Inflammatory Diseases of the Meninges
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Neuroimaging is of major importance in all cases of suspected infectious meningitis in order to get quick information about the extent of the disease, typical lesion patterns, and potential complications, such as hydrocephalus, involvement of the underlying brain parenchyma, or vasculitis. In bacterial meningitis, abnormal and asymmetrical enhancement of the leptomeninges and the subarachnoid space is typical. Initial neuroimaging has to rule out infectious foci of the skull base such as purulent sinusitis or mastoiditis. In patients with focal deficits or seizures, MRI is the tool of choice to diagnose vascular or septic complications. Neoplastic, viral, or fungal infections of the CNS may present with similar changes of the meninges; however, fungal meningitis normally causes a thicker and more nodular enhancement. In case of basal accentuation of the leptomeningeal contrast enhancement and conspicuous signal changes in the basal cisterns, one has to consider tuberculous meningitis for differential diagnosis, especially in patients with HIV infection. Non-infectious causes of meningeal enhancement comprise several primary and secondary tumors (e.g., CNS lymphoma, medulloblastoma, or breast cancer), granulomatous diseases, intracranial hypotension, and post-operative changes.
KeywordsBacterial Meningitis Cranial Nerve Palsy Tuberculous Meningitis Intracranial Hypotension Basal Cistern
Inflammation of the protective membranes covering the brain and spinal cord, known collectively as the meninges, may develop in response to a number of causes, most prominently bacteria and viruses, but also fungi, parasites, radiation, or neoplasm. Moreover, a number of systemic diseases, such as sarcoidosis or vasculitis, may involve the meninges.
In cases of acute infectious meningitis, rapid diagnosis and identification of the probable pathogen is mandatory, as early effective antimicrobial treatment is of major importance. While examination of the CSF, laboratory analysis, and biopsy remain the gold standard to identify the infectious agent, neuroimaging plays an important role in visualizing typical lesion patterns, the extent of the disease, and the potential involvement of deeper brain structures. In addition, imaging may help to identify sources of infection, such as fractures of the skull base, infection of the temporal bone or mastoid, and to rule out other, non-infectious causes of inflammatory disease of the meninges, such as granulomatous or neoplastic processes.
2 General Pathophysiological Considerations
Anatomically, the meninges consist of three layers: the dura mater; the arachnoid mater; and the pia mater. However, for a better understanding of meningeal inflammation in neuroimaging, it is helpful to use the anatomic—functional classification of lepto- and pachymeninges (Smirniotopoulos et al. 2007).
Probable causes of predominant leptomeningeal contrast enhancement in neuroimaging
Type of enhancement
Asymmetrical, thin, linear enhancement of the leptomeninges and the SAS, typically affects convexities
Tuberculous meningitis predominantly affects the basal meninges and cisterns, often cranial nerve involvement
Thin, linear enhancement
Often no enhancement
Thick, lumpy, or nodular enhancement
May also cause pachymeningeal enhancement
Wide range from thin and linear to thick, lumpy, or nodular enhancement; may also involve dural structures
May also involve underlying cortex or pachymeningeal structures; most often in CNS lymphoma, breast cancer, medulloblastoma, and ependymoma
Wide spectrum of leptomeningeal (and pachymeningeal) enhancement, especially in basal cisterns, often cranial nerve involvement
Probable causes of predominant pachymeningeal contrast enhancement in neuroimaging
Type of enhancement
Intracranial hypotension, e.g., after surgery, lumbar puncture
Linear enhancement of the dura and falx cerebri with global homogeneous thickening
Additional findings: enlargement of the pituitary gland; low cerebellar tonsils; subdural effusions/hemorrhage
Curvilinear enhancement adjacent to the bulky tumor (“dural tail”)
Thick, nodular irregular enhancement
Most often from breast cancer and prostatic cancer
Granulomatous diseases, e.g., sarcoidosis, Wegener’s granulomatosis
Wide spectrum of pachymeningeal and leptomeningeal, often irregular enhancement, typically affecting basilar meninges and the cranial nerves
3 Bacterial Meningitis
3.1 Epidemiology, Clinical Presentation, Therapy
Bacterial meningitis is the purulent infection of the cerebral and spinal leptomeninges. The incidence in the U.S. and Western Europe is about 5–10/100,000 persons. Meningitis is the most common form of CNS infection in children. Mortality ranges between 20 and 30 %, and neurological sequelae occur in 15–40 % of surviving patients. Infection may arise from hematogenous spread during systemic infection, from a chronic suppurative focus, or per continuitatem during acute or chronic infections of the paranasal sinus, the middle or inner ear, or the mastoid. Another path of infection is brain injury with open or covered disruption of the dura mater, especially when the paranasal sinus or the air-filled cavities of the temporal bone are involved in the fracture.
The type of microorganism responsible for meningitis depends on the age of the patient and the way of infection: while in neonates the most common pathogens are group-B Streptococcus and Escherichia coli, in infants it is Haemophilus influenzae, Streptococcus pneumoniae, and Neisseria meningitidis. In adolescents and adults Streptococcus pneumoniae and Neisseria meningitidis are found most often. In a study on the epidemiology of 696 episodes of community-acquired meningitis in adults, S. pneumoniae was determined to be the responsible pathogen in 51 %, N. meningitides in 37 %, and Listeria monocytogenes in 4 % of cases (van de Beek et al. 2004); however, due to vaccination against H. influenzae and S. pneumoniae, epidemiology of bacterial meningitis changes constantly.
In patients with ENT infections or after splenectomy, S. pneumoniae are the most common causative species in bacterial meningitis. After neurosurgery and in patients with open brain injury or with dural fistulae, S. aureus and Pseudomonas aeroginosa are found frequently beside S. pneumoniae and H. influenzae. Immunocompression and alcoholism are associated with Listeria monocytogenes, different types of Enterococcus, S. aureus, and S. pneumoniae.
In most of the cases meningitis starts with unspecific prodromes such as abnormal fatigue growing pains that may last for several hours or days before the onset of meningeal symptoms. On admission more than 90 % of patients with bacterial meningitis present with at least two of the following four symptoms: fever; neck stiffness; changes in mental status—the “classical triad” and headache. Headache is the most common symptom in meningitis and is found in more than 80 % of the patients. Further symptoms indicating irritation of the leptomeninges are nausea, conjunctivitis, hyperesthesia, and hyperacusis. Approximately one fourth of the patients develop petechial rash, with N. meningitidis as the most frequent causative pathogen. One third of the patients have focal neurological deficits such as cranial nerve palsy, aphasia, hemiparesis, or seizures. These symptoms are associated with a lower level of consciousness and indicate a more severe course of the disease; they are more frequent in pneumococcal than in meningococcal meningitis (van de Beek et al. 2004). Bacterial meningitis may be complicated by cortical and subcortical infarctions due to septic vasculitis of the cerebral arteries, hydrocephalus, brain edema, empyema, or pyogenic abscess. Systemic complications result from bacteremia and comprise the Waterhouse–Friderichsen syndrome (e.g., meningococcal sepsis with disseminated intravasal coagulation and petechial bleeding), the adult respiratory distress syndrome (ARDS), and septic emboli into the lung or peripheral vessels.
Empirical antimicrobial treatment has to be started immediately after lumbar puncture and sampling blood cultures. Therapeutic regimens comprise antibiotic combinations from the penicillin, rifamycine, cephalosporin, and aminoglycoside groups. Antiedematous treatment with dexamethasone before or with the first dose of antimicrobial therapy has been proven to reduce the risk of unfavorable outcome, including mortality and neurological complications (Weisfelt et al. 2006). In cases of transmitted bacterial meningitis from infections of the sinus, mastoid, or middle ear, surgical removal of the focus is mandatory.
In uncomplicated cases and the initial phase of the disease, neuroimaging might reveal normal findings of the brain and meninges; however, a CT exam should be performed in all patients with suspected bacterial meningitis prior to lumbar puncture to rule out brain edema and potential herniation. As a sign of beginning disturbance of the CSF circulation, CT might reveal mild enlargement of the ventricles and the SAS; the basal cisterns can be effaced. After administration of contrast medium, CT might demonstrate linear leptomeningeal enhancement in the sulci and cisterns that might increase during the course of the disease, especially if antibiotic treatment is not started or is started with delay (Kastrup et al. 2005). Parenchymal lesions are often difficult to distinguish; however, CT is a simple and fast tool for monitoring critically ill patients and to rule out severe complications of bacterial meningitis, such as resorptive hydrocephalus, swelling, venous thrombosis, or infarction. Besides cerebral structures, CT provides important information about probable pathologies of the skull base, the temporal bone, and the nasal sinus, such as fractures, purulent sinusitis, otitis media, or mastoiditis; therefore, CT of patients with bacterial meningitis should always include a reconstruction of the skull base in the “bony window”.
3.3 Differential Diagnosis
Isolated enhancement of the leptomeninges is not specific for bacterial infection. Viral or fungal meningitis may present with similar changes of the meninges and the SAS, however, fungal meningitis normally causes a thicker, lumpy, or nodular enhancement in the SAS. Subarachnoid hemorrhage (SAH), acute stroke, high inspired oxygen, or imaging artifacts may cause an increased FLAIR signal in CSF that can be mistaken for infectious exudates in the SAS. Additionally, several primary and secondary tumors, e.g., medulloblastoma, breast cancer, or CNS lymphoma, may cause leptomeningeal enhancement as well, known as “carcinomatous meningitis.” In the majority of cases, clinical presentation, medical history, and analysis of the CSF will provide the clue for differential diagnosis.
4 Tuberculous Meningitis
4.1 Epidemiology, Clinical Presentation, Therapy
In Central Europe tuberculous meningitis (TBM) has become relatively rare; however, due to socio-economic changes and the increasing number of HIV infections, the incidence of TBM is rising again. Worldwide, more than 8 million patients come down with TB annually. The TBM is the most frequent manifestation of CNS TB and is more common in children. The meninges are affected secondarily through hematogenous spread in patients with miliary tuberculosis or from ruptured tuberculous granulomata. In adults, the primary focus often cannot be identified.
Clinically, TBM starts with unspecific symptoms such as fatigue, ill humor, diminished appetite, elevated temperature, and headache that may last for several weeks. Signs of meningeal affection often begin slowly and without disturbances of consciousness. Because of the predominant affection of the basal parts of the meninges, TBM frequently causes cranial nerve palsy, primarily of the abducent nerve, the oculomotor nerve, and the facial nerve. In severe cases TBM may affect also caudal cranial nerves and spinal nerves. Hydrocephalus and secondary vasculitis are main complications. Mortality is still 10–20 %; it is even higher in underdeveloped countries and after delayed diagnosis.
Treatment has to be started as soon as possible, even without direct proof of the causative pathogenic agent, when clinical presentation and liquor results (e.g., moderate pleocytosis of 100–200 cells, strong positive lactate and protein, low glucose) suggest the diagnosis of TBM. Modern regimens comprise an antituberculostatic combination with Isoniazid, Rifampicin, Pyracinamid, or Ethambutol for at least 2 months or longer, when CSF is still positive for tuberculosis. In complicated cases intrathecal injection of streptomycin has been proposed as adjunctive treatment. Steroids should be given to prevent secondary vasculitis.
Further imaging findings in TBM comprise hydrocephalus malresorptivus in approximately 50–80 % and infarcts due to secondary vasculitis in 30–40 % of TBM cases. Both ischemic and hemorrhagic infarcts are diagnosed best with DWI and T2*-sequences on MRI; however, studies comparing CT and MRI have shown that advantages of MRI are minimal in terms of hydrocephalus and basal enhancement (Garg 2010). Advantages of MRI are confirmed for patients with cranial nerve palsy: Imaging should always be performed in the axial and coronal plane using contrast-enhanced T1-weighted images with fat saturation to check for potential cranial nerve enhancement in the basal cisterns, the cavernous sinus, or the orbital cavities (see also " Neurotuberculosis").
4.3 Differential Diagnosis
Other causes of infectious and carcinomatous meningitis have to be considered for differential diagnosis. While TBM causes predominantly basilar meningeal enhancement, bacterial meningitis affects more often the leptomeninges of the convexities. Furthermore, the combination of meningitis and parenchymal lesions suggests tuberculosis; however, some primary or metastatic tumors and some parasitic CNS infections (e.g., coccidiomycosis) may be indistinguishable from TBM.
5 Viral Meningitis
5.1 Epidemiology, Clinical Presentation, Therapy
Isolated inflammation of the meninges due to virus infection is rare. Most viruses cause encephalitis or meningoencephalitis (described in detail in Chap. 9). Virus predominantly affecting leptomeningeal structures and the underlying cortex are HSV type 1, the most common causative agent for viral meningoencephalitis, and the arbovirus, that causes tick-borne meningoencephalitis (TBME). Additionally, parainfectious meningitis is a common finding in many systemic viral infections and after antiviral vaccination. Initial symptoms of viral meningitis are lassitude, fever, headache, and an altered sensorium. Epileptic seizures, aphasia, hemiparesis, clouded consciousness, or psychotic symptoms indicate an advanced “encephalitic state” of viral CNS infection. Analysis of the CSF might reveal mild, mononuclear pleocytosis (< 300 cells/m³), normal glucose and lactate, and normal or elevated protein. Specific treatment with antiviral chemotherapeutics (e.g., acyclovir, gancyclovir, foscarnet) is not always possible and depends on the causative agent which should be diagnosed with PCR.
5.3 Differential Diagnosis
In cases of isolated viral meningitis, other infectious and neoplastic diseases, especially bacterial meningitis, have to be excluded. The diagnosis is made by testing of the CSF. In case of HSV meningoencephalitis, differential diagnosis includes paraneoplastic (limbic) encephalitis, ischemia, infiltrating neoplasm, other encephalitides (e.g., neurosyphilis), and status epilepticus.
6 Fungal Meningitis
6.1 Epidemiology, Clinical Presentation, Therapy
Fungal infections of the CNS are most frequent in immunocompromised patients with AIDS, long-lasting diabetes mellitus, or after organ or bone marrow transplantation. Fungal hyphae (e.g., Candida albicans) primarily affect the meningeal microcirculation, whereas infections with Cryptococcus neoformans, Aspergillus fumigatus, or Aspergillus flavus involve predominantly larger cerebral vessels, leading to encephalitis, brain abscess, or vasculitis. The most common fungal infection of the CNS is cryptococcal meningoencephalitis, followed by aspergillosis and candidiasis. Cryptococcal meningoencephalitis manifests weeks after asymptomatic lung infection with clinical symptoms of basal meningitis, cranial nerve palsy, and hydrocephalus. The diagnosis is made through direct confirmation of the fungus in the CSF. Even under intensified treatment with amphotericin B and 5-flucytosine, mortality of cryptococcal meningoencephalitis is high; treatment is successful in only 30–50 % of cases.
Aspergillus may reach the CNS via hematogenous spread or through direct invasion from sinunasal aspergillosis. The infection manifests predominantly with solitary or multiple brain abscess or granulomata, less often with meningitis or ventriculitis. Mortality of CNS infection with Aspergillus is extremely high.
Cryptococcal meningoencephalitis typically manifests with diffuse meningeal enhancement and ventriculitis beside characteristic cystic, punctuate lesions in the basal ganglia due to cryptococcal invasion of the perivascular spaces, the “soap-bubble lesions” (Kastrup et al. 2005; Hähnel et al. 2005). Hydrocephalus is found more often in immunocompetent patients as arachnoid reactions with exudates in the basal cisterns often do not manifest in immunocompromised individuals. Generally, fungal meningitis may cause subarachnoid hyperintensity on DWI, predominantly around the frontal lobe (Kawaguchi et al. 2012).
Imaging features of Aspergillus meningeal infection comprise pachymeningeal enhancement nearby the affected nasal sinus or the orbit; typically, bony structures are involved in the inflammatory process. More than 50 % of the patients develop hemorrhagic infarctions due to vasculitis of the perforating arteries of the basal ganglia. Parenchymal aspergillosis may appear as edematous and hemorrhagic lesions or solid, ring-like enhancing “tumoral” lesions with low signal intensity on T2-weighted images, which may be due to paramagnetic elements such as manganese and iron as well as blood-breakdown products. As laboratory findings of fungal infection do not always confirm the causative pathogen, knowledge of neuroradiological appearance of aspergillosis is helpful for early diagnosis (see also " Fungal infections").
6.3 Differential Diagnosis
Other infectious and neoplastic diseases, especially bacterial meningitis and TBM, have to be excluded. Fungal meningitis often causes a thicker and lumpier meningeal enhancement than bacterial or viral meningitis. In case of pachymeningeal enhancement and involvement of the skull base, neoplasms arising from the nasopharynx of the sinus have to be ruled out.
7.1 Epidemiology, Clinical Presentation, Therapy
Syphilis is a curable sexually transmitted disease caused by the spirochete Treponema pallidum. The use of penicillin has reduced the incidence of syphilis during the past century; however, the trend has reversed since the 1980s due to the exchange of sex for drugs, unprotected sex, and the number of people with multiple sexual partners. The incidence of syphilis in industrialized countries is approximately 2–4/100,000 persons. The central nervous system may be involved at any stage of the infection in about 5–10 % of untreated patients; it is most common in patients with HIV infections. Neurosyphilis (Neurolues) is classified into four syndromes: syphilitic meningitis; meningovascular syphilis; as well as parenchymatous and gummatous neurosyphilis, these latter ones ending in general paresis and tabes dorsalis.
Syphilitic meningitis occurs usually in the second stage of the disease within the first 2 years after infection. It is thought to be the consequence of direct meningeal inflammation due to small-vessel arteritis. Patients present with headache, meningeal irritation, and cranial nerve involvement, especially the optic nerve, facial nerve, and the vestibulocochlear nerve. Meningovascular syphilis is assigned to the tertiary or late stage of syphilis. After prodromal symptoms that may last for weeks to months, focal deficits with unilateral numbness, paresthesias, hemiparesis, headache, vertigo, or psychiatric abnormalities are identifiable. These symptoms are caused directly by the inflammation of the meninges and the parenchyma or secondarily by infarctions and (aneurysm associated) bleedings due to vasculitis. The first-choice treatment for all manifestations of syphilis, including neurolues, is penicillin.
There is only little systematic data about neuroradiological findings in neurosyphilis. Approximately one-third of the patients have normal findings (Brightbill et al. 1995). The majority of cases presents with non-specific white matter lesions or cerebral infarctions, less often with cerebral gummata. Syphilitic meningitis is a rare finding: The leptomeninges may present with thick and lumpy enhancement; predominantly the basal cisterns and the prepontine SAS are affected. In case of cranial nerve palsy, the involved nerve shows swelling and increased enhancement. Vasculitis is a common finding in MRA or DSA. Typical features include stenosis and interruption of large and medium-large arteries, and vasculitic aneurysms (see also " Neurolues").
7.3 Differential Diagnosis
In case of isolated syphilitic meningitis, other granulomatous diseases, especially tuberculosis, have to be excluded. The diagnosis is made by serological testing of the CSF and blood.
8.1 Epidemiology, Clinical Presentation, Therapy
Sarcoidosis is a multisystem inflammatory disease characterized by non-caseating epithelioid-cell granulomas. Women are affected more frequently than men, and the onset of the disease is in the third and fourth decade. The CNS is involved in approximately 10 % of cases. In up to 50 % of cases, neurosarcoidosis is asymptomatic or self-limiting, and the remainder develop a chronic relapsing–remitting course of the disease. Typically, patients present with cranial nerve palsy, most often the facial nerve or the abducens nerve is affected. Further symptoms comprise meningeal irritation, signs of increased intracranial pressure, seizures, and hypothalamic or pituary gland dysfunction (e.g., diabetes insipidus). A specific treatment is not known, but corticosteroids are useful in most patients.
Plain radiography and native CT may reveal osteolytic skull lesions. Contrast-enhanced CT and MRI will show a wide spectrum of leptomeningeal enhancement, especially of the basal SAS, and cranial nerve involvement; therefore, imaging of neurosarcoidosis should always include contrast-enhanced T1-weighted images with a slice thickness of 1–2 mm. Typically, neurosarcoid infiltration affects the infundibulum, chiasma, and hypothalamus. The granulomatous changes of the pachymeninges and in the SAS show focal or diffuse low signal intensity on T2-weighted images and isointense on T1-weighted images. More than 50 % of the patients present with periventricular hyperintense lesions on FLAIR and T2-weighted images, representing perivascular infiltrates in the Virchow–Robin spaces and vasogenic edema due to vasculitis of the small arteries. Diffusion-weighted imaging helps to distinguish acute cytotoxic edema from neurosarcoid-induced vasogenic edema (see also " Cerebral vasculitis" and " Granulomatous disease").
8.3 Differential Diagnosis
Known as the “great mimicker,” differential diagnosis of neurosarcoidosis should include all types of meningitis, as well as neoplastic infiltration of the dura or the meninges (e.g., meningioma). The diagnosis is made by analysis of the chest X-ray, laboratory findings, and the CSF. In unclear cases, biopsy has to be considered for validation of the diagnosis.
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