are the same as in other encephalitides and gradually resolve within 1–2 weeks. Death occurs in less than 2% of reported cases.
The symptomatology of the neurologic phase presents in two different types—“furious” or “paralytic” presentation. The furious type is characterized by agitation, hyperactivity, bizarre behavior, aggressiveness with attempts to bite other persons, disorientation and hydrophobia, fever, hypersalivation, and seizures which may cause death in one-fourth of patients. The paralytic type affects approximately 10–15% of patients and presents with a progressive, ascending flaccid, symmetric paralysis or as an asymmetric paralysis involving the exposed extremity. Patient’s death may occur during the acute stage from cardiac and respiratory abnormalities. The diagnosis can be made by histopathology, virus cultivation, serology, or detection of viral antigen.
Steihauer DA, Holland JJ. Rapid evolution of RNA Viruses. Ann Rev Microbiol 1987;41:409–431
Holmes EC. The evolution and Emergence of RNA Viruses. Oxford University Press; 2009
13.2.2 DNA Viruses
Herpes simplex virus Type 1 (HSV-1)
The reactivation and replication of the HSV leads to inflammation and extensive necrosis and edema of the medial temporal lobe and orbital surface of the frontal lobe of immunocompetent patients producing the characteristic clinical picture. Patients develop fever, headache, irritability, lethargy, confusion and focal neurologic signs, such as aphasia, motor and sensory deficits, and seizures (major motor, complex partial, focal, and absence attacks). CSF examination, electroencephalography (widespread, periodic, stereotyped complexes of sharp and slow waves at regular intervals of 2–3 seconds), brain imaging, and biopsy make the HSV encephalitis (HSE) most amenable to diagnosis from all other viral encephalitides.
Herpes simplex virus Type 2 (HSV-2)
Usually two neurologic conditions may develop:
i. Aseptic meningitis for about 5% of all cases of aseptic meningitis in the United States are caused by the genital HSV-2. The typical clinical picture of headache, fever, stiff neck, and marked CSF lymphocytic pleocytosis often is preceded by pain in the genital or pelvic region.
ii. Encephalitis identical to that caused by the HSV-1 encephalitis occurring most often in the newborn and rarely in the immunocompromised adult.
Differential diagnosis: Clinically, infectious diseases of the CNS can present with unspecific symptoms including headaches, nausea, and fever. Thus, bacterial and fungal infections should be considered in the differential diagnosis of acute viral encephalitis. Patients are often empirically treated for a potential infection with bacterial and viral pathogens with both antibiotics and antiviral agents until the diagnosis of HSE has been established. Predominantly lymphocytic or monocytic pleocytosis in the CSF can be present in tuberculous or fungal CNS infection as well as in HSE; however, the former infections are associated with a dramatic elevation in protein levels and with hypoglycorrhachia, which are not typical for HSE. Many other viruses, including CMV, influenza A, and echovirus, have been shown to affect the temporal lobe and mimic HSE, and HSE has no particular clinical characteristics to distinguish it from other CNS infections. In addition, HSV-2 is a putative cause of HSE, and a 2008 study reported that 12% of all CNS infections with HSV-2 are encephalitic and often have neurological sequelae. Tumors, brain abscesses, and hematomas can also mimic HSE. In addition, vascular disorders and toxic encephalopathies can be mistaken for HSE.
Two neurologic conditions usually develop:
i. Causes chickenpox (varicella) in childhood, becomes latent in dorsal root ganglia, and reactivates decades later to produce shingles (zoster) in adults. Subacute encephalitis develops on a background of cancer, immunosuppression, and acquired immune deficiency syndrome (AIDS), and death is common.
ii. Granulomatous arteritis characterized by an acute focal deficit with transient ischemic attack (TIA) or stroke and mental symptoms may develop. In immunocompetent individuals, VZV causes large-vessel vasculitis manifested as ischemic or hemorrhagic stroke, generally weeks to months after herpes zoster ophthalmicus. In immunosuppressed patients, VZV causes a multifocal small-vessel vasculopathy. On MRI it presents as ovoid, round lesions in the gray–white matter junction. PCR can detect VZV DNA in CSF; however, a negative test does not exclude the diagnosis of VZV encephalitis. Mortality is 25% of patients.
Most congenital CMV infections are asymptomatic, although many carriers develop sensorineural hearing loss and intellectual handicaps, and less often seizures, hypotonia, and spasticity and in severe meningoencephalitis lethargy and coma occur. The hallmark is periventricular calcifications detected by CT. CMV has a special affinity for the neuroblasts of the subependymal matrix and regional vasculature with a result of subependymal degeneration and calcification. The acquired CMV infections in the immunocompromised adults, particularly AIDS patients, are very common. CMV is an important cause of encephalitis (progressive dementia, headache, focal or diffuse weakness, and seizures, attributed to CMV vasculitis or foci of demyelination), myelitis, and polyradiculitis (beginning insidiously as a cauda equina syndrome with distal weakness, paresthesias, incontinence, and sacral sensory loss).
EBV causes infectious mononucleosis and is being associated with the nasopharyngeal carcinoma and Burkitt’s lymphoma. EBV meningoencephalitis affects both immunocompetent and immunocompromised individuals causing acute cerebellar ataxia, athetosis and chorea, chiasmal neuritis, or in more serious cases meningoencephalopathy stupor and coma. EBV DNA has been detected in CNS lymphoma tissue.
Van Etten JL, Lane LC, Dunigan DD. DNA viruses: the really big ones (giruses). Annu Rev Microbiol 2010;64:83–99
Weller SK, Sawitzke JA. Recombination promoted by DNA viruses: phage ? to herpes simplex virus. Annu Rev Microbiol 2014;68:237–258
13.2.3 Slow viruses
Subacute sclerosing panencephalitis (SSPE)
SSPE is a chronic measles infection of children between 5 and 15 years and young adults. The brain shows a diffuse and wide spread inflammation and necrosis in both gray and white matter. The disease leads to severe neurologic dysfunction (i.e., Stage 1: decline in school performance and behavioral changes, Stage 2: myoclonic jerks, Stage 3: decerebrate rigidity and coma, Stage 4: loss of cortical functions) and on the average patients survive about 3 years.
Progressive multifocal leukoencephalopathy (PML)
PML is a subacute demyelinating disease caused by the human papovavirus JCV and the simian virus SV40 and usually affects immunocompromised individuals. Patients develop progressive multifocal neurologic symptoms and signs (i.e., mental deficits: 36.1%, visual deficits: 34.7%, motor weakness: 33.3%, speech deficits: 17.3%, incoordination: 13.0%, tone alterations: 2.8%, miscellaneous: 17.3%) that typically result in death in 6–12 months and occasionally up to 3–5 years.
Spongiform encephalopathies (SEs) or prion diseases
Of the four human diseases CJD, Gerstmann–Sträussler–Scheinker syndrome (GSS), Kuru, fatal familial insomnia), CJD is by far the most common, whereas the Kuru was the first to be described. Patients with CJD have behavioral disturbances which progress to frank dementia characterized by memory loss, sleep disorders, and intellectual decline, myoclonic spasms, seizures, visual disturbances, cerebellar signs, and lower motor neuron disturbances. Most patients live 6–12 months, and few up to 5 years.
Brooks BR, Jubelt B, Swarz JR, Johnson RT. Slow viral infections. Annu Rev Neurosci 1979;2:310–340
ter Meulen V, Hall WW. Slow virus infections of the nervous system: virological, immunological and pathogenetic considerations. J Gen Virol 1978;41(1):1–25
Thomson RA, Green JR. Infectious Diseases of the centralnervous system MTP Press Ltd. International Medical Publication; 2012
13.2.4 Human Immunodeficiency Virus (HIV)
Among AIDS patients, 40–60% develop significant neurologic symptoms or signs in their life time and approximately 10–20% present with symptoms of neurologic illness. Most opportunistic CNS infections and neoplasms are associated with headache, fever, meningismus, altered level of consciousness, or focal neurological deficit. The presence of one or more of these symptoms should alert the medical care provider to the possibility of CNS infection. In people with AIDS, a normal (“nonfocal”) neurologic examination can be present with PML, cryptococcal meningitis, HIV-associated dementia, or CMV encephalitis (CMVE). Bacterial or viral meningitis can occur at any stage of HIV infection and is typically accompanied by fever.
Two forms of meningitis have been described with HIV-1 infection. At the time of seroconversion to HIV-1 most patients will develop CSF abnormalities and a few of them will develop symptoms of headache, meningitis, encephalitis, myelopathy, and plexitis. This acute meningitis is clinically indistinguishable from other forms of aseptic meningitis.
Chronic recurring meningitis can also occur, characterized by headaches and CSF abnormalities without signs of meningeal irritation. Late in the course of the HIV-1 infection, particularly when immunosuppression is prominent, the patients may develop HIV-1 associated encephalopathy (AIDS–dementia complex), HIV-1 associated myelopathy (spinal vacuolar myelopathy), and neurologic problems secondary to opportunistic processes.
Infection of the CNS may occur during any stage of HIV infection, but opportunistic infection occurs only during late-stage infection, when the CD4 count falls below 200 cells/dl. Opportunistic infections may affect the brain or spinal cord, and onset may be acute, subacute, or chronic. The most common opportunistic CNS infections and neoplasms are: Toxoplasma encephalitis (TE), cryptococcal meningitis, primary CNS lymphoma (PCNSL), PML, AIDS–dementia complex (ADC, also known as HIV-associated dementia), and CMVE. Focal brain lesions occur in up to 17% of people with AIDS and are most often caused by TE, PML, or PCNSL. Since the introduction of potent antiretroviral therapy (previously called highly active antiretroviral therapy or HAART), the incidence of TE and PCNSL has decreased, whereas the incidence of PML has increased.
Evaluation of potential CNS infection should include neuroimaging with CT scanning or MRI with and without administration of an intravenous contrast agent. The most common causes of focal CNS lesions in people with AIDS are TE and PCNSL. Evaluation of a solitary ring-enhancing CNS mass lesion in a patient with AIDS should be guided by: (1) CD4 count; (2) serologic status to Toxoplasma gondii and Cryptococcus neoformans; (3) findings on neurologic examination, and (4) presence or absence of headache or fever. Lumbar puncture may be useful for differentiating between TE and PCNSL. The CSF testing should include cell count with differential, glucose, protein, bacterial culture, and VDRL. Other tests include fungal cultures, cryptococcal polysaccharide capsular antigen (CrAg), and PCR assays. If symptoms of brain imaging are consistent with herpes virus infection or PML < PCR assays are high. In people with AIDS, an elevated level of b2 microglobulin in the CSF (greater than 3.8 mg/l) is specific, but not sensitive for the diagnosis of HIV-associated dementia. If the CD4 count is greater than 200 cells/dl, opportunistic CNS infection or neoplasm is unlikely, and the differential diagnosis should include atypical bacterial abscess, fungal, or mycobacterial abscesses, cryptococcoma, syphilitic gumma, tuberculoma, cerebrovascular disease, and neoplasms other than PCNSL.
Stereotactic brain biopsy (SBB) of a CNS lesion may be necessary for certain clinical scenarios, such as if a solitary CNS lesion is accompanied by negative serology, if a contrast-enhancing lesion is atypical for TE or does not respond to anti-toxoplasma treatment; if a new lesion develops during anti-toxoplasma maintenance treatment protocol. SBB provides a diagnosis for 88–98% of contrast-enhancing lesions, and 67% of nonenhancing lesions.
13.3 Central Nervous System Infections in the Compromised Host: Differential Diagnosis
The differential diagnostic approach depends on the patient’s clinical manifestations of CNS disease, the acuteness of the clinical presentation and the type of immune defect. Most patients with CNS infections may be grouped into those with meningeal signs, or those with mass lesions. Other common manifestations include encephalopathy, seizures, or a stroke-like presentation.
Most pathogens have a predictable clinical presentation that differs from that of the normal host. CNS Aspergillus infections present either as mass lesions (e.g., brain abscess) or as a meningitis. Cryptococcus neoformans, in contrast, usually presents as a meningitis, but not as a cerebral mass lesion even when cryptococcal elements are present. Aspergillus and Cryptococcus CNS infections are manifestations of impaired host defenses, and rarely occur in immunocompetent hosts. In contrast, the clinical presentation of Nocardia infections in the CNS is the same in normal and compromised hosts, although more frequently in compromised hosts.
The acuteness of the clinical presentation coupled with the CNS symptomatology further adds to limit differential diagnosis possibilities. Excluding stroke-like presentations, CNS mass lesions tend to present subacutely or chronically. Meningitis and encephalitis tend to present more acutely.
The type of immune defect predicts the range of possible pathogens likely to be responsible. Patients with diseases that decrease B-lymphocyte function are particularly susceptible to meningitis caused by encapsulated bacterial pathogens. The presentation of bacterial meningitis is essentially the same in normal and compromised hosts with impaired B-lymphocytic immunity. Compromised hosts with impaired T-lymphocyte or macrophage function are prone to develop CNS infections caused by intracellular pathogens. The most common intracellular pathogens are the fungi, particularly Aspergillus, other bacteria (e.g., Nocardia), viruses (i.e., HSV, JC, CMV, HHV-6), and parasites (e.g., T. gondii).
The presence of extra-CNS sites of involvement also may be helpful in the diagnosis. A patient with impaired cellular immunity with mass lesions in the lungs and brain that have appeared subacutely or chronically should suggest Nocardia or Aspergillus rather than cryptococcus or toxoplasmosis. Patients with T-lymphocyte defects presenting with meningitis generally have meningitis caused by Listeria or Cryptococcus rather than toxoplasmosis or CMV infection.
A clinician must be ever vigilant to rule out the mimics of CNS infections caused by noninfectious etiologies. Bacterial meningitis, cryptococcal meningitis, and tuberculosis easily are diagnosed accurately from stain, culture, or serology of the CSF. In contrast, patients with CNS mass lesions usually require a tissue biopsy to arrive at a specific etiologic diagnosis. In a compromised host with impaired cellular immunity in which the differential diagnosis of a CNS mass lesion is between TB, lymphoma, and toxoplasmosis, atrial of empiric therapy is warranted. Anti-toxoplasmosis therapy may be initiated empirically and usually results in clinical improvement after 2–3 weeks of therapy. The nonresponse to anti-toxoplasmosis therapy in such a patient would warrant an empiric trial of anti-tuberculous therapy. Lack of response to anti-toxoplasma and anti-tuberculous therapy should suggest a noninfectious etiology (e.g., CNS lymphoma).
Fortunately, most infections in compromised hosts are similar in their clinical presentation to those in the normal host, particularly in the case of meningitis. The compromised host is different than the normal host in the distribution of pathogens, which is determined by the nature of the host defense defect. In compromised hosts, differential diagnosis possibilities are more extensive and the likelihood of noninfectious explanations for CNS symptomatology is greater.
Nelson M, Manji H, Wilkins E. 2 Central nervous system opportunistic infections HIV Med 2011;12(Suppl 2):8–24
Zunt JR. CNS infection during immunosuppression. Neurol Clin 2002;20(1):1–v
Dougan C, Ormerod I. A neurologist’s approach to the immunosuppressed patient. J Neurol Neurosurg Psychiatry 2004;75(Suppl 1):i43–i49
Porter SB, Sante MA. Toxoplasmosis of the CNS in the acquired immunodeficiency syndrome N Engl J Med 1992;327:1643–1648
Lusso P, Gallo RC. Human herpesvirus 6 in AIDS. Immunol Today 1995;16(2):67–71
13.4 Fungal Infections
Fungal infections of the CNS are becoming more frequent because of the expansion of at-risk populations and the use of treatment modalities that permit longer survival of these patients. These are patients who have received transplants, those prescribed with immunosuppressive and chemotherapeutic agents, HIV-infected patients, premature infants, the elderly, and patients undergoing major surgery. Prior to the 21st century, blood stream infections were more frequently caused by Candida albicans, C. neoformans, and agents of invasive pulmonary infections included primarily endemic mycoses and Aspergillus fumigatus. Nowadays fungi that were previously considered nonpathogenic, such as mucoraceous genera (formerly called Zygomycetes) and a variety of both hyaline and dematiaceous molds (Acremonium, Scedosporium, Paecilomyces, and Trichoderma species), are commonly seen in immunocompromised patients.
13.4.1 Differential diagnosis
Infectious: viral meningitis; encephalitis; brain abscess; mycobacterial meningitis; toxoplasmosis; primary HIV infection; syphilis; PML.
Noninfectious: carcinomatous meningitis; lymphomatous meningitis; cerebrovascular accident; CNS vasculitis; sarcoidosis; drugs.
Histopathology continues to be a rapid and cost-effective means of providing a presumptive or definitive diagnosis of an invasive fungal infection. However, the use of fungal silver impregnation stains cannot alone solve these challenges, and newer diagnostic techniques may be required. Recent advances in fungal genomics is helping in this regard as PCR-based identification of clinical isolates is proving to be far superior as compared to conventional biochemical identification panels (e.g., API-20C-AUX, VITEK ID-YST, etc.). Pyrosequencing (+) is a relatively inexpensive and very productive rapid DNA-sequencing method for the identification of medically important yeasts. Advanced imaging techniques, such as diffusion-weighted imaging, MR perfusion, and MR spectroscopy, when combined with clinical findings, may help in differentiating fungal disease from other mimickers such as pyogenic infection or cystic metastases.
Candida CNS infection is a manifestation of disseminated disease (candidemia) and is associated with intravenous drug use, indwelling venous catheters, abdominal surgery, and corticosteroid therapy. CNS infection with candida species often results in scattered intraparenchymal granulomatous microabscesses secondary to arteriolar occlusion. Meningitis is a common feature of CNS candidiasis, resulting from invasion of meningeal microvasculature by small group of yeast cells.
The portal of entry of cryptococcus in the body is the lungs. The pulmonary infection is not demonstrable in healthy individuals. But it becomes invasive in immunocompromised patients. C. neoformans is neurotropic and most patients with cryptococcal meningitis suffer from defective cellular immunity. Cryptococcal meningitis is the most common CNS infection (50%) in chronically immunosuppressed but non-AIDS patients. It is the second most common cause of opportunistic fungal infections in AIDS patients. Cryptococcal meningitis presents as a chronic febrile syndrome with headache. The ensuing aseptic meningoencephalitis reflects cognitive changes or dementia, irritability, personality changes, mass lesions with focal neurologic deficits, and less often ocular abnormalities (papilledema, with or without loss of visual acuity, and cranial nerve palsies) in 40% of patients. Cryptococcal antigen (CrAg) is detected in 99% of serum and 91% of CSF samples; therefore, a negative serum CrAg virtually excludes the diagnosis of cryptococcal meningitis.
Mucormycosis (formerly zygomycosis)
Mucormycosis describes a group of frequently lethal mold infections that have a predilection for diabetic patients, patients on steroid therapy, and severely immunocompromised hosts, such as hematopoietic stem cell transplantation (HSCT) recipients. The majority of human infections are due to fungi that mostly belong to the genera Rhizopus, Mucor, Rhizomucor, Cunninghamella, and Absidia. Despite the emergence of mucormycosis as a significant cause of mycosis, it remains much less frequent than other more common forms like invasive aspergillosis. Mucormycosis are generally acute and rapidly progressive with mortality rates of 70–100%. Rhinocerebral mucormycosis typically occurs in a patient with diabetic ketoacidosis or with leukemia, whereas pulmonary infection occurs more often in those with malignancy. The infection often begins as ulcerations in the paranasal sinuses or in the palate and may spread along perivascular and perineural channels through the cribriform plate into the frontal lobe or through the orbital apex into the cavernous sinus. The Mucorales characteristically invade blood vessels, causing thrombosis and hemorrhagic infarctions as well as cerebritis.
Out of approximately 175 species of genus Aspergillus, only Aspergillus fumigatus, A. flavus, A. terreus, and A. niger, are associated with human disease. A. fumigatus has become the most prevalent airborne fungal pathogen accounting for > 90% of human fungal infections. Risk factors for Aspergillus infection (IA) include prolonged and profound neutropenia, high-grade graft-versus-host diseases (GvHD), use of corticosteroids, age > 40 years, in HSCT recipients and patients with advanced AIDS.
Aspergillosis involving the CNS has similar findings with mucormycosis. CNS aspergillosis may result either from direct extension of nasal cavity/paranasal sinus infection or more commonly from hematogenous dissemination. By a direct extension Aspergillus invades the cavernous sinus and circle of Willis, resulting in angiitis, thrombosis, and infarction. In hematogenous spread septic infarction occurs with associated cerebritis and abscess formation. Aspergillus infection is associated with high rates of mortality, i.e., more than 50%. Higher rates were noted in HSCT recipients (68%) and in neutropenic patients the rates were even higher (89%). Aspergillosis is also emerging as a serious form of mycosis in the ICU with a mortality rate of 75–95%. Infections by non-fumigatus Aspergillus spp. are becoming increasingly common, especially infections caused by A. terreus and A. flavus, which have recently been recognized as a cause of frequent lethal infections. These tend to be resistant to amphotericin B. In addition, A. flavus produces aflatoxin which is extremely toxic and potent hepatocarcinogen.
Infection with Coccidioides can cause numerous problems, ranging from the usually benign Valley fever to a lethal meningitis. Without treatment approximately 95% of patients with coccidioidal meningitis will die within 2 years. Hematogenous spread of the endospores into the intracranial space results in meningeal inflammation with infectious purulent and caseous granulomas, particularly at the base of the brain. Multiple coccidioidal microabscesses may be found in cerebellum, periventricular area causing secondary hydrocephalus. The diagnosis is best done by examination of the CSF, where antibodies for the organism can be tested. Rarely, a biopsy of the tissues surrounding the brain (meninges) may be needed for an accurate diagnosis. Imaging is not specific, but may show hydrocephalus in up to 30–50% of patients.
Blastomycosis is caused by Blastomyces dermatitidis that is a dimorphic (mycelia/yeast) fungus found in eastern North America and parts of India and Africa. Annual incidence of the disease ranges from < 1 to 100 per 100,000 in endemic areas. Except for rare inoculation cutaneous disease, the organisms enter the body via inhalation of conidia from the environment (wind or excavation dust, digging, direct contact) into the lungs. Pulmonary blastomycosis has a wide differential diagnosis and may be asymptomatic or present as mild, moderate, or severe acute pneumonia. The latter may be complicated by acute respiratory distress syndrome (ARDS). Subacute to chronic infiltrates, cavitary lung disease, or both may occur instead. In addition, acute or chronic dissemination of B. dermatitidis to the skin, brain, genitourinary system, bone or any other organ system may result. Hematogenous dissemination results in blastomycosis meningitis with an acute/fulminant onset of headache, stiff neck, and focal signs.
Scedosporium apiospermum and S. prolificans represent two medically important antifungal-resistant opportunistic pathogens. S. apiospermum causes mycetoma and deep-seated infections (e.g., brain abscesses) and could disseminate in neutropenic bone marrow transplant (BMT) recipients and immunosuppressed individuals; crude mortality rate is about 55%. S. prolificans causes bone and soft-tissue infections in immunocompetent individuals and deeply invasive and disseminated infections in immunocompromised patients with crude mortality rate of 90%.
These are the fungi with hyaline-branched septate hyphae. Of all filamentous fungi, Fusarium spp. remain the second most common cause of invasive disease in immunosuppressed patients (neutropenia, GvHD, hematological malignancies and in the HSCT recipients). Clinical manifestations of fusariosis are more often characterized by cutaneous involvement and fungemia than those of Aspergillus spp. Typical presentation of disseminated fusariosis includes positive blood culture (up to 75%) and the appearance of multiple purpuric cutaneous nodules with central necrosis. High mortality is due in part to high rates of resistant to available antifungals.
These are becoming increasingly recognized as opportunistic fungal pathogens in patients (children and adults) with prolonged corticosteroid therapy, splenectomy, neutropenia, and BMT. Following entry through penetrating injuries, they can cause foot mycetomas and corneal infections even in immunocompetent hosts.
These are cosmopolitan filamentous fungi that inhabit the soil, decaying plants, and food products. The genus Paecilomyces contains several species including the emerging pathogens P. lilacinus and P. variotii. P. lilacinus infections include oculomycosis (51.3%) and cutaneous and subcutaneous infections (35.3%); the rest (13.4%) were miscellaneous infections. Peritonitis and sinusitis are the most common infections caused by P. variotii. Differential diagnoses are usually associated with varying sets of predisposing factors. In that, while oculomycosis, subcutaneous infections occur in solid organ transplants (SOT) and neutropenic BMT recipients, neutropenic and immunodeficient hosts, and patients undergoing surgery.
These have traditionally been employed in the biotechnology industry as sources of enzymes and antibiotics, as well as in agriculture as plant growth promoters and biofungicides. It is now recognized that fatal disseminated disease due to Trichoderma longibrachiatum occurs in patients undergoing peritoneal dialysis, in patients with hematologic malignancies and in BMT or SOT transplant recipients.
Dematiaceous molds (phaeohyphomycosis)
The long and taxonomically diverse list of infections caused by dematiaceous (pigmented thick-walled) fungi are grouped under phaeohyphomycosis. Dematiaceous molds are characterized by the presence of a pale brown-dark melanin-like pigment in the cell wall. They may cause a variety of cutaneous and subcutaneous infections in immunocompetent hosts and invasive or disseminated infections in immunocompromised hosts. The number of dematiaceous molds being reported as etiologic agents of phaeohyphomycosis is growing, several of which target the nervous system (neurotropic fungi). Common neurotropic fungi include Cladophialophora bantiana, Bipolaris spicifera, Exophiala spp., Wangiella dermatitidis, Ramichloridium obovoideum, and Chaetomium atrobrunneum. Brain abscess is the most common CNS presentation. However, Bipolaris ssp. and Exserohilum rostratum infections may initially present as sinusitis and then extend into the CNS.
Histoplasmosis or Darling’s disease is pulmonary mycosis caused by the soil-inhabiting dimorphic fungus Histoplasma capsulatum. There are two varieties H. capsulatum and H. duboisii that are pathogenic to humans.
H. capsulatum is most commonly encountered in North and Central America and in Europe; H. duboisii occurs in Africa. In the United States, H. capsulatum is endemic in the Mississippi and the Ohio river valleys. It also exists in localized foci in many Middle Eastern countries. Humans acquire
H. capsulatum infections during occupational or recreational activities in areas where the pathogen is highly endemic (disrupted soil, accumulated dirt, and guano in old buildings and bridges, or in caves where bats roost). Most individuals with histoplasmosis are asymptomatic; symptomatic episodes manifest within 3–17 days after exposure. The acute phase is characterized by nonspecific respiratory (cough or flu-like) symptoms. Chest X-ray findings are unremarkable in 40–70% of cases. In some cases, chronic histoplasmosis may resemble tuberculosis; disseminated histoplasmosis affects multiple organ systems and is often fatal unless treated. Severe infections can cause hepatosplenomegaly, lymphadenopathy, and adrenal enlargement. Leakage from scar tissues left on the retina following ocular histoplasmosis damages the retina and could result in loss of vision. Immunosuppressed patients and those who do not have effective cell-mediated immunity against the organism are likely to manifest symptomatic disease during acute/disseminated episodes.
Guarner J, Brandt ME. Histopathologic diagnosis of fungal infections in the 21st century. Clin Microbiol Rev 2011;24(2):247–280
Mathur M, Johnson CE, Sze G. Fungal infections of the central nervous system. Neuroimaging Clin N Am 2012;22(4):609–632
Abu-Elteen KH, Hamad MA. Changing epidemiology of Classical and Emerging Human Fungal Infections: A Review. Jordan J Biol Sci 2012;5(4):215–230
Richardson M, Lass-Flörl C. Changing epidemiology of systemic fungal infections. Clin Microbiol Infect 2008;14(Suppl 4):5–24
Phaller MA, Pappas PG, Wingard JR. Invasive fungal pathogens: current epidemiological trends. Clin Infect Dis 2006;43(Suppl 1):S3–S14
Miceli MH, Díaz JA, Lee SA. Emerging opportunistic yeast infections. Lancet Infect Dis 2011;11(2):142–151
Related posts:
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
