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Abstract
Chronic meningitis is defined as the persistence of clinical symptoms and signs of meningitis, with or without abnormal cerebrospinal fluid, for more than four weeks. In as many as one third of cases, no cause is found. In the remainder, infective, neoplastic and so-called aseptic disorders may be identified. Important infective causes include partially treated bacterial (pyogenic), tuberculous, syphilitic, Lyme and fungal meningitis. Sarcoidosis, Behçet’s disease, vasculitis and drugs are major non-infective, non-malignant causes. The definitive diagnosis of the cause of chronic meningitis may be made only after extensive investigation. This review describes the clinical features and causes of chronic and recurrent meningitis, and provides an algorithm for investigation and treatment.
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Chronic meningitis is defined arbitrarily as a syndrome of meningeal inflammation, on the basis of the clinical features and/or cerebrospinal fluid (CSF) findings, persisting for four weeks or more. Patients may present with headache, which can be mild or severe, in varying combination with fever, a stiff neck, and focal neurological signs. Recurrent meningitis may occur in a patient with chronic meningitis when clinical episodes are separated by asymptomatic periods, or sometimes the meninges may revert to normal between recurrent episodes of meningitis. Although there are many well-known causes of chronic meningitis, infective (table 1) and non-infective (table 2), management can be problematic as no cause is ever found in about one third of cases.1 Other patients may be diagnosed only after lengthy delay and extensive investigations (table 3). An algorithm for the investigation and management of chronic meningitis is given in fig 1. In this article we will describe the important causes of chronic meningitis, and end with an account of recurrent meningitis.
INFECTIVE CAUSES
Tuberculous meningitis
The well-known at-risk groups for tuberculous meningitis (TBM) are people in or from developing countries, individuals with a history of alcoholism, and the HIV/AIDS population.2 However, the disease may still occur outside these obvious risk groups and so it is important to think about TBM in all patients presenting with chronic meningitis. The underlying pathology is a basal meningitis, with parenchymatous involvement of brain, cranial nerves, spinal cord or roots. Endarteritis contributes to these complications. Obstruction of CSF flow may lead to hydrocephalus.
Patients present in a relatively non-specific way with headache (50% of cases), fever, malaise, lethargy and confusion. The illness typically evolves over 1–2 weeks or longer,3, 4 in contradistinction to the more fulminant course of pyogenic meningitis. Signs of meningism are found in three quarters of cases. Only one fifth of patients have cranial nerve palsies, the oculomotor being affected more frequently than the facial or vestibulo-cochlear nerves. In addition to cranial nerve signs, there may be evidence of cerebral infarction, raised intracranial pressure and spinal cord or root involvement. Systemic features can include hypothermia rather than fever, and evidence of extraneural tuberculosis. Untreated, patients progress to coma with increasing intracranial pressure, accumulating focal neurological deficits, and death in 4–8 weeks.
Lumbar puncture is the most important investigation. Typical CSF findings include raised pressure, predominant lymphocytosis up to 500 cells/μl, raised protein concentration and low glucose. Occasionally, there is an excess of polymorphs, especially early in the course of the illness. Tubercle bacilli may be identified by direct microscopy but this is notoriously sensitive to obtaining a large enough sample volume and to the time spent searching for the organisms. Culture results may be delayed for weeks, even with modern techniques. Detection of mycobacterial nucleic acid by the polymerase chain reaction (PCR) is probably no more sensitive than carefully studied repeated direct smears of multiple CSF samples (PCR can help in patients who have received anti-tuberculous chemotherapy before CSF is taken, because mycobacterial nucleic acid may still be detected when smear and culture are negative, but a negative PCR does not exclude the diagnosis). These considerations mean that many patients with suspected TBM are treated without a firm microbiological diagnosis, as delayed treatment is strongly associated with poor outcome.5
Routine haematological and biochemical tests yield non-specific results, such as hyponatraemia, but a markedly raised blood white cell count argues against the diagnosis.4 The tuberculin skin test may be falsely negative, especially in severe disease and the immunocompromised. Conversely, inactive tuberculosis, unrelated to a patient’s presentation with chronic meningitis, may produce a positive tuberculin reaction. The chest x ray occasionally shows miliary tuberculosis. Brain imaging by CT or ideally MRI is important to look for hydrocephalus, tuberculomas or infarcts in patients with signs of raised intracranial pressure or focal neurological features. Basal meningitis may be revealed on contrast-enhanced scans, although the appearances are non-specific, being seen in other causes of chronic meningitis, and they are subject to observer-dependent interpretation.
By analogy with pulmonary tuberculosis, drug treatment for TBM is initially intensive, followed by a continuation phase (http://guidance.nice.org.uk/CG33/?c = 91521). Four drugs are usually used initially, that is for at least two months—rifampicin, isoniazid with pyridoxine cover, pyrazinamide and either ethambutol or streptomycin (the latter two drugs penetrating the CSF relatively poorly). Isoniazid is probably the most important agent as it is bactericidal and reaches high CSF concentrations, but isoniazid-resistant organisms and multi-drug resistant organisms (resistant at least to rifampicin and isoniazid) are becoming more prevalent worldwide. Moxifloxacin is a useful additional drug if there are concerns about resistance. If the organism is fully sensitive to first-line agents, pyrazinamide and ethambutol are discontinued after two months. Rifampicin and isoniazid are continued to complete a year’s therapy in total. The anti-tuberculous regime must be altered appropriately in the case of drug resistance, and therapy may need to be prolonged for up to two years.
A randomised trial of corticosteroids (dexamethasone 0.4 mg/kg daily for one week then tapering over three weeks) in combination with anti-tuberculous drugs versus anti-tuberculous drugs alone showed a reduction in case fatality but no effect on residual morbidity.6 Neurosurgery is reserved for patients whose level of consciousness or other physical signs are deteriorating despite medical therapy, and in whom re-imaging shows a clear structural cause, such as evolving hydrocephalus or abscess formation.
Response to anti-tuberculous therapy is gradual, over weeks. Tuberculomas may arise during any stage of treatment. They are managed symptomatically, with steroids, anti-epileptic drugs or shunting. The development of tuberculomas does not usually indicate treatment failure, or the development of drug resistance if the initial organism was fully sensitive and the patient has been concordant with therapy. The overall prognosis of TBM remains poor—10–20% case fatality (worse if treatment is delayed and the patient is comatose) and 20–30% long-term morbidity (cognitive and behavioural impairment, epilepsy, cranial nerve palsies and hemiparesis).
Syphilis
The incidence of neurosyphilis, which fell with the advent of penicillin, may be rising again, given the increasing number of cases of early syphilis (defined as within the first two years of infection) reported both in immunocompetent individuals and more particularly in the HIV/AIDS population. The primary pathological process when Treponema pallidum invades the nervous system is a meningitis, typically occurring within months of the original inoculation with the organism, and affecting approximately a quarter of all patients with syphilis.
This meningitis is frequently asymptomatic but potentially very chronic—persisting for years before progressing to parenchymatous damage, or regressing spontaneously. Occasional patients have florid clinical features of syphilitic meningitis—meningism, seizures, raised intracranial pressure or hydrocephalus, cranial nerve palsies—but these are a minority. Fever is less likely than in TBM. Symptomatic meningitis is particularly likely to occur in early syphilis.
The more common scenario of syphilitic meningitis remaining asymptomatic has in the past been used as an argument for precautionary CSF examination in all patients diagnosed with syphilis, to help determine the duration of treatment. However, in patients with latent (asymptomatic) syphilis, a negative non-treponemal (that is, cardiolipin) serological test for syphilis in the peripheral blood, in the form of the VDRL test, is 100% sensitive in excluding CSF abnormalities consistent with a diagnosis of neurosyphilis.7 Furthermore, the significance of CSF abnormalities in asymptomatic neurosyphilis is uncertain. A wide range of penicillin doses appears effective in preventing clinical progression.
Nowadays, therefore, there is evolving consensus that lumbar puncture should be reserved solely for patients with neurological symptoms and signs, or those who have failed therapy (see http://www.bashh.org/guidelines/draft/SyphilisGuideline2007Draft.pdf). Brain imaging will usually be required first. The typical CSF findings in syphilitic meningitis are a predominant lymphocytosis with raised protein concentration (and oligoclonal bands, which may be unmatched in a paired serum sample), normal glucose and positive serological tests for syphilis. The interpretation of these tests may be complex. In an appropriate clinical setting, a positive CSF VDRL test is diagnostic of neurosyphilis, but a negative test does not exclude it.8 A negative treponemal serological test in the CSF does exclude neurosyphilis. Paradoxically, however, a positive treponemal test, although sensitive, is not specific for neurosyphilis, because immunoglobulin may have reached the CSF from the blood by mechanisms independent of the infection.9
If early syphilis is missed, or incompletely treated, patients are at risk of late neurological complications. Nowadays, especially in the HIV/AIDS population, this is more likely to mean meningovascular syphilis than the classical parenchymatous forms of the disease (tabes dorsalis and general paresis). Meningovascular syphilis typically occurs 2–7 years after inoculation. The pathological basis is an endarteritis in association with meningitis (Heubner arteritis). All patients with young-onset ischaemic stroke should have serological tests for syphilis because of the possibility of meningovascular disease. In elderly patients presenting with stroke, positive syphilis serology may be coincidental and the underlying vascular pathology is more likely to be conventional degenerative disease of large or small vessels. However, this is no reason to deny these patients antibiotic treatment if there is any uncertainty about whether they have been treated for syphilis in the past. Treatment of meningovascular syphilis has a good chance of arresting further progression but is unlikely to reverse any existing deficits.
First-line treatment of neurosyphilis, including for those with neurological involvement in early syphilis, comprises procaine penicillin 1.8–2.4 g daily im plus oral probenecid 500 mg four times daily, for 17 days. This regime may be contrasted with that for uncomplicated early syphilis—procaine penicillin 600 mg daily im for 10 days or a single im dose of benzathine penicillin 2.4 MU. For late latent syphilis, defined as syphilis diagnosed on the basis of positive serological tests in an asymptomatic individual in whom the infection is likely to have been present for more than two years, the penicillin dose is the same as for early syphilis. However, the course is extended to 17 days for procaine penicillin or 3 doses at weekly intervals for benzathine penicillin. The much higher dose in neurosyphilis reflects the need to achieve treponemicidal antibiotic levels in the CSF. For individuals with penicillin allergy, or those refusing parenteral therapy, there are many alternative regimes (see http://www.bashh.org/guidelines/draft/SyphilisGuideline2007Draft.pdf).
Lyme disease—neuroborreliosis
The spirochaete Borrelia burgdorferi, transmitted by the bite of ixodid ticks, is responsible for Lyme disease, a multisystem disorder involving the skin, heart and joints as well as the nervous system. The earliest manifestations, within a month of exposure, are cutaneous—erythema migrans, an annular erythematous lesion, sometimes with satellite lesions, spreading from the site of the tick bite. Patients may also experience influenza-like symptoms in the early phase of the illness. Within weeks or months, neurological complications develop, but only in a minority of cases. Classically, a painful radiculopathy is associated with an aseptic meningitis, which may be complicated by cranial and peripheral mononeuropathies. Peripheral nerve involvement distinguishes Lyme from syphilitic meningitis. The facial nerve is the most commonly affected cranial nerve in Lyme disease, unilateral or bilateral, but the optic nerve may also be involved. Painful polyradiculopathy affecting the cauda equina, known as Bannwarth’s syndrome, has a differential diagnosis of cytomegalovirus or herpes simplex virus infection, though these viruses more usually affect the cauda equina in immunocompromised individuals. Neurological Lyme disease may also be complicated by encephalopathy, seizures, involuntary movements, ataxia and, rarely, myelitis. Guillain-Barré syndrome may follow borrelia infection, as may a more chronic polyneuropathy. Occasionally, Lyme meningitis is recurrent.
The CSF typically shows a lymphocytosis with a moderately raised protein concentration and normal glucose. The diagnosis can be difficult without a history of exposure, or typical skin lesions. Serological tests for antibodies to B burgdorferi can be helpful, but false positive and false negative results occur. The situation is straightforward when a patient has a history of exposure and IgM antibodies are detected in blood or, better still, CSF. However, in patients with vague neurological symptoms and no history of tick bite, the discovery of serum IgG antibodies may be incidental and merely indicative of past infection. Detection of B burgdorferi by PCR in the CSF can be useful.
Around the time of the neurological manifestations, a small group of patients (<10%) may have cardiac complications (myocarditis, pericarditis, conduction disorders). If patients remain untreated, the most chronic feature of Lyme disease is arthropathy, occurring in up to 60% of patients, and persisting for months after exposure, although Lyme disease is generally ultimately self-limiting.
Treatment, once the nervous system has become involved, is with ceftriaxone 2 g daily iv for 10–14 days, or iv benzyl penicillin 20 MU daily for at least as long. Doxycycline may be used in patients with penicillin or cephalosporin allergy.10
Fungal meningitis
Although fungi can invade the meninges without any predisposing cause, fungal meningitis is most commonly seen in immunocompromised individuals, as exemplified by the frequent occurrence of cryptococcal meningitis in AIDS patients. The clinical features of cryptococcal meningitis may mimic TBM. Some patients present without headache and meningism, but instead with features of encephalopathy, hydrocephalus, cerebellar ataxia, spastic paraparesis or other focal neurological deficits. The latter may be caused by meningovascular (endarteritic) events, similar to those in syphilis, or the presence of mass lesions (cryptococcomas). Occasionally explosive in onset, cryptococcal meningitis more usually follows a subacute or chronic course, progressing over weeks, months or even years. The meningitis may coexist with extra-neural involvement, especially of the lungs, skin and urinary tract.
The CSF shows a lymphocytosis, though not necessarily in AIDS patients. Glucose concentration is usually low and protein content may be very high. A microbiological diagnosis is reached by microscopy of India ink preparations (up to 95% sensitivity) or detection of cryptococcal antigen in serum and CSF by ELISA (95% sensitivity). Culture results may take several days.
Treatment is with intravenous amphotericin B, to which flucytosine may be added initially. Long-term secondary prophylaxis with high-dose fluconazole is used to prevent relapse after initial response to treatment. The development of raised intracranial pressure threatening vision may require repeated daily lumbar puncture, or lumbar or ventricular drainage.11 Even in patients without AIDS or other evidence of immunocompromise the case fatality of cryptococcal meningitis remains high, up to 40%.
Other fungal causes of meningitis are less common than cryptococcal meningitis and are listed in table 1.
Viral meningitis
While several viruses cause an acute aseptic meningitis, HIV may involve the meninges chronically, from the time of seroconversion to the later stages of AIDS. HIV meningitis may be responsible for chronic headache in AIDS patients, exacerbated by intercurrent infection, such as pneumocystis pneumonia. The typical CSF findings are a lymphocytosis with raised protein concentration and normal glucose. These changes may complicate the interpretation of CSF obtained to investigate other possible neurological problems in AIDS—that is, opportunistic infections, neurosyphilis, TBM, parameningeal infection, lymphoma, connective tissue disorders and drug reactions.
Chronic enteroviral meningitis may complicate common variable immunodeficiency.
NON-INFECTIVE CAUSES
The uveo-meningitic syndromes
The uvea consists of the iris, the ciliary body and the choroid. Uveitis is said to be anterior when the iris and anterior ciliary body (the pars plicata) are inflamed (iritis, cyclitis and iridocyclitis), intermediate when the posterior ciliary body (the pars plana) is involved, and posterior when the inflammation arises within the choroid:
Anterior uveitis presents with eye pain, photophobia, redness and watering. Vision is noticeably blurred. The conjunctival redness is characteristically circumcorneal, rather than generalised as in the case of conjunctivitis. On slit lamp biomicroscopy, inflammatory cells can be seen and, when clumped together, form keratic precipitates (fig 2). Pus within the anterior chamber denotes hypopyon (fig 3). In chronic cases, the iris may become adherent to the lens to produce posterior synechiae, and nodules may develop within the iris, known as Koeppe nodules if adjacent to the pupillary margin and Busacca if elsewhere. These nodules and the presence of large or “mutton-fat” keratic precipitates reflect a granulomatous inflammatory process.
Inflammation of the ciliary body, or cyclitis, is associated with a cellular response within the vitreous, leading to mild blurring of vision with the appearance of floaters.
Choroiditis is also associated with floaters and blurred or distorted vision—visual symptoms may be mild despite rather striking abnormalities on slit lamp examination or indirect ophthalmoscopy (fig 4).
Posterior uveitis may be associated with retinal involvement and optic neuritis.
A pan-uveitis may also arise.
These appearances of uveitis may help the neurologist evaluating uveo-meningitic syndromes; the retinal appearances of sarcoidosis and Behçet’s disease, for example, are sufficiently distinct to allow a clear differentiation between the two conditions, even when the neurological syndrome could fit either cause.
Sarcoidosis
Sarcoidosis is an uncommon inflammatory disorder in which granulomatous inflammation arises in a variety of tissues, most commonly the lungs, skin, joints and eye. The nervous system is affected in around 5% of cases,12, 13 but patients may present with a granulomatous disorder confined to the nervous system. Meningitis is uncommon; it occurred in 7–18% of recent small series and 2% of the Royal Free series of 86 patients (Kidd, unpublished data) (fig 5). Frequently, the meningitis is steroid responsive and recurrent.12 It is however common at autopsy to see a chronic basal granulomatous leptomeningitis or arachnoiditis, even in patients without overt neurological involvement in life.14 Cranial neuropathies may arise due to spread of inflammation from the adjacent meningitis, and hydrocephalus may be caused by foraminal obstruction by thickened meningeal tissue; this complication in particular is difficult to manage since ventriculoperitoneal shunts tend quickly to become blocked by viscid CSF. A chronic hypertrophic pachymeningitis associated with headache and no other neurological symptoms is not unusual (fig 6) (see below).
Ocular involvement arises in around half of all cases of systemic sarcoidosis. The anterior uveitis is characteristically of granulomatous type, and posterior involvement occurs due to retinal vasculitis, with the retinal lesions looking like candle wax dripping. Ischaemic and haemorrhagic lesions may occur in the retina, and choroidal and optic disc granulomas may be seen (fig 4).15 There is an association between posterior uveal involvement and subsequent neurological complications in sarcoidosis.16
Patients with sarcoidosis who present with symptoms and signs of meningitis must be evaluated promptly; spinal fluid examination should always be performed because there is a high prevalence of infective meningitis caused by opportunistic infections in sarcoidosis; cryptococci may be present with a progressive meningoencephalitis leading to cranial neuropathies including visual loss and progressive cognitive decline simulating a neurodegenerative disease. Listeria infection is less common. Progressive multifocal leucoencephalopathy is most uncommon; it presents with a chronic progressive encephalopathy with white matter lesions and is often fatal despite treatment, although not always so.17 Clearly it is vital to establish whether or not such a complication exists, otherwise additional immunosuppressive therapy may make matters worse.
Those without an infective cause show a modest CSF lymphocytosis with a slightly low glucose and modest protein rise. Intrathecal synthesis of oligoclonal bands is not seen in neurological complications of sarcoidosis.12
The treatment of non-infective meningitis is with a short course of oral corticosteroids, the duration depending on the symptomatic response. That of a more chronic meningitis with pachymeningeal thickening requires a more prolonged course, and the addition of methotrexate may lead to more rapid and complete resolution of both symptoms and MRI abnormalities in these patients.
Behçet's disease
Behçet’s disease is a rare inflammatory disorder characterised by recurrent oral and often orogenital ulceration with skin lesions. Uveitis is common and can be severe, refractory to treatment and hence sight-threatening.18 Neurological complications arise in around 5%19–22 but aseptic meningitis is uncommon in all the large recent series; it occurred in 4/50 of a UK series,20 and only one each in two large Turkish series.21, 22 Patients develop subacute progressive headache with meningism and drowsiness. Imaging is normal when the meningitis is isolated. Other neurological signs will not be present, but meningitis is a concomitant of the most common neurological complication, a meningoencephalitis, which affects the brainstem in around 50% of cases.20–22 Characteristically, the CSF shows an inflammatory cell infiltrate which includes polymorphs and lymphocytes, with a modest protein rise and normal glucose. Oligoclonal bands are not present.20 Treatment is with corticosteroids. Relapse may occur and if so tends to be recurrent; hence it is best to treat patients who relapse with immunosuppression.
Wegener’s granulomatosis is a severe necrotising granulomatous small and medium sized vessel vasculitis associated with the cytoplasmic form of the antineutrophil cytoplasmic antibody (cANCA). The systemic disease is characterised by the involvement of the upper respiratory pathways and kidneys, but neurological and ophthalmic involvement occurs in 20–50%.23 The ophthalmic complications reflect spill over of the disease into the orbit from adjacent paranasal air sinuses, and also there is a localised form of the disease with only nasal sinus and orbital disease. Anterior uveitis with scleritis is more common than a posterior uveitis. The neurological complications include a mononeuritis multiplex most commonly; cranial neuropathies are also common and due to meningeal involvement either from hypertrophic pachymeningitis (see below) or meningitis itself. Focal cerebritis may occur. The latter is rare, occurring as an isolated phenomenon in only 1.5% of 324 Mayo Clinic patients.23 Isolated meningitis is in fact exceedingly rare; only 0.6% of the Mayo Clinic series and the paper does not provide specific details. Treatment is with high dose corticosteroids and cyclophosphamide. A trial of etanercept failed to show benefit, but recent reports point to the effectiveness of the CD20 antagonist rituximab in cases refractory to cyclophosphamide.
Vogt-Koyanagi-Harada syndrome
Vogt-Koyanagi-Harada syndrome is an immunological activation directed against melanocytes. As such, it is very rare in white-skinned people and more common in Afro-Caribbean, Asian and Hispanic people. It begins with a flu-like illness and meningitic symptoms with fever, headache, neck stiffness, drowsiness and tinnitus with deafness. Cranial neuropathies may arise; deafness is virtually universal, but other complications may occur, for example optic neuropathy24 and transverse myelitis.25 Some patients develop a fluctuating encephalopathy with focal neurological signs, for example hemiparesis and ataxia. In one series of 22 patients, 12 developed neurological complications, of which the majority were meningism and hearing loss with or without vertigo.26
The uveitis develops after the meningitis and is characterised by an acute granulomatous-type anterior uveitis, a vitritis and multiple serous retinal detachments (fluid develops between the retina and choroid in blebs). There is often optic disc oedema. The uveitis is associated with the development of cataracts, posterior synechiae and glaucoma. As the uveitis subsides, depigmentation occurs, leading to alopecia, vitiligo and poliosis of the eyelashes, eyebrows and hair. The choroid also loses pigment leading to a mottled “sunset glow” fundus and numerous pale lesions known as Dalen-Fuchs nodules in the inferior retina.
The disorder may recur repeatedly.27 The meningitis is lymphocytic with normal CSF glucose and only modestly raised protein; some cases have only very mild CSF abnormalities. Brain imaging may be normal but can show white matter lesions.
Treatment is with corticosteroids and immunosuppression. There is evidence that the dose of steroids needs to be very high28 in order to be effective for neurological complications.
Sjögren’s syndrome
Isolated aseptic meningitis is very uncommon—in a series of 48 patients from Scandinavia only one patient was noted to have this complication, and this was induced repeatedly by trimethoprim (see below).29 In a more recent series from France, aseptic meningitis was not a feature of 82 patients with neurological complications of the disease.30 Isolated cranial neuropathy, particularly the trigeminal nerve, transverse myelitis and a Devic’s syndrome phenotype are more common. Uveitis is also uncommon compared with dry eyes due to lacrimal gland infiltration, which is one of the hallmarks of the disease.
Systemic lupus erythematosus
Like other connective tissue diseases, it is often stated that aseptic meningitis may develop in lupus, but a review of the literature does not confirm this. Although there are isolated reports, most patients who present with meningitis usually have a meningoencephalitis, associated with imaging abnormalities and focal neurological signs.31 In the series from Scandinavia,29 aseptic meningitis occurred in only two of 42 patients followed for 10 years; again one occurred more than once in conjunction with treatment with trimethoprim, but in the other patient, no such cause was found. Uveitis may arise in lupus but is rare and a retinal vasculitis is more common; an ischaemic retinopathy with neovascularisation is common.
As with sarcoidosis, infective meningitis is not uncommon in lupus; in a series of 3165 patients from Taiwan, 17 had had central nervous system infections over a 20-year period.32 Ten were due to Cryptococcus neoformans, four to Listeria monocytogenes, two to Streptococcus pneumoniae and one to Enterobacter aerogenes. All presented as acute pyogenic meningitis. 94% had active lupus at the time and 15/17 had received steroids within the previous six months. Seven had also received immunosuppression. The case fatality was 50%.
Hypertrophic pachymeningitis
This is a rare disorder in which a localised or diffuse inflammation of the meninges leads to progressive thickening and fibrosis of the dura mater.33, 34 It may be associated with infections such as tuberculosis, syphilis, borrelia, fungal diseases and HTLV1, and with systemic inflammatory disorders, particularly sarcoidosis (see above), but more rarely with Wegener’s granulomatosis, Sjögren’s syndrome, giant cell arteritis and rheumatoid arthritis. The idiopathic form is more common.
It is a disorder of middle to late age, although young patients have been reported, with a male predominance. The presenting symptom is invariably headache which is generalised and often very severe. Subacute worsening cranial neuropathies then develop, most commonly an optic neuropathy, then ophthalmoparesis then deafness. Localised forms of the disease produce mass lesions which may be associated with focal neurological signs and seizures, and myelopathy is common when the spinal meninges are involved.
The erythrocyte sedimentation rate is usually raised. The CSF is active in only half the cases, with a modest protein rise (to 64–243 mg/dl in one series),33 a cellular response is even less common. CSF glucose is not reduced and the CSF pressure is usually not increased, although this has been reported.33 MRI shows striking enhancement of the meninges in all cases (fig 6). The tentorium and falx are most commonly affected, followed by the middle cranial fossa, particularly adjacent to the cavernous sinus.33 The histological features show infiltration of inflammatory cells of three types; granulomatous inflammation, lymphocytic infiltration and plasma cell predominance. The pia and arachnoid are not involved. Occasionally a vasculitis may be seen affecting meningeal vessels.
Treatment is with corticosteroids and in most cases the headache and enhancement on MRI resolve.33 Recurrence on steroid reduction is common, however, and additional immunosuppression may be required to prevent further deterioration. Furthermore, the neurological consequences tend not to improve, and over time may progressively deteriorate despite treatment.33
Drug-induced meningitis
This is uncommon but important to recognise because repeated exposure to the drug will provoke recurrent and mysteriously unexplained episodes until the cause is recognised. The clinical features are similar to other forms of meningitis; systemic features such as myalgia, arthritis, lymphadenopathy and skin rashes may also occur. Occasionally, a more severe form of meningitis may arise associated with focal neurological signs, including seizures, coma, hemiparesis and cranial neuropathy.35
CSF findings, too, are non-specific; the cellular response is prominent, however, with white cell counts ranging from several hundred to thousands. A polymorph infiltration is more common than a lymphocytic one; eosinophils can predominate in the absence of systemic hypereosinophilia, particularly in intravenous immunoglobulin-associated meningitis.36 The protein levels are modestly elevated and the glucose is normal. Hence, a high, predominantly polymorph, CSF leucocytosis with a normal CSF glucose would suggest drug-associated meningitis. MRI findings again are in keeping with meningitis, with diffuse meningeal enhancement. The treatment is withdrawal of the drug, and rapid recovery follows.
Non-steroidal anti-inflammatory drugs and COX-2 inhibitors have been associated with meningitis, with relapse on re-exposure to the drug. This is more common with connective tissue disease, particularly lupus, and in females.37 When a patient is re-challenged with the drug, the symptoms typically settle within 12 hours.
Anti-microbial agents. Trimethoprim, trimethoprim-sulphamethoxazole, and penicillins are the most commonly reported to cause aseptic meningitis.
Intravenous immunoglobulin. Several studies of intravenous immunoglobulin in different diseases have reported aseptic meningitis in around 11% of cases. It is more common in high dose (2 g/kg) treated patients. The risk may be less with lower rates of infusion (<6 g per hour) and with pre-hydration measures. Corticosteroids do not prevent the complication.37 In a trial of immunoglobulin in 40 patients with asthma, 3/16 treated with 2 g/kg infusions had aseptic meningitis and 27% had headache following infusion.38 In a retrospective review of the use of immunoglobulin in neuromuscular disorders, meningitis was seen in 11% of 54 patients and headache occurred in 54%, more in those with migraine (50%) than those without (4%).36
Immunosuppressants. There is a single report of meningitis associated with infliximab therapy; methotrexate, cytarabine and azathioprine have also been associated with meningitis.
Vaccination. Certain strains of the mumps virus contained within the MMR vaccine may cause meningitis; the risk is 1 in 11 000 vaccinations. It is thought that the problem is predominantly due to the mumps virus, as mumps virus was grown in the CSF in half of the cases reported. No serious adverse reactions have been reported, and the risk of meningitis is substantially lower than in mumps infection itself. The mechanism is not understood but is likely to relate to immunological activation, particularly in those with an already disordered immune system.
Carcinomatous and lymphomatous meningitis
Leptomeningeal metastasis arises in 1–6% of epithelial cancers and is most common in small cell lung cancer and breast cancer.39 In high grade non-Hodgkin’s lymphoma and in leukaemias, it is more common still (5–15%), such that central nervous system prophylaxis is part of the treatment.
Neoplastic meningitis presents in a subacute way with multifocal meningeal-based disease causing cranial neuropathies, radiculopathies, cord or brain lesions.39 Intracranial lymphoma may present with a vitritis; it is therefore important to recognise this possibility when an apparently aseptic meningitis and vitritis coexist.
Leptomeningeal enhancement is seen on MRI in around 60% of cases. The CSF is abnormal in 30–80% of cases, with a pleocytosis, raised protein concentration and reduced glucose. Malignant cells, however, are not identified so frequently; 50% with the first lumbar puncture, 75% with a second, but further lumbar punctures may still fail to identify the cells. Nonetheless, it is important, when the diagnosis is considered, to perform repeated lumbar punctures.
The disorder is relentlessly progressive. Untreated, the median survival is 4–6 weeks; intrathecal chemotherapy with methotrexate, cytarabine and thiotepa prolonged life in one study to 2–6 months.40 Cranial irradiation may be helpful, particularly when there is CSF block.
RECURRENT MENINGITIS
Recurrent pyogenic meningitis may occur in the context of immunodeficiency—as seen, for example, with recurrent meningococcal meningitis in patients with agammaglobulinaemia or defects of the terminal complement system. A more common mechanism underlying recurrent pyogenic meningitis is an anatomical communication between the subarachnoid space and the skin, or a non-sterile body cavity. These defects may be congenital or acquired. Congenital lesions include those of the skull base or middle ear, persistent dermal sinuses of the vertebral column (resulting from incomplete closure of the neural tube) and neurenteric fistulae and cysts. Acquired defects arise from neurosurgery or trauma—classically a fracture of the cribriform plate of the ethmoid. In addition to the risk of recurrent meningitis, a history of CSF rhinorrhoea or otorrhoea may accompany these lesions.
If there is nasal discharge of clear fluid, confirmation that it is CSF rests on the detection of glucose or, better, β-2 transferrin. The next investigative step, if a patient has a history of recurrent pyogenic meningitis and/or a proven CSF leak, is localising the leak by MRI or CT, if necessary CT cisternography (fig 7). Scintigraphy of isotope instilled into the lumbar CSF is rarely needed nowadays.
The management of recurrent pyogenic meningitis consists of treating the acute episode with appropriate antibiotics and support, then if possible correcting the underlying anatomical or immunological defect. The former may require surgical closure but, in some cases, responds to conservative management—bed rest with head-up tilt and avoidance of straining.
Recurrent aseptic meningitis has many causes:41
Chronic inflammatory diseases—many of the disorders listed in table 2, and described in detail earlier in this article, may cause recurrent attacks of meningitis.
Drugs—as listed in table 2, and described above, may cause recurrent aseptic meningitis. Repeated use of intrathecal agents (contrast medium, chemotherapy) is also associated with this complication.
Structural lesions—such as craniopharyngiomas, epidermoid cysts and gliomas—may discharge their contents periodically into the CSF, causing a recurrent “chemical” meningitis.
Infection—chronic infective meningitis may manifest as recurrent clinical episodes separated by asymptomatic periods, despite the CSF being abnormal throughout—as seen with syphilis, Lyme disease, brucellosis, fungal meningitis and HIV. In other cases, the alternative mechanism of genuine reactivation of latent infection applies, for example herpes simplex virus (HSV), Epstein-Barr virus and Toxoplasma.
Mollaret’s meningitis is a syndrome of benign recurrent aseptic meningitis. Patients present with episodes of fever and meningism developing abruptly and lasting 3–4 days. Seizures and focal neurological signs may occasionally occur. These episodes may be separated by weeks, months or even years—the condition typically “burns out” after several attacks. During an episode, the CSF shows a pleocytosis, and sometimes there are thousands of cells per μl, with lymphocytes, neutrophils and “Mollaret cells”—large friable cells with faintly staining vacuolated cytoplasm (fig 8). Originally thought to be of endothelial lineage, these cells are now considered to be activated macrophages, and are not pathognomonic of the disorder. For decades labelled an idiopathic condition, there is now increasing evidence of a link with HSV infection, particularly HSV-2.42
Practice points
Chronic meningitis is defined as meningeal inflammation persisting for at least 4 weeks.
The presentation may be non-specific and the diagnosis of an underlying cause difficult; no cause is found in up to one third of patients.
Tuberculosis is the commonest identifiable cause worldwide—a febrile patient with cranial nerve palsies, cerebrospinal fluid (CSF) lymphocytosis and low CSF glucose is likely to have tuberculosis, whereas an afebrile patient with normal or mildly reduced CSF glucose is more likely to have malignant meningitis.
If infection and malignancy have been reasonably excluded, a trial of corticosteroids may be warranted.
In patients with syphilis, CSF examination should be performed in those with neurological symptoms and signs, or those who have failed therapy.
In patients with sarcoidosis or systemic lupus erythematosus, opportunistic infection should be excluded as the cause of CSF lymphocytosis before attributing meningitis to the underlying disease.
Hypertrophic pachymeningitis may complicate many diseases, both infective and non-infective, but is usually idiopathic.
Recurrent pyogenic meningitis implies an underlying anatomical or immunological defect.
Recurrent aseptic meningitis may be caused by infection, chronic inflammatory diseases, drugs or repeated rupture of cystic structures into the subarachnoid space.
Meningeal biopsy is diagnostic in a minority of patients.
Acknowledgments
This article was reviewed by Andrew Chancellor, Tauranga, New Zealand. We also thank Ian Cropley, Infectious Diseases Consultant at the Royal Free Hospital, for his valuable comments.
REFERENCES
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