on 18-Jun-2022 (Sat)

The clinical manifestations of enteroviral meningitis depend on host age and immune status. 24,219,220

The findings in neonates contrast to the clinical findings of enteroviral meningitis beyond the neonatal period (>2 weeks), in which severe disease and poor outcome are rare. 24,222

Infants usually present with fever, irritability, feeding difficulties, and rash; the majority of them have a good clinical outcome. 222

A study of 187 children with meningitis identified the following variables to be associated with a positive CSF EV PCR assay result: May to November presentation, a CSF protein concentration < 100 mg/dL, and normal findings on neurologic examination. 223 If ≤1 variable was present, the probability of having EV was 0%.

Headache is nearly always present in adults; photophobia is seen in approximately one-third of patients with EV meningitis. 30 Nonspecific symptoms and signs include vomiting, anorexia, rash, diarrhea, cough, upper respiratory tract findings (especially pharyngitis), and myalgias. Other clues to the presence of enteroviral disease include the time of year (more prevalent in the summer and autumn months), known epidemic disease in the community, exanthems, myopericarditis, conjunctivitis, and specifically recognizable enteroviral syndromes such as pleurodynia, herpangina, and hand-foot-and-mouth disease. 220

In addition, specific clinical stigmata may be associated with certain enteroviral serotypes. 220 For example, echovirus 9 is associated with scattered maculopapular rashes. Herpangina, in particular the finding of painful vesicles on the posterior oropharynx, is associated with coxsackievirus A; the presence of pericarditis or pleurisy may identify coxsackievirus B.

The duration of illness in enteroviral meningitis is usually less than 1 week, with many patients reporting improvement after lumbar puncture, presumably from reduction in intracranial pressure.

A unique clinical situation is seen in children and adults with absent or deficient humoral immunity that impairs clearance of EVs. In persons who are agammaglobulinemic, a chronic enteroviral meningitis or meningoencephalitis may develop and last several years, often with a fatal outcome 219,220 ; this syndrome has been designated chronic enteroviral meningoencephalitis in agammaglobulinemia (CEMA). 227 CEMA can manifest with headache, seizures, hearing loss, lethargy or coma, weak- ness, ataxia, paresthesias, loss of cognitive skills, and quadriplegia and can be fatal. Extraneurologic manifestations may include a chronic skin rash, fever, arthralgias, hepatitis, myositis, peripheral edema, endocri- nopathies, retinopathy, and myocarditis

In contrast, during an outbreak of EV 71 infection in Taiwan in patients 3 months to 8.2 years of age, the chief neurologic complaint was rhombencephalitis (seen in 90% of children), which carried a case-fatality rate of 14%. 224

Meningitis associated with HSV-2 infection is usually characterized by stiff neck, headache, and fever. 19,24

HSV-2 is the main cause of recurrent benign lymphocytic meningitis (Mollaret meningitis), which can develop in up to 10 recurrent episodes of meningitis that last 2 to 5 days followed by spontaneous recovery. 20

In sharp contrast to encephalitis, acyclovir has not been shown to improve outcomes in meningitis, a benign illness

The majority of patients are women in their fourth decade of life who have no active or history of genital herpes. HSV-1 and EBV can also occasionally cause recurrent meningitis. 20

VZV is the second most common herpesvirus causing aseptic meningitis, with the majority of cases occurring without the typical vesicular rash (zoster sine herpete). 228

An acute presentation with a mononucleosis-like picture with rash, pharyngitis, lymphadenopathy, and splenomegaly should suggest EBV infection. 24

West Nile virus Neuroinvasive disease develops in approximately 1% of patients with WNV infections during the summer months in the United States. 27 Patients can present with meningitis, encephalitis, or AFP; up to 50% of patients with encephalitis have concomitant chorioretinitis. 229 Patients with meningitis typically present with fever, headache, nausea, vomiting, stiff neck, photophobia, and occasionally a maculopapular rash. 230

In addition, patients may have persistent headaches, abnormal neurologic examination findings, neurocognitive impairment, and chronic fatigue years after infection. 231,232

Mumps Virus In patients with mumps, CNS symptoms usually follow the onset of parotitis, when present, by about 5 days.

The most frequent clinical manifestation of mumps CNS infection is the triad of fever, vomiting, and headache (Table 87.8). 233 The fever is usually high and lasts for 72 to 96 hours. Salivary gland enlargement is present in only about 50% of patients. Other findings include neck stiffness, lethargy or somnolence, and abdominal pain.

Defervescence is usually accompanied by clinical recovery, and in uncomplicated cases the total duration of illness is 7 to 10 days. Rarely, mumps may cause encephalitis, seizures, polyradiculitis, polyneuritis, cranial nerve palsies, myelitis, Guillain-Barré syndrome, and death

Patients with bacterial meningitis classically present with fever, headache, meningismus, and signs of cerebral dysfunction (i.e., confusion, delirium, or a declining level of consciousness ranging from lethargy to coma) (Table 87.9). 60

A change in the child’s affect or state of alertness is one of the most important signs of meningitis

In children 1 to 4 years of age, fever, vomiting, and nuchal rigidity are the most common initial symptoms. 234

Accordingly, physicians should have a low threshold for performing lumbar puncture in patients at high risk for bacterial meningitis, given the serious nature of this disease

In a review of 493 cases of acute bacterial meningitis in adults, 71 the triad of fever, nuchal rigidity, and change in mental status was found in only two-thirds of patients, but all had at least one of these findings

In a study of 1412 episodes of community-acquired bacterial meningitis in the Netherlands, the triad of fever, neck stiffness, and altered mental status was present in only 41% of episodes, 60 with the most common clinical manifestations being headache (83%), neck stiffness (74%), fever (74%), altered mental status (71%), and nausea (62%).

The meningismus may be subtle, marked, or accompanied by the Kernig or Brudzinski sign or both. 238

However, in a prospec- tive study of 297 adults with suspected meningitis, the diagnostic accuracy of meningeal signs was poor; both Kernig and Brudzinki signs had a 5% sensitivity, and nuchal rigidity a 30% sensitivity, 239 indicating that they did not accurately distinguish patients with meningitis from those without meningitis. Therefore the absence of these findings does not rule out the diagnosis of bacterial meningitis.

Cranial nerve palsies (especially those involving cranial nerves III, IV, VI, and VII) and focal neurologic deficits (aphasia, hemiparesis, monoparesis) are seen in 9% and 22% of cases, respectively. 47

Cranial nerve palsies probably develop as the nerve becomes enveloped by exudate in the arachnoid sheath surrounding the nerve, or they may be a sign of increased intracranial pressure.

Seizures occur in 14% of patients. 47 Focal neurologic deficits and seizures arise from cortical and subcortical ischemia, which results from inflammation and thrombosis of blood vessels, often within the subarachnoid space.

In a study of 696 patients with community-acquired bacterial meningitis, cerebral infarction occurred in 174 (25%) episodes and was seen in 128 (36%) of 352 patients with pneumococcal menin- gitis 240 ; an unfavorable outcome occurred in 62% of patients with cerebral infarction. Diffuse cerebral disseminated intravascular coagulation may be another explanation for cerebral infarction complicating pneumococcal meningitis.241

Papilledema is seen in less than 5% of cases early in infection, and its presence should suggest an alternative diagnosis

With disease progression, signs of increased intracranial pressure may develop, including coma, hypertension, bradycardia, and palsy of cranial nerve III.

Endocarditis complicates 2% of episodes of community- acquired bacterial meningitis in adults and is also associated with a high case-fatality rate 243 ; clues suggesting the diagnosis of endocarditis in patients with bacterial meningitis are cardiac murmurs, persistent or recurrent fever, a history of heart valve disease, and S. aureus as the causative pathogen

To further characterize the accuracy and precision of the clinical examination in adult patients with acute meningitis, 845 episodes of acute meningitis (confirmed with lumbar puncture or autopsy) in patients aged 16 to 95 years were reviewed 244 ; the majority of patients in this review had acute bacterial meningitis, although 62 had tuberculous or “aseptic” meningitis. The results demonstrated that individual items of the clinical history (i.e., headache, nausea, and vomiting) had a low accuracy for the diagnosis of acute meningitis in adults. However, on review of the accuracy of physical examination findings, the absence of fever, neck stiffness, and altered mental status effectively eliminated the likelihood of acute meningitis; the sensitivity was 99% to 100% for the presence of one of these findings in the diagnosis of acute meningitis

The clinical presentation in older adults differs significantly from that younger adults and represents a diagnostic challenge that can delay appropriate therapy. 245–247 In a study of 619 adults with community- acquired meningitis, elderly patients were less likely to complain of headache, stiff neck, photophobia, and nausea, but more likely to present with fever or with abnormal neurologic examination findings. 246 Elderly patients also had higher rates of abnormal cranial imaging findings and worse clinical outcomes.

In a study of 185 patients 65 years of age and older, the diagnosis of community-acquired bacterial meningitis was more difficult because of the absence of characteristic meningeal signs 233 ; compared with adult patients younger than 65 years, older patients showed greater neurologic severity, with a high number presenting with coma on admission, seizures, and hemiparesis.

In a study of 160 adults with health care–associated ventriculitis or meningitis, older patients had more comorbidities, altered mental status, and worse CSF abnormalities (higher CSF pleocytosis and protein, and lower CSF glucose concentrations). 248

In patients with head trauma, the symptoms and signs of meningitis may be present as a result of the underlying injury and not meningitis.

In patients who have sustained a basilar skull fracture in which a dural fistula is produced between the subarachnoid space and the nasal cavity, paranasal sinuses, or middle ear, a common finding is rhinorrhea or otorrhea secondary to a CSF leak 70 ; in these patients, meningitis may be recurrent and is most commonly caused by S. pneumoniae. Fortunately, the incidence of posttraumatic CSF leaks in patients with head trauma is low (0.1%–0.2%) 249

The diagnosis of bacterial meningitis in neutropenic patients requires a high index of suspicion, because symptoms and signs may initially be subtle because of the impaired ability of the patient to mount a subarachnoid space inflammatory response. 189 In all of these subgroups of patients, altered or changed mental status should not be ascribed to other causes until bacterial meningitis has been excluded with CSF examination

A specific etiologic diagnosis in patients with bacterial meningitis may be suggested by certain symptoms or signs. 189 About 50% of patients with meningococcemia, with or without meningitis, present with a prominent rash located principally on the extremities. Early in the course of illness, the rash is typically erythematous and macular, but it quickly evolves into a petechial phase with further coalescence into a purpuric form.

The rash often matures rapidly, with new petechial lesions appearing during the physical examination.

In one review of the clinical manifesta- tions of 255 patients with acute meningococcal meningitis, 250 a petechial rash was observed in three-fourths of the patients; the rash was more commonly seen in children and adults younger than 30 years (81%) than in patients 30 years and older (62%). However, others have observed a rash to be present in only up to 26% of cases and (if present) to be more likely to be scanty or more atypical than that seen in patients with meningococcal septicemia. 251 A similar rash may also be seen in splenectomized patients with rapidly overwhelming sepsis caused by S. pneumoniae, H. influenzae type b, or Capnocytophaga canimorsus (seen after a dog bite).

Patients with L. monocytogenes meningitis have an increased tendency to have seizures and focal deficits early in the course of infection, and some patients may present with ataxia, cranial nerve palsies, or nystagmus secondary to rhombencephalitis 117–119 ; however, patients with Listeria meningitis may not present with any focal signs.

In a large review of CNS infections caused by L. monocytogenes, 118 the most frequent findings were fever, headache, and altered sensorium but 42% had no meningeal signs.

In a nationwide French study, a total of 818 cases of listeriosis were analyzed of which 252 (31%) were neurolisteriosis. 252 The majority of patients with neurolisteriosis presented with encephalitis (87%), with brainstem involvement in 17%. The most common findings were nuchal rigidity (65%), aphasia (19%), seizures (18%), and focal limb weakness (12%)

Finally, another large study of 375 patients with neurolisteriosis in the Netherlands documented that mortality has remained high, especially in older patients and those with concomitant bacteremia. 54

The clinical manifestations of neurosyphilis that have been described are based on studies compiled before the availability of penicillin, and it is not known whether the clinical findings of symptomatic neurosyphilis have been modified in the antibiotic era or by associated HIV infection. 166

Although the clinical manifestations of neurosyphilis are numerous, only patients with acute meningitis and meningovascular syphilis are discussed here.

Patients with syphilitic meningitis usually present in a manner similar to that of patients with other forms of aseptic meningitis—that is, with complaints of headache, nausea, and vomiting. In one series, these complaints were present in 91% of patients. 237 Meningismus occurred in 59% and fever in less than half of the patients with syphilitic meningitis. Seizures occurred in 17% of patients, whereas cranial nerve palsies were found in 45% of cases (most commonly cranial nerves VII and VIII, followed by II, III, VI, and V).

Focal abnormalities such as hemiplegia, aphasia, and mental status changes were seen less commonly. Syphilitic meningitis rarely affects the spinal cord

Meningovascular syphilis is clinically distinguished from syphilitic meningitis temporally and on the basis of focal neurologic findings as a result of focal syphilitic arteritis, which almost always occurs in association with meningeal inflammation. 166

Most patients experience weeks to months of episodic prodromal symptoms and signs, including headache or vertiginous episodes, personality changes (e.g., apathy or inattention), behavioral changes (e.g., irritability or memory impairment), insomnia, or seizures. Focal deficits, which reflect episodes of ischemia in regions of the brain with involved blood vessels (usually in the distribu- tion of the middle cerebral artery), may also occur; if untreated, these deficits may progress to a stroke syndrome with attendant irreversible neurologic deficits

Case reports and small series have suggested that patients with HIV infection are more likely to progress to develop neurosyphilis and have accelerated disease courses. 167–169 However, few clinical data currently support these hypotheses.

Neuroborreliosis due to B. burgdorferi, Borrelia garinii, or Borrelia afzelii is identified in approximately 15% of infected individuals. 254

Meningitis is the most common neurologic manifestation of acute disseminated Lyme disease, usually following erythema migrans by 2 to 10 weeks 170 ; however, only about 40% (range, 10%–90%) of cases of Lyme meningitis are preceded by this characteristic rash. 170,171

Headache is the single most common symptom (30%–90% of patients) in Lyme meningitis, whereas neck stiffness is seen in only 10% to 20% of cases. Photophobia, nausea, and vomiting are intermediate in frequency between headache and neck stiffness

About two-thirds of patients have accompanying systemic symptoms, including malaise, fatigue, myalgias, fever, arthralgias, and involuntary weight loss

In untreated cases, the duration of symptoms ranges from 1 to 9 months. Patients typically experience recurrent attacks of meningeal symptoms lasting several weeks and alternating with similar periods of milder symptoms. 5,66,170,171,254

About half of patients with Lyme meningitis have mild cerebral symptoms consisting most commonly of somnolence, emotional lability, depression, impaired memory and concentration, and behavioral symptoms. 170,254 These symptoms may fluctuate in severity in untreated patients before resolution.

Transverse myelitis, spastic paraparesis or quadriparesis, disturbances of micturition, and Babinski sign are also reported during this stage

Approximately 50% of patients also have cranial neuropathies. Facial nerve palsy is the most common (80%–90%) of the cranial nerve palsies overall and occurs with rapid onset (often in 1–2 days), frequently accompanied by slight ipsilateral facial numbness or tingling or ipsilateral ear or jaw pain. The facial palsy is bilateral in 30% to 70% of cases, although the two sides are affected asynchronously in most cases.

Other cranial nerves affected less commonly are cranial nerves II and III, the sensory portion of V, VI, and the acoustic portion of VIII. Recovery usually takes place within 2 months.

In a large study of 431 patients with neuroborreliosis in Denmark, residual symptoms were seen in 28% and were associated with a delay in therapy. 254

Amebas PAM occurs in two forms. 169–171 The acute form (incubation period, 3–8 days) is characterized by the sudden onset of high fever, photophobia, bifrontal or bitemporal headache, nuchal rigidity, and progression to stupor or coma and is usually indistinguishable from acute bacterial meningitis, although focal neurologic signs and seizures are more common in PAM.

A review of 138 cases of PAM in the United States from 1962 to 2015 showed that the mortality rate was 97%; a few recent cases have been described in lakes in Minnesota (a result of global warming) and related to tap water. 255

Because of early involvement of the olfactory area, early symptoms of abnormal smell or taste may be reported. Confusion, irritability, and restlessness progress to delirium, stupor, and, finally, coma. Death in untreated patients generally occurs within 2 to 3 days from the onset of symptoms

The rapid progression of infection presents challenges to identify N. fowleri and initiate therapy before the onset of severe symptoms and death. 172 Therefore the key to early diagnosis is physician awareness and clinical suspicion. 256,257

In contrast, the subacute or chronic form of PAM manifests more insidiously with low-grade fever, headache, and focal signs (e.g., hemiparesis, aphasia, cranial nerve palsies, visual field disturbances, diplopia, ataxia, seizures) 169,170 ; the olfactory bulbs are usually spared. Deterioration occurs over a period of 2 to 4 weeks until death. However, longer durations of illness have also been reported (range, 5–18 months)

Angiostrongylus cantonensis Symptoms of meningitis begin 6 to 30 days (typically 1–2 weeks) after the ingestion of raw mollusks or other sources of the parasite. 176–178 Findings include severe headache (90%), stiff neck (56%), paresthesias (54%), and vomiting (56%). Moderate fever is present in about half of the cases.

In a review of 18 cases in Hawaii from 2001 to 2005, 94% of patients had headache and 65% had sensory symptoms consisting of paresthesias, hyperesthesias, and/or numbness; those symptoms lasted a median of 17 and 55 days, respectively. 258 Disease usually resolves spontaneously after 1 to 2 weeks, but headaches and paresthesias can persist for weeks to months. 178