Clinical Vignette

A 19-year-old woman presented to the emergency department with confusion, lethargy, and neck stiffness. Her dorm mates reported that she had experienced upper respiratory symptoms for 3 or 4 days before presentation. She had no significant past medical history. On physical examination, her temperature was 37° C (98.6° F), her pulse was 100 beats/min, respirations were 20/min, and her blood pressure was 110/70 mm Hg. Although her neck was stiff, Kernig and Brudzinski signs were absent. The pharynx was slightly injected without exudate. Heart and lung examination results were normal. No rash was present. Neurologic examination revealed a slightly obtund, sleepy woman with otherwise intact mental status, intact cranial nerves, no motor or sensory deficits, and normal reflexes.

The patient’s white blood cell (WBC) count was 22,900/mm³, with a marked left shift, including 34% bands and 62% polymorphonuclear neutrophils (PMNs). Her platelet count was 120,000/mm³. Her electrolytes revealed a mild metabolic acidosis. A chest radiograph and brain computed tomography (CT) were normal.

Initial cerebrospinal (CSF) fluid examination was normal. However, she was admitted for observation. Very soon thereafter, she complained of increasingly severe headache and neck pain. On exam, she was definitely confused and now had a fever of 39.1° C (102.4° F). Repeat lumbar puncture demonstrated a cloudy CSF with 670 WBCs (90% PMNs), a glucose level of 1 mg/dL, and a protein level of 220 mg/dL. Gram stain revealed rare gram-negative diplococci that on culture grew Neisseria meningitidis. Blood cultures also grew N. meningitidis. She was treated with 24 million U/day intravenous (IV) penicillin G and recovered completely. Before discharge, she was given rifampin to eliminate nasopharyngeal carriage of N. meningitidis.

One of the most serious neurologic emergencies involves the evaluation and care of patients with bacterial meningitis. Usually, these individuals are vigorous and previously healthy when they suddenly develop a severe headache, fever, and stiff neck. Despite more than 50 years of experience with antibiotic therapies, bacterial meningitis remains a very lethal disease. Expedient diagnosis is essential to prevent such an outcome. In the preceding vignette, typical for meningococcal meningitis, despite the history and findings suggestive of a meningeal infection, the initial CSF examination was normal. Emergency physicians wisely admitted the patient for observation. When she experienced sudden deterioration, repeat CSF examination led to diagnosis and appropriate therapy. Any delay in diagnosis and therapy of bacterial meningitis can be irretrievable as death may occur soon after a clinical change unless appropriate antibiotic therapy is begun immediately.

Pathophysiology

Bacterial meningitis is defined as a microbial infection primarily involving the leptomeninges (Fig. 48-1). Typically, bacteria seed the leptomeninges via the bloodstream or from a contiguous site of infection, such as sinusitis, otitis media, or mastoiditis. Rarely a defect in the normal anatomic barriers, as with a perforating cranial or spinal injury or congenital dural defect, leads to a predisposition to recurrent bacterial meningitis.

Figure 48-1 Bacterial Meningitis–I.

The responsible microorganisms often differ between children and adult patients. Those commonly responsible for meningitis in adults include Streptococcus pneumoniae, N. meningitidis, and Listeria monocytogenes. Haemophilus influenzae still causes 20–50% of meningitis in developing countries, but in the United States, this rate has been reduced 90% with the H. influenzae type b vaccine. In neonates, Escherichia coli and group B β-hemolytic streptococci comprise most cases. L. monocytogenes particularly leads to meningitis in immunocompromised patients and rarely in the newborn. N. meningitidis infection often occurs with a primary sepsis, and a characteristic petechial and/or purpuric rash, or disseminated intravascular dissemination. Conditions predisposing to pneumococcal meningitis in adults include sickle cell disease as well as conditions predisposing to immune deficiencies, including alcoholism, cirrhosis, splenectomy, and HIV/AIDS.

Gram-negative bacilli (E. coli, Proteus, Pseudomonas, Serratia, Klebsiella, and Citrobacter) are rarely found in community-acquired meningitis but more commonly occur in association with head or spinal trauma or after neurosurgery. These organisms always need to be considered with the immunocompromised hosts. Meningitis due to Staphylococcus aureus may follow penetrating trauma, neurosurgery, or bacteremia. Coagulase-negative staphylococci (Staphylococcus epidermidis) or S. aureus and other organisms are associated with infected ventricular shunts.

Clinical Presentation and Diagnosis

The onset of acute bacterial meningitis is rapid: hours to a day or so. Classic clinical findings include signs of an acute cerebral disorder, with lethargy, seizures, and agitation as well as specific signs of meningeal involvement manifested by severe neck stiffness, called meningismus, and fever that may not be immediately present. The patient rapidly becomes confused, sleepy, obtunded, and often comatose.

The examining physician needs to carefully search for signs of nuchal rigidity in any febrile patient who presents with a headache or any changes in level of alertness. Two clinical maneuvers are very important for identifying the presence of inflamed meningeal coverings involving the lumbosacral nerve roots: the Kernig and Brudzinski signs (Fig. 48-2). The Kernig sign is elicited by flexing the patient’s hip to a 90-degree angle and then attempting to passively straighten the leg at the knee; pain and tightness in the hamstring muscles prevent completion of this maneuver. This sign should be present bilaterally to support a diagnosis of meningitis. The Brudzinski sign is positive if the patient’s hips and knees flex automatically when the examiner flexes the patient’s neck while the patient is supine. Because host responsiveness to the infection varies, these signs of meningeal irritation are not invariably present, especially in debilitated and elderly patients and infants. When the clinical picture is typical of meningitis, it is also very important to exclude the concomitant presence of a focal parameningeal source such as a brain abscess. Further history, careful neurologic examination, and various imaging studies are essential (Figs. 48-3 and 48-4). Frequently there may be concomitant dermatologic findings present. A maculopapular or petechial/purpuric rash usually indicates infection with N. meningitidis although an echovirus may mimic such. However, in these instances, the CSF findings are significantly different, usually with predominant lymphocytosis, normal CSF sugar, and negative Gram stain. The dermatologic findings of N. meningitidis are usually secondary to an underlying vasculitis; they are rarely related to concomitant coagulation defects or a combination of the two. Meningococcal infection more commonly has a rash that affects the trunk and extremities in contrast to the echovirus exanthem that usually involves the face and neck early in the infection. Purpuric lesions may also rarely be found in a fulminant pneumococcal bacteremia with meningitis as well as staphylococcal endocarditis, the latter primarily involving the finger pads.

Figure 48-2 Bacterial Meningitis–II.

Figure 48-3 Parameningeal Infections.

Figure 48-4 Multiple brain abscesses in a 32-year-old with septicemia.

Diagnostic Approach

CSF examination is essential to the diagnosis of bacterial and other microbial forms of meningitis. Generally, a brain CT must precede CSF examination to rule out a primary brain abscess or a parameningeal focus with significant mass effect, potentially causing cerebral herniation secondary to a sudden change in CSF dynamics. When there are signs of focal neurologic involvement or increased intracranial pressure in patients with suspected meningitis, a lumbar puncture may be contraindicated. These include papilledema, coma, and focal neurologic findings, such as dilated pupils, hemiparesis, and aphasia. Accompanying signs of increased intracranial pressure may include bradycardia, Cheyne–Stoke respirations, and even projectile vomiting.

As soon as diagnosis of meningitis is considered, even before proceeding with a CT scan and lumbar puncture, administration of empiric antibiotics covering the broad spectrum of gram-positive and gram-negative organisms is essential. One can later adjust the treatment once CSF culture examination results are available. If CT exam confirms that there is no mass lesion suggestive of a parameningeal focus with potential for herniation, one can then safely proceed with a CSF examination. If a parameningeal mass lesion is identified as a source of the meningitis, its treatment is paramount. The precise identification of the pathogenic bacteria, per se, will then become possible at the time of surgical decompression, and the spinal tap as such is not required.

CSF analysis provides the only conclusive proof of bacterial infection of the subarachnoid space. It must include a Gram-stained smear to define the offending organism morphology. The Gram stain correlates with the precise microbial etiology, as defined by the more specific bacteriologic culture, in approximately 80% of patients. This is a simple technique that allows for better selection of appropriate antibiotic therapy before definitive culture and sensitivity data are available. However, one does not need to await the results of the Gram stain before immediate initiation of appropriate antibiotic therapy. Rapid detection of microbial antigens by counterimmunoelectrophoresis or latex agglutination tests can aid diagnosis when CSF Gram stain and cultures are not diagnostic. Newer molecular diagnostic techniques are anticipated.

The initial CSF analysis needs to include measurement of the opening pressure, color (clear, turbid, or purulent), WBC count and differential, and levels of glucose and protein. Typically in bacterial meningitis, the CSF opening pressure is increased (>200 mm of CSF lying down and >35 mm Hg upright). The fluid is usually turbid or frankly purulent and contains predominantly (>90%) polymorphonuclear leukocytes. The CSF glucose level is very low, usually less than 50% of that found with measurement of concomitant serum glucose. A low glucose level (<40 mg/100 mL) is also found in some other types of microbial meningitides including L. monocytogenes, Mycobacterium tuberculosis, and Cryptococcus neoformans. Normal glucose levels are common in viral meningitis. Usually, CSF protein levels are increased, often greater than 100 mg/dL (reference range, <45 mg/dL). In patients with parameningeal foci, such as a brain or epidural spinal abscess, or with multiple septic emboli, CSF glucose may not be as low as with typical bacterial meningitis, even though in these instances the CSF protein level is significantly increased.

Optimum Treatment

Bacterial meningitis is an extremely life-threatening infection. Any delay in its diagnosis by not initially assessing the patient or not beginning therapy at the first consideration of this critical diagnosis will increase morbidity and mortality. Antibiotic treatment must be initiated as soon as possible, and later guided by CSF examination results. When CSF examination cannot be performed promptly, empiric therapy must be instituted immediately. Patients must receive at least 10 days of high-dose IV antibiotics that easily cross the blood–brain barrier. Empiric IV therapy with a third-generation cephalosporin, such as ceftriaxone or cefotaxime, plus vancomycin must commence pending results of the bacterial cultures. High-dose corticosteroids, administered before antibiotic therapy, are recommended for all children and should be seriously considered for adults with community-acquired meningitis. When culture and sensitivity data are available, a specific antimicrobial therapy can be determined. Penicillin G is recommended for documented meningococcal meningitis.

Antimicrobial therapy for meningitis caused by S. pneumoniae must be based on antibiotic sensitivity test results. If the strain is susceptible to penicillin, penicillin or ceftriaxone are recommended. Ceftriaxone or cefotaxime are recommended when the strain is not susceptible to penicillin and is susceptible to cephalosporins. If the strain is susceptible to neither cephalosporins nor penicillin, vancomycin must be added to a third-generation cephalosporin (cefotaxime or ceftriaxone). In patients older than age 50 years, empiric therapy with ampicillin must be added to vancomycin and a third-generation cephalosporin to provide coverage for L. monocytogenes.

Complications

Of patients with bacterial meningitis, approximately 15% experience acute and chronic complications, including various cranial nerve dysfunction, particularly those affecting extraocular function (cranial nerves [CNs] III, IV, and VI), CN-VII, and sometimes CN-VIII, although this is less common today with the antibiotics lacking specific ototoxicity or vestibular toxicity. However, permanent sensorineural hearing loss occurs occasionally, most commonly with pediatric meningococcal infections. Assorted cranial neuropathies are generally secondary to the exudate common with the more purulent forms of bacterial and tuberculous meningitis.

Focal or generalized seizures, various focal cerebral signs, coma, and acute cerebral edema occasionally occur. Findings mimicking a stroke, such as a hemiparesis, aphasia, and hemianopsia, are relatively infrequent; persistence of such findings suggests secondary cerebral arteritis, cerebral venous thrombosis, or rarely a mass lesion, especially an abscess. Even with astute and early diagnosis, mortality rates are still at least 10% for meningococcal and 30% for pneumococcal meningitis, although the latter has very significantly decreased in frequency with the recent introduction of a pneumococcal immunization. Whenever any diagnostic delay occurs leading to less than immediate treatment, mortality and morbidity are significantly higher.

Chemoprophylaxis

Chemoprophylaxis is particularly recommended for persons in close contact with patients who acquired meningococcal meningitis, especially in confined settings such as college dormitories and army barracks. Rifampin is preferred; ciprofloxacin is also effective.

Future Directions: Vaccines

Vaccines are available for three common organisms. H. influenzae type b protein-polysaccharide vaccine is highly effective in preventing meningitis in newborns and young infants. N. meningitidis (meningococcus) serogroups A, C, Y, and W135 polysaccharide vaccine is recommended for high-risk adults and contacts of persons with meningococcal disease. Although group B accounts for >50% of cases, its capsule is an autoantigen and thus not a suitable vaccine target; several recombinant protein vaccines are in late-stage clinical development. S. pneumoniae (pneumococcus), pneumococcal protein-polysaccharide heptavalent vaccine, is recommended for children and is under study in adults. Currently, 23-valent pneumococcal polysaccharide vaccine is recommended for adults. Several new vaccines are in development.

Clinical Vignette

A 26-year-old woman had the sudden onset of numbness in her right hand and face. This cleared within a few minutes only to recur on two more occasions within the next 48 hours. She then suddenly became aphasic with numbness and weakness of her right hand and face. Neurologic examination demonstrated a fluent aphasia, with a right central facial and hand weakness. Her muscle stretch reflexes were enhanced in her right arm associated with a right Babinski sign. She had a grade III/IV systolic murmur at the apex of her heart. Brain imaging demonstrated a left parietal temporal mass suggestive of a cerebritis or an abscess. Empirical antibiotics were begun. Within 36 hours, blood cultures demonstrated a gram-positive diplococcus. The antibiotics were adjusted appropriately. Within 48 hours, her condition had stabilized. Repeat imaging studies 1 week later showed improvement. Surgical decompression was considered early on; however, the antimicrobial therapy was sufficient. She gradually improved having an almost complete recovery. When her speech improved, she subsequently recalled having had a dental hygiene appointment a few weeks before the onset of her illness. Previously, she had not been aware of having a mitral valve lesion. She was instructed that she needed antimicrobial therapy prior to any dental or other medically invasive procedure in the future.

Brain abscess, which may be indolent or fulminant, results from direct extension of a contiguous focus, such as middle ear or sinus infections, congenital heart disease with a right-to-left shunt, or very rarely a pulmonary arteriovenous malformation having similar shunt mechanisms. Hematogenous spread may occur from distant infection sites in the head and neck, heart (infectious endocarditis), lung, or abdomen, or direct introduction of bacteria after penetrating head injuries. Brain abscess can occur after surgical procedures, as in the vignette on p. 408. The cardinal symptom of brain abscess is relentless and progressive headache, usually followed by focal neurologic manifestations. Only two thirds of patients have fever. Papilledema and other signs of increased intracranial pressure may occasionally develop; however, the availability of imaging studies makes it more likely that the abscess will be identified prior to its obtaining significant enough mass to create increased intracranial pressure.

Most brain abscess cases are polymicrobial. Etiologic agents often include aerobic bacteria, such as streptococci, Enterobacteriaceae, and staphylococci. Streptococcus milleri normally resides in the oral cavity, appendix, and female genital tract and has a proclivity for abscess formation. Anaerobic microorganisms, such as Bacteroides and Prevotella species, are present in up to 40% of cases. Fungi are uncommon but increasingly recognized among immunosuppressed patients.

MRI is most helpful for making the initial diagnosis (Fig. 48-3). The characteristic appearance is a focal cerebral lesion with a hypodense center and a peripheral uniform ring enhancement subsequent to contrast material injection. Sometimes there is a concomitant area of surrounding edema. In these circumstances, if at all possible lumbar puncture should be avoided to prevent abscess herniation or rupture into the ventricular system.

Therapeutically, the abscess may be directly aspirated. Empiric medical therapy is started with a third- or fourth-generation cephalosporin or penicillin plus metronidazole, depending on the setting. Surgery may not be necessary if follow-up CT demonstrates decreased abscess size. Brain edema associated with acute brain abscess necessitates use of steroids and mannitol, as well as phenytoin, to prevent convulsions.

Clinical Vignette

A 52-year-old diabetic man experienced a nonspecific upper respiratory tract syndrome typically thought of as influenza. Within just a few days, he developed increasingly severe midthoracic spine pain. He soon developed rigors, chills, and vomiting. His symptoms rapidly worsened over the subsequent 12–24 hours. He then suddenly noted numbness in both legs spreading up to his midback. He soon had trouble climbing stairs and after lying down to regain his strength was unable to arise from bed even with his wife’s attempted help. He could not urinate. His family called the local emergency ambulance and had him taken to the hospital.

Neurologic examination demonstrated that he was paraplegic and had a T6 sensory level with marked loss of sensation below his nipple line. The patient required urinary catheterization. Spinal MRI demonstrated an epidural abscess extending between T4 and T10. Although an immediate neurosurgical decompression was carried out, unfortunately this patient had only partial resolution of his neurologic deficit.

Epidural spinal abscess patients typically present with fever and relatively severe back pain, sometimes with varying degrees of leg weakness. There are four clinical stages: (1) focal vertebral pain, (2) radicular pain corresponding to the dermatomal course of the specific involved nerve roots, (3) early signs of spinal cord compression such as paresthesias, weakness, or delayed ability to urinate, and (4) paralysis below the lesion level.

A purulent or granulomatous collection within the spinal epidural space may overlie or encircle the spinal cord, nerve roots, and nerves (Fig. 48-5). Although the infection is usually localized within three to four vertebral segments, it rarely extends the length of the spinal canal.

Figure 48-5 Spinal Epidural Abscess.

S. aureus is the most common organism leading to a spinal epidural abscess, but aerobic or anaerobic streptococci and gram-negative organisms are occasionally isolated. Mixed anaerobic and aerobic organisms are sometimes responsible. When no organism is isolated or if granulomas are identified, M. tuberculosis infection of the spine, for example, Pott disease, also requires consideration. A skin infection, especially a furuncle, is the most common focus for a hematogenous spread to the epidural space. An antecedent vertebral osteomyelitis with a prior hematogenous source is responsible for approximately 40% of spinal epidural abscess. Dental and upper respiratory tract infections are other common predisposing lesions.

Any patient presenting with back pain, fever, and localized tenderness or signs of cord compression requires immediate and complete spinal MRI. Surgical or CT-guided needle aspiration is necessary to define an accurate diagnosis and possible decompression. Blood cultures are recommended. Lumbar puncture should not be performed. Appropriate parenteral antibiotics are necessary for 3 to 4 weeks in uncomplicated cases and for up to 8 weeks or more if osteomyelitis is present.

Clinical Vignette

A 39-year-old woman presented with complaints of fatigue progressing over a month followed by aching in her back behind her right shoulder for 2 weeks. She developed a severe headache with photophobia and nausea over the week before admission. On questioning, she remembered a bug bite followed by a 5-cm rash at about the time her fatigue began. At the time, she developed upper back and neck stiffness that she sought chiropractic treatment for. She was afebrile on examination, with no neck stiffness or neurologic deficits. A 5-cm oval area of erythema was noted near her left axilla. WBC was 6.58 and metabolic profile normal. CSF examination showed 129 WBC (89% lymphocytes, 3% neutrophils) and 363 RBC, glucose 48, and protein 54. CT scan of the brain was unremarkable. Serum Lyme Western blot testing was positive. A Lyme IgM was positive in the patient’s CSF and Lyme polymerase chain reaction (PCR) was negative. She was treated with 1 month of ceftriaxone 2 g IV daily with complete resolution of symptoms.

Comment: Lyme disease, which is caused by the tick-borne spirochete Borrelia burgdorferi, is endemic in parts of the United States, particularly northeast Atlantic coastal areas from Maine to Maryland, the upper Midwest, including Minnesota and Wisconsin, as well as the northern Pacific including California and Oregon. Currently, about 15,000 cases per year are reported in the United States. It is also endemic in Europe and Asia in forested areas.

Clinical Presentation

In 80% of patients in the United States, Lyme disease presents with a slowly expanding skin lesion called erythema migrans that occurs at the site of the tick bite (Fig. 48-6). Influenza-like symptoms, such as malaise, fatigue, fever, headache, arthralgias, myalgias, and regional lymphadenopathy, frequently accompany the rash and are often the presenting manifestation of Lyme disease. Early localized infection is followed within days to weeks by a systemic dissemination that variously affects the nervous system, heart, or joints. Untreated, late or persistent Lyme infection ensues.

Figure 48-6 Lyme Disease Clinical Settings.

In the United States, 15% of untreated neuroborreliosis patients develop objective signs and symptoms of early disseminated infection. A variety of neurologic manifestations develop, including lymphocytic meningitis with episodic headache and mild neck stiffness, a subtle encephalitis with impaired memory, a cranial neuropathy (most commonly uni- or bilateral facial palsy, sometimes an optic neuropathy), cerebellar ataxia, myelitis, motor or sensory radiculoneuritis, or a mononeuritis multiplex.

Untreated, acute neurologic abnormalities usually improve or resolve within weeks or months. However 5% of untreated patients may develop a chronic neuroborreliosis with subtle cognitive changes. This is termed Lyme encephalopathy. Although the cerebrospinal fluid in these patients shows no inflammatory changes, intrathecal antibody production against B. burgdorferi is often demonstrated. Sometimes a chronic axonal polyneuropathy, generally presenting as spinal radicular pain or distal paresthesias, may develop. Diffuse involvement of proximal and distal nerve segments is found on electromyography (EMG).

Diagnosis

Culture of B. burgdorferi from specimens in Barboud–Stoenner–Kelly medium allows definitive microbiologic diagnosis, but is only possible early in the illness and usually only from biopsies of erythema migrans lesions. In late infection, PCR detection of B. burgdorferi is superior to culture from joint fluid. In the United States, diagnosis of Lyme disease is usually made based on characteristic clinical findings, history of exposure in an endemic area, and antibody response to B. burgdorferi by enzyme-linked immunosorbent assay (ELISA) and Western blotting interpreted according to Centers for Disease Control and Prevention (CDC) criteria. Serology is insensitive during the first several weeks of infection (only 20–30% positive and usually IgM alone), but by four weeks 70–80% are seropositive (generally IgM and IgG), even after antibiotic treatment. A positive IgM test alone after 1 month of illness is likely to represent a false-positive result. Patients with acute neuroborreliosis, especially meningitis, often demonstrate intrathecal production of IgM, IgG, or IgA antibody against B. burgdorferi.

MRI may demonstrate meningitic findings (Fig. 48-7a&b), as well as cranial nerve involvement. Intraparenchymal white matter changes in the corpus callosum as well as centrum semiovale mimicking multiple sclerosis may be seen. Active enhancement is a good marker of active disease (Fig. 48-7c–f).

Figure 48-7 Lyme Disease.

Treatment

Evidence-based recommendations for Lyme disease have been developed by the Infectious Diseases Society of America. Early or localized disseminated infection can be successfully treated with 14–21 days of oral doxycycline. Children and pregnant women may be treated with amoxicillin. An advantage of doxycycline is efficacy against Anaplasma phagocytophilum, a possible coinfecting pathogen that causes human granulocytic ehrlichiosis. Cefuroxime axetil is a third alternative in those allergic to the first options. Patients with objective neurologic abnormalities can be treated with 14–28 days of intravenous ceftriaxone (cefotaxime and penicillin G are possible alternatives). Manifestations of acute neuroborreliosis usually resolve within weeks, but chronic neuroborreliosis generally resolves over a period of months. Objective evidence of relapse is rare after 4 weeks of therapy.

Clinical Vignette

A 51-year-old Vietnamese woman presented with 7 days of headache, vomiting, and episodic left facial and arm tingling numbness while visiting the United States. She reported diplopia, having fallen twice and fractured her nose. Some seizurelike activity was witnessed. The patient’s temperature was equivocally febrile. On neurologic examination, she was confused and only intermittently fluent. She had bilateral sixth cranial nerve palsies and early papilledema. Her neck was stiff, and her lungs were clear.

A lumbar puncture revealed a CSF opening pressure of 500 mm CSF, protein of 218 mg/dL, glucose of 22 mg/dL (serum glucose level 137 mg/dL), an RBC count of 190/mm³, and a WBC count of 1390/mm³ (4% polymorphonuclear leukocytes, 94% lymphocytes). CSF acid-fast bacilli smear and PCR results were negative. Cranial CT and MRI results were normal. The patient was treated with isoniazid, rifampin, ethambutol, pyrazinamide, and methylprednisolone (Solu-Medrol). The CSF ultimately grew M. tuberculosis.

The incidence of CNS tuberculosis in the United States has markedly decreased; it most commonly occurs in foreign-born adults and those infected with HIV. Neurologically, it presents as a meningitis, mass lesion, or vertebral lesion. Because tuberculosis is still endemic in Southeast Asia, it must be considered in the differential diagnosis of patients immigrating from this area who present with a meningoencephalopathy, especially with cranial neuropathies; the vignette in this chapter is classic. It is important to make a clinical diagnosis and begin treatment while awaiting CSF culture results.

Tuberculous Meningitis

Tuberculous meningitis usually results from hematogenous meningeal seeding or contiguous spread from a tuberculoma or parameningeal granuloma, with subsequent rupture into the subarachnoid space (Fig. 48-8). Local foci of infection along the meninges, brain, or spinal cord, thought to be present from hematogenous seeding of the primary infection, also release bacilli directly into the subarachnoid space. Infection then spreads along the perivascular spaces into the brain. An intense inflammatory reaction at the brain base causes an occlusive arteritis, with small vessel thrombosis and resultant brain infarction. Direct cranial nerve compression and obstruction of CSF flow at the foramina of the fourth ventricle or at the basal cisterns may result in subarachnoid block and cerebral edema.

Figure 48-8 Tuberculosis.

Tuberculous meningitis progresses rapidly, with headache, fever, meningismus, and cranial nerve deficits, especially sixth nerve palsy. Focal cerebral or cerebellar deficits are followed by altered sensorium and coma.

CSF examination is critical in establishing the diagnosis. Classically, the CSF glucose level is less than two thirds that of the serum glucose level; the CSF protein level is greater than 50 mg/dL; and the WBC count is increased, with a lymphocyte predominance. PCR analysis and culture are the most sensitive diagnostic tools. PCR can detect fewer than 10 organisms in clinical specimens compared with the 10,000 necessary for smear positivity. False-negative PCR results have been reported (sensitivity in acid-fast smear-negative cases varies from 40% to 77%). Unfortunately, acid-fast (Ziehl–Neelsen) smears are positive only 25% of the time, and more commonly with concentrated CSF specimens.

It is imperative to initiate therapy at the slightest suspicion of CNS tuberculosis as death may follow within a matter of weeks if this is present and left untreated. Because of worldwide increases in drug resistance, whenever there is a clinical suspicion of this diagnosis, therapy must be instituted immediately. Isoniazid, rifampin, ethambutol, and pyrazinamide are the medications of choice until diagnostic identification and sensitivity testing are available. Both isoniazid and pyrazinamide achieve CSF concentrations equaling those in blood, and rifampin crosses the blood–brain barrier adequately. Corticosteroids are added when cerebral edema, subarachnoid block, or both occur. Mortality is greatest at the extremes of age (20% at <5 years and 60% at >50 years) or if the illness has been present more than 2 months (80%). HIV infection does not seem to alter the clinical course or prognosis of tuberculous meningitis, although CNS mass lesions are more likely to occur in this setting.

Cerebral Tuberculomas

Cerebral tuberculomas are less common than tuberculous meningitis. These are often calcified and are usually located in the posterior fossa, particularly the cerebellum. Although most frequently multiple, tuberculomas can be single. Contrast-enhanced MRI is generally considered the modality of choice in detecting and assessing CNS tuberculosis (Fig. 48-8). PCR and CSF culture or culture of biopsied lesional material confirms the diagnosis. Because standard medical therapy is usually successful if multidrug resistance is not identified, antituberculous therapy must be attempted before surgery is contemplated. Of course, if there are signs of impending herniation, immediate surgery is indicated.

Vertebral Tuberculosis (Pott Disease)

Future Directions

Reliable methods for rapid determination of M. tuberculosis drug susceptibility are needed. Multiple investigators have identified chromosomal mutations associated with drug resistance. Genotypic assays are highly specific but of variable sensitivity. Phenotypic susceptibility assays under development use mycobacteriophages to detect metabolically active mycobacteria grown in the presence of antituberculous drugs. Although these assays are not widely clinically available, they reduce turnaround time for results from 3 weeks to as little as 54–94 hours.

Clinical Vignette

A 56-year-old woman from Cambodia was evaluated because she had been tripping on her left foot for 6 months. For the past month, she noticed difficulty gripping objects with her right hand and had associated elbow and median forearm pain.

Neurologic examination demonstrated weakness of finger abduction and adduction, mild clawing of the fourth and fifth digits, and sensory loss of the medial fingers, consistent with a right ulnar neuropathy affecting ulnar innervated structures in her right hand. Examination of the left leg revealed focal weakness of foot dorsiflexion and eversion with sensory loss on the lateral aspect of the left calf and the dorsum of the foot indicating a left common peroneal neuropathy. Both ulnar and peroneal nerves were thickened and palpable. Two subtle hypopigmented, anesthetic macules were found on her upper arm and trunk. Sensation was diminished on the ear pinna and tip of the nose.

EMG confirmed moderately severe right ulnar and left peroneal axonal neuropathies. Skin biopsy revealed noncaseating granulomas with lymphocytic infiltration and giant cells; acid-fast bacilli were seen on the modified Fite–Faraco stain. The diagnosis was tuberculoid leprosy; dapsone and rifampin were administered.

Hansen disease is a chronic infectious granulomatous disease of skin and peripheral nerves. The reader should understand that although leprosy has been the name of this disorder for many years, its use has led to unfortunate discrimination. Therefore Hansen disease, in recognition of the scientist who discovered the responsible mycobacterium, is now the preferred nomenclature. However, these names are still interchangeably used in some circles.

Worldwide, Hansen disease is one of the most common causes of neuropathy. Any patient from an area endemic for this disorder who has multiple mononeuropathies, particularly ulnar and peroneal, and has skin lesions, especially in superficial sensory areas that have cooler ambient temperatures, is most likely to have this disorder. The etiologic agent is Mycobacterium leprae, an acid-fast bacillus identified by Hansen in 1873. Today this occurs primarily in Asia, Africa, and Latin America. Subsequent to the World Health Organization redefining Hansen disease cases as only those under active treatment, and active case detection is now eliminated, the global registry of new cases has steadily declined since 2001, with 259,017 new cases reported in 2006. Active case detection is now relegated to the primary care physician. However, these bureaucratic finesses create a false sense of security. Thus, we feel that the actual numbers of patients with Hansen disease are grossly underestimated.

Bacteriology

The leprosy bacillus’s genome demonstrates reductive evolution with extensive deletion and inactivation of genes and abundant pseudogenes; <50% of the genome contains functional genes. That may explain the unusually long generation time and the inability to culture M. leprae in artificial media.

Hansen disease is transmitted by respiratory droplets and direct skin contact during frequent, close exposure to untreated patients. Other routes of infection include contact with armadillos (a reservoir in Texas), infected soil, and rarely direct dermal implantation during procedures such as tattooing. The incubation period is usually 5–7 years. M. leprae/laminin-α₂ complexes bind to alpha/beta dystroglycan complexes expressed on Schwann cells and induce rapid demyelination by a contact-dependent mechanism. Myelinated Schwann cells are resistant to M. leprae invasion but undergo demyelination on bacterial attachment; Schwann cells proliferate and generate a nonmyelinated phenotype, where M. leprae multiply intracellularly in large numbers. The clinical development of leprosy depends on host immune responses and genetic factors. The disease spectrum varies widely from limited tuberculoid forms (where few bacilli can be demonstrated) to an extensive lepromatous (LL) form (where more than 10 million organisms per high power field can be seen on skin biopsies).

Clinical Presentation and Diagnosis

The three cardinal diagnostic criteria are anesthetic skin patches, thickened nerves, and acid-fast bacilli in skin smears (Fig. 48-9). The World Health Organization (WHO) recommends classification based on clinical criteria: paucibacillary if less than five skin lesions and/or one nerve is involved, or multibacillary if there are five or more skin lesions, more than two nerves involved, or both. This system determines the therapy type and duration for patients evaluated in the field where laboratory help is not available. The commonly used classification is based on the disease’s clinical spectrum, extending from tuberculoid (TT) to borderline tuberculoid (BT), borderline (BB), borderline lepromatous (BL), and lepromatous (LL). Indeterminate leprosy, seen early in the infection, is diagnosed by the presence of a single or a few skin macules having variable sensory loss.

Figure 48-9 Leprosy.

In tuberculoid (TT and BT) Hansen disease, preserved cell-mediated immunity prevents significant dissemination of the bacillus precluding more severe disease. Patients usually have asymmetrically distributed hypopigmented anesthetic lesions with erythematous margins and an associated asymmetric multifocal neuropathy (mononeuritis multiplex). Involved nerves are concomitantly enlarged, particularly the ulnar, posterior auricular, peroneal, and posterior tibial nerves. Skin or nerve biopsies demonstrate well-demarcated, noncaseating granulomas with many lymphocytes, Langhans giant cells. Acid-fast bacilli are infrequently seen, especially in tuberculoid leprosy. Nerve biopsies are infrequently needed to make this diagnosis.

Borderline (BB) leprosy stands between lepromatous and tuberculoid leprosy in severity and disease manifestation. Once patients receive treatment, they usually move toward the tuberculoid pole of the spectrum.

Lepromatous Hansen disease (LL and BL) is the most severe form, with unrestricted bacterial multiplication and hematogenous dissemination. The organisms have a predilection for multiplying in cooler body areas such as the superficial nerves, nose, earlobes, skin, testes, and eyes. Nerve involvement is symmetric and more extensive than in tuberculoid leprosy but more frequently involves the superficial cutaneous nerves. Large nerves are less frequently affected than in tuberculoid leprosy. Cutaneous lesions are skin-colored nodules or papules that coalesce to form extensive symmetric raised plaques or more diffuse infiltration of the skin. On the face, they result in leonine facies. Skin biopsies demonstrate vacuolated foam cells within the dermis containing large numbers of M. leprae, with few inflammatory cells, and rare granulomas.

The ulnar nerve is the most commonly affected peripheral nerve; when this is associated with median nerve involvement, the combination leads to clawing of the hand. Peroneal neuropathies are most common in the leg. At its extreme, patients with leprotic neuropathies develop auto-amputation of digits, recurrent nonhealing ulcers that often result in osteomyelitis, and nasal bridge collapse.

Erythema Nodosum Leprosum and Reversal Reactions

Leprosy can be complicated by different reactional states, namely, erythema nodosum leprosum (ENL) and reversal reactions. ENL is thought to be an immune complex–mediated process and is characterized by the development of crops of new, small tender subcutaneous nodules accompanied by fever, arthralgias or arthritis, adenopathy, and neuritis. Reversal reactions present as inflamed, indurated skin plaques with neuritis and represent an upgrading of the cell-mediated response in the patient’s immunity to the infection. Both ENL and reversal reactions can occur before, during, and after the completion of antimycobacterial treatment for leprosy. Tumor necrosis factor–alpha and other proinflammatory and anti-inflammatory cytokines are considered key mediators in these reactional states.

Diagnostic Approach and Treatment

Other disorders that may present with similar skin lesions include sarcoidosis, leishmaniasis, lupus vulgaris, syphilis, yaws, and granuloma annulare. However, no other disease has hypopigmented anesthetic skin lesions. Hansen disease diagnosis depends on clinical findings and skin biopsy, a much less invasive procedure than nerve biopsy.

Multidrug treatment (MDT) with the antibiotic combination of rifampin, dapsone, and clofazimine is highly effective. The risk of recurrence is increased with higher bacterial loads and may not occur until 5–10 years after completion of treatment. Severe neural damage is the major complication of reactional states and responds to oral prednisone. Thalidomide, the preferred medication for severe ENL, has significant teratogenic potential. Additionally, thalidomide usage can be complicated by a dose-dependent sensory polyneuropathy; electrophysiologic studies have shown that monitoring sural sensory amplitude may help in the early diagnosis of an emerging sensory neuropathy. Management also includes injury prevention to anesthetized areas, hygiene maintenance, and reconstructive plastic surgery such as nasal reconstruction.

Future Directions

Multidrug treatment has resulted in a 90% reduction in disease prevalence. The global Hansen disease elimination campaigns of early disease detection, prevention of deformity, and completion of predefined treatment regimens are now replaced by the integration of detection and treatment of cases into the less than adequate primary care framework of endemic countries. The WHO definition of a case of leprosy includes only any patient who is on active MDT and therefore excludes the treatment of Type 1 and 11 reactions (that may occur for up to 10 years after effective MDT) with the ensuing deforming neuropathies. Although specific preventive vaccines are not available, bacille Calmette-Guerin (BCG) is variably effective. The successful mapping of the genome for the M. leprae bacterium and a better understanding of disease pathogenesis may result in more effective prevention and therapies.

The main drawback to treating this eminently curable disease is the limited resource availability in countries where Hansen disease is endemic. Although the decrease in prevalence rates due to MDT is admirable, this has also led to decreased funding of leprosy research and treatment programs. Greater provision of funds and medical expertise by the international community would help overcome this.

Clinical Presentation

Generalized Tetanus varies from mild to severe, depending on the incubation period, usually 2–14 days. It is occasionally delayed by weeks to months after the injury. A more severe clinical picture occurs when the incubation period is less than 8 days and the onset period is less than 48 hours.

In patients with partial or complete immunization, tetanus sometimes occurs as a mild form. It is often more severe in nonimmunized patients. Muscles close to the infection site are more severely affected initially. Typically trismus (lockjaw) and risus sardonicus (a spasmodic tetanic involuntary smile) are early and constant signs.

Subsequently shocklike painful spasms of all muscles are provoked by the slightest disturbance, including sight, sound, or touch, or occur spontaneously. Between the intermittent severe spasms, continuous muscle rigidity is often characterized by the clenched jaw, risus sardonicus, and a stiff back, neck, abdominal wall, and limbs, sometimes associated with laryngeal and respiratory muscle spasms that may cause airway obstruction.

Tetanus patients are fully conscious because this toxin does not affect cortical function or sensory nerves. They experience severe pain with every muscle contraction. The spasms become progressively severe in the first week after onset, gradually improving over 1–4 weeks. Sympathetic overactivity may occur with tachycardia, labile hypertension, and arrhythmias.

Focal Tetanus is an unusual manifestation, and is limited to muscles at the wound site. It is thought to occur when circulating antitoxin neutralizes the toxin, preventing systemic circulation of the toxin. However, this does not prevent the spread of the tetanus toxin regionally. Painful muscle spasms adjacent to the wound site may last a few weeks. Sometimes, focal tetanus proceeds to generalized tetanus. If generalization does not occur, there is eventually good recovery.

Diagnosis

Abdominal rigidity, generalized spasms, trismus, and risus sardonicus are highly characteristic clinical signs of tetanus. They may be mistaken for encephalitis, encephalomyelitis, meningitis, intracranial hemorrhage, or even stiff man syndrome. Normal CSF parameters and absence of an altered level of consciousness differentiate tetanus from primary CNS infections. Certain local conditions, including dental and peritonsillar abscesses, may also mimic tetanus. Hypocalcemic tetany is usually distinguished by carpopedal spasms and a positive Chvostek sign. Phenothiazine toxicity sometimes results in dystonia and opisthotonus mimicking tetanus; prompt response to IV diphenhydramine helps to distinguish this medication-induced partial mimic of tetanus. Epileptic seizures and drug withdrawal reactions also occur in the differential diagnosis.

Fortunately, tetanus has a characteristic clinical picture, because C. tetani organisms are isolated from the wound in only one third of affected patients. There are no specific confirmatory blood studies or CSF analyses for tetanus. Sometimes EMG supports the diagnosis.

Treatment and Prognosis

Tetanus is entirely preventable with immunization. Treatment modalities include appropriate antibiotics and tetanus immunoglobulin, local wound care, control of spasms with muscle relaxants such as benzodiazepines and magnesium sulfate, anticonvulsants, ventilatory support, meticulous nursing care, and maintenance of adequate nutrition and hydration.

The incubation period and time to onset are important predictors of prognosis. If the incubation period is less than 8 days, the onset period is less than 48 hours, and reflex spasms have been present during more than 12– 24 hours, the prognosis is generally poor. With multimodality treatment, mortality from tetanus may be substantially reduced in the coming years throughout the world.

Clinical Vignette

A 27-year-old man was brought to the hospital by his friends who reported he had been “acting strange” before complaining of headache, nausea, and vomiting. He was afebrile and his examination was normal except for anisocoria, palsies of the right seventh and eighth cranial nerves, and a positive Romberg sign. CSF examination revealed 105 WBC (96% lymphocytes), protein 87, glucose 49. CSF VDRL (Venereal Disease Research Laboratory) was positive, as was serum rapid plasma reagin (RPR). HIV testing was negative. He was treated with 14 days of penicillin G 4 million units IV every 4 hours, with complete resolution of his symptoms.

Syphilis, or lues, is an uncommon disorder occurring primarily within the immune-compromised population, particularly in those with AIDS. Treponema pallidum, a spiral bacterium that is difficult to culture in the laboratory, causes syphilis. The diagnosis is made by spirochete identification in material from primary lesions using dark-field microscopy or serologic methods. CNS syphilis occurs in less than 20% of patients with primary infection. Typical of many patients with CNS lues, the diagnosis is made only by clinical signs, particularly the disparate pupillary responses to light and accommodation, along with often subtle findings of posterior spinal cord column and dorsal root ganglion involvement.

Untreated, T. pallidum causes chronic inflammation of CNS cellular and interstitial tissues, culminating in a granulomatous process, producing endarteritis and gummatous lesions. In the United States, syphilis occurs primarily in persons aged 20 to 39 years. Reported rates in men are one and a half times greater than those found in women. The incidence is highest in women aged 20–29 years and men aged 30–39 years.

Cases of primary and secondary syphilis in the United States increased 2% between 2000 and 2001 and 12% between 2001 and 2002. Increases were observed only in men; several outbreaks, associated with high rates of HIV coinfection and high-risk sexual behavior, were seen among men who had sex with men. From 2000 to 2002, the number of primary and secondary syphilis cases decreased 19% among women and 10% among African Americans. Poverty, inadequate health care access, and lack of education are associated with disproportionately high syphilis incidence in certain populations.

Clinical Presentation

There are five classic neurologic presentations: meningitis, meningovascular syphilis, tabes dorsalis, general paresis, and gumma.

Syphilitic meningitis develops early on after primary infection, usually coinciding with the secondary-stage syphilis rash. Common symptoms are nocturnal headache, malaise, stiff neck, fever, and cranial nerve palsies. CSF examination demonstrates increased lymphocyte count and total protein; serum RPR test results are usually positive.

Meningovascular syphilis is a more chronic disorder. Usually evident 20 or more years after initial exposure, it rarely occurs as early as 2 years after the primary untreated infection. Chronic inflammation produces brain or spinal cord infarction leading to cranial nerve palsies, cerebrovascular accidents, seizures, or paraplegia. Argyll Robertson pupils, which are small and irregular and accommodate to near vision but do not react to light or painful stimuli, are present.

Tabes dorsalis develops 10 to 20 years after primary infection, usually in persons aged 25–45 years. Both direct invasion by the spirochete and an immunologic reaction may occur, producing degenerative and sclerotic changes in the posterior nerve root fibers of the spinal cord, spinal ganglia cells, long fibers of the posterior columns of the spinal cord, optic nerves, and oculomotor nuclei. Symptoms may include lightning-like, very brief severe nerve root pains, gastric crisis, and spastic gait, failing vision, and urinary and sexual dysfunction. Optic nerves show progressive primary atrophy; Argyll Robertson pupils are small and irregular. Impaired vibration sense, ataxia, and a positive Romberg sign are present. Knee and ankle jerks are absent. In 54 patients with tabes dorsalis and positive serum VDRL, CSF VDRL and fluorescent treponemal antibody (FTA) test were positive in only 18% and 73%, respectively.

General paresis (dementia paralytica) occurs most commonly in patients older than age 40 years, from direct spirochete invasion of neural tissue causing neuronal degeneration, astrocytic proliferation, and meningitis (Fig. 48-11). Resultant degenerative and sclerotic changes produce a thickened dura mater, chronic subdural hematoma, cortical cell atrophy, and astrocyte proliferation. The frontal lobes are disproportionately affected. Progressive dementia occurs in 60% of patients, but headaches, insomnia, personality change, impaired judgment, disturbed emotional responses, slurred speech, and tremors can also develop. Argyll Robertson pupils are characteristic. RPR test results in blood and VDRL test results in CSF are positive in more than 90% of patients.

Figure 48-11 Neurosyphilis.

Gumma of the brain and spinal cord are rare. Symptoms are consistent with expanding CNS lesions.

Diagnosis and Treatment

Diagnosis is based on serologic tests with blood RPR and CSF VDRL tests for screening and FTA absorption test or microhemagglutination–T. pallidum test for specific confirmation. The CSF usually demonstrates a modest increase primarily in lymphocytic cells, with a moderate protein increase and normal glucose level.

Penicillin is the treatment for all forms of syphilis. Repeated therapeutic blood and CSF levels are necessary to effect a cure if the syphilis stage is treatable.

Future Directions

Although no large-scale randomized trial has compared azithromycin directly to benzathine penicillin, preliminary studies support the efficacy of azithromycin (a single oral dose of 1 or 2 g) in treatment of early-stage syphilis. Evidence does not yet support its use in late- or tertiary-stage disease. Additional data support the use of ceftriaxone in early-stage disease. Ceftriaxone (2 g intramuscular once daily for 10 days) produced similar CSF responses for treatment of neurosyphilis in HIV-infected individuals. In aggregate, the data do not establish the equivalence or superiority of these agents to standard penicillin regimens but support their use as alternatives when penicillin is not a therapeutic option. Concurrent HIV infection may modify the natural history of syphilis, but the overall response to standard therapy has been no different than in HIV-seronegative individuals.