+++
Acute Leptomeningitis
++
Acute leptomeningitis is an acute inflammation of the pia mater and arachnoid. Most cases are caused by infectious agents; rarely, release of keratinaceous contents from an intradural epidermoid cyst or teratoma causes a chemical meningitis. When the term meningitis is used without qualification, it means leptomeningitis.
++
Acute meningitis may be classified according to etiology.
+++
Acute Bacterial Meningitis
++
The incidence of bacterial meningitis in the United States is five to ten cases per 100,000 persons per year. Approximately 2000 deaths are reported per year. The bacterium involved varies with the age of the patient and other factors (Table 63-1). About 70% of all cases occur in children under 5 years of age.
++
++
Neonatal meningitis is acquired during passage of the fetus through the birth canal. Organisms found in the maternal vagina, commonly Escherichia coli and Streptococcus agalactiae (a group B streptococcus), are responsible.
++
In children up to 5 years of age, the most common pathogen causing meningitis is Haemophilus influenzae. In adolescents, Neisseria meningitidis (meningococcus) is the most common cause. Streptococcus pneumoniae (pneumococcus) causes meningitis in all age groups. Listeria monocytogenes and gram-negative bacilli are important causes in older, debilitated, and immunosuppressed patients.
+++
Acute Viral Meningitis
++
Viral meningitis has an incidence of 10,000 cases per year in the United States, and 90% of these occur in patients under 30 years of age. This is a mild, benign illness, which rarely causes death. It is caused most commonly by enteroviruses, mumps virus, and lymphocytic choriomeningitis (LCM) virus. An acute meningitis occurs in 10% of patients with human immunodeficiency virus (HIV) infection, most commonly at the time of seroconversion.
+++
Tuberculous Meningitis
++
Tuberculous meningitis is typically chronic; however, in the early stages there may be an exudative phase that resembles acute meningitis.
++
The fungi Cryptococcus neoformans, Histoplasma, Blastomyces, and Candida albicans may cause meningitis in immunocompromised patients. Free-living amebas belonging to the genera Naegleria and Acanthamoeba are rare causes of pyogenic meningitis.
+++
Routes of Infection of the Meninges
++
Bloodstream spread accounts for the majority of cases; the primary entry site of the organism may be the respiratory tract (N meningitidis, H influenzae, S pneumoniae, C neoformans, many viruses), skin (bacteria causing neonatal meningitis), or intestine (enteroviruses).
++
Meningitis may also result from direct spread of organisms from an infected middle ear or paranasal sinus, especially in childhood. Meningitis may be associated with skull fractures, especially those at the base of the skull causing free communication between the subarachnoid space and the upper respiratory tract; brain surgery; or lumbar puncture. Organisms may also gain entry through the intact nasal cribriform plate (eg, free-living soil amebas in stagnant swimming pools).
++
Tuberculous meningitis may occur during severe tuberculous bacteremia (miliary tuberculosis) or as a result of reactivation of a meningeal focus, in which case the patient may have no evidence of tuberculosis elsewhere.
++
Grossly, the leptomeninges are congested and opaque and contain an exudate. Microscopically, acute meningitis is characterized by hyperemia, fibrin formation, and inflammatory cells. In bacterial meningitis, neutrophils dominate (Figures 63-1A and 63-2); in acute viral meningitis, neutrophils are rare and lymphocytes dominate (Figure 63-1B). In acute tuberculous meningitis, there is an inflammatory exudate that contains increased numbers of both neutrophils and lymphocytes.
++
++
++
Acute meningitis presents with fever and symptoms of meningeal irritation, which include headache, neck pain, and vomiting. Physical examination reveals neck stiffness and a positive Kernig sign (inability to straighten the raised leg because of pain), both of which are due to reflex spasm of spinal muscles, a consequence of irritation of nerves passing across the inflamed meninges.
++
In general, bacterial meningitis is a serious disease with considerable risk of death while viral meningitis is usually a mild, self-limited infection. Tuberculous meningitis has an insidious onset and a slow rate of progression but is frequently a severe illness with a fatal outcome if not treated.
++
The diagnosis is made by examination of the cerebrospinal fluid (CSF), a sample of which is obtained by lumbar puncture. The leptomeningeal exudate becomes admixed with the CSF, which reflects the type of inflammatory response and contains the infectious agent (see Table 63-2 and Chapter 14: Infectious Diseases: II. Diagnosis of Infectious Diseases).
++
++
Antibiotic treatment is urgent in bacterial and tuberculous meningitis. The initial choice of antibiotic should be based on a presumptive etiologic diagnosis as suggested by the clinical features and CSF findings: chemical examination, type of inflammatory cells present, and Gram or acid-fast stain (Table 63-2). Drug treatment must be started immediately after lumbar puncture with a combination of antibiotics that are effective against all possible causative agents and the choice of drugs reconsidered if necessary when results of culture and sensitivity assays become available.
++
Viral meningitis usually requires only supportive treatment.
++
Chronic meningitis is caused by facultative intracellular organisms such as Mycobacterium tuberculosis, fungi, and Treponema pallidum. It is now relatively uncommon in the United States but more prevalent in parts of Africa, India, South America, and Southeast Asia.
+++
Pathology & Clinical Features
++
Chronic tuberculous and fungal meningitis are characterized by caseous granulomatous inflammation with fibrosis (Figure 63-1C). Marked fibrous thickening of the meninges is the dominant pathologic feature. The entire brain surface is involved, with the basal meninges more severely affected in cases of tuberculosis. The causative agent may be identified in tissue sections specially stained for acid-fast bacilli and fungi.
++
The meningovascular phase of syphilis also causes a basal chronic inflammation with marked fibrosis and obliterative vasculitis, with large numbers of plasma cells infiltrating the meninges; granulomas are not present.
++
Complications of chronic meningitis include (1) obliterative vasculitis (endarteritis obliterans), which may produce focal ischemia with microinfarcts in the brain and brain stem; (2) entrapment of cranial nerves in the fibrosis as they traverse the meninges, resulting in cranial nerve palsies; and (3) fibrosis around the fourth ventricular foramina, causing obstructive hydrocephalus.
++
Clinically, chronic meningitis is characterized by an insidious onset with symptoms of diffuse neurologic involvement, including apathy, somnolence, personality change, and poor concentration. These symptoms are thought to stem from a concomitant diffuse encephalopathy (Figure 63-1C). Headache and vomiting are less severe than in acute meningitis, and fever is often low-grade. Focal neurologic signs and epileptic seizures result from ischemia, cranial nerve palsies, or hydrocephalus.
+++
Diagnosis & Treatment
++
The diagnosis is established by lumbar puncture (Table 63-2). Serologic tests for syphilis performed on both serum and CSF are positive in meningeal syphilis. Culture is commonly positive in cases caused by tuberculosis and fungal infection unless the patient has received antibiotics prior to lumbar puncture. Skin tests for tuberculosis and fungal infection are positive unless the patient is anergic.
++
Antibiotic therapy is indicated once the organism is identified. Treatment begun after extensive fibrosis has occurred does not produce complete recovery.
++
Cerebral abscess is a localized area of suppurative inflammation in the brain substance. The cavity contains thick pus formed from necrotic, liquefied brain tissue and large numbers of neutrophils and is surrounded by a fibrogliotic wall.
++
Cerebral abscesses are caused by a large variety of bacteria; several organisms may occur in a single abscess, and anaerobic bacteria such as Bacteroides and anaerobic streptococci are common. Nocardia, Staphylococcus aureus, and gram-negative enteric bacteria may also be isolated.
++
Cerebral abscesses occur as complications of other diseases (Figure 63-3).
++
++
Chronic suppurative infections of the middle ear and mastoid air spaces and of the paranasal sinuses. The middle ear is separated from the middle and posterior cranial fossas by thin bony plates that may be eroded by infection. The temporal lobe and the cerebellum are usually involved. Infections of the paranasal sinuses are occasionally associated with frontal lobe abscesses.
Infective endocarditis with embolization to brain. These patients commonly develop parietal lobe abscesses, which are often small and multiple.
Right-to-left shunts (eg, in patients with congenital cyanotic heart disease) may divert infected systemic emboli to the brain.
Suppurative lung diseases such as chronic lung abscess and bronchiectasis are rarely complicated by embolization of infected material to the brain, leading to parietal lobe abscesses.
++
Grossly, a cerebral abscess appears as a mass lesion in the brain. It has a liquefied center filled with pus and a fibrogliotic wall whose thickness depends on the duration of the abscess (Figure 63-4). The surrounding brain tissue frequently shows vasogenic edema.
++
+++
Clinical Features & Diagnosis
++
Cerebral abscess presents with (1) features of a space-occupying lesion, including evidence of increased intracranial pressure (headache, vomiting, papilledema) and focal neurologic signs, depending on the location of the abscess; (2) features relating to the source of infection, such as chronic otitis media, suppurative lung disease, and endocarditis; and (3) general evidence of infection, such as fever, rapid (elevated) erythrocyte sedimentation rate, and weight loss in chronic cases.
++
In untreated cases, the abscess progressively enlarges and may cause death from increased intracranial pressure or rupture into the ventricular system.
++
The diagnosis of cerebral abscess is made clinically and confirmed by computed tomography (CT) scan or magnetic resonance imaging (MRI). Lumbar puncture is dangerous because of the risk of precipitating tonsillar herniation. The CSF may be normal or may show mild increases in protein, neutrophils, and lymphocytes (Table 63-2). CSF cultures may or may not be positive.
++
Surgical evacuation of the abscess followed by antibiotic therapy is effective treatment and has reduced the previously high mortality rate of cerebral abscess to about 5–10%.
++
The frequency of viral encephalitis is difficult to estimate. In the United States, about 1500 cases are reported every year. Most of these are presumptive diagnoses—the etiologic virus is identified in only about 30% of cases. Worldwide, many cases of acute cerebral dysfunction in which no attempt is made to identify a virus probably go unreported.
++
Epidemics of encephalitis are most commonly the result of arthropod-borne viruses (arboviruses), mainly togaviruses and bunyaviruses (Table 63-3). Arboviruses have animal hosts, are transmitted to humans by arthropod bites, and have a distinctive geographic distribution. Sporadic cases of encephalitis may be caused by a large number of other viruses, most commonly herpes simplex virus.
++
++
The virus usually reaches the brain via the bloodstream. It infects brain cells, causing neuronal necrosis and marked cerebral edema, which in turn leads to acute cerebral dysfunction and increased intracranial pressure. Perivascular lymphocytic infiltration (perivascular cuffing) is characteristic (Figure 63-5). In severe cases, hemorrhages occur.
++
++
Viral encephalitis has an acute onset with fever, headache, and signs of brain dysfunction, the nature of which depend on the areas of brain involved. Convulsions may occur. There may be papilledema if cerebral edema is severe. In many cases of viral encephalitis, there is concomitant meningeal inflammation causing neck stiffness and CSF abnormalities typical of viral meningitis. The diagnosis is based on the clinical picture. Lumbar puncture with examination and culture of CSF may provide an etiologic diagnosis.
++
Therapy is supportive. Control of cerebral edema with high doses of corticosteroids is important in preventing death in the acute phase from increased intracranial pressure. The mortality rate from severe viral encephalitis is high, and patients who recover are frequently left with permanent neurologic deficits due to irreversible neuronal necrosis.
+++
Herpes Simplex Encephalitis
++
Herpes simplex encephalitis occurs in 3 classes of patients:
++
Neonates are infected during delivery to a woman with active genital herpes. The presence of herpes genitalis in the mother is an absolute indication for cesarian section. Herpes simplex type 2 is responsible for most cases.
++
Adults are infected through the bloodstream from a minor focus of viral replication, usually in the mouth. Herpes simplex type 1 is commonly involved.
++
Immunocompromised persons, particularly patients undergoing chemotherapy for the treatment of cancer, have an increased susceptibility not only to become infected by herpes simplex virus but also to develop viremia and encephalitis.
++
Herpes simplex encephalitis affects the temporal and inferior frontal lobes selectively, producing a necrotizing, hemorrhagic acute encephalitis that may rapidly cause death. Patients who survive frequently suffer permanent neurologic defects, the nature of which depends on the neuronal loss.
++
The diagnosis may be made by brain biopsy, which shows cerebral edema, necrosis, lymphocytic infiltration, and the presence of intranuclear Cowdry A inclusions in infected cells. Electron microscopy or, preferably, immunohistochemical or in situ hybridization tests demonstrate the virus in the majority of cases (Figure 63-6).
++
++
Treatment of herpes simplex encephalitis with antiviral agents such as vidarabine improves prognosis if undertaken early.
++
HIV is a neurotrophic virus that causes subacute encephalitis characterized pathologically by small nodules composed of demyelination, reactive astroglial proliferation, and infiltration by lymphocytes and microglial cells. These microglial nodules occur in about 30% of patients with acquired immunodeficiency disease (AIDS). Their relationship to the occurrence of dementia in AIDS patients is uncertain.
++
Poliomyelitis is caused by the poliovirus, an enterovirus transmitted by the fecal–oral route. The virus enters the body through the intestine (Figure 63-7) and infects the brain and spinal cord via the bloodstream. Poliomyelitis was once common but has become rare worldwide because of routine immunization during childhood. Poliomyelitis is expected to be eradicated in the early part of the next century.
++
++
The poliovirus selectively infects (1) the meninges, producing acute lymphocytic meningitis; and (2) the lower motor neurons in the anterior horn of the spinal cord and medulla oblongata. Loss of motor neurons causes acute paralysis of affected muscles. The paralysis is typically asymmetric and flaccid, with muscle atrophy and loss of deep tendon reflexes. With time, the atrophic muscles may undergo fibrous contracture.
++
Poliomyelitis is a very serious disease associated with a significant mortality rate in the acute phase, when paralysis of respiratory muscle results in failure of ventilation. Patients who survive are commonly left with permanent muscle paralysis.
++
Rabies is rare in humans but occurs in a variety of wild animals and domestic pets, including dogs and cats, in whom it causes a fatal illness called hydrophobia characterized by abnormal behavior, difficulty in swallowing, and convulsions. Humans are infected when bitten by an infected animal. The rabies virus enters the cutaneous nerve radicles at the site of inoculation and passes proximally to the central nervous system. The incubation period is 1–3 months and is shortest in facial bites.
++
Rabies virus causes a severe necrotizing encephalitis that maximally affects the basal ganglia, hippocampus, and brain stem. Infected neurons show diagnostic eosinophilic intracytoplasmic inclusion bodies (Negri bodies). The virus can also be identified in the infected cells by electron microscopy and immunoperoxidase techniques.
++
Clinically, rabies presents with fever and generalized convulsions that are precipitated by the slightest of sensory stimulations such as a gust of wind, a faint noise, or the sight of water. Death is inevitable.
++
Because there is no treatment, prevention is essential and consists of controlling the disease in wild animals, rabies immunization of domestic pets, and administration of antirabies vaccine to humans immediately after viral exposure.
+++
Cytomegalovirus Encephalitis
++
Cytomegalovirus infection of the brain occurs in the fetus during the last trimester of pregnancy as a result of transplacental infection. Periventricular necrosis and calcification lead to microcephaly and mental retardation; chorioretinitis is common. Cytomegalovirus encephalitis also occurs in immunocompromised persons, particularly patients with AIDS.
+++
Progressive Multifocal Leukoencephalopathy (PML)
++
PML is caused by Jamestown Canyon (JC) virus, a specific serologic type of human papovavirus, and occurs particularly in patients with AIDS and those undergoing chemotherapy for cancer.
++
PML is characterized pathologically by widespread focal demyelination of cerebral white matter. Giant atypical astrocytes and intranuclear inclusions in oligodendroglial cells are typically present, along with a lymphocytic infiltrate. The JC virus can be identified by immunohistochemical techniques.
++
Clinically, PML presents as an acute, rapidly progressive illness associated with multifocal cerebral dysfunction. The diagnosis can be established by brain biopsy. The mortality rate is high.
+++
Subacute Sclerosing Panencephalitis (SSPE)
++
SSPE is an uncommon disease that affects children several years after a known attack of measles. Boys are five times more commonly affected than girls. The measles virus, which has been demonstrated in the cerebral lesions of SSPE, is the causal agent, and SSPE is therefore regarded as a chronic measles virus infection. The exact mechanism by which the virus causes encephalitis is unknown. Immunologic factors may play a role, or there may be some alteration of the measles virus itself. The incidence has declined following measles vaccination.
++
Pathologically, SSPE is characterized by degeneration of neurons in the cerebral gray matter and basal ganglia. Intranuclear inclusions are present in infected cells, and measles virus particles are present on electron microscopy. The white matter shows demyelination, reactive astrocytic proliferation, and perivascular lymphocytic infiltration.
++
Clinically, patients present with personality changes and involuntary myoclonic-type movements. The disease is relentlessly progressive, causing extensive brain damage and leading to death, usually within 1–2 years after onset.
+++
Prion (Slow Virus) Infections
++
Creutzfeldt-Jakob disease and kuru are infections of the human brain that are characterized by a long latent period after infection followed by a slowly progressive disease ending in death. Scrapie, an encephalopathy in sheep and goats, and bovine spongiform encephalopathy (BSE), or mad cow disease) in cattle are apparently animal counterparts. All of these diseases were once thought to be caused by slow-acting viruses because material remained infectious after passage through a filter sufficiently fine to exclude all bacteria. In the early 1980s, evidence began to accumulate that these diseases might be caused by an agent consisting solely of protein, a prion (for proteinaceous infectious particle). The mode of transmission and whether or not activation of host genes is involved in pathogenesis remain unclear. About 10% of cases of Creutzfeldt-Jakob disease may be inherited as a dominant trait; a gene responsible for production of prion proteins has been located in chromosome 20.
++
Creutzfeldt-Jakob disease has occurred in patients who had received transplants of infected tissue (eg, corneal and dural transplants). It is also important medically because the infectious agent is resistant to inactivation by formalin; this imposes a great risk of infection on pathologists and other medical personnel who handle infected tissues. Historically, Creutzfeldt-Jakob disease mainly affects persons 50–75 years old and occurs worldwide. The recent correlation of cases in younger persons in Great Britain with an outbreak of BSE in cattle that has been given feed containing protein derived from sheep carcasses has caused investigators to focus on possible transmission between species. Kuru has occurred mainly among cannibalistic tribes in Papua New Guinea, where the disease is believed to be transmitted by the ritualistic practice of eating brain tissue from deceased persons. The incidence of kuru is rapidly decreasing.
++
Clinically, patients present with confusion and dementia followed by ataxia. Symptoms progress slowly but relentlessly to a fatal outcome. There is no treatment.
++
Pathologically, both Creutzfeldt-Jakob disease and kuru are characterized by slowly progressive degeneration of the brain, with neuronal loss, demyelination, and spongiform change in the cerebral white matter. There is no inflammatory cell infiltration. Kuru tends to affect the cerebellum and is characterized microscopically by the presence of kuru plaques, which are amyloid bodies with radially arranged spicules. The plaques appear to consist of filaments of prion protein.
++
Congenital syphilis and adult syphilis in its late tertiary phase may involve the nervous system in many ways (Table 63-4); it has, however, become relatively rare following the use of penicillin in the treatment of early syphilis.
++
++
The parenchymatous and meningovascular lesions of late syphilis may occur together in a given patient or separately. Parenchymatous disease may affect the cerebral cortex (general paresis) and the spinal cord (tabes dorsalis). Spirochetes are present in the brain in general paresis but not in the spinal cord in tabes dorsalis. Penicillin may prevent progression of neurosyphilis but will not reverse deficits already present (Table 63-4; see also Chapter 64: The Central Nervous System: III. Traumatic, Vascular, Degenerative, & Metabolic Diseases).
+++
Granulomas of the Brain
++
Typical infectious granulomas due to Mycobacterium tuberculosis or fungi occur rarely in the brain. Tuberculomas represent a common mass lesion of the brain in countries such as India that have a high prevalence of tuberculosis. Granulomas present as mass lesions with increased intracranial pressure and focal neurologic signs depending on the location of the mass. Clinically and on radiologic examination, they resemble neoplasms. The diagnosis is made by biopsy, which shows typical histologic changes. The organisms can be identified with special stains and by culture.
++
Toxoplasma gondii is a protozoal parasite that has its definitive cycle in the intestine of cats. Humans become infected through contact with cat feces containing infective forms of the parasite. Cerebral toxoplasmosis occurs in two distinct forms, congenital and acquired.
+++
Congenital Toxoplasmosis
++
Fetal infection with T gondii occurs transplacentally in the third trimester of pregnancy. The organism infects the fetal brain and the retina, leading to extensive necrosis, calcification, and gliosis. Many infants die soon after birth, and those who survive have a variety of defects such as microcephaly, hydrocephalus, mental retardation, and visual disturbances. Toxoplasma pseudocysts can be identified in the brain and retinal lesions.
+++
Acquired Toxoplasmosis
++
Acquired toxoplasmosis rarely causes cerebral lesions in normal individuals. It may, however, occur as an opportunistic infection in patients with AIDS and in other patients with deficient cell-mediated immunity.
++
Cerebral toxoplasmosis in AIDS is characterized by the presence of multiple necrotic lesions ranging in size from 0.5 to 3 cm. Toxoplasma pseudocysts and tachyzoites may be seen in biopsies of lesions. Diagnosis in tissues is aided by staining for Toxoplasma antigens by immunoperoxidase techniques.
++
Clinically, patients present with fever and symptoms of acute cerebral dysfunction. Computerized tomography shows ring-enhancing mass lesions that are often multiple. Treatment with anti-Toxoplasma agents is effective.
+++
Other Parasitic Diseases
++
Other parasitic diseases rarely involve the brain in the United States. In other countries, the following parasitic diseases occur commonly:
++
Cerebral malaria, due to Plasmodium falciparum.
African trypanosomiasis (sleeping sickness). This is caused by Trypanosoma rhodesiense in East Africa and Trypanosoma gambiense in West Africa.
Cysticercosis, due to the larval form of Taenia solium, the pork tapeworm.
Hydatid cyst, due to the larval form of Echinococcus granulosus.
Trichinosis, due to Trichinella spiralis.
Schistosomiasis, due to Schistosoma haematobium and Schistosoma mansoni (in the Middle East).
Amebiasis, due to Entamoeba histolytica, which causes brain abscesses. Free-living amebae of the genera Acanthamoeba and Naegleria are rare causes of meningoencephalitis.