Infectious Diseases of the Nervous System

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Contents 1 Infectious Diseases of the Nervous System 1.1 MENINGITIS 1.1.1 Acute Meningitis 1.1.2 Acute Bacterial Meningitis 1.1.3 Clinical Features. 1.1.4 Evaluating the Cerebrospinal Fluid. 1.1.5 Organisms. 1.1.6 Management. 1.1.7 Acute Aseptic Meningitis 1.1.8 Clinical Features. 1.1.9 Management. 1.1.10 Subacute Meningitis 1.1.11 Tuberculous Meningitis. 1.1.12 Clinical Features. 1.1.13 Cerebrospinal Fluid Studies. 1.1.14 Treatment. 1.1.15 Cryptococcal Meningitis. 1.1.16 Other Causes. 1.1.17 Chronic Meningitis 1.1.18 Chronic Spinal Arachnoiditis. 1.1.19 Recurrent Meningitis 1.1.20 Differential Diagnosis of Meningitis 1.1.21 Complications of Meningitis 1.2 ENCEPHALITIS 1.2.1 Typical Encephalitis 1.2.2 Causative Organisms. 1.2.3 Clinical Features. 1.2.4 Differential Diagnosis. 1.2.5 Laboratory Findings. 1.2.6 Treatment. 1.2.7 Herpes Simplex Encephalitis 1.2.8 Clinical Features. 1.2.9 Laboratory Findings. 1.2.10 Treatment. 1.3 RABIES 1.4 ACQUIRED IMMUNODEFICIENCY SYNDROME 1.5 ABSCESS 1.5.1 Epidural Abscess 1.5.2 Intracranial Epidural Abscess. 1.5.3 Spinal Epidural Abscess. 1.5.4 Differential Diagnosis. 1.5.5 Subdural Abscess (Empyema) 1.5.6 Causes. 1.5.7 Organisms. 1.5.8 Clinical Features. 1.5.9 Laboratory Findings. 1.5.10 Treatment. 1.5.11 Intracerebral Abscess 1.5.12 Causes. 1.5.13 Clinical Features. 1.5.14 Diagnosis. 1.5.15 Treatment. 1.6 OTHER NEUROLOGIC INFECTIONS 1.6.1 Herpes Zoster 1.6.2 Clinical Features. 1.6.3 Herpes Zoster Ophthalmicus 1.6.4 Cytomegalovirus 1.6.5 Poliomyelitis 1.6.6 Diagnosis. 1.6.7 Coxsackievirus 1.6.8 Infectious Mononucleosis 1.6.9 Influenza 1.6.10 Tick Paralysis 1.6.11 Tetanus 1.6.12 Treatment. 1.6.13 Botulism 1.6.14 Toxoplasmosis 1.6.15 Syphilis 1.6.16 Primary Syphilis. 1.6.17 Secondary Syphilis. 1.6.18 Tertiary (Late) Syphilis. 1.6.19 Meningovascular Syphilis. 1.6.20 Tabes Dorsalis. 1.6.21 General Paresis. 1.6.22 Gummas. 1.6.23 Congenital Syphilis. 1.6.24 Management of Syphilis. 1.6.25 Lyme Disease 1.6.26 Slow Virus Infections of the Nervous System 1.6.27 Creutzfeldt-Jakob Disease 1.6.28 New Variant of Creutzfeldt-Jakob Disease 1.6.29 Subacute Sclerosing Panencephalitis 1.6.30 Progressive Multifocal Leukoencephalopathy 1.7 NEUROLOGIC COMPLICATIONS OF OTHER INFECTIONS 1.7.1 Acute Toxic Encephalopathy 1.7.2 Acute Postinfectious Encephalomyelitis 1.7.3 Clinical Features. 1.7.4 Treatment. 1.7.5 Differential Diagnosis. 1.7.6 Bacterial Endocarditis 1.7.7 Cerebral Thrombophlebitis 1.7.8 Causes. 1.7.9 Clinical Features. 1.7.10 Differential Diagnosis. 1.7.11 Treatment. 1.8 ADDITIONAL READINGS

[edit] Infectious Diseases of the Nervous System

T. Jock Murray

William Pryse-Phillips

The central nervous system (CNS) has no lymphatic system as such, and although usually well protected from direct infection, its resistance to any infection that does occur is low. The patterns of infective illness are relatively few, but the organisms that can produce disease are many. In this chapter we will outline the features of those kinds of infection more commonly seen (Box 165-1).

Box 165-1 - Overview of CNS Infections✢

Meningitis✢ Acute Subacute Chronic Recurrent Encephalitis Viral (e.g., herpes simplex, rabies, polio, arbor) Fungal Parasitic Acquired immunodeficiency syndrome Abscess Epidural (intracranial, spinal) Subdural Intracerebral Other Herpes zoster Cytomegalovirus Poliomyelitis Coxsackievirus Infectious mononucleosis Influenza Tick paralysis Tetanus Botulism Toxoplasmosis Syphilis Lyme disease Rabies Behçet's syndrome Slow virus infections Creutzfeldt-Jakob disease Subacute sclerosing panencephalitis Progressive multifocal leukoencephalopathy Neurologic complications of other infections Acute toxic encephalopathy Acute postinfectious encephalomyelitis Epidemic myalgic encephalomyelitis Bacterial endocarditis Cerebral thrombophlebitis ✢From Mandell GL, Bennett JE, Dolin R, editors: Principles and practice of infectious diseases, ed 4, New York, Churchill Livingstone, 1995.✢These may be bacterial, viral, fungal, or parasitic.

[edit] MENINGITIS

Although the word meningitis suggests an inflammation of the meninges only, there is always some involvement of the most superficial parts of the brain that are contiguous to the meninges. Often there are also alterations in the flow of cerebrospinal fluid (CSF). An occlusive arteritis is common in the subpial cortex, so meningitis is properly considered as a meningoencephalitis in all cases. Causative organisms include bacteria, spirochetes, viruses, fungi, and protozoa; sometimes carcinomatous invasion of the meninges produces meningeal inflammation that is hard to clinically differentiate from infective meningitis.

The most common organisms responsible for bacterial meningitis in people over the age of 2 months are Neisseria meningitidis, Streptococcus pneumoniae, Haemophilus influenzae, and Listeria monocytogenes, but other organisms such as Escherichia coli and group B streptococci must be considered in neonates. Any of the above organisms and also staphylococci, anaerobes, and mixed infections can be identified in patients with CNS defects or local infections and in those taking immunosuppressants. Most cases of meningitis are associated with infection in the upper respiratory tract, but one should always consider whether the patient may have a lowered resistance to infections or an abnormal portal of entry for organisms to reach the nervous system.

When managing a patient with possible meningeal inflammation, the first step is to confirm the diagnosis and the second is to start appropriate therapy (even before the results of the Gram's stain are available) selected on the basis of an educated guess as to the most likely organism. One has also to consider why this patient developed this infection at this time.

Meningitis may present as an acute, subacute, chronic, or recurrent inflammation of the meninges. It is classed as bacterial (or septic or purulent) when organisms are isolated by routine culture methods. With bacterial infection, polymorphonuclear leukocytes predominate in the CSF. Viruses usually cause an aseptic meningitis in which mononuclear cells predominate and routine cultures do not grow the organism.

Certain pathologic conditions consistently predispose to CNS infections (meningitis, abscess, and encephalopathy) and they must be considered in all patients, if not in the acute stage at least immediately after it. Thus immunosuppressed patients (those with leukemia, lymphoma, or acquired immunodeficiency syndrome [AIDS]; those receiving immunosuppressive drugs including steroids; or after splenectomy) are at risk of infection by measles, herpes zoster, cytomegaloviruses (CMVs), fungi, streptococci, Listeria, or gram-negative bacilli. Skull defects and cranial trauma, including brain surgery, make pneumococcus, staphylococcus, and gram-negative infections more likely. Progressive multifocal leukoencephalopathy is always associated with impaired immune responsiveness, and toxoplasmosis is a common infecting agent in patients with AIDS.

In children, prematurity, perinatal complications, and neural tube defects are predisposing factors for meningitis, which in such cases is usually due to gram-negative organisms.

[edit] Acute Meningitis

Acute meningitis is a neurologic emergency. It is most common in the earliest years of life, particularly in premature infants, of whom up to half may die as a result. The peak incidence is in the first 2 years and about three fourths of all cases occur before the age of 10. The death rate in older patients has decreased to about 20%, but continuous developments in therapy do not seem to have lowered it further. H. influenzae vaccine has almost eliminated this agent as a cause of childhood meningitis.

[edit] Acute Bacterial Meningitis

[edit] Clinical Features.

Acute meningitis evolves over hours or, at most, days. Patients who have been quite healthy or have only had an upper respiratory infection now begin to complain of the symptoms of meningeal irritation and of raised intracranial pressure (ICP). Malaise; fever; headaches of traction type; nausea; vomiting; anorexia; stiff, painful neck; and photophobia are the usual initial symptoms. Depression in the level of consciousness, delirium, seizures, and various focal neurologic signs may follow. The association of fever and any form of mental deterioration must make one consider meningoencephalitis as a possible diagnosis. Inflammatory cells in the CSF and accompanying cerebral edema may cause a rapid rise in ICP and produce false localizing signs.

Examination usually shows meningism, with stiff neck and resistance to flexion of the spine or to straight leg raising. Such signs may be absent in overwhelmingly ill adults and in neonates, who may just show the features listed in Box 165-2, such as a bulging fontanelle, neck stiffness, and drowsiness. Children may also show head retraction, which can be so marked as to warrant the term opisthotonos.

Box 165-2 - Signs of Meningitis in Infants and Children✢

Neonates Fever Lethargy Anorexia Vomiting Respiratory distress Convulsions Irritability Jaundice Bulging fontanelle Older Infants Fever Vomiting Irritability Drowsiness Convulsions Bulging fontanelle Over Age 2 Fever Drowsiness Headache Stiff neck Vomiting Convulsions ✢From Mandell GL, Bennett JE, Dolin R, editors: Principles and practice of infectious diseases, ed 4, New York, Churchill Livingstone, 1995.

General examination may show a rash (particularly if the meningococcus is involved or echovirus or coxsackievirus is involved); signs of infection in the ears, joints, bones, chest, or heart; and sometimes purpura and hypotension. Shock is common if a gram-negative organism is the cause of septicemia with secondary meningitis and in meningococcal septicemia causing adrenal infarction (WaterhouseFriderichsen syndrome). The combination of fever and purpura in this context can occur with N. meningitidis, echovirus, E. coli, Pseudomonas, Proteus, L. monocytogenes, streptococcus, gonococcus, or Staphylococcus aureus infections.

[edit] Evaluating the Cerebrospinal Fluid.

Whenever there is evidence of meningeal inflammation, a lumbar puncture (LP) must be done eventually, even though some patients with meningitis show early papilledema. Intracerebral abscess or expanding mass lesions, particularly in the posterior fossa, must be ruled out by physical examination, although in the presence of any focal signs an emergency computed tomography (CT) scan is necessary. In this situation an expert opinion should be requested if available. LP should be performed when any such masses are excluded because identification of the organism and determination of its sensitivities are essential; however, if a bacterial process is suspected, antibiotics should be started as soon as blood cultures are drawn and before an LP is done. A patient may be transferred to specialist care from remote areas, with the CSF sample kept warm beside him or her and after the first dose of antibiotic. In infants, LP is indicated in the investigation of pyrexia of unknown origin and may be indicated in any ill child with fever or septicemia, with or without neurologic signs and in the investigation of failure to thrive or seizures.

If the result of the first LP is not conclusive (i.e., no organisms are seen and the cells present are not polymorphonuclear neutrophil leukocytes [PMNs]) the patient can be carefully observed for a period without antibiotics and the test repeated in 12 to 18 hours with a greater chance of finding organisms or diagnostic cell patterns.

The CSF pressure need not be taken if the initial fluid is cloudy or bloodstained because knowledge of the pressure does not contribute to diagnosis in these circumstances. The fluid may be turbid or clear; microscopy may show any number of mononuclear or polymorphonuclear cells. PMNs almost always predominate in acute bacterial meningitis. Mononuclear cells usually predominate in the other forms of meningitis (due to Mycobacterium tuberculosis, viruses, or fungi).

CSF protein levels are raised in all forms of meningitis, particularly those of longer duration or with very high cell counts. Apart from Gram's and Ziehl-Neelsen stains, auramine stains for M. tuberculosis, India ink preparations for fungi, special stains for other organisms, and specific antigen or antibody studies may be needed. The sample should be examined immediately. Many of the above tests are being replaced by DNA amplification techniques. Current polymerase chain reaction (PCR) technology (using the LightCycler) can identify the causative organism within 30 minutes. In many instances a physician will have to rely on the conventional Gram's stain, and occasionally may have to do this personally (Boxes 165-2 and 165-3).

Box 165-3 - How to Do a Rapid Gram's Stain

A rapid Gram's stain can be performed by drying and fixing the centrifuged deposit of CSF and staining it with fresh gentian violet for 2 seconds and Gram's iodine for 2 seconds. The sample is then rinsed in water. 95% ethyl alcohol is dripped onto the slides until the gentian violet is completely eluted (up to 3 seconds), and the slide is then rinsed in water, counterstained with 2% safranin O or carbol, fuchsin for 3 seconds, and then again rinsed in water. (Use fresh reagents with little or no precipitated granules of gentian violet.)

A simultaneous estimation of the CSF blood sugar is mandatory when the LP is done. With most viral meningitides and parameningeal foci of infection, CSF sugar values are often normal. Values will be low (i.e., less than 50% of the blood level) in bacterial meningitis. High PMN counts are to be expected in all cases—over 50,000/mm³ if the meningitis is due to rupture of an abscess.

If there is clinical uncertainty as to whether the patient has bacterial or aseptic meningitis and the patient is not seriously ill, the physician may properly maintain careful observation, withhold antibiotics, and repeat the LP in 12 to 18 hours. With aseptic meningitis, the second CSF sample will almost always show a shift toward mononuclear cell predominance, whereas later examinations will show the eventual disappearance of all PMNs. In bacterial meningitis, PMNs increase quickly, CSF sugar falls, and the protein level rises (Box 165-4).

Box 165-4 - When to Suspect Meningitis

Immediate referral to a specialist is necessary in the following circumstances: When a patient has both fever and meningism Ill patients with a petechial rash or impaired consciousness Adults with the combination of fever and seizures Babies with fever and a bulging fontanelle, especially if they have been vomiting; dehydration would normally lead to depression of the fontanelle, and bulging now indicates intracranial pathology Patients with fever who have been in contact with persons with meningococcal infection

[edit] Organisms.

Specific organisms that cause meningitis may be suspected from certain clinical features. Thus (apart from the clinical features of meningitis in general) meningococcal meningitis has a peak appearance between the ages of 2 and 25, tends to occur in epidemics (Table 165-1), and may lead to disseminated intravascular coagulation, a purpuric skin rash, and shock from adrenal hemorrhage. Pneumococcal meningitis is mainly a disease of adult life, with a peak incidence in old age. It is particularly common in subjects with an obvious focus of infection elsewhere (e.g., ears, chest, recent skull fracture with CSF leak, or ear, nose, and throat [ENT] operation), in patients with immunologic deficiency, and in alcoholics. H. influenzae infection is common in children up to the age of 2 years in countries in which the vaccine is not used, but it is far less common after the age of 6 years. Patients have often had recent otitis or upper respiratory infection. Adults infected with H. influenzae are likely to have otitis or another parameningeal infection, a CSF leak, or immunologic deficiency.

Table 165-1 Occurrence of Organisms in Bacterial Meningitis in Adults✢

From Mandell GL, Bennett JE, Dolin R, editors: Principles and practice of infectious diseases, ed 4, New York, 1995, Churchill Livingstone.

Organisms	%
N. meningitidis	30-40
H. influenzae	5
S. pneumoniae	40-50
Other organisms	10

✢In about 10% of cases, usually caused by prior antibiotic treatment, no organism can be cultured.

Staphylococcal and gram-negative meningitis are usually complications of endocarditis or prior head trauma. In such cases the CSF may not show many leukocytes and may be sterile; a blood culture is mandatory in all cases of meningitis, however, so the correct diagnosis should not be missed. L. monocytogenes infections occur in neonates, the elderly, and patients with compromised host defenses. The abrupt onset of signs suggesting meningitis, encephalitis, or abscess in such patients should make one consider this organism. In the first 3 months of life, other commonly responsible organisms include streptococcus (group B), S. aureus, E. coli, and other Enterobacteriaceae.

[edit] Management.

Urgent management of bacterial meningitis is vital because severe cortical damage or death can result from delay. Blood cultures should be obtained and any skin lesions swabbed before the antibiotic is started. Having obtained the CSF, the physician should hold it up to the light to see if it is cloudy (over 500 cells/ml) or clear, and then take it to the laboratory, where a Gram's stain, culture, cell count, and differential should be performed and the protein and sugar levels estimated. Virus cultures and cytology might be indicated if septic meningitis is excluded by these tests.

Antibiotics should be started at once if the CSF is cloudy and bacterial infection is suspected. In many instances the physician won't know the exact organism until the cultures return, but treatment cannot be delayed that long. Unless clinical clues suggest one particular organism, the patient should begin an empirical regimen likely to be effective against the most common organisms (Table 165-2). The smear will indicate the type of organism responsible and thus the correct therapy. If meningococcal meningitis is suspected, intravenous benzylpenicillin should be given even before the patient is transferred to the hospital; the organism may still be grown from the CSF, and this is no time for diagnostic niceties.

Table 165-2 Treatment of Meningitis of Uncertain Etiology in Adults✢

From Mandell GL, Bennett JE, Dolin R, editors: Principles and practice of infectious diseases, ed 4, New York, Churchill Livingstone, 1995.

Antibiotic	Dosage
Ampicillin	1 gm intravenously every 3 hours
Ampicillin and chloramphenicol†	1 gm intravenously every 6 hours
Penicillin	1-2 megaunits intravenously q2h
Penicillin and sulfadiazine	2-4 gm intravenously stat and every 6 hours
Penicillin and chloramphenicol	1 gm intramuscularly or intravenously every 6 hours

✢What to give until the cultures come back.

†The authors' preference.

For the choice and doses of antibiotics commonly used to treat meningitis see Table 165-3. Seventy-five percent of adult cases of meningitis will be due to meningococcus or pneumococcus organisms. Penicillin-resistant D. pneumonia is now common in many countries, including the United States and Canada. This has changed our approach to the empiric treatment of meningitis. In children, when Haemophilus infection is at all likely, the treatment plan must take into account the occurrence of ampicillin-resistant strains. The antibiotics usually used against each organism are listed in Tables 165-4 and 165-5.

Table 165-3 Doses of Antibiotics Commonly Used to Treat Meningitis

From Mandell GL, Bennett JE, Dolin R, editors: Principles and practice of infectious diseases, ed 4, New York, Churchill Livingstone, 1995.

Drug	Child✢	Adult
Aqueous penicillin G†	50,000-75,000 units/kg every 4 hours	3-4 megaunits intravenously every 4 hours
Ampicillin†	200-300 mg/kg/day in 4-6 doses intravenously	2 gm intravenously every 4 hours
Cloxacillin‡	40 mg/kg intravenously every 4 hours	2 gm intravenously every 4 hours
Cefotaxime	50 mg/kg intravenously every 8 hours	2 gm intravenously every 6 hours
Ceftriaxone	75 mg/kg loading dose; then 50 mg/kg every 12 hours	2 gm every 12 hours
Ceftazidime	50 mg/kg every 8 hours	2 gm every 12 hours
Chloramphenicol	25 mg/kg every 6 hours (not in neonates)	1-2 gm intravenously every 6 hours to a maximum of 6 gm/day
Gentamicin	1.5 mg/kg intravenously every 8 hours

✢Different doses will be needed in neonates.

†If the patient is allergic to penicillin, use chloramphenicol.

‡Vancomycin should be used in patients allergic to penicillin.

Table 165-4 Initial Antibiotic Therapy for Suppurative Meningitis of Unknown Cause

Patient group	Suspected pathogen	Preferred therapy	Alternative therapy
Neonate (1 month or younger)	Group B streptococci, E. coli, Listeria	Ampicillin plus cefotaxime	Ampicillin and gentamicin
Child	S. pneumoniae, H. influenzae	Ampicillin plus cefotaxime or ceftriaxone plus dexamethasone	Chloramphenicol plus gentamicin plus dexamethasone
Adult	N. meningitidis, S. pneumoniae,H. influenzae, Listeria	(Ampicillin or penicillin G) plus ceftriaxone	Chloramphenicol or cefotaxime
Adult or child resident in a community with >2% high level (≥2 μg/ml) penicillin resistant S. pneumoniae	Penicillin resistant S. pneumoniae, N. meningitidis	Vancomycin plus cefotaxime or ceftriaxone	Possible meropenem
Immunocompromised adult (e.g., older than 60, with cirrhosis or neoplastic disease)	Listeria, Pseudomonas, S. pneumoniae, N. meningitidis	Cefotaxime plus ampicillin	Trimethoprim-sulfamethoxazole (TMP-SMX) plus chloramphenicol
Postcraniotomy patient	Staphylococcus aureus, Staphylococcus epidermidis,Pseudomonas, Enterobacteriaceae	Nafcillin plus cefotaxime plus gentamicin	Vancomycin and cefotaxime and gentamicin
	H. influenzae	Cefotaxime or chloramphenicol	Ampicillin only if isolate is susceptible
	N. meningitidis	Aqueous penicillin G or cefotaxime	Chloramphenicol
	E. coli, Klebsiella, Proteus, and similar organisms	Gentamicin plus cefotaxime	Chloramphenicol
	Pseudomonas	Ceftazidime plus gentamicin	—

Table 165-5 Adjunctive Therapy for Bacterial Meningitis

Therapy	Comments
Dexamethasone 0.15 mg/kg every 6 hours for 4 days	Best studied in children with meningitis. Resulted in decreased incidence of sensorineural hearing loss and other neurologic sequelae
Control of increased intracranial pressure (ICP)	Patients with signs of increased ICP may benefit from insertion of an ICP measuring device and treatment of the ICP
Plasmapheresis	Has proven useful in fulminant meningococcemia
Supportive care	Meticulous attention to fluid and electrolyte balance, high index of suspicion for complications such as subdural empyema
Eradication of nasopharyngeal carriage of N. meningitidis and H. influenzae	Mucosal colonization may persist despite successful treatment of the meningitis; rifampin should be given to eradicate this colonization

Chloramphenicol and the sulfonamides always cross the blood-brain barrier, whereas penicillin and cephalosporins cross well only when there is inflammation of the meninges. Even with inflammation, however, penetration into the CSF is poor with tetracyclines, streptomycin, kanamycin, gentamicin, polymyxin, and colistin. Thus the choice of agents is crucial. The dose should be arrived at by consideration of the severity of the infection and the age of the patient.

Gram-negative meningitis in adults usually complicates trauma, surgery, spinal anesthesia, or chronic debilitating diseases, but is uncommon. Pseudomonas is the organism most often cultured. Ciprofloxacin, 400 mg every 6 hours intravenously, is probably the best agent, but all such cases should be referred to a specialist in infectious diseases.

The duration of antibiotic therapy varies with the organism, the age of the patient, and the clinical course but is usually at least 10 days (2 weeks with pneumococcal infections). Isolation of patients with undiagnosed or meningococcal disease is wise for the first 24 hours after treatment is started.

Steroids are recommended as adjunctive therapy in patients with meningitis who are in a coma or who have markedly raised ICP, and in children with H. influenzae meningitis, in whom there is evidence that deafness can be prevented.

Prophylaxis should be used for all household contacts and others closely associated with patients suffering from meningococcal disease (e.g., children in the same nursery school). Rifampin, 600 mg bid for 2 days, is a recommended treatment for adult contacts, whereas in children the dose is 10 mg/kg bid, and in infants 3 months to 1 year of age, 5 mg/kg bid. Prophylaxis is also recommended in contacts of cases of H. influenzae meningitis; rifampin is recommended at a dosage of 20 mg/kg/day (not to exceed 600 mg/day) for adults and children in households or day care centers containing children 4 years of age and younger. The index case should also receive rifampin at the end of the definitive course of treatment. Vaccination against meningococcal disease is also available and is an important public health measure. At diagnosis, the public health service should be informed of all cases of meningitis.

[edit] Acute Aseptic Meningitis

[edit] Clinical Features.

Acute aseptic meningitis is characterized by fever, headache, and meningeal signs. Change in consciousness and localizing neurologic signs are rare. Patients with this disease look and feel wretched but are not severely ill. CSF examination will usually show an increase in mononuclear cells to fewer than 500/mm³ (although PMNs may be increased in the early stages); the protein is normal or only slightly elevated, and the CSF sugar is usually normal, except with mumps infection.

As can be seen from Box 165-5, 70% of the known causes of aseptic meningitis are common viral infections (coxsackievirus, echovirus, Epstein-Barr virus, mumps, and lymphocytic choriomeningitis [LCM]). In about 25% of the cases the virus is not defined. The remaining long list of viruses identified includes measles, chickenpox, and influenza. Rarely, the clinical picture of aseptic meningitis may be seen in the preicteric stage of infectious hepatitis or in uremia and in patients with inadequately treated bacterial meningitis.

Box 165-5 - Causes of Aseptic Meningitis✢✢

Common Viral Causes† Mumps Coxsackievirus Lymphocytic choriomeningitis Echovirus Epstein-Barr Less Common Viral Causes Measles Rubella Chickenpox Herpes simplex Influenza Inectious mononucleosis Arbovirus Encephalomyocarditis Behçet's disease Polio Nonviral Causes Tuberculosis Brucellosis Syphilis Lyme disease Leptospirosis Fungi Parameningeal infections (e.g., intracerebral, epidural abscess) Mycoplasma Infectious hepatitis Bacterial endocarditis Bacterial meningitis, inadequately treated Noninfectious Causes Chemical meningitis Collagen-vascular disease Malignancy ✢Routine cultures negative.✢From Mandell GL, Bennett JE, Dolin R, editors: Principles and practice of infectious diseases, ed 4, New York, Churchill Livingstone, 1995.†70% of causes.

[edit] Management.

Management of acute septic meningitis requires only analgesics and reduction in fever; the prognosis here is much better than in bacterial meningitis—the patient is seldom as ill and usually recovers readily. One may attempt to identify the virus by culture of the CSF or by PCR. A chest radiograph, tuberculosis skin test, syphilis serology, blood cultures, and a collagen-vascular screen are commonly ordered. A CT scan may be required to rule out a parameningeal focus. Acute and convalescent antibody titers may implicate enteroviruses or other viruses, but usually no agent is incriminated.

[edit] Subacute Meningitis

Inadequately treated bacterial meningitis, fungal infections, and tuberculous meningitis (TBM) are the more common causes of subacute meningitis; viral causes are much less common. TBM is the prototype and will be discussed at greatest length.

[edit] Tuberculous Meningitis.

Tuberculosis is most likely to occur in North America among the native and immigrant populations, among alcoholics, and in those patients with immunologic deficiency or generalized illness. A third of the cases occur before the age of 10. About half of the patients will be known cases of tuberculosis. The illness usually occurs in the active stage of primary infection but may present years later. Tuberculin skin tests are positive in 85% of cases. The organism may be recovered in the sputum as well as from CSF.

[edit] Clinical Features.

Moderate but increasing signs of meningeal inflammation develop over days or weeks. Children present with lethargy, failure to thrive, anorexia, irritability, nausea, and vomiting. In adults, similar symptoms lead to a mild and gradual reduction in consciousness, with confusion and headaches, occasionally seizures, but only moderate evidence of meningeal irritation. Symptoms may have been precipitated by an initial flulike illness or measles.

If untreated, there occurs the slow but relentless progression of extraocular palsies, deafness, cerebellar signs, convulsions, optic atrophy, pupillary abnormalities, delirium, and possibly dementia. In the latest stages decerebrate rigidity occurs. The CSF contains mononuclear cells mainly, up to 500/mm³; the protein is high and the sugar is low.

Unusual presentations include a single seizure in infants and children, isolated focal neurologic signs, the picture of acute meningitis, transverse myelopathy, or a preponderance of psychiatric symptoms in adults. Complications include blindness, deafness, hydrocephalus, spinal block, hypothalamic abnormalities, focal signs from persistent arachnoiditis, and cortical damage caused by subpial vasculitis and predisposing to seizures.

The lesion is essentially a basal meningitis with secondary vasculitis. An accumulation of purulent cellular infiltrate over the inferior surface of the brain and brainstem, blocking CSF flow through the fourth ventricle roof foramina, is responsible for the nerve palsies and raised ICP. In meningococcal and pneumococcal meningitis the purulent material is seen over all of the brain surface.

[edit] Cerebrospinal Fluid Studies.

In subacute meningitis, laboratory studies of CSF find large numbers of lymphocytes and elevated protein levels. In TBM, PMNs may predominate in the early stages, and the glucose level is almost always depressed, even to zero. The chance of finding the organism varies with the time taken looking for it on the Ziehl-Neelsen smears. PCR has revolutionized the diagnosis of TBM. Other causes of lymphocytic meningitis are listed in Box 165-5.

[edit] Treatment.

TBM can be treated successfully in almost all cases if therapy is started before the patient becomes unconscious. The generally accepted antibacterial regimen consists of quadruple therapy, with isoniazid, rifampin, pyrazinamide, and ethambutol (Table 165-6).

Table 165-6 Treatment of Tuberculous Meningitis in the Adult

From Mandell GL, Bennett JE, Dolin R, editors: Principles and practice of infectious diseases, ed 4, New York, Churchill Livingstone, 1995.

Drug	Dosage
Isoniazid✢	10-20 mg/kg/day orally up to 300 mg/day
Rifampin	10 mg/kg/day orally (usual dose 600 mg/day)
Ethamutol	25 mg/kg/day orally for 2 months; then 15 mg/kg/day orally
Pyrazinamide	25 mg/kg/day up to 2.5 gm/day maximum

✢The usual regimen comprises isoniazid and two of the three other drugs listed. Pyridoxine, 40 mg daily, should be added to prevent neuropathy caused by isoniazid.

There is disagreement about the use of intrathecal therapy, particularly with antibacterial agents, but it is a good general rule not to inject anything into the intrathecal space if possible. Perhaps the use of steroids intrathecally in TBM is an exception, because this tends to reduce the fibrotic reaction that may block CSF pathways as healing takes place. However, as better antituberculous agents are developed, the need for intrathecal steroids is decreasing.

[edit] Cryptococcal Meningitis.

Cryptococcal meningitis also has an insidious onset, with evidence of a confusional state, focal signs, and raised ICP. Although a smoldering meningitis is the usual presentation, abscesses may form. This condition also occurs in those with immunologic deficiencies, AIDS, diabetes, or chronic alcoholism.

A clinical point of interest in cryptococcal meningitis is the prolonged and severe nature of the headache that precedes cranial nerve palsies, meningism, or increased ICP. The sequential loss of cranial nerve function may be both dramatic and devastating. Diagnosis may be made with India ink–stained CSF preparations, but cryptococcal antigen should be detected in the blood and CSF.

Treatment is with amphotericin B, 0.6 mg/kg/day intravenously to a total dose of 2.5 gm with oral 5-fluorocytosine, continued for 6 weeks. Patients with AIDS need long-term suppressive treatment with fluconazole.

[edit] Other Causes.

Secondary syphilis, brucellosis, sarcoidosis, and infiltration of the meninges by carcinoma, lymphoma, larval cysts, or fungi are uncommon causes of a similar subacute syndrome.

The term meningismus refers to the condition of meningism without any actual infection of the meninges. Tonsillitis, cervical adenitis, pyelonephritis, and lobar pneumonia are common causes. Other sources of meningeal irritation include blood in the CSF from any cause: otitis, sinusitis, spinal osteomyelitis, and epidural abscess (all parameningeal foci).

[edit] Chronic Meningitis

Chronic meningitis is uncommon, although it is produced by the same organisms that cause subacute meningitis. The characteristic symptoms include mild fever, headache, depression, lethargy and malaise, and subtle personality change progressing to confusion. Signs include meningism and, frequently, cranial nerve palsies and evidence of raised ICP.

The CSF may show a persistent lymphocytosis with high protein and low glucose levels. In such cases viruses, fungi, bacteria (including leptospira, treponema, and acid-fast bacilli), or malignant cells have variously been found. In sarcoidosis, a chronic basal meningitis may cause focal neurologic signs and, rarely, hydrocephalus, cranial nerve palsies, paraplegia, optic atrophy, or seizures. Meningeal carcinomatosis and leukemias cause headaches and cranial nerve palsies, but seldom long tract signs.

The appropriate treatment of chronic meningitis depends, naturally enough, on its cause and will not be detailed here.

[edit] Chronic Spinal Arachnoiditis.

Chronic spinal arachnoiditis is a variant of chronic meningitis. It usually follows intrathecal injection of contrast media, steroids, anesthetics, or antibiotics, but spinal injury or surgery, prolapsed intervertebral disks, and numerous infections (e.g., tuberculosis, syphilis, or viral) have also been held responsible. The thickened meninges, usually in the lumbar region, entrap the nerve roots, causing bilateral burning leg pain at many root levels and local backache. Signs of multiple root lesions are usually detectable, and there may be loss of bladder function. If symptoms begin acutely after spinal surgery, fever may also occur.

Myelography (even though suspected to be a cause) and magnetic resonance imaging (MRI) scanning will confirm the diagnosis. Treatment is surgical, but it is not very effective and the condition tends to recur.

[edit] Recurrent Meningitis

Recurrent acute or subacute meningitis should lead one to search for the reason why repeated infections have involved the CNS. Although spontaneous repeated infection by different organisms is possible, some defect opening up a pathway allowing organisms to penetrate the nervous system is far more likely. In such cases a midline sinus running to the meninges from the upper respiratory tract or from the skin of the head, neck, or spine should be carefully sought, possibly using a magnifying glass. Chronic mastoiditis, sinusitis, agammaglobulinemia, and immunodeficiency syndromes are other possibilities. The condition may occur after splenectomy, in infancy, and also in association with skull fractures, particularly if there has been CSF leakage. Pneumococcus is the most common organism cultured.

[edit] Differential Diagnosis of Meningitis

Acute meningitis may be mimicked by subarachnoid hemorrhage, encephalopathy of bacterial endocarditis, malignant hypertension, lead poisoning, porphyria, migraine, or viral encephalitis. It may also be hard to differentiate bacterial meningitis from autoallergic acute postinfectious (disseminated) encephalomyelitis (described below). Cerebral abscesses usually have a less acute onset, but thrombophlebitis in association with chronic mastoid or sinus infection and the toxic encephalopathy associated with bacterial endocarditis may present similarly, except that focal signs and evidence of increased ICP are usual in all of these latter conditions.

Certain causes of endarteritis, such as collagen-vascular disease, may also present a similar but milder picture, as may slow virus infections, neoplasms seeding throughout the CSF, and local infections such as spinal osteitis or cranial osteomyelitis (parameningeal foci).

Subacute or chronic meningitis can be confused with cerebral tumor, subdural hematoma, a rapidly progressive dementing illness such as Creutzfeldt-Jakob disease (CJD), or the paraneoplastic encephalopathy of carcinoma.

[edit] Complications of Meningitis

In patients who recover from meningitis there may be evidence of significant focal residua caused by bacterial vasculitis, cortical infarction, or hydrocephalus. Seizures occur in 10% of those recovering. In infants, subdural effusions and deafness may be associated with H. influenzae and pneumococcal infections, whereas acute or chronic obstructive or normal pressure hydrocephalus may follow meningitis from any cause. Obstructive hydrocephalus is particularly common with TBM, as are deafness or other lower cranial nerve palsies, which occur in 15% of patients with meningitis. Hypothalamic damage and optic atrophy are much less common, except in chronic basal meningitis (Fig. 165-1).

Small infants and children who recover from meningitis may show signs of cerebral palsy, and such upper motor neuron signs may occur temporarily in adults recovering from severe meningitis. Because of the dangers of serious neurologic impairment, early diagnosis and appropriate specific therapy are essential to prevent such tragedies.

[edit] ENCEPHALITIS

Infection of the brain parenchyma is most commonly viral. When the infection is bacterial, the condition is known as cerebritis, which may progress to abscess formation. Viral encephalitis may be widespread or focal. Both DNA and RNA viruses may be responsible, certain viruses in each group having a particular affinity for the nervous system. These neurotropic viruses include polio, rabies, herpes zoster, and arboviruses. Viruses that are usually nonneurotropic but that sometimes still involve the nervous system include herpes simplex, mumps, measles, coxsackievirus, echovirus, CMVs, and Epstein-Barr virus. Finally, measles, the papovaviruses, and perhaps others may give rise to slow virus infections. Other organisms causing encephalitis are listed in Box 165-6.

Box 165-6 - Causes of Encephalitis✢

Viruses Sporadic Herpes simplex✢ Herpes zoster Monkey B Cytomegalovirus Epstein-Barr (mononucleosis)✢ Mumps✢ Lymphocytic choriomeningitis✢ Rabies Human immunodeficiency virus Epidemic Arboviruses (California, E✢ and W equine, St. Louis) Enteroviruses (polio, coxsackievirus, and echovirus) Measles✢ Slow viruses Bacteria, rickettsiae, and spirochetes Bacterial endocarditis Cerebritis (early cerebral abscess) Syphilis Coxiella burnetii Fungi Cryptococcus neoformans Histoplasmosis Aspergillosis Protozoa and Metazoa Malaria Toxoplasmosis Amoebas (Naegleria, Acanthamoeba) Echinococcus, cysticercosis, and trichinosis Schistosomiasis, trypanosomiasis Possible viral Encephalitis lethargica Behçet's syndrome Encephalomyocarditis ✢From Mandell GL, Bennett JE, Dolin R, editors: Principles and practice of infectious diseases, ed 4, New York, Churchill Livingstone, 1995.✢The more common conditions in North America.

In the following discussion, the classical picture of encephalitis in general and that caused by herpes simplex in particular will be discussed. Other viral infective syndromes will be mentioned in brief. Most of the viruses causing encephalitis cannot be clinically differentiated, however, and specific identification techniques are needed to determine which virus is involved.

[edit] Typical Encephalitis

[edit] Causative Organisms.

Arboviruses are found in ticks and mosquitos. They include Eastern and Western equine, Venezuelan, St. Louis, Japanese B, Powassan, California, La Crosse, Jamestown Canyon, Snowshoe hare, Rift Valley, and Orbivirus 1 agent of Colorado tick fever. Enteroviruses such as polio, coxsackievirus, and echovirus, and the viruses responsible for rubella, measles, chickenpox, mononucleosis, mumps, viral hepatitis, and influenza can all produce a more or less similar clinical picture because of direct parenchymal invasion of the nervous system and the subsequent antibody reaction.

In North America, herpes simplex, enteroviruses (polio, echovirus, and coxsackievirus), and arboviruses are the most common causative agents, with LCM and mumps the next most frequently identified causes. The prognosis in mumps and LCM is excellent, but arbovirus and herpes simplex infections are sometimes lethal or result in severe sequelae. Epstein-Barr virus is another cause of encephalitis, especially in younger subjects.

Enteroviral infection is most common in the summer months; the arbovirus infections spread by ticks occur mainly in the spring and those by mosquitos in the late summer. Mumps is the most common cause of encephalitis in the earlier part of the year, whereas LCM is more common in the fall and winter. During the great influenza pandemic of 1917, many patients developed the syndrome of von Economo encephalitis characterized by marked drowsiness (sleeping sickness), which often developed years later into a form of Parkinson's disease with oculogyric crises. It is not certain whether such an illness still exists sporadically because the virus was never isolated.

In North America, arboviruses other than St. Louis and Eastern and Western equine (see Box 165-3) are rare indeed, as are protozoal and metazoal infections. Bacteria, meningovascular syphilis, and fungi cause encephalitis usually only in association with frank meningitic signs. Although herpes and other arbovirus infections are often exceedingly severe, most other viruses produce a milder illness. Tertiary neurosyphilis smolders to produce the features of general paresis or tabes or meningovascular syphilis. Obviously many of the causative agents listed are unlikely causes of encephalitis in, for example, Eastern Canada, but one always must ask about visits a patient may have made to another country in these days of frequent air travel.

[edit] Clinical Features.

Typical features of encephalitis include fever, meningism, and signs of raised ICP. Reduction in consciousness level from drowsiness to coma, seizures that are often focal, and various other focal signs also occur, depending on which areas of brain are affected by the inflammatory process. As with cerebral abscesses, the combination of fever and meningism with evidence of cerebral dysfunction, either generalized (delirium, seizures, coma) or focal (hallucinations, hemiparesis, and so forth) must make one consider encephalitis.

Major pathologic features include edema and petechiae within the brain, with mononuclear perivascular cuffing and neuronal degeneration, mainly in the grey matter, cortex, and deep nuclei of the brainstem.

[edit] Differential Diagnosis.

The list of differential diagnoses is rather long. Any form of meningitis may be accompanied by evidence of cortical inflammation. Abscesses, septic emboli, cortical septic thrombophlebitis, and postinfectious and toxic encephalopathies may be hard to distinguish from encephalitis; all are described here. Subdural and subarachnoid hemorrhage, bleeding into a tumor, porphyria, poisoning, and even multiple sclerosis can produce encephalopathy with meningism and sometimes fever.

Encephalopathy without actual invasion of the brain substance occurs with bacterial endocarditis, pertussis, and typhoid. These cannot be differentiated by their neurologic signs from viral encephalitis, but other clinical findings may allow diagnosis.

[edit] Laboratory Findings.

CSF taken during the acute stage of encephalitis shows a moderate rise in protein and contains lymphocytes up to about 250/mm³. The sugar level is usually normal, except in mumps (and occasionally in herpes simplex virus [HSV] and LCM) encephalitis, when it is low, as it is in bacterial, fungal, and carcinomatous meningitis.

Specific laboratory diagnosis requires a fourfold increase in the level of viral antibody titers between acute and convalescent sera or virus isolation from the CSF or brain. Specimens must be frozen immediately after collection and shipped on dry ice to a laboratory for direct virus isolation, whereas acute and convalescent paired serum specimen can be sent unfrozen. If enterovirus infection is suspected, feces, CSF, or throat washings may be used for virus isolation. Throat washings and CSF are used for mumps identification, blood and CSF are used to detect LCM, and CSF or occasionally brain biopsy material is used to check for herpes simplex. Other viruses may be isolated from blood or CSF, and CMV can be found in the urine, saliva, or liver biopsy specimens. Cryptococcal or other fungal antigens may need to be sought as well. The heterophile test and tests for IgM antibody to viral capsid antigen should be positive in cases of Epstein-Barr virus encephalitis.

PCR is so sensitive for the diagnosis of herpes simplex virus encephalitis that brain biopsy is now rarely, if ever, necessary to diagnose this serious infection.

[edit] Treatment.

The treatment of encephalitis is improving. General measures include maintaining the patient's hydration and metabolic status, reducing fever, and preventing seizures. Antiviral agents are now available for treatment of herpes simplex (see below) and varicella-zoster forms of encephalitis.

[edit] Herpes Simplex Encephalitis

In North America, herpes simplex is the most common single cause of acute, sporadic, severe encephalitis. Both human and monkey types of herpesvirus occur, and both can cause severe neurologic infection, although the latter is usually seen only in laboratory workers or monkey handlers. Infections occur at any age, but particularly in the first three decades. Of the two serologic types of human herpesvirus, type I causes sporadic encephalitis and oral ulcers, whereas type II produces aseptic meningitis and genital ulceration. In adults, nearly all cases of herpes simplex virus encephalitis (HSVE) are caused by type I virus.

[edit] Clinical Features.

Herpes simplex encephalitis may have an acute or subacute onset. Typically, a few days of malaise, fever, headache, anorexia, nausea, and other nonspecific symptoms progress to a subtle change of personality, with evolving depression, paranoia, or abnormal behavior and confusion. Photophobia, signs of raised ICP, meningeal irritation, and focal signs appear next; the latter include hemiparesis, facial weakness, dysphasia, dysarthria, decerebrate rigidity, ocular palsies or nystagmus, seizures, and in the late stages stupor or coma. Although the whole brain is involved, the temporal lobes are particularly affected.

[edit] Laboratory Findings.

With herpes simplex encephalitis, the CSF shows an increase in pressure and protein levels; lymphocytes and red cells are often present. A characteristic electroencephalogram (EEG) pattern (diffuse, mainly temporal-region slow activity with periodic discharges) is described but is not specific. The CT scan may demonstrate swelling and enlargement of the temporal lobes (usually asymmetrically), although MRI scans show this even better. The specific methods of diagnosis are PCR of the CSF, fluorescent antibody staining, or culture of a brain biopsy specimen. Because of the mass effect of the lesion, LP may be dangerous and CT or MRI should be done first to rule out the presence of a pressure cone.

[edit] Treatment.

Acyclovir reduces mortality and morbidity if it is given early, and the low toxicity of this drug has led to its use empirically in most cases of acute, sporadic encephalitis. Acyclovir, 10 mg/kg given intravenously every 8 hours for 10 days, reduces mortality to about 20%; half of the patients completely recover.

Herpes simplex virus can also cause aseptic meningitis or a sacral plexopathy, with perineal numbness, impotence, and retention of urine and feces.

[edit] RABIES

The virus of rabies is introduced into the body through the bite of an infected dog, fox, vole, bat, or other wild animal (see Chapter 101 ). It travels centrally along peripheral nerves, producing a focal encephalitis that mainly involves the cervical cord, the brainstem, and the temporal lobes. The latent period between the bite and the clinical features of the disease may be as long as a year.

Clinically, early irritability and agitated delirium progress to muscle hypertonia, especially affecting the pharyngeal muscles, which go into spasm—hence the term hydrophobia. Convulsions and death usually occur within 10 days of the onset.

Human diploid rabies virus vaccine has been found to be strongly immunogenic, and its introduction is an important breakthrough in the prevention of rabies. Rabies immune globulin should be given as soon as possible after a bite. Usually, 50% of the dose is infiltrated at the bite site and the remainder is given intramuscularly.

[edit] ACQUIRED IMMUNODEFICIENCY SYNDROME

Infection with the human immunodeficiency virus (HIV) ultimately results in profound deficits in function of the immune system, predisposing the infected individual to severe opportunistic infections and to certain malignancies. In addition to the neurologic involvement caused by HIV itself, these patients are also susceptible to a variety of CNS infections. Ten percent of patients with AIDS present with neurologic problems, but these ultimately occur in at least 75% of cases.

Syndromes of encephalopathy, aseptic meningitis with cranial neuropathy, myelopathy, or multiple mononeuropathy may occur at the time of initial infection with the virus; recovery occurs within a week or so in most cases.

Toxoplasma encephalitis is the most common cause of mass lesions in the brains of patients with AIDS. Headache, confusion, lethargy, focal deficits, seizures, fever, and coma result; chorea, dystonias, myoclonus, and tremor are less common. Mass lesions in patients with AIDS are due either to such opportunistic infections or to tumors. A CT scan typically shows ring-enhancing lesions when toxoplasma, tubercular, candida, or CMV infection is present and with primary CNS lymphoma.

AIDS dementia is a manifestation of the subacute encephalitis that occurs in one third of HIV-infected patients, and it is accompanied by a host of neurologic signs. Apart from the major cognitive symptoms, such as forgetfulness, impaired concentration, confusion, and slowing of thought processes, signs such as apathy, organic psychoses, headache, depression, seizures, myoclonus, cerebellar and pyramidal deficits, neuropathy, and retinopathy are common.

Vacuolar myelopathy leads to paraparesis with spastic weakness, ataxia, and paresthesias in the legs. It is considered to represent the effect of direct HIV infection of the spinal cord.

Cryptococcal and tuberculous meningitis, CMV retinitis, toxoplasma chorioretinitis, herpes simplex myelitis, and spirochetal or viral encephalomyelitis are other frequent complications, as are progressive multifocal leukoencephalopathy, CNS lymphomas, and a painful symmetrical sensorimotor peripheral neuropathy. Again these entities are probably related to direct infection with the HIV virus.

AIDS remains a fatal disease, but prompt diagnosis and treatment of the opportunistic infections have prolonged survival. Toxoplasmosis is treated with pyrimethamine, 200 mg as a loading dose, then 50 to 75 mg daily, with sulfadiazine, 4 gm/day, or clindamycin. All patients who are treated with pyrimethamine or sulfadiazine should also receive folinic acid, 10 mg orally each day.

[edit] ABSCESS

Abscesses may occur in the epidural or subdural spaces or within the substance of the brain, in which case they are examples of suppurative bacterial encephalitis.

[edit] Epidural Abscess

[edit] Intracranial Epidural Abscess.

Intracranial epidural abscess is usually associated with a local skull fracture, osteomyelitis, or inflammation of the transverse or sagittal sinuses. The abscess is frequently situated over the convexity of the brain, and the clinical features are those of a generalized infection, of a local destructive lesion compressing the brain, and of raised ICP.

[edit] Spinal Epidural Abscess.

The usual organism found in spinal epidural abscesses is Staphylococcus aureus in the lumbar region or tuberculosis at thoracic levels. In tuberculosis, granulation tissue, pus, and the products of vertebral body and disk collapse to cause cord compression and local pain. Acute angulation (angular kyphosis) may result from the local infection and should be treated first by the usual antituberculous agents to render the contents of the abscess sterile; it can then be surgically drained, with later stabilization of the spine. Should the abscess cause neurologic signs, emergency surgical intervention will be required.

[edit] Differential Diagnosis.

Problems may arise in the differential diagnosis of acute lumbar spinal epidural abscess and acute transverse myelopathy that is usually of viral origin (and eight times as common). Both cause root pain in girdle distribution, stiff neck, marked muscle spasms, and local tenderness of the spine, with the usual neurologic deficit of paraparesis with a sensory level, fever, and increased cells and protein in the CSF. However, the erythrocyte sedimentation rate (ESR) is always high in epidural abscesses, but not necessarily with transverse myelitis. Evidence of block of CSF passage, radiographic findings of osteomyelitis of the appropriate vertebrae, recent bacterial infection elsewhere, and perhaps slower clinical development (so that the maximal deficit is not reached until the third or fourth day) are all factors in favor of epidural abscess. Transverse myelitis is also more common at thoracic levels and less so at lumbar levels. In children, transverse myelitis sometimes presents without any pain in the back.

[edit] Subdural Abscess (Empyema)

[edit] Causes.

The underlying cause in at least 80% of cases of subdural abscess is disease of the nasal sinuses or of the middle ear, whether by direct extension or as a result of thrombophlebitis leading to focal intracranial infection. Paranasal infection commonly results in frontal abscesses, and otitis causes posterior cerebral and cerebellar abscesses. Subdural abscesses also occur when a subdural hematoma or effusion (particularly if secondary to meningitis in infants) becomes infected, when a cerebral abscess ruptures into the subdural space, or after a penetrating wound.

[edit] Organisms.

The bacteria responsible for subdural abscesses are usually mixed aerobic and anaerobic streptococci, less commonly staphylococci, gram-negative cocci, or Clostridia. The disease occurs particularly between the ages of 10 and 20 years with paranasal infection and after the age of 40 with an otitic origin.

[edit] Clinical Features.

The usual features of subdural abscess include evidence of skull osteomyelitis (local tenderness, swelling, and cellulitis), systemic signs of infection, altered consciousness, headache, fever, meningism, and focal signs appropriate to the area of cerebral involvement. These patients are severely ill, and seizures of any type are common. The diagnosis is suggested by the findings of nasal sinus or middle ear infection in the presence of the above signs.

[edit] Laboratory Findings.

An EEG will show local slow wave activity, and plain skull radiographs may show sinus opacity or osteomyelitis (and sometimes a shift of the pineal gland). An enhanced CT scan localizes the abscess precisely.

[edit] Treatment.

The abscess should be surgically drained. Cloxacillin and metronidazole are recommended in the same regimen as for intracerebral abscess (see below), and the treatment should be continued for 1 month. The mortality rate in subdural abscess is about 10%; residual seizures and focal neurologic deficits are common, so anticonvulsants are routinely prescribed. Consultation and referral are mandatory to ensure timely and optimal treatment for all intracranial abscesses.

[edit] Intracerebral Abscess

[edit] Causes.

Over half of all cases of intracerebral abscess complicate an ear or paranasal sinus infection. Skull fractures, facial or dental infections, and congenital heart disease also predispose, and hematogenous spread of infection from chronic lung disease (bronchiectasis, lung abscess) is responsible for another 20%. The intracerebral abscess is truly a local purulent encephalitis and although it is usually single and well-localized to frontal or temporal regions when the infection extends from an adjacent source, multiple abscesses can occur with hematogenous spread (Fig. 165-2). This usually occurs in elderly patients, particularly those with diabetes, among whom multiple staphylococcal microabscesses are becoming more common.

Neonates, diabetics, immunocompromised patients, heroin and alcohol addicts, patients with prosthetic or congenitally damaged heart valves, and those with lymphomas are especially at risk. Immunocompromised patients may develop candidal abscesses with intracerebral vasculitis; they present with fever but few focal signs. In many patients the infection can be traced to endocarditis or other septic foci.

An abscess may spread directly or as a result of septic thrombophlebitis, in which the infected clot may extend backwards along a large vein to infect other areas of the brain. The organisms most frequently cultured include streptococci, staphylococci, klebsiella, proteus, bacteroides, pneumococcus, and anaerobic organisms.

[edit] Clinical Features.

The symptoms of intracerebral abscess may for a time be vague and nonspecific; they include fever, mild drowsiness, and headache, followed by evidence of focal brain destruction, meningism, and raised ICP. Seizures are particularly common with cerebral abscesses in the frontal, temporal, and parietal regions. Often there is little systemic evidence of sepsis, and the patient presents in lethargic delirium. However, cerebellar abscesses produce rapidly rising ICP and brainstem signs.

[edit] Diagnosis.

Diagnosis of an intracerebral abscess should be suggested by the clinical pictures of lung, ear, or sinus disease with signs of intracranial infection and seizures; meningitis with a focal deficit; stroke with fever; or raised ICP with no obvious cause. The EEG is invariably abnormal, with prominent focal slow waves. A CT or MRI scan will localize the abscess and will determine the degree of capsule formation. LP is potentially lethal.

[edit] Treatment.

Initial treatment consists of surgical aspiration of pus from the abscess cavity; this will allow identification of the organisms and use of appropriate intravenous antibiotics in high doses.

If the origin of the abscess is sinusitis, anaerobic streptococci will grow in culture and penicillin and chloramphenicol or metronidazole should be given to the patient. Otitic abscesses imply mixed organisms and will respond to gentamicin, as well as the above drugs. Traumatic abscesses usually yield staphylococci, for which cloxacillin is recommended. Multiple broad-spectrum antibiotic therapy is required for abscesses of metastatic origin; cloxacillin 12 g/day, with metronidazole, 500 mg every 8 hours, and a third-generation cephalosporin might be employed.

ICP is likely to be raised as a result of vasogenic edema around the abscess; steroids may be expected to help relieve it, but antibiotic treatment should be started before steroids are given. Patients who have recovered from an acute cerebral abscess frequently go on to have seizures. If it is likely that the abscess developed by hematogenous spread, congenital heart disease with a right-to-left shunt, pulmonary disease such as bronchiectasis, and sepsis elsewhere in the body must be excluded. The physician should look for needle marks and other signs of intravenous drug use; many younger patients use dirty syringes to mainline drugs.

Cerebral abscesses are serious emergencies and require rapid diagnosis so that antibiotic therapy can begin and surgical intervention is expedited. Even in these days of new antibiotics, steroids, and CT scanning, these abscesses still carry a 10% mortality rate.

[edit] OTHER NEUROLOGIC INFECTIONS

[edit] Herpes Zoster

The varicella-zoster virus is neurotropic. After many years of latency, it may be reactivated (by unknown mechanisms) and primarily affects the dorsal root ganglion cells of spinal nerves and the sensory ganglia of cranial nerves, certainly the gasserian (V) ganglion and perhaps the geniculate (VII). At the spinal level, the involvement is usually unilateral, and 75% of cases occur in the abdominal or upper thoracic regions. The virus occasionally attacks anterior horn cells of the spinal cord. Edema, monocytic infiltration, and perivascular cuffing with neuronal degeneration are seen histologically, with later fibrosis and secondary degeneration of the distal part of the nerve fiber.

Among elderly patients, recurrent herpes should put one on guard for the presence of an underlying malignancy, lymphoma, or immune deficiency syndrome. Chickenpox itself may be complicated by acute allergic encephalomyelitis (see below), polyradiculitis, and cerebellar ataxia.

[edit] Clinical Features.

With herpes zoster viruses, burning or shooting pain with local hyperalgesia within the affected dermatomes is followed in 3 or 4 days by a typical vesicular eruption that fades over the next few days, with scarring and depigmentation of the skin. Within the affected area the skin may be anesthetic but at the same time painful or itchy. Motor involvement may affect the face, eye, diaphragm, or limb musculature. Postherpetic neuralgia is exceedingly painful. During the acute phase, valacyclovir and famciclovir both reduce the rate of postherpetic neuralgia.

[edit] Herpes Zoster Ophthalmicus

Herpes zoster ophthalmicus may produce the feared complications of corneal damage and secondary infection. The eye should be treated immediately with topical idoxuridine. The region of the forehead and eye may be exceedingly painful at the time of diagnosis, and postherpetic neuralgia may follow. When herpes zoster attacks the VII nerve, the V nerve is often involved as well, which explains why there are vesicles in the auricle and inside the mouth. Intracranial CNS involvement is uncommon, but arteritis causing stroke, and meningoencephalitis do occasionally occur.

[edit] Cytomegalovirus

CMVs are members of the herpesvirus family. They may cause eye and brain damage in utero, and adults (especially if immunocompromised) may develop meningoencephalitis, retinitis, or polyneuropathy. Ganciclovir has been used to treat serious CMV infections.

[edit] Poliomyelitis

Poliomyelitis is still prevalent throughout much of the world, and children who have not been immunized in the most advanced nations are susceptible to infection. Thus primary care physicians must remain informed about its clinical presentation and acute management. The neurotropic poliovirus has three serotypes, of which type 1 is the most common. Spread from person to person is by fecal contamination. After entering the gastrointestinal (GI) tract, the virus passes into the blood stream to invade the nervous system. The incubation period is 7 to 14 days, and in nonimmunized populations the disease may be either epidemic or sporadic. Subclinical infection frequently occurs and produces immunity; this is also the basis of live virus immunization.

If the poliovirus invades the nervous system, a minor illness occurs, with headache, drowsiness, fever, and mild GI symptoms. The illness may stop at that stage, or after 1 or 2 days of apparent remission severe muscle pains, meningism, and delirium progress within 24 hours to sudden asymmetric or generalized paralysis (the paralytic form of the major illness). The muscles are tender, and fasciculations may be seen (and felt) in the earliest stages. After a week, some degree of improvement usually begins. Truncal and bulbar involvement may give rise to severe respiratory and bulbar paralysis that requires artificial ventilation and skilled nursing attention in an intensive care unit. The lower motor neuron lesions produced may eventually progress to contractures, trophic changes, failure of limb growth, and eventual joint disorganization.

A nonparalytic form of the major illness also occurs, with signs of meningoencephalitis (as in the paralytic form) but without anterior horn cell involvement.

[edit] Diagnosis.

In the earliest stages, the disease can only be easily diagnosed during an epidemic because the mild symptoms resemble many other nonspecific viral illnesses. A paretic illness can also be caused by other enteroviruses, in which case the prognosis is much better. Weakness may also occur in association with other inflammatory bone or joint diseases.

Other fast-advancing peripheral motor neuropathies include those caused by porphyria, Guillain-Barré syndrome, and polyarteritis nodosa. Lower motor neuron lesions seldom complicate other CNS infections, although mumps may rarely produce encephalomyelitis. Even in these days, however, the presence of an acute infective illness associated with signs of anterior horn cell involvement must always make one suspect poliomyelitis.

The development of new weakness, muscle atrophy, fatigue, and pain decades after acute poliomyelitis, accompanied by a mixed picture of active and chronic denervation on an electromyogram (EMG), suggests the diagnosis of postpolio syndrome. This condition appears to be due to the late death of neurones that regrew or sprouted after the initial illness, but the reason why they die at this late stage remains unknown.

[edit] Coxsackievirus

Although coxsackievirus infection may cause aseptic meningitis, epidemic myalgia (Bornholm disease) is a more common manifestation. In this condition, the sudden onset of acute chest pain, with severe tenderness of the intercostal muscles in one or more spaces and great difficulty in breathing because of pleuritic pain, frequently raises suspicion of pulmonary embolism, pneumonia, or even myocardial infarction. The pain may occur so acutely that patients sometimes fear that they may have had a heart attack. Very few systemic signs are associated, and after a few days of useless symptomatic treatment, complete recovery occurs.

[edit] Infectious Mononucleosis

About 5% of patients with infectious mononucleosis develop neurologic complications as a result of inflammatory infiltrates and neuronal degeneration in the nervous system. The most common of these complications is aseptic meningitis, a benign and relatively transient disorder. Encephalitis and encephalomyelitis present with seizures, reduction in level of consciousness, raised ICP, focal neurologic signs, and meningism. A generalized peripheral neuropathy indistinguishable from Guillain-Barré syndrome is well recognized, but patients may also have mononeuropathies, and virtually every cranial nerve has been reported as affected. Less commonly, illnesses resembling Reye's syndrome, dysautonomia, brachial neuropathy, movement disorders, or a syndrome such as multiple sclerosis have been described.

[edit] Influenza

The neurologic complications of influenza are usually indirect, taking the form of an acute postinfectious encephalomyelitis. Depression frequently occurs after influenza, and some patients with multiple sclerosis may have a relapse after even a mild attack. Neuralgic amyotrophy is another occasional complication (see Chapter 167 ).

[edit] Tick Paralysis

Particularly in western North America, wood ticks may attach themselves to persons exploring the undergrowth, especially children. The tick can be found attached to the head or to any other hairy body parts. Its toxin may block neuromuscular transmission, causing a rapidly progressive, symmetric, flaccid paralysis, with signs resembling a severe myasthenic crisis.

The weakness may be so severe that respiratory and bulbar paralysis occur and the patient may die of respiratory insufficiency. The sudden onset of such profound weakness over the course of a day or less should make one think of tick paralysis. Treatment consists of removal of the tick, but it may be difficult to find and may require shaving the child or searching through the hair with a fine comb. With supportive measures, recovery should occur within a few days.

[edit] Tetanus

Although Clostridium tetani is not as widespread now as it was in the days of horse-drawn transport, tetanus still constitutes an important disease despite a fairly high level of immunization in Western communities. The organism enters a wound (which may be very small) or follows surgical procedures, otitis media, or puerperal or umbilical sepsis. Its toxin then ascends the peripheral motor nerves to block inhibitory postsynaptic potentials affecting the anterior horn cells.

After an incubation period of up to 3 weeks, patients develop pain and stiffness of the muscles (especially in the neck, back, and abdominal wall). Trismus, dysphagia, and reflex spasms are common, often beginning in the back, neck, and jaw muscles and lasting up to 30 seconds. The strong muscular contractions may induce hyperpyrexia, and respiratory arrest may occur. Laryngospasm, chest infections, and cardiac arrest are occasional lethal complications. Diagnosis is only achieved early if a high index of suspicion is maintained.

[edit] Treatment.

Treatment for tetanus is along several lines.

• Human antitetanus immunoglobulin has replaced horse serum antitoxin, and 2000 to 4000 units are given intramuscularly, after which a course of intramuscular penicillin is necessary.
  
• Tetanus toxoid is required to achieve active immunization.
  
• The wound must be excised and cleaned, with all dead tissue removed.
  
• Symptomatic treatment depends on the severity of the case. Mild cases will need only diazepam and sedatives. Respiratory difficulty requires tracheostomy and possibly curarization, as well as the above measures. The most severe cases must be anesthetized and paralyzed, so all patients must be transferred urgently to an intensive care unit. Many metabolic and urinary problems complicate the acute illness, and close nursing attention is essential.
  

Even in the best facilities, about 10% of patients with tetanus die, mainly because of complications. The most seriously affected patients are those with cephalic tetanus infection from invasion in the head and neck area, and those in whom symptoms begin within a few days of wounding.

[edit] Botulism

The toxin of Clostridium botulinum impairs acetylcholine release at motor nerve endings. The source of this toxin is often improperly canned foods, although wounds are sometimes the portal of entry. In infants, progressive weakness, hypotonia, poor gag and suck reflexes, and constipation are the main signs. In adults, extraocular muscle, respiratory, facial, and bulbar palsies occur; the limbs are flaccid and paretic, and reflexes are lost. The pupils usually dilate and are poorly responsive. Treatment consists of urgent ventilatory support with neutralization of toxin using the specific trivalent (ABE) antiserum, penicillin, and cathartics.

[edit] Toxoplasmosis

Toxoplasmosis may occur as a congenital infection or may be acquired later in life, usually in immunosuppressed patients. This protozoan organism commonly affects the nervous system and produces an inflammatory reaction with formation of miliary granulomas. These may later calcify or undergo necrosis, resulting in hydrocephalus, or they may be completely asymptomatic.

Congenital toxoplasmosis may be evident shortly after birth. Failure to thrive, convulsions, spasticity, opisthotonos, and eye defects such as chorioretinitis or microphthalmos are possible presentations. Optic atrophy is a common later development, as is hydrocephalus. Some children do not develop symptoms until the age of 4 or 5, when hepatomegaly and splenomegaly are found. Radiographs of the skull often show scattered calcifications.

Acquired toxoplasmosis is often traceable to infected animals. Clinical features include skin lesions, pulmonary and lymphatic involvement, acute meningitis, encephalitis, myositis, and chronic granulomatous meningitis.

Laboratory findings will depend on the type and extent of involvement. The CSF may be under increased pressure, and the protein will usually be increased with a slight or moderate increase in mononuclear cells. Skull radiographs and funduscopy are often extremely helpful in making a diagnosis, but more definitive support comes from complement-fixation and fluorescent antibody tests.

Children with symptomatic congenital toxoplasmosis often have significant mental and neurologic defects, if they survive. In the adult form (which is much less common), the prognosis depends on the severity of the infection; patients with overt encephalitis do poorly. Treatment is with sulfonamides combined with pyrimethamine.

[edit] Syphilis

Although a request for specific serology is (or should be) routine on all patients admitted to neurologic wards, the overall return on these tests is relatively small. The request is still important because the prevalence of syphilis is probably increasing (in part associated with the spread of AIDS) but the number of patients who are coming for treatment is not, suggesting that we are going to be faced with an increasing number of cases of late and congenital syphilis in the future (see Chapter 29 ).

Serodiagnostic tests for syphilis may be classified as reagin tests and specific antitreponemal antibody tests. In the former group, the one most commonly used in North America is the rapid plasma reagin (RPR), a slide test that detects the presence of cardiolipin antigens. This is positive in between 75% and 95% of patients with primary, secondary, late, or latent syphilis. Unfortunately, false positive tests are common with reagin tests, being seen in conditions accompanied by abnormal globulins or excessive normal globulins. These include almost all of the collagen-vascular diseases, pregnancy, vaccination for smallpox, Hansen's disease (leprosy), infectious mononucleosis, measles, and atypical pneumonia. Narcotic addicts and patients with chronic rubella, viral hepatitis, viral pneumonia, hemolytic anemia, and the tropical diseases yaws and pinta may show such biologic false-positive reactions (Box 165-7).

Box 165-7 - Causes of Biologic False-positive Serologic Test Results for Syphilis✢

Transient (negative after 3 months) Recent vaccination, typhoid inoculation Infective hepatitis Infectious mononucleosis, measles, varicella-zoster Viral encephalitis Pregnancy Undetermined (30%) Persistent (positive after 3 months) Collagen-vascular diseases Hashimoto thyroiditis Rheumatic heart disease Hepatic cirrhosis Hemolytic anemia Chronic nephritis Peripheral vascular disease Undetermined (50%) ✢From Mandell GL, Bennett JE, Dolin R, editors: Principles and practice of infectious diseases, ed 4, New York, Churchill Livingstone, 1995.

The specific antitreponemal antibody test in common use is the microtreponema pallidum hemagglutination test (MTPHA). It is the first to react in syphilis and is positive in about 95% of cases of primary, secondary, late, and latent syphilis. It can be performed on the CSF and the blood and is seldom positive in the conditions causing false-positive RPR reactions (except for yaws and pinta, when it may give a weak positive reaction).

One single positive serologic test for syphilis does not make the diagnosis, however, and clinical evidence or repeat testing by different methods is always necessary. In the following discussion, the classical patterns of syphilis are described (Box 165-8), but today the intercurrent use of penicillin has changed the clinical picture of syphilis, and seizures, strokes, confusional states, depression, and visual field alterations may be the sole presenting signs.

Box 165-8 - Forms of Syphilis✢

Latent Primary CSF lymphocytosis Secondary Acute syphilitic meningitis Tertiary Meningovascular: cerebral or spinal endarteritis, cerebral or spinal leptomeningitis, meningomyelitis Parenchymatous: tabes dorsalis, general paresis, isolated optic atrophy, gummas Congenital ✢From Mandell GL, Bennett JE, Dolin R, editors: Principles and practice of infectious diseases, ed 4, New York, Churchill Livingstone, 1995.

[edit] Primary Syphilis.

The chancre is the only lesion that occurs in primary syphilis. This lesion, classically on the pudenda, appears after an incubation period of 3 weeks to 3 months. There may be some increase in CSF lymphocytes at this time, but no clinical signs appear.

[edit] Secondary Syphilis.

The secondary syphilis stage follows immediately after the primary stage, 2 or 3 months after the appearance of the chancre. Constitutional symptoms are those of fever in association with a symmetric, nonitchy skin rash over all of the body, but particularly on the palms and soles. Snail-track ulcers (mucous patches on the mucosa of the mouth and genitalia), generalized lymphadenopathy, loss of hair, and iritis may occur. A meningoencephalitis presenting the usual features of fever, meningeal irritation, raised ICP, and occasionally with focal signs including seizures, is the main neurologic problem. The CSF shows a small increase in protein but a marked increase in lymphocytes, reduced glucose levels, and positive serologic reactions.

[edit] Tertiary (Late) Syphilis.

After the lesions of secondary syphilis clear, a latent stage occurs, even in untreated cases in which there are no signs of the underlying infection. Tertiary syphilis may appear years later and involves the skin, mouth, eyes, bones, joints, gut, or genitourinary system. Cardiovascular problems related to tertiary syphilis include aortitis, granulomas of the myocardium or arterial walls (gummas), or a generalized vasculitis; the nervous system may also show a variety of abnormalities. The three most common syndromes are described below. The diversity of involvement led to the old adage that syphilis is the great mimicker of virtually every known medical disease; lupus erythematosus and AIDS now have the same distinction.

[edit] Meningovascular Syphilis.

In the meningovascular form of tertiary syphilis, a chronic basal meningitis results in increased ICP, cranial nerve lesions, or cerebral infarction. The CSF will show positive serology, increased protein and lymphocytes, and occasionally decreased sugar levels.

[edit] Tabes Dorsalis.

Tabes dorsalis is characterized by degenerative changes in the posterior roots and root entry zone of the spinal cord (Fig. 165-3). This results in numerous sensory signs. Because of the atrophy of the large sensory fibers in the posterior roots and dorsal columns, the patients show poor proprioception, loss of deep pain, absent reflexes, hypotonia, a “stamping” gait, and a positive Romberg's test. Lancinating lightning pains may be felt in girdle distribution or in the smooth muscles of the bowel, bladder, or larynx. They are much diminished by carbamazepine. The loss of “thick fiber” or “dorsal column” sensation may result in ulcers of the feet and painless destruction of joints (Charcot's joints). Impotence and bladder dilation caused by deafferentation are also common; optic atrophy, ptosis, and Argyll Robertson pupils complete the clinical picture.

[edit] General Paresis.

General paresis is a subacute meningoencephalitis and is characterized by progressive dementia with major frontal lobe signs and evidence of involvement of the motor cortex and the parietal and temporal lobes (Fig. 165-4). Tremors and a parkinsonian picture may also result from basal ganglion involvement.

Optic atrophy and Argyll Robertson pupils are usually found. Seizures are frequent and may be the presenting problem. The basal ganglion and corticospinal lesions combine to produce severe dysarthria, with tremors of the tongue and lips and variable motor disturbances in the arms and legs (Fig. 165-5). These patients often show marked emotional changes and mental deterioration and typically have delusions of grandeur. It is the patient with general paresis who has been typified as the “insane” patient who believes that he is God, Napoleon, or Batman.