Chapter 25 - Infectious diseases of the central nervous system

Infection of the nervous system can involve the meninges (meningitis) or the brain substance itself (encephalitis), or both (meningoencephalitis). Additionally, infections can be acute or chronic. The organisms that are involved in infection are bacterial, parasitic or viral. Additionally, prions represent an unusual class of infectious agent that can damage the brain. We will discuss each of these scenarios and consider the differential diagnosis.

Meningitis

Acute bacterial meningitis (purulent meningitis)

Bacteria reach the subarachnoid space via the bloodstream or, less often, by extension from contiguous structures such as the sinuses or ears. The infection is usually confined to the subarachnoid space, but toxins (from bacteria or leukocytes) can result in edema and also can damage blood vessels, causing additional damage. Patients with bacterial meningitis therefore present with changes in alertness (sensorium) in addition to headache, fever, and meningismus (a stiff neck that is most resistant to flexion.) Intracranial pressure is increased because of cerebral edema and due to interference with the normal circulation and resorption of cerebrospinal fluid (CSF) by the inflammatory process.

The lumbar puncture is diagnostic. The CSF is usually under increased pressure. There are often more than 1,000 WBCs/cu mm, particularly neutrophils (PMNs). However, very early in the course (especially of meningococcal meningitis) there may be few or no cells or the cells may be mainly lymphocytes. The amount of protein is usually elevated and the amount of glucose low. The fluid should be gram stained (even if there are no cells); often the organism can be accurately identified. Both aerobic and anaerobic cultures should be obtained and bacterial antigens can be rapidly tested, often determining the particular organism responsible. The lumbar puncture is usually accurate up to several hours after antibiotics are started. Therefore, if there will be delay in performing the lumbar puncture, antibiotics can be started since this is, indeed, an emergency.
Prompt treatment (without waiting for the results of culture) is essential. The choice of antibiotic may be guided by the appearance of the organism on the gram stain or, if identification is not certain, by the clinical picture. In neonates, group B beta-hemolytic streptococci and enteric gram-negative bacilli are the most common pathogens, accounting for 60-70% of the cases of meningitis. From the age of two months to ten years, more than 90% of the cases of meningitis are caused by Hemophilus influenzae, meningococci, or pneumococci. Currently, infants can be vaccinated against H. influenza (group B) and N. pneumonia. Hemophilus meningitis is rare after the age of ten. Although other organisms, such as Listeria or Streptococcus, occasionally cause meningitis in otherwise healthy individuals, the occurrence of unusual organisms should raise the suspicion of an immune deficiency or an unusual source of infection. Table 25-1 summarizes the common intracranial bacterial infections and the recommended initial therapy.
The complications of acute bacterial meningitis are listed in Table 25-2. Cerebral edema may at times be severe and may lead to transtentorial or foramen magnum herniation and death early in the course of meningitis. The inflammatory process causes a vasculitis that affects the smaller arteries and veins. Usually this does not produce focal neurologic signs; but in more severe cases of meningitis, focal signs of ischemia or stroke may develop, often during the second or third week. Arterial occlusion may occur. Cortical vein thrombosis produces hemorrhagic infarction of the cortex, with resultant focal signs and (often) seizures. The thrombophlebitis may spread to involve the venous sinuses, resulting in diminished absorption of CSF and raised intracranial pressure. Raised intracranial pressure may also result from damage to the arachnoid granulations (the sites of resorption of CSF), with resultant communicating hydrocephalus. This may occur after the meningitis has been cured and may require shunting of CSF. In infants, increased intracranial pressure and continued fever may result from a subdural effusion. These are usually sterile but may be infected (empyema). If subdural effusions are symptomatic, repeated subdural taps via the anterior fontanelle are necessary in this rare condition.
There are various systemic complications of meningitis. Inappropriate antidiuretic hormone (ADH) secretion may result in hyponatremia from water excess and salt loss. Water restriction is usually effective in treating this transient complication. A more serious complication is disseminated intravascular coagulation, which occurs with purpura, cyanosis, pain, fever, and hypotension. This is due to vasculitis with intravascular deposition of fibrin. Adrenal hemorrhage may accompany this, but the symptoms are thought not to be secondary to adrenal insufficiency. Treatment of the underlying condition is probably the only effective therapy, although steroids (particularly in children) and heparin have been advocated. Lactic acidosis also occurs and frequently requires therapy with bicarbonate.
Following recovery from purulent meningitis, residual brain damage may be evidenced by cranial nerve palsies, mental retardation, or seizures. The incidence of brain damage varies with the severity of the meningitis and the organism, and tends to be high in neonatal meningitis.
An unusual bacterial meningitis may accompany early Lyme disease, with meningitis presenting several weeks after infection (often while the rash of erythema migrans is still present). This can occur along with damage to the facial nerve.

Viral meningitis

Although pathologically some cerebral involvement is seen in most cases of viral meningitis, the clinical picture is more often one of pure meningitis: headache, fever, stiff neck, and sometimes lethargy, but with no focal neurologic signs or seizures. When there are signs of cerebral involvement, the process is called meningoencephalitis.

The CSF is usually under normal pressure and there is a moderate number of WBCs (usually fewer than 500/cu mm). Initially, these cells are often polys, but after a day or two lymphocytes begin to predominate. The amount of protein in the CSF is normal (or slightly elevated); the level of sugar is normal. The illness is self-limited and sequelae are unusual. The term "aseptic meningitis" has been used for this and some of the chronic meningitis problems, since there are no bacteria grown on cultures.
Lymphocytic choriomeningitis infections are atypical in that the CSF pleocytosis is more marked (often several thousand cells, with a marked lymphocytic preponderance) and the pleocytosis may take several weeks to disappear. In other respects, they resemble other varieties of viral meningitis, with recovery being the rule.
HIV can result in a meningitis usually early on, at the time of initial seroconversion.

Chronic (granulomatous) meningitis

There is a clinical picture of more slowly evolving meningitis. There are fewer signs of meningeal inflammation (headache, neck stiffness, etc), and more findings of focal neurologic damage (cranial nerves, focal sensorimotor deficit, cognitive deterioration, etc). There are infectious and non-infectious forms of chronic meningitis. The most common infectious types are tuberculous and cryptococcal meningitis. Atypical bacteria, such as brucella, spirochetes (syphilis and Lyme) may produce subacute or chronic infections and uncommon parasites such as ehrlichia can invade the meninges. Non-infecti0us types include carcinomatous meningitis and some other granulomatous forms, like sarcoid. With the diversity of causes and the nonspecificity of presentation, it is no wonder that diagnosis may be extremely difficult. We will consider some of the more common causes.

Tuberculous meningitis. This occurs most often in children and debilitated and immune incompetent adults. The meningitis results from seeding of a tuberculoma in the brain or meninges. The tuberculoma, in turn, arises from the hematogenous spread from a primary focus (usually in the lung). The patients present with headache, malaise, and fever. Weight loss may be prominent. A physical examination may show normal results, or nuchal rigidity may be present. The thick basilar meningitis may produce hydrocephalus, cranial nerve palsies, or an arteritis of the small penetrating arteries of the brain stem. The CSF shows a moderate pleocytosis (usually fewer than 300 WBCs/cu mm), mostly lymphocytes. The level of protein is high, and the amount of sugar low (these changes may be mild early in the course). The organism is occasionally demonstrable by acid-fast bacillus (AFB) strains of the CSF sediment, but often it is not. Routine cultures are negative, but specialized cultures may take 4 to 8 weeks to grow. The chest x-ray and tuberculin skin test may be helpful, but both can show normal results (the latter is the result of anergy). Polymerase chain reaction testing is rapid and fairly accurate. However, there can be false negative findings if there are few organisms.
If the diagnosis of tuberculous meningitis is suspected on clinical grounds, treatment should be instituted. Isoniazide (INH), streptomycin, rifampin and pyrazinamide are used in combination. Ethambutol may be useful if given in high doses. Treatment is continued for at least 6-9 months. Corticosteroids may be helpful in reducing the inflammatory response, which itself can contribute to the patient's symptoms. Sequelae are common.
Cryptococcal meningitis. Cryptococcus neoformans (Torula) often produces an indolent infection; its symptoms occasionally may extend back months or even years before the diagnosis is made. A debilitated state, immune incompetence or suppression, and diabetes mellitus are frequently associated conditions. Headache is the most common symptom, and mental deterioration may occur. Cranial nerve palsies and focal brain stem dysfunction secondary to arteritis can be prominent. The CSF is similar to that seen in persons with tuberculous meningitis. The fungus may be seen on India ink preparations and may grow in culture. It is not rare, however, for the organism not to show itself. Cryptococcal antigen can often be detected in the CSF, providing a valuable aid to the diagnosis. Treatment is with systemic and intrathecal amphotericin B and 5-fluorcytosine. Rarely, other fungal infections (such as Coccidioides, Mucor, Candida, Actinomyces, Histoplasma, or Aspergillus) can present with chronic meningitis (usually in an immunocompromised host).
Other forms of chronic meningitis. Sarcoidosis is a rare granulomatous condition of uncertain etiology. The symptoms may be nonspecific (headache, nuchal rigidity) and the CSF may be identical to that in persons with tuberculous or fungal meningitis. Transient cranial nerve signs as well as evidence of CNS dysfunction can occur. The diagnosis may be suspected if there is evidence of systemic sarcoidosis, but this is not always the case. Direct involvement of brain parenchyma can occur even in the absence of meningeal involvement. Multifocal lesions in the periventricular region, sometimes also involving the optic nerves, may masquerade as multiple sclerosis. Treatment with immune suppressing drugs and corticosteroids has proven effective in most patients.
Carcinomatous meningitis is a condition of infiltration of the meninges by cancer cells. This usually occurs as a complication of advanced metastatic disease. However, particularly with lymphoma, it may occur without other evidence of systemic disease. Patients are usually very ill and many of the symptoms are due to hydrocephaly or damage to exiting cranial nerves or nerve roots. CSF protein is very high and centrifugation of large volumes of spinal fluid may yield cancerous cells. Flow cytometry can demonstrate the monoclonal nature of lymphocytes when the condition is due to lymphoma. Rarely, biopsy of the inflamed meninges may be necessary to definitively diagnose the condition.
There are some other, rare, infections that can be chronic. Brucellosis can produce waxing/waning meningitis. Spirochetes, such as neurosyphilis and Lyme can produce chronic inflammation and certain parasites (such as Erlichia) can also present this way.
Certain drugs can inflame the meninges in a rare, idiosyncratic reaction, when taken orally (such as NSAIDs or sulfa drugs). Many drugs can irritate when delivered to the spinal fluid (i.e., chemotherapy, antiviral/antifungal agents, contrast agents).

Viral Encephalitis

Meningeal involvement is present in most forms of encephalitis; however, the clinical picture is dominated by evidence of brain dysfunction. In addition to headache and fever, patients often have strikingly depressed levels of consciousness, and seizures are common. Behavioral changes and focal neurologic signs are sometimes present. The CSF contains a moderate number of cells. The level of protein is normal or high, and the amount of sugar is usually normal.

The major causes of viral encephalitis are listed in Table 25-3. The arbovirus encephalitides are usually epidemic; the others are usually sporadic. Because the clinical findings are similar in most cases of encephalitis, the diagnosis of the offending agent must rest on laboratory investigations (polymerized chain reaction, antigen detection, growing the virus or detecting increasing levels of antibody titers). We briefly discuss three varieties that can be distinctive.

Herpes simplex encephalitis (HSE)

This is the most common sporadic (nonepidemic) form of encephalitis. Although many encephalitides are seasonal in their appearance, especially prominent in the summer, herpes simplex occurs any time of the year. It is caused by the type I herpes simplex virus, normally present in cold sores. The portal of entry in many is presumed to be through the nasal mucosa or by direct extension from the adjacent trigeminal ganglion (in whose cells the virus is dormant). This portal of entry presumably accounts for the localization of the disease to the orbitofrontal and anteromedial temporal cortices. The pathologic reaction is unusually severe, with inflammation, edema, necrosis, and hemorrhage. Clinically, patients often have personality changes (secondary to the involvement of the limbic system). They have difficulty with memory (imprinting) because of involvement of the mesial temporal lobe (hippocampi), and a decreased or lost sense of smell (anosmia) because of involvement of the olfactory bulbs. Olfactory hallucinations are not uncommon, caused by both irritation of the olfactory bulbs and the olfactory cortex. Headache, fever and somnolence are the usual complaints. If edema is severe, papilledema can be seen and seizure may result from irritation of the cortex. If the involvement is asymmetric, hemiparesis or aphasia may be present, leading to suspicion of stroke or mass lesion and complicating the assessment. The CT scan may show focal abnormality (including hemorrhage) in one or both temporal lobes. Magnetic resonance imaging can show changes sooner, but the changes are not specific for HSE. The polymerase chain reaction in the CSF is the most effective diagnostic tool and can be run fairly rapidly in most major medical centers. However, since it does take time for results of this test to return, it may be necessary to treat the patient while awaiting results. The electroencephalogram (EEG) usually shows bitemporal slowing and sharp activity and is frequently the first laboratory abnormality to be positive. Occasionally, it may be difficult to differentiate encephalitis from a temporal lobe abscess without surgical exploration and biopsy.

Treatment with an antiviral agent (acyclovir) has been shown to be effective. Combating the host inflammatory response with steroids has been considered by some an effective supplementary therapy, despite the theoretical risk of exacerbating the infection and the lack of concrete evidence of efficacy. Survivors may show severe cognitive changes; not uncommonly, there is a specific deficit in recent memory (imprinting) because of bilateral hippocampal destruction. Acyclovir is a relatively benign medication and, therefore, when herpes simplex encephalitis is suspect, acyclovir should be started immediately, even prior to beginning diagnostic tests because the morbidity and mortality due to this destructive encephalitis poses a much greater risk than the therapy. It is advisable to also cover for possible bacterial cerebritis until the issue is clarified.

Arbovirus

Arboviruses are the leading cause of epidemic encephalitis. The most common forms in the US are eastern and western equine encephalitis, St Louis encephalitis, California encephalitis and, most recently, West Nile virus. The infections range from very mild to fatal. The usual incubation period is 2-18 days after mosquito bite and the incidence is highest in late summer and early autumn, until the first hard frost does away with the mosquito population for that year. Birds and other animals (such as horses) are the usual reservoir for the infection, and they are involved in its spread. Initial viral symptoms may give way to high fever and neck stiffness (meningeal signs). However, as with most forms of encephalitis, it is the confusion and depressed levels of consciousness (stupor) that mark the infection as being of the brain (encephalitis) and not just the meninges.

Rabies

The incubation period after the bite of a rabid animal may be prolonged (as long as one year). The further from the CNS that the infection is introduced to the body, the longer the incubation period. The infection appears to gain access to the nervous system through retrograde transmission and it attacks neurons in specific areas, particularly the limbic system, hypothalamic area, and brain stem nuclei. There may be little or no meningeal inflammation (i.e., the CSF may be normal).

Behavioral changes (particularly an agitated delirium), seizures, and painful spasms of the throat musculature are prominent, particularly precipitated by swallowing food or liquids. This latter feature is the source of the ancient name for rabies, "hydrophobia." If bitten by or exposed to the saliva of a suspected rabid animal, effective immune therapy is available and should be initiated while waiting for proof of the suspect animal's disease, since there is no effective therapy once neurologic symptoms develop.

Poliomyelitis

Encephalitis is usually a minor aspect of this infection, which has a predilection for anterior horn cells and the cells of the brain stem motor nuclei. A prodromal gastrointestinal illness and a nonspecific viral meningitis usually precedes the development of lower motor neuron signs (spotty asymmetric weakness, reflex loss, and fasciculations). The success of the polio vaccines (Salk and Sabin) has made polio a rare infection in the western world. It has always been unusual in the third world because of poor sanitation that results in infection early in life when susceptibility to nervous system invasion by the poliovirus is low.

Brain Abscess

Bacterial brain abscesses can arise either from direct extension from a parameningeal focus of infection (ear and sinus infections) or by hematogenous spread. Pulmonary pathology (especially bronchiectasis) is the most common source of the hematogenous spread. Persons with cyanotic congenital heart disease and pulmonary arteriovenous malformations are also prone to develop abscesses. This is because bacteria originating in the bowel and reaching the vena cava and the right side of the heart via the portal system, liver, and hepatic veins are short-circuited to the left side of the heart and systemic circulation. Thus they miss filtration by the pulmonary macrophage system. Although subacute and acute bacterial endocarditis may be associated with mycotic aneurysms and meningoencephalitis, it is infrequently the cause of brain abscess. This may be because the bacteria that usually cause endocarditis are aerophilic and therefore unlikely to propagate within an infarct or ischemic zone; the arterial wall is more prone to involvement because of its high oxygen saturation. The pia-arachnoid surface is also highly vascularized and a favorable site for aerobe propagation.

In hematogenously spread abscesses, they are most likely to occur in areas of ischemic injury to the brain and most likely to include anaerobic or microaerophilic organisms (such as come from the bowel). On the other hand, aerobic bacteria are frequently cultured from abscesses that have sinus tracts connecting them to the exterior, i.e., sinus infections, middle-ear infections, and skull fractures.
Abscesses secondary to ear infections are usually in the middle third of the temporal lobe, or less often, in the cerebellum. Abscesses secondary to spread from the paranasal sinuses or from dental infections are more often in the frontal lobes. Hematogenous spread can result in an abscess in any location, and multiple abscesses are not uncommon.
There are two stages in the development of a bacterial brain abscess. In the first stage, the primary infection is often active, and the brain infection is a cerebritis - an inflammatory response with some tissue breakdown. The patient is usually febrile and may complain of headache. The intracranial pressure is usually raised. There may be focal signs, but lesions in the temporal lobes or frontal lobes may have no symptoms localizing a lesion to the brain. The CT scan or MRI is usually abnormal and the EEG is usually focally abnormal. Arteriography does not show any well-defined mass. The spinal fluid may show a pleocytosis, with a raised level of protein and a normal amount of glucose, but it can be entirely normal. Of course, spinal tap in a patient with potentially elevated intracranial pressure should only be done after scanning to ascertain the risk of potential herniation. Treatment with antibiotics alone at this stage may produce complete resolution and surgery is not recommended due to the lack of clear margins or a defined wall to the infection.
In the second stage, the region of the cerebritis becomes organized and walled off, and a true abscess forms. Fever often subsides. There may be signs of an expanding mass. The CSF and EEG and brain scan are as before. A mass is seen on CT scan or MRI. Treatment with antibiotics alone may not be effective because the abscess is walled off; surgical drainage may be necessary.
Untreated, the brain abscess may cause cerebral herniation or rupture into the ventricles, causing severe (and often fatal) meningitis. The WBC count in the CSF in the latter instance is often more than 10,000/cu mm.

Empyema

Infection may form in the epidural or subdural spaces; it is usually the result of spread from an adjacent infection (in the bone, skin, or sinuses), but sometimes it arises from hematogenous spread. The diagnosis of cerebral subdural or epidural empyema can be difficult unless there is a high index of suspicion. The symptoms of spinal epidural empyema are somewhat more uniform, but the diagnosis is still often missed. The presenting complaint is usually pain over the infected region, and there is usually fever. The patient then experiences pain in the distribution of the spinal nerve roots in the area. Finally, symptoms referable to the spinal cord occur as a result of compression or infarction secondary to thrombophlebitis. If treatment (surgical drainage and antibiotics) can be instituted before the spinal cord is affected, the outcome should be good, otherwise irreversible cord damage and paralysis can result.

Miscellaneous Infections

Bacterial

Numerous bacterial infections may be manifested by processes other than acute purulent meningitis or brain abscess. Tuberculous meningitis has been mentioned. Encephalitis symptoms may be present with pertussis, tularemia, typhoid, and other acute infections. Brucellosis may appear as chronic meningitis. Neurosyphilis, uncommonly seen in this country today, is nevertheless important.

Syphilis

Syphilis produces an amazing array of CNS disorders, which can mimic infectious, vascular, neoplastic, or degenerative disease. Meningitis (rarely of clinical significance) may occur within five years of a person contracting the infection. From seven to 15 years after contact, an inflammatory vasculitis (meningovascular syphilis) can produce infarction in virtually any area of the CNS. Tertiary syphilis (15-20 years after contact) has two classic presentations: tabes dorsalis and paretic neurosyphilis (general paresis of the insane). Tabes is an inflammatory process that affects the dorsal root ganglia, producing loss of position and vibration sensation, loss of deep-tendon reflexes, and severe "lightning" pains in the abdomen and legs. Periodic attacks of abdominal cramps and vomiting are common. The Argyll-Robertson pupil (small and irregular with light reaction lost and accommodation preserved) is usually present, and bladder dysfunction is common. General paresis consists of an infection of the cerebral cortex, particularly in the frontal lobes, producing a progressive frontal lobe dementia. Pupillary changes, myoclonic jerks, and tremor are also frequently present.

Neurosyphilis may be diagnosed serologically using nonspecific (reagin) tests such as rapid plasma reagin (RPR) or Venereal Disease Research Lab test (VDRL) or specific treponemal antibody tests such as the fluorescent treponemal antibody test (FTA). The former may have normal results in the serum in tertiary syphilis, and therefore an FTA must always be ordered when this form of the disease is being considered. The CSF VDRL is diagnostic of neurosyphilis because false positives occur only when false-positive blood is inadvertently introduced into the CSF by a traumatic lumbar puncture (see Chapter 11). Occasionally all these tests are negative. If symptoms and signs are compatible with CNS syphilis, and if CSF pleocytosis or increased concentrations of CSF protein suggest active disease, treatment should be instituted. Prolonged treatment with penicillin is the treatment of choice.

Lyme disease

This is another spirochaetal disorder with both acute and chronic phases and multisystems involvement. The spirochete (Borrelia burgdorferi) is blood borne and transmitted by ticks. The disease usually first manifests itself as an enlarging circiform rash (erythema chronicum migrans) which may then be followed by a migrating arthritis which has been misdiagnosed as atypical rheumatoid arthritis in the past. Later, the meninges may be involved with cranial neuropathies prominent. The seventh nerve appears to be involved most frequently. This may be followed, in some patients, by a condition where multifocal parenchymal lesions occur with a fluctuating course, giving rise to misdiagnoses of multiple sclerosis. Diagnosis is suspected when the course is typical and can usually be confirmed by serological testing. The treatment of choice is doxycyclin or amoxicillin and is successful early in the course but less so in chronic, late stage illness. When there is involvement of the brain parenchyma or heart, certain other intravenous antibiotics may be necessary.

Leprosy

Because the leprosy bacillus can multiply only at temperatures a few degrees below core body temperature, CNS leprosy is rare if it exists at all. Leprosy produces a peripheral neuropathy, which is characterized by the involvement of nerves only in the cooler parts of the body. In persons with tuberculoid leprosy, nerve trunks are involved; the nerves situated immediately subcutaneously are affected (for example, the ulnar nerve at the elbow). In lepromatous leprosy, terminal nerve endings are involved, producing a patchy sensory loss; the cooler areas of the skin (ears, back of the hands) are affected first. Leprosy is rare in the United States, but worldwide it is one of the most important causes of peripheral neuropathy. An influx of new cases appeared in the U.S. when veterans who contracted the disease in southeast Asia returned home.

Rickettsial infections

The various rickettsial diseases may be accompanied by nonspecific meningoencephalitis. In this country, Rocky Mountain spotted fever is the most common of these conditions and may occur in almost any location. The initial symptoms are often neurologic (headache, stiff neck, lethargy). The diagnosis is suggested by a history of a tick bite and the characteristic rash. Treatment with antibiotics (tetracycline or chloramphenicol) is effective and may be lifesaving.

Fungal infections

Most often fungal infections occur in persons who have altered immune mechanisms: the debilitated, those with advanced diabetes or receiving immunosuppressant therapy. Aspergillosis and candidiasis are not uncommon in these persons. Mucormycosis is usually seen in diabetics, and is often associated with ketoacidosis. CNS involvement is usually secondary to spread from the nasal sinuses to the orbit (causing proptosis and ophthalmoplegia) through the cribriform plate into the brain. Coccidioidomycosis and cryptococcosis may occur in the normal host. Granulomatous meningitis is the usual presentation. Various fungi can produce cerebral granulomata or abscesses. Treatment of fungal infections is generally less satisfactory than treatment of bacterial or rickettsial infections, but some improvement is often obtained with intrathecal amphotericin B or 5-fluorocytosine.

Protozoal infections

Amoeba, trypanosomes, malaria, toxoplasma, and other protozoa may affect the CNS. Toxoplasmosis, a ubiquitous organism, may cause infection in utero producing underdevelopment of the cerebrum and resulting in microcephaly and mental retardation. Retinal involvement and intracerebral calcifications (seen on skull x-rays) may aid in making the diagnosis. This infection is also becoming more common in immunosuppressed persons. The syndrome presents as destructive meningoencephalitis, usually with multiple small abscesses in the basal ganglia region and particularly in the patient with the acquired immune deficiency syndrome (AIDS), caused by systemic retrovirus infection (see below). This infection is common enough in this group of patients that multiple small abscesses (ring-enhancing lesions), when found in an AIDS patient, are treated presumptively for toxoplasma before considering other diagnoses.

Helminth infestations

Helminth infestations may produce various CNS findings, including meningoencephalitis (trichinosis), vasculitis (filariasis, schistosomiasis), or focal granulomata (cysticercosis). The patient may have a meningitis or encephalitis picture, or the process may be manifested as a mass lesion or seizure disorder. Cerebral cysticercosis is the most common cause of focal onset epilepsy in Central and South America.

Prion diseases (Table 25-4)

This fascinating group of uncommon diseases is pathologically similar and has the following characteristics:

They are transmissible experimentally.
They have a long latent period (up to many years).
Pathologically they resemble degenerative diseases; there is neuronal degeneration with astrocytic reaction but no evidence of inflammation.
Clinically they produce a chronic or subacute illness, which is steadily progressive.
The nature of the infectious agent is an abnormally folded protein.

The group of diseases (scrapie, kuru, Creutzfeldt-Jakob disease, bovine spongiform encephalopathy) are caused by abnormal proteins that result in the neuronal degeneration, reactive gliosis and spongiform changes (microscopic cystic cavities in the brain). These conditions are transmissible, but the "infectious agent" appears to be an abnormal protein rather than a virus, bacteria or parasite. It appears that some cases can be sporadic due to de-novo configurational changes in proteins.
The recognition of this group of unusual infectious disorders has lead to re-examination of many other progressive diseases of the nervous system to determine if these are similarly infectious. However, to the present, prion diseases represent a clear, but fortunately isolated, example of slowly progressive infectious disease of the nervous system.

Atypical conventional virus infections (Table 25-4)

In persons with these conditions, virus particles can be identified pathologically, immunologically, and by culture. Inflammatory reactions can be seen, and inclusion bodies may be present. As opposed to most acute viral infections, they cause a subacute or chronic disease, usually after a long latent period.

Subacute sclerosing panencephalitis (SSPE) is a disease that affects children or adolescents; it presents with progressive mental deterioration, myoclonic jerks, and then progressive pyramidal and extrapyramidal involvement, which leads to death within a few years. The CSF may be normal except for a high level of gamma globulin and high measles antibody titers. A measles-like virus can be grown from infected brain tissue. Some of these children have defective immune responses. The disease may result from infection at an early age with a form of measles virus, but the exact pathogenesis is still unknown.
Progressive multifocal leukoencephalopathy (PML) is a disease that occurs almost exclusively in debilitated persons (most often patients with lymphoma and more recently in patients with AIDS). Pathologically there are small areas of demyelination, and inclusion bodies are seen in oligodendroglia (the cells of the CNS that elaborate myelin). Clinically, patients have focal cortical signs, and as lesions become more numerous, the clinical course becomes one of progressive deterioration. Death usually occurs within one to two years. Two different papovaviruses have been isolated: One of them (the JC virus) is a virus with which most adults have had contact.
The acquired immune deficiency syndrome (AIDS) is a disease caused by a retrovirus, which has the capacity to elude and destroy the body's various immune defenses. The virus has relatively low infectivity and is passed by repeated sexual contact, blood and blood products and direct introduction into tissue or the blood stream by infected needles, surgical instruments, etc. In this country, the major victims have been promiscuous homosexuals, drug addicts, prostitutes and hemophiliacs although worldwide this appears to be mainly passed by heterosexual contact. The virus causes direct problems by tissue invasion (the central nervous system is a prominent target) and indirect problems as a result of the immune deficiency state. Slowly progressive encephalitis is caused by direct involvement that is, however, usually overshadowed by the appearance of the various infections of immune compromise. The most prominent co-infections are toxoplasmosis in its various parenchymal and meningeal forms, cytomegalic virus encephalitis, cryptococcal meningitis, progressive multifocal leukoencephalopathy, tuberculous meningitis or granuloma and syphilis. In the absence of immune surveillance various malignancies are also predisposed (lymphomas appear most common). A Guillain-Barre-like polyneuropathy, believed to be caused by autoimmune attack against viral involved myelin or Schwann cells, may be an early and reversible involvement before the retrovirus destroys the body's capacity to have an autoimmune reaction.
There are therapies for many of the secondary phenomena. A variety of antiretroviral therapies are now available which effectively slow the progression of the disease but no curative agent is available yet. Prophylactic measures have begun to decrease the incidence in some at-risk populations. Drug addicts and their sexual partners remain a significant reservoir, and attitudes (both ignorance of risk and fatalistic acceptance) are barriers to prevention. There is growing risk of individuals misinterpreting successful treatment with cure and therefore not recognizing the seriousness of the condition. Poor education, cultural barriers and the limited availability of treatments remain major barriers to progress in the third world, where AIDS remains a major cause of mortality.

Cerebrospinal Fluid in Infectious Disease and Related Conditions

The CSF findings in persons with the three major varieties of meningitis have been discussed and are summarized in Table 25-5. Although the differences noted are helpful, it is important to realize that there are exceptions to these rules. Patients with viral meningitis may have more than 1,000 WBCs/cu mm. Acute bacterial meningitis may present with few WBCs for a variety of reasons: (1) the patient's immune response may be inadequate, (2) the leukocyte response may be suppressed by the presence of alcohol in the blood and tissues, (3) the meningitis may have been partially treated, and (4) the tap may have been done early in the course of the disease before cells appeared. In the second and last instances, a repeat tap in two to six hours usually reveals a brisk pleocytosis. Many conditions other than viral infections can produce a modest pleocytosis, normal or elevated levels of protein, and normal (or low) amounts of sugar. These are listed in Table 25-6. Finally, a low level of glucose in the CSF is not pathognomonic of infection. Several mechanisms are invoked to explain the low level of CSF glucose in persons with meningitis: The glucose may be metabolized by organisms, by phagocytes, or by the inflamed meninges and brain. In addition, transport of glucose into the CSF is often blocked in cases of meningitis. Some of these mechanisms may also explain the low level of CSF glucose found in persons with other conditions (Table 25-7).

It should be clear, therefore, that although the CSF findings provide important clues to the diagnosis of CNS infections, the definitive diagnosis rests on identifying the causative organism microscopically or by culture. Serologic methods may be useful, but, in general, evidence of rising titers of antibodies to an infectious agent appears after the illness is over. Recent studies indicate that counter immunoelectrophoresis and polymerized chain reaction may be capable of detecting minute amounts of bacterial antigens in the CSF rapidly and thereby enable the rapid and specific diagnosis of meningitis.

References

Baker, A.B., Baker, L.H.: Clinical Neurology. New York, Harper& Row, 1974, Chaps. 14-19.
Dodge, P.R., Swartz, M.N.: Bacterial meningitis - A review of selected aspects. N. Engl. J. Med. 272:954, 1965.
Thompson, R.A., Green, J.R. (eds): Infectious Diseases of the Central Nervous System, in: Advances in Neurology, Vol. 16, New York, Raven Press, 1974.
Mandell, L.A., Ralph, E.D. (eds): Essentials of Infectious Diseases, Boston, Blackwell, 1985.

Questions

Define the following terms:

meningitis, encephalitis, hydrocephaly (communicating and internal), meningismus, Kernig's sign, pleocytosis, Brudzinski's sign, parameningeal.

Meningitis is inflammation or infection of the meninges.

Encephalitis inflammation or infection of the brain.

Hydrocephaly (communicating and internal) is accumulation of cerebrospinal fluid due to deficient resorption (communicating) or obstruction of the flow pathway through the brain (internal). Hydrocephaly ex-vaccuo is when the brain shrinks and CSF replaces it.

Meningismus is resistance to neck flexion due to pain when inflamed meninges are stretched.

Kernig's sign is involuntary flexion of the knee when the lower limb is flexed at the hip. This occurs because the inflamed meninges are stretched by stretch of the sacral nerve roots.

Brudzinski's sign is involuntary flexion of the knees when the neck is flexed. This occurs because the inflamed meninges are stretched by flexing the neck and tension can be relieved somewhat by taking tension off of the sacral nerve roots by flexing the knees.

Pleocytosis is the presence of an excessive number of white blood cells in the spinal fluid.

Parameningeal refers to processes (particularly infections) that occur outside of the dura but which are adjacent to it (producing some signs - particularly in the CSF) of inflammation.

25-1. What broad classes of meningitis are there (name 4)?

Answer 25-1. Meningitis may be acute or chronic, bacterial or aseptic.

25-2. What are the most common causes of acute meningitis?

Answer 25-2. Most acute meningitis is bacterial or viral (chemical meningitis is rarer).

25-3. What are the most common causes of acute bacterial meningitis?

Answer 25-3. The most common cause of acute bacterial meningitis are strep pneumonia, Neisseia meningitides, group B strep, Listeria monocytogenes, Hemophilus influenzae.

25-4. Which bacterial would you suspect in adults? In older children/adolescents? In young children? In infants? In the elderly?

Answer 25-4. The most common organism producing meningitis: strep pneumonia (especially in adults); Neisseria meningitis (In children and young adults); group B strep (In infants); H flu (In young children); Listeria (In elderly and immunosuppressed).

25-5. What are the signs and symptoms of acute bacterial meningitis?

Answer 25-5. The most common symptoms of acute bacterial meningitis are headache, fever, meningismus, confusion progressing to stupor, elevated intracranial pressure. Young children and particularly infants may not have fever or neck stiffness. Infants may have a bulging fontanelle.

25-6. What are some potential complications of meningitis?

Answer 25-6. Potential complications of meningitis include: cranial nerve palsy, hydrocephalus, stroke, seizure, abscess.

25-7. What is the most critical diagnostic procedure for suspected meningitis?

Answer 25-7. Lumbar puncture is critical for diagnosis and for determining the best treatment.

25-8. What are the findings in the CSF in acute bacterial meningitis?

Answer 25-8. Increased protein is nonspecific. Lymphocytes are most common with viral meningitis or some chronic infections while PMNs are numerous with most bacterial meningitis (but some may be present early in viral meningitis). Glucose (as a percentage of systemic blood glucose) may be low with bacteria or some chronic meningitis.

25-9. What are the principles of treatment of acute meningitis?

Answer 25-9. Do not wait for cultures - empiric antibiotics are used to cover potential organisms. A third generation cephalosporin + vancomycin are most common, but you should consider adding ampicillin if over 55 or immunocompromised. Steroids may be useful in children to cut down on complications (not sure about adults, but they are often used).

25-10. What is the most common cause of aseptic meningitis?

Answer 25-10. Most aseptic meningitis is viral.

25-11. What are the symptoms of aseptic meningitis?

Answer 25-11. The symptoms of aseptic meningitis include headache, neck stiffness, photophobia, viral syndrome.

25-12. What are the CSF findings in aseptic meningitis?

Answer 25-12. The CSF usually shows fewer than 500 WBC - some polys early then lymphocytes. There may be slight elevation of protein but glucose is usually normal.

25-13. What are causes of chronic meningitis?

Answer 25-13. The causes of chronic meningitis include atypical bacteria (mycobacteria), fungi, spirochetes (syphilis, Lyme) and parasites. It may also result from neoplasm (carcinomatous meningitis) - especially lymphoma.

25-14. What are the signs and symptoms of chronic meningitis?

Answer 25-14. The signs and symptoms of chronic meningitis include headache and mental status change. The patients are usually debilitated and have constitutional symptoms although there is usually no meningismus. It may result in damage to cranial nerves or cause hydrocephaly and stroke.

25-15. What is the key to diagnosis of chronic meningitis?

Answer 25-15. CSF is critical to diagnosis of chronic meningitis. Exam may be difficult due to number of causes.

25-16. What are parameningeal infections?

Answer 25-16. Parameningeal infections are outside the dura but adjacent to it (sinuses, otitis, mastoiditis, epidural empyema, epidural abscess - including the spine, osteomyelitis). These often result in elevated protein and mononuclear pleocytosis in the CSF.

25-17. What are the features of acute viral encephalitis?

Answer 25-17. Patients with acute viral encephalitis may have meningeal signs but patients are more encephalopathic (sleepy, stuporous, not thinking clearly).

25-18. What are the potential complications of acute viral encephalitis?

Answer 25-18. Potential complications of encephalitis include increased intracranial pressure, and seizures.

25-19. What are the potential causes of acute viral encephalitis?

Answer 25-19. Potential causes of acute viral encephalitis include many arboviruses (seasonal and some in epidemics) including the several types of equine encephalitis as well as West Nile virus. The most common sporadic encephalitis is Herpes simplex which is critical to recognize since it is treatable and is fatal in most untreated cases.

25-20. What are the potential causes of chronic encephalitis?

Answer 25-20. The most common causes of chronic encephalitis are viral - HIV, myxovirus (progressive multifocal leukoencephalopathy) or subacute sclerosing panencephalitis (the measles virus). Creutzfeldt-Jacob disease is a subacute infectious disease in which a prion is the infectious particle. This usually produces a subacute dementia with minimal signs of infection and no meningeal signs.

25-21. What are the causes of brain abscesses?

Answer 25-21. Brain abscesses may follow focal infections such as otitis media, sinusitis, mastoiditis, but it may also result from hematogenous spread (teeth, bacterial endocarditis, etc).

25-22. What are the symptoms of brain abscess?

Answer 25-22. The symptoms of brain abscess include headache and focal deficits. The patient may or may not show signs of systemic illness. Seizures may develop, requiring anticonvulsants.

25-23. What are the most common organisms in brain abscess?

Answer 25-23. Brain abscess are usually mixed infection including anaerobes. There is a cerebritis stage, encapsulation stage, and potential rupture (sometimes fatal).

25-24. What is the treatment for brain abscesses?

Answer 25-24. Empiric antibiotics are used in the cerebritis stage of brain abscess (third generation cephalosporin and metonidazole or chloramphenacol). The patient requires close observation and may require surgical drainage or aspiration when capsule forms.

25-25. What about lumbar puncture in brain abscesses?

Answer 25-25. Spinal taps are extremely dangerous in brain abscesses due to potential herniation when pressure is released below.

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Thursday 7 May 2015

Chapter 25 -Infectous diseases of the central nervous system

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