Investigating chronic meningitis
- Correspondence to L Hartley, University Hospital of Wales, Cardiff, CF14 4XW, UK; lmhartley{at}gmail.com
- Accepted 28 July 2009
Abstract
Chronic meningitis is a syndrome characterised by persistent and progressive signs and symptoms of meningitis along with cerebrospinal fluid (CSF) pleocytosis and elevated protein that fail to improve over 4 weeks. A detailed and careful history and examination is required along with CSF parameters to guide a clinician towards the aetiology of the problem. Neuroimaging modalities have become a useful tool in the quest for a diagnosis in such cases.
An interesting case is described in real time illustrating the process of making a diagnosis in chronic meningitis with an insight into investigations and subsequent management.
A 12-year-old boy, Gareth, presents with a 4-day history of headache. The headache is dull, frontal and associated with vomiting. He is a fit rugby enthusiast with no ongoing medical concerns. He had a course of oral antibiotics from his general practitioner 6 weeks prior to presentation for a sore throat and cough. There is no history of recent foreign travel. On initial review a diagnosis of migraine is made. He responds to analgesics and is discharged home. At 2 days later he presents again with worsening headache associated with vomiting and fever of 39°C. On examination bilateral papilloedema is noted (fig 1). His visual fields and visual acuity are normal. He is colourblind and unable to read Ishihara charts. There are no other neurological signs. His consciousness level is normal and vital signs are stable. He has no signs of meningism.
Papilloedema. Image of fundus.
The case is discussed with the on-call paediatric consultant who is worried that the patient may have a space-occupying lesion and requests a CT brain scan.
CT of the head is normal. The radiologist also performs a CT venogram that is normal.
Comment: the presence of papilloedema in the context of headaches with a normal CT scan suggests the possibility of idiopathic intracranial hypertension (IIH). A normal CT venogram excludes venous sinus thrombosis as a cause for this. To confirm the diagnosis, a lumbar puncture is required to measure the opening pressure and cerebrospinal fluid (CSF) constituents. Detailed visual assessment is important including colour vision to distinguish papilloedema from papillitis.
A lumbar puncture (LP) is performed with an opening pressure of 30 cm of H2O. The CSF shows 40 white cells, predominantly lymphocytes with no polymorphs. CSF protein is raised at 0.57 g/litre and CSF glucose is 2.3 mmol/litre (table 1). The plasma glucose was not taken.
Cerebrospinal fluid (CSF) results
Comment: the opening pressure is raised, a normal CSF opening pressure in an older child or young adult is less than 20 cm. However the abnormal CSF constituents exclude the diagnosis of IIH. The presence of the white cells points to a diagnosis of lymphocytic meningitis. The raised CSF protein suggests an inflammatory process. The CSF glucose should always be compared with plasma glucose for accurate interpretation.
Gareth is given aciclovir, ceftriaxone and clarithromycin to cover the possibility of infective meningitis. His full blood count, blood film, electrolytes, kidney function and liver function tests are all normal. His inflammatory markers are raised with C-reactive protein (CRP) of 44 and erythrocyte sedimentation rate (ESR) of 53. Blood, CSF, urine and stool cultures are sent. CSF PCR for herpes simplex virus, varicella zoster virus, enteroviruses including Coxsackie virus, adenovirus, parvovirus, Epstein–Barr virus and Borrelia burgdorferi are also requested. A Mantoux test is performed.
Comment: viral meningitis would be the most common diagnosis in acute lymphocytic meningitis. The approach to this condition would be to empirically treat with aciclovir and antibiotics while awaiting culture and PCR results.
Gareth has transient improvement of his headache after the initial LP but the headache and vomiting persist. He continues to have nocturnal fever. A LP is repeated on day 7 of treatment. It reveals a similar opening pressure of 30 cm of H2O; however his CSF parameters deteriorate from the initial LP. The CSF has 227 white cells with 90% lymphocytes, protein has risen to 1.06 g/litre and CSF glucose dropped to 2.2. CSF, blood, urine and stool cultures and virology screen sent earlier are negative as is the Mantoux test. At this point he is referred to a tertiary centre for further management.
Comment: although Gareth had shown some clinical improvement after his initial LPs his paediatric team are concerned by the deterioration in the CSF parameters and consider rare infective and non-infective causes of lymphocytic meningitis with papilloedema.
He is reviewed by the paediatric neurologist and ophthalmologist in the tertiary centre. His investigations are broadened to include more rare, non-infective causes of meningitis. His autoimmune profile, complement profile, angiotensin-converting enzyme, β2 microglobulin and rheumatoid factor tests are all negative. He has a normal echocardiogram. Ophthalmology assessment confirms papilloedema but does not reveal evidence of any vasculitic conditions. He undergoes a brain and spine MRI, which are normal. His antibiotics and antiviral are stopped after 10 days. As he has improved clinically he is discharged home.
Comment: papilloedema is unusual with lymphocytic meningitis and indicates a chronic underlying process. Parameningeal infections can present insidiously and need to be excluded by an MRI of the spine.
He remains well for a week. He then presents again with similar complaints of headache, vomiting, decreased appetite and lethargy. He has lost 10 kg since he first presented 4 weeks ago. He also reports new onset clumsiness on walking. He has an ataxic gait, dysarthria and mild dysmetria on examination. He does not have nystagmus. His ophthalmic examination shows improving papilloedema with no signs of a vasculitic process. He is systemically well and remains afebrile. He has no genital or oral ulcers suggestive of neuro-Behçet syndrome.
The presence of new cerebellar signs concerns the paediatric neurologists, who are now worried about the possibility of a lymphoproliferative disorder with cerebellar deposits or a paraneoplastic disorder with antibodies to the cerebellum.
Comment: presentation with persistence of neurological symptoms and the emergence of new signs indicates an ongoing process. In view of a course of antibiotics and antiviral treatment, partially treated meningitis or a non-infective meningeal process should be kept in differential diagnosis. The development of new neurological signs mandates repeat neuroimaging.
Gareth has an MRI of the brain (fig 2), which reveals extensive high signal abnormalities in the white matter of both cerebellar hemispheres. Repeat lumbar puncture demonstrates a normal opening pressure of 16 cm, 82 white cells (100% monocytes), protein 0.88 g/litre, glucose 2.3 mmol/litre (plasma glucose 5.7). CSF cytospin revealed no evidence for malignancy. A chest and abdominal CT scan to look for malignant process was normal.
Comment: neurological presentation of lymphoproliferative diseases in children is rare; however it is probably the most worrying differential of chronic lymphocytic meningitis.
On review a week later, Gareth’s mother reports subtle alterations in his behaviour: he has become inattentive, restless and is behaving in a childish manner. She is also concerned about his memory.
Neuropsychological testing reveals problems with anterograde memory especially frontal lobe function with deficits also in verbal fluency.
A repeat MRI scan (figs 3 and 4) demonstrates abnormal meningeal enhancement. There is increased signal in the cerebellar peduncles with the involvement of deep grey nuclei as well as basal meninges.
Axial T1 MRI post contrast demonstrating abnormal meningeal enhancement seen anterior to the midbrain and pons.
Comment: Gareth has had symptoms and abnormal CSF parameters for more than 4 weeks: he therefore has chronic meningitis (table 2), which is a syndrome of meningeal inflammation for at least 4 weeks.
Causes of chronic meningitis1
Many of the causes of chronic meningitis have been excluded for Gareth (table 3). However the presence of meningeal enhancement on his last MRI scan suggests a possible diagnosis of neurosarcoidosis.
Investigation list for the patient
The patient has investigations to look for other signs of systemic sarcoidosis: he has a normal chest x ray, high-resolution chest CT scan and gas transfer studies. Pituitary function tests are normal as is the CSF CD4/CD8 ratio and CSF angiotensin-converting enzyme (ACE). There is no evidence for systemic sarcoidosis, however his clinical presentation does suggest a diagnosis of a possible neurosarcoidosis, which is recognised to present with papilloedema, headache and vomiting.
Meningeal biopsy is considered for a definitive diagnosis. However, due to the location of the meningeal enhancement this is not possible.
Gareth is given oral prednisolone. He improves gradually over a period of 2 weeks with improvement in cerebellar signs, behaviour and memory. His neuropsychological tests return to normal.
MRI performed 1 month later shows improvement with no evidence of abnormal intraparenchymal or meningeal enhancement.
He continues on a reducing dose of prednisolone and gradually improves completely and is back in school after a few weeks of treatment. The repeat MRI of the brain at the end of treatment is entirely normal.
He remains on careful follow-up pending any recurrence of his symptoms now that he is no longer on steroid treatment.
Chronic meningitis
Definition
Chronic meningitis is a syndrome of meningeal inflammation, on the basis of clinical features and/or cerebrospinal fluid findings, persisting for 4 weeks or more.1 The symptoms include low-grade fever, headache, nausea, vomiting, stiff neck and lethargy or confusion. This is usually associated with cerebrospinal fluid pleocytosis and elevated protein concentration with no improvement for at least 4 weeks.
Although it accounts for fewer than 10% of all case of meningitis, management can be problematic as it is difficult to find a cause in nearly one-third of patients.2 Many patients’ conditions are diagnosed only after lengthy and extensive investigations.3 4
Detailed history with emphasis on infectious diseases, exposure to drugs, recent travel or occupational risk may be helpful in delineating the aetiology of chronic meningitis. The disease onset is usually gradual and symptoms are chronic.
In contrast, in acute meningitis clinical improvement is seen with improvement in CSF parameters.
Diagnostic findings on physical examination are rare, but one should look carefully for signs in the skin, eyes, brain and lungs. Some of the physical findings can take weeks to months to evolve.
If the CSF has >50 white blood cells (WBC)/cm2 it is more suggestive of infectious origin although normal WBC in CSF does not exclude infection.5 The usual CSF parameters in most cases of chronic meningitis are WBC up to 500 cells/mm2, with lymphocyte predominance, raised protein and normal or slightly decreased CSF sugar. Usually, apart from routine investigations CSF, blood, urine and stool samples are sent for specialised laboratory tests depending on the differential diagnosis. Neuroradiological and other radiographic investigations also play an important part in the diagnosis of chronic meningitis.
Investigation of chronic meningitis
Investigations should be tailored according to the history and examination. Table 2 provides a list of investigations that may be performed.
Repeated LP is needed for those patients who don’t respond to treatment and have persistent neurological symptoms. Meningeal biopsy is considered in selected cases where symptoms are not settling before a trial of steroids.
Childhood neurosarcoidosis (NS)
Sarcoidosis is an idiopathic multisystem granulomatous disease usually diagnosed between 20 and 40 years of age but rarely seen in children. The pathological hallmark is non-caseating epitheloid granulomata, which are structured masses of activated macrophages and their derivatives. The cause of sarcoidosis is not known but genetic predisposition is suggested on the basis of histocompatibility and familial case reports.6 There is accumulation and activation of CD4+ helper T cells and macrophages in affected organs with depressed cellular immunity.7
The incidence of neurosarcoidosis is unknown in children. Clinical evidence of central nervous system (CNS) involvement is seen in up to 10% of adult patients7 with sarcoidosis. Children with neurosarcoid may have a different presentation to adults. Children are more likely to have seizures, less likely to have cranial nerve palsies, and possibly likely to have a space-occupying lesion.8
Among postpubertal children sarcoidosis is primarily a pulmonary or ocular disorder,9 with younger children presenting with a triad of skin, joint and eye disease.10 11 12 Prepubertal children are likely to present with seizures.8 The adult pattern of cranial neuropathies appears after puberty. Evidence of hypothalamic dysfunction is common in children.8 Children also appear to have CNS mass lesions which may be asymptomatic.8
In the adult population, although sarcoidosis is rarely confined to the CNS, neurological features often occur early in the course of the disease which can lead to diagnostic difficulty.7 A recent review of neurosarcoidosis in adults found 70% presented with CNS features.7 In this series the most common NS manifestation was cranial neuropathy, seen as a presenting feature in 50% of patients. Subacute optic neuropathy was seen in one-third of patients and was part of the presentation in 17%. Headaches were a feature at presentation in over 25% of patients, often with vomiting and ataxia. Papilloedema is a well recognised presentation of NS.7 8 Lower motor neuron facial palsy is classical feature of neurosarcoidosis which is unilateral in 65% and bilateral in 35%.14 In this series only 23% of patients had facial palsy. None of the patients in biopsy proven group had facial palsy.
Unless a lesion is present that can be biopsied, NS remains a diagnosis of exclusion and therefore it is important to consider the broad differential diagnosis that is more common than neurosarcoidosis.
Neurological involvement is a significant cause of mortality and morbidity in patients with sarcoidosis. Detection and management of isolated neurosarcoidosis (table 4) remains a diagnostic challenge.
The criteria on which a diagnosis of neurosarcoidosis is made in the absence of CNS histology are not firmly established. A series of diagnostic criteria were formulated by Zajicek and colleagues in 1999, revised by Marangoni et al in 2006.
A diagnosis of isolated neurosarcoidosis requires a biopsy to show non-caseating granuloma and to exclude other causes. When the biopsy is not possible, a diagnosis of neurosarcoidosis can be made by MRI findings and exclusion of other disorders.16 MRI with contrast is currently widely used for the diagnosis and follow-up of neurosarcoidosis lesions. It has a good sensitivity (up to 82%) for intracranial abnormalities but poor specificity with a wide spectrum of imaging findings.17
In nearly half of the patients with neurosarcoidosis leptomeningeal enhancement with gadolinium or multiple white matter lesions in a periventricular distribution can be seen.18 Recently published studies have suggested that MRI findings change in concordance with the improvement in clinical symptoms (80%) and therefore it is a reliable tool for follow-up.19
Cerebrospinal fluid examination usually reveals chronic lymphocytic meningitis (as in our case) with raised protein and usually high pressure and low glucose. Opinion is divided regarding CSF angiotensin-converting enzyme. It is not performed routinely for diagnosis and follow-up as it may be raised in infections and malignancy,20 specificity and sensitivity of this test are very low. A CD4:CD8 ratio >5 in the CSF is suggested as useful diagnostic criterion in establishing neurosarcoidosis.13
The electroencephalogram is usually non-specifically abnormal and adds very little in making a diagnosis although it can detect the early epileptiform discharges of the disease process.15 Electroencephalography (EEG) is therefore not routinely recommended.
A diagnosis of neurosarcoidosis can only be secured by direct biopsy showing non-caseating granulomatous lesions. Even with a positive biopsy it is important to rule out the other possibilities of non-caseating granulomata (ie, infections, tumours, inflammatory disorders and so on). As brain biopsy is often not possible, it is not surprising that there are few patients with neurosarcoidosis in isolation who are histologically proven. Biopsy of other organs such as skin, lung and liver can be considered blindly if there is a suspicion of neurosarcoidosis without any significant clinical abnormality.21
The Kveim–Siltzbach test is highly sensitive (77% to 85%) in cases of neurosarcoidosis.7 15 However due to the safety concerns (the infection risk of injecting human material), the time (4–6 weeks) required for an accurate result and masking of the test by steroids, it has been abandoned.
Treatment with corticosteroids is the mainstay for neurosarcoidosis. There is no randomised control trial for the treatment. The required steroid dosage can be high and usually ranges between 40–80 mg/day.7 15 Response to steroids is usually good but withdrawal can be problematic as symptoms tend to recur on less than 20 mg/day.22
In patients where steroids are contraindicated, methotrexate,23 cyclophosphamide,23 azathioprine and ciclosporin have been used. In some patients chloroquine and hydroxychloroquine have been used with steroids with good results.24 The decision to use these drugs mainly depends on the discretion of clinician based on their experience because of lack of randomised control trials.
There is a growing body of evidence in the literature supporting the use of infliximab as a safe treatment with good steroid sparing effects.25 The risk of anaphylactic reaction, immune compromise and the development of lymphoproliferative disorders should be kept in mind while treating with infliximab.
Neurosurgical resection of intracranial granulomas can be considered in life-threatening conditions or when not responding and deteriorating with medical treatment. Ventriculoperitoneal shunts are required in significant hydrocephalus while mild symptomatic hydrocephalus can respond to steroids.
Conclusions
Neurosarcoidosis is a rare disease that has protean manifestations. The most common neurological finding is facial nerve palsy but chronic meningitis and seizures are also frequent manifestations. The mainstay of treatment is steroids, often combined with other immunosuppressants.
Take home messages
-
Plasma glucose is an essential investigation to accompany a lumbar puncture.
-
Papilloedema with a normal CT scan necessitates measuring the opening pressure to make a diagnosis of idiopathic intracranial hypertension (IIH).
-
Abnormal cerebrospinal fluid (CSF) constituents exclude the diagnosis of IIH.
-
Chronic meningitis has many aetiologies: a definite diagnosis may only become apparent with time and careful investigation.
Footnotes
-
Funding None.
-
Competing interests None.
-
Provenance and Peer review Commissioned; externally peer reviewed.
-
Patient consent This is a real case scenario and patient and parental consent was obtained.
