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Lumbar puncture in bacterial meningitis

Costerus, J.M.

Publication date 2018 Document Version Other version License Other Link to publication

Citation for published version (APA): Costerus, J. M. (2018). Lumbar puncture in bacterial meningitis.

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Download date:01 Oct 2021 TECHNOLOGICAL ADVANCES AND CHANGING INDICATIONS FOR LUMBAR PUNCTURE IN NEUROLOGICAL DISORDERS

Joost M. Costerus Matthijs C. Brouwer Diederik van de Beek

Lancet Neurology. 2018 Mar;17(3): 268-278 15475-J-Costerus_BNW.indd 87 728-08-18 16:37 Chapter 7

Abstract Technological advances have changed the indications for and the way in which lumbar puncture is done. Suspected CNS infection remains the most common indication for lumbar puncture, but new molecular techniques have broadened CSF analysis indications, such as the determination of neuronal autoantibodies in autoimmune encephalitis. New screening techniques have increased sensitivity for pathogen detection and can be used to identify pathogens that were previously unknown to cause CNS infections. Evidence suggests that potential treatments for neurodegenerative diseases, such as Alzheimer’s disease, will rely on early detection of the disease with the use of CSF biomarkers. In addition to being used as a diagnostic tool, lumbar puncture can also be used to administer intrathecal treatments as shown by studies of antisense oligonucleotides in patients with spinal muscular atrophy. Lumbar puncture is generally a safe procedure but complications can occur, ranging from minor (eg, back pain) to potentially devastating (eg, cerebral herniation). Evidence that a conic needle tip design reduces complications of lumbar puncture is compelling, and reinforces the need to change clinical practice.

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INTRODUCTION Lumbar puncture is imperative to diagnose many neurological diseases. The procedure is reasonably easy to do and highly available, even in resource-limited settings.1 Principal indications for diagnostic lumbar puncture are a suspected CNS infection and measurement of the CSF opening pressure, but it is also used in the differential diagnosis of subarachnoid haemorrhage, CNS autoimmune disease, neoplastic meningeal disease, and dementia.2 Over the past 10 years, technological advances have decreased the necessity of CSF examination for some diseases—eg, improved neuroimaging techniques in cases of leptomeningeal metastasis3 and the introduction of imaging-guided stereotactic aspiration of brain abscess.4 However, new laboratory techniques have broadened indications for CSF examination in other diseases—eg, biomarkers of neurodegenerative diseases,5 neuronal autoantibodies in autoimmune encephalitis,6 and discovery of previously unidentified pathogens by sequencing.7 Intrathecal delivery of antisense oligonucleotides or other treatments can be used in patients with previously untreatable neurodegenerative disease.8 Also, technological advances in lumbar puncture are continuously taking place, with new findings from many randomised controlled studies on the use of atraumatic 7 lumbar puncture needles9 and the emergence of ultrasound and x-ray guidance.10 In this Review, we summarise indications for lumbar puncture, describe clinical applications and contraindications, and discuss technological advances in lumbar puncture, CSF diagnostics, and the use of biomarkers. We propose some practical guidance for lumbar puncture and the interpretation of CSF analysis and discuss ongoing developments in the field.

Clinical Applications CNS infection remains the major indication for diagnostic lumbar puncture.2,11 CSF analysis can aid diagnosis of various neurological inflammatory diseases—eg, autoimmune encephalitis,6 acute transverse myelitis,12 Guillain-Barre syndrome,13 and primary CNS vasculitis.14 In patients with suspected subarachnoid haemorrhage and non-conclusive results from neuroimaging, the presence of CSF haemoglobin breakdown products are crucial for clinical management decisions.15 In suspected leptomeningeal metastases, cytology and flow cytometry of CSF can confirm the diagnosis.3 One retrospective study16 including 326 patients who underwent elective diagnostic lumbar puncture in an academic hospital (Iowa City, IA, USA) showed that the procedure was successful in 264 patients (81%), and high body-mass index was identified as the most predictive factor for an unsuccessful procedure (p<0·0001). Lumbar puncture was regarded successful if quantifiable CSF was obtained.16

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Lumbar puncture can itself be used therapeutically—eg, in patients with cryptococcal meningitis and acute communicating hydrocephalus, the procedure directly relieves headache as a result of lowering of CSF pressure.17,18 In an observational cohort study19 including 248 patients with HIV-associated cryptococcal meningitis, therapeutic lumbar punctures were associated with a 69% relative improvement of survival. Lumbar puncture is essential in the diagnosis of idiopathic intracranial hypertension because the diagnostic criteria include a raised CSF opening pressure (>25 cm H2O) and normal CSF composition.20 In hydrocephalus with normal CSF opening pressure, the CSF tap test can be done by removal of 30–50 mL CSF to predict efficacy of CSF catheter placement.21 In a prospective case series22 including 115 patients with idiopathic normal pressure hydrocephalus, the tap test had a positive predictive value of 88% and a negative predictive value of 18% for clinical improvement after catheter placement.

Lumbar puncture can also be used to deliver treatment—eg, intrathecal injection of nusinersen, an antisense oligonucleotide that increases the amount of functional survival motor neuron protein that is deficient in patients with spinal muscle atrophy.23 A phase 2 randomised controlled study23 in 20 patients aged 3–7 months showed acceptable safety of nusinersen in this previously untreatable disease and an encouraging clinical response. A randomised doubleblind sham-controlled phase 3 study8 in 121 patients aged 7 months or younger was ended early after a positive interim analysis. In the nusinersen group 37 (51%) of 73 infants had a motor-milestone response compared with none of 37 infants in the control group. In an ongoing open-label phase 3 study (SHINE, NCT02594124) long-term safety of intrathecal nusinersen is being assessed in patients with spinal muscle atrophy. Intrathecal administration is also commonly used in chemotherapy, allowing treatment of CNS or leptomeningeal localisation of malignancies,3,24 and intrathecal baclofen is used to treat spasticity.25 Additionally, perioperative intrathecal administration of fluorescein enables visualisation of CSF leaks in the skull base.26

Contraindications Lumbar puncture has several contraindications to be aware of (panel 1). In patients with hydrocephalus, care should be taken to differentiate between communicating and non-communicating obstructive hydrocephalus (which is a contraindication for lumbar puncture).27 In patients with a cerebral mass lesion causing brain shift, withdrawal of CSF in the lumbar region reduces the counter pressure from below, which can increase brain shift leading to compression of vital brain structures (figure 1).4,28

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To exclude a cerebral mass lesion as a cause of brain shift, cranial imaging can be done (figure 2; panel 2). The bacterial meningitis guideline of the European Society of Clinical Microbiology and Infectious Diseases29 recommends doing cranial CT before lumbar puncture in patients with new-onset seizures, a severe immunocompromised state, focal neurological deficits, or a moderate-to-severe impairment of consciousness defined as a score less than ten on the Glasgow Coma Scale. This guideline29 was composed by an international committee consisting of European experts on neurological infectious diseases, and the Meningitis Research Foundation, a UK-based patient organisation, participated in its development.

Panel 1. Contraindications for lumbar puncture

Relative contraindications: • Platelet count 20-40 x 109/L50* • Thienopyridines therapy34† Absolute contraindications: • Non-communicating hydrocephalus27 • Uncorrected bleeding diathesis34 7 • Anticoagulant therapy34 • Platelet count <20 x 109 /L50 • Spinal stenosis/ spinal cord compression above level of puncture30 • Local skin infections31 • Spinal or cranial developmental abnormalities32

* Lumbar puncture has been described as safe in patients with a platelet count of 20-40 x 109 /L, but more studies are needed to establish definite safety. †In our clinical experience the risk for haemorrhagic complications due to lumbar puncture in patients on monotherapy thienopyridines is low and should be weighed carefully against risks of treatment withdrawal. In patients with dual antiplatelet therapy, continuation of aspirin and and temporally cessation (1 week) of thienopyridine therapy is advised.32

Spinal cord compression is also a contraindication for lumbar puncture (figure 1).30 Suboccipital puncture can be considered in patients with spinal cord compression or lumbar anatomical abnormalities who urgently need CSF examination. In our clinical experience suboccipital puncture is a safe and well-tolerated procedure when done by an experienced physician. Other contraindications are local skin infections at the site of lumbar puncture (eg, abscess)31 or developmental abnormalities (eg, a myelomeningocele, tethered cord, or Chiari malformation).32

Severe coagulopathy is another contraindication for lumbar puncture because it can cause spinal subdural or epidural haematomas. The minimum platelet count to safely do a lumbar puncture has not been clearly defined. A retrospective analysis33 of lumbar punctures in 440 children with cancer reported no complications in the 272 lumbar punctures done in

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those with a platelet count lower than 40 × 10⁹ cells per L. Consensus guidelines32 advise a platelet count of over 40 × 10⁹ cells per L before lumbar puncture in adults on the basis of level 3 evidence. A post-mortem study34 suggested an absolute minimum platelet count of 20 × 10⁹ cells per L for lumbar puncture because two (15%) of 13 patients with a platelet count less than 20 × 10⁹ cells per L were found to have spinal subarachnoid haematoma after lumbar puncture.

We propose intervals of discontinuation of anticoagulant therapy before lumbar puncture (table 1) to reduce the risk of haemorraghic complications (eg, spinal haematoma). The intervals are based on the recommendations for regional anaesthesia of the European Society of Anaesthesiology,35 which were mainly based on pharmacokinetics of all drugs mentioned.

Figure 1. Contraindications for lumbar puncture. (A) Undertaking lumbar puncture in patients with a space-occupying lesion, such as a subdural empyema, can elicit brain herniation. Types of herniation include: cingulate herniation (horizontal movement under the falx), uncal herniation (craniocaudal movement through the tentorial notch), foraminal herniation (movement of cerebellar tonsils through the foramen magnum), or more diffuse herniation (combination of above). (B) A cervical stenosis with myelopathy contraindicates lumbar puncture, which can elicit spinal coning.

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Table 1. Proposed intervals of discontinuation of anticoagulant drug before lumbar puncture.

Anticoagulant Discontinuation interval Laboratory test 3-7 days (can be reversed for International normalised ratio Coumarin derivatives immediate lumbar puncture) <1·4 Novel oral anticoagulants 48 h (depending on renal function) None Activated partial thromboplasin Unfractioned heparin 4 h time (<1·5x reference value) Low molecular weight heparin 24 h None Profylactic low molecular weight heparin None None Aspirin None None Clopidogrel 7 days None Ticlopidine 10 days None Prasugrel 10 days None Ticagrelor 5 days None All proposed intervals were adapted from the European Society of Anaesthesiology.35

Figure 2. Generalised oedema on cranial CT before and after lumber puncture in a patient with bacterial meningitis (A) Generalised oedema, and hydrocephalus. Generalised oedema causing brain shift and obliteration of basal cisterns are contraindications for lumbar puncture. (B,C) Axial 5 mm CT showing partial obliteration of basal cisterns. (D) Axial 5mm CT showing increase of oedema, complete obliteration of basal cisterns, and cerebral herniation through the foramen magnum, and increase of oedema (E,F). CT=computerised tomography

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Complications Lumbar puncture is generally a safe procedure but complications can occur (table 2). Most complications of lumbar puncture can be regarded as minor (eg, back pain, nerve root irritation) or as having a short-term disabling effect (eg, postdural puncture headache), but potentially devastating complications can also occur (eg, spinal haematoma, bacterial meningitis, cerebral venous sinus thrombosis, or cerebral herniation).

Back pain occurs in about 15% of patients after lumbar puncture and can last several days.9 In a prospective cohort study36 in 3456 patients who underwent lumbar puncture in memory clinics across Europe and Brazil, the number of attempts of lumbar puncture (more than four attempts compared with one attempt) was the only procedure-related risk factor detected for back pain (OR 5·4 [95% CI 2.·9–10·2]). Back pain was more often reported in patients with a history of headache than those without a history of headache, whereas being older than 65 years or a diagnosis of mild cognitive impairment or dementia were protective against back pain after lumbar puncture in this study. A meta-analysis9 of randomized controlled trials showed that nerve root irritation, defined as pain radiating to lower limbs following lumbar puncture, occurred in 11% of the patients during the procedure. The use of an atraumatic needle was associated with a lower incidence of nerve root irritation compared with the use of a conventional needle (relative risk 0·71 [95% CI 0·54–0·92]) in a meta-analysis9 on the safety of atraumatic needles including 13 randomised controlled trials with 1496 patients.

Postdural puncture headache is an orthostatic headache caused by CSF leakage and can be accompanied by nausea, neck stiffness, tinnitus, hypacusia, or photophobia.37 The reported incidence varies from 1% to 50%9 and is associated with patient factors such as young age,36,38 female sex,39 low body-mass index,38,40 and a medical history of headache,36 as well as technical factors such as doing the puncture in a sitting position,38 and, most importantly, the needle tip design.9 A meta-analysis of randomised controlled trials9 on the safety of atraumatic needles pooled data from 97 trials including 24903 patients on the incidence of postdural puncture headache. The study found an incidence of 4·2% in the atraumatic needle group and 11·0% in the conventional needle group, with a relative risk of 0·40 (95% CI 0·37–0·47). Although 74 neurologists from the UK indicated in a 2012 survey that they were aware of the benefit of atraumatic needles on incidence of postdural puncture headache, only 12 (16%) were routinely using them.41 A retrospective study2 in two university hospitals in France found that a total of 6594 lumbar punctures had been done in 2014 but atraumatic needles were used in only 527 patients (8%).

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Postdural puncture headache can be treated conservatively with analgesics combined with bed rest since pain is exacerbated by sitting and standing.42 Caffeine has shown some effectiveness, but the evidence is insufficient to use caffeine as standard treatment because of the small sample sizes of studies and their limited generalisability.42 Hydrocortisone, theophylline, and gabapentin have been reported to decrease pain but evidence is scarce.42 Evidence does not support bed rest or fluid supplementation for preventing postdural puncture headache.43 An observer-blind randomised controlled study44 on the effect of an epidural blood patch in 42 patients with more than 24 h of postdural puncture headache within 7 days of lumbar puncture, reported that at day 7 after study treatment, three patients (16%) allocated to epidural blood patch versus 18 patients (86%) allocated to conservative treatment (relative risk 0·18 [95% CI 0·06–0·53]) had postdural puncture headache.44 A blood patch is generally considered after 5 days of conservative therapy without sufficient improvement.44,45

Cerebral herniation following lumbar puncture is a rare complication. In a meta-analysis46 of 1030 patients with brain abscess, which can cause brain shift contraindicating lumbar puncture, clinical deterioration attributed to lumbar puncture was reported in 76 patients 7 (7%). In a retrospective study47 in 296 adults with community-acquired bacterial meningitis, autopsies were available for 27 of 40 patients who died shortly after lumbar puncture, showing cerebral herniation in eight of these patients (2·7%). The incidence of cerebral herniation following lumbar puncture for other diseases is uncertain.

Rare complications of lumbar puncture include bacterial meningitis, spinal haematoma, and cerebral venous thrombosis. Estimated incidence of bacterial meningitis after lumbar puncture is less than 0·1%.48 Possible causes include contamination of the puncture site by skin bacteria or aerosolised mouth commensals from medical personnel, with the most common reported causative organisms being Streptococcus salivarius and Viridans streptococci.49 A spinal haematoma might cause cauda equina compression and is most likely to occur in patients taking anticoagulant therapy or in those with an uncorrected coagulopathy,50 although the incidence is unknown due to absence of prospective studies. A poor outcome was described in 15 (43%) of 35 patients with spinal haematoma as a complication of lumbar puncture in a literature review of case reports published between 1974 and 2014.51 Cerebral venous thrombosis is hypothesised to be a complication of intracranial hypotension following lumbar puncture of which the incidence is unknown. Case reports of 54 patients (18 patients with spinal anaesthesia for obstetrics, 18 with diagnostic lumbar puncture, and 18 with various other indications for lumbar puncture) suggest an increased risk of cerebral venous thrombosis in patients with prothrombotic diseases, such as factor V Leiden mutation or protein C defiency.52

15475-J-Costerus_BNW.indd 95 28-08-18 16:37 Chapter 7 No prospective data; no cohortNo prospective studies Limitations Meta-analysis of randomised controlled trials;Meta-analysis of randomised controlled observational the majority excluded; studies were of patients underwent spinal for lumbar puncture anaesthesia trials;Meta-analysis of randomised controlled observational the majority excluded; studies were of patients underwent spinal for lumbar puncture anaesthesia trials;Meta-analysis of randomised controlled observational the majority excluded; studies were of patients underwent spinal for lumbar puncture anaesthesia data; risk depends on indication for No prospective lumbar puncture data; no cohortNo prospective studies; majority of epidural anaesthesia evidence is from data; no cohortNo prospective studies /L and 9 /L 9 three patients with three count >140 x platelet 10 Participants 5431 patients 1496 patients 24903 patients 1030 patients with brain abscess; 296 patients with community- bacterialacquired meningitis 179 patients with dural puncture-related meningitis 18 patients with platelet count 1-63 x 10 52 patients with lumbar spinal for puncture anaesthesia or for purpose diagnostic 49 retrospective retrospective 46 9 9 9 47 50 52 Case reportsCase Study characteristics Study Meta-analysis of studies atraumatic vs needles conventional Meta-analysis of studies atraumatic vs needles conventional Meta-analysis of studies atraumatic vs needles conventional Meta-analysis of clinical characteristics and in brain abscess; outcome seriesCase and case reports reportsCase study of characteristics of adults with acute bacterial meningitis *

on the safety of atraumatic needles found an incidence 4·2% in needle group and 11·0% conventional group. The Unknown Frequency 15% (range 2-61%) 11% (range 2-40%) 7% (range 1-50%) 3-7% <0·1% Unknown 9 Most common complications of lumbar puncture Cerebral venous venous Cerebral thrombosis Complication Back pain Nerve root irritation Post-dural puncture headache Cerebral herniation Bacterial meningitis Spinal haematoma The meta-analysis overall incidence in the meta-analysis was 7%. * Table 2. Table

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CSF Diagnostic Uses CSF samples can be subjected to various analyses depending on the clinical differential diagnosis. Some of the common CSF analyses and their reference values (appendix) have been determined in prospective studies. For example, the reference range for CSF opening pressure in children was determined in a prospective study53 of 197 children aged 1–18 years of whom none was taking medications or had signs of a disease or condition that would alter opening pressure on lumbar puncture (eg, use of diuretics or papilloedema, hydrocephalus, cerebral oedema, Chiari malformation, or meningitis). The upper limit of CSF opening pressure, defined as the 90th percentile, was 28 cm of water.53 The reference range for CSF opening pressure in adults was determined in a prospective study54 of 242 adults who underwent their first ever lumbar puncture for neurological symptoms. In this study the 95% reference interval for CSF opening pressure was 12–25 cm of water.54

Normal CSF is crystal clear but in pathological conditions can appear cloudy, purulent, or bloody. Bloody CSF can either indicate subarachnoid haemorrhage or a traumatic lumbar puncture. Siderophages, erythrophages, and elevated CSF ferritin concentrations can be 7 found in patients with subarachnoid haemorrhage when examined at least 3 days after the ictus because it takes approximately 3 days for the CSF ferritin levels to increase, and cytological findings of CSF siderophages have a low sensitivity within the first 3 days, but spectrometric analysis of CSF haemoglobin and bilirubin concentrations is considered more accurate and can be assessed at least 12 h after the ictus.15,55 Routine chemical analysis of CSF includes cell count, total protein, and glucose concentration. Because the blood–brain barrier prevents many macromolecules from entering the brain, the protein concentration of CSF is much lower than that of blood plasma.56 The CSF–serum albumin ratio is a reliable biomarker for the permeability of the blood– brain barrier and can be easily determined.57

Gram staining of CSF remains a quick and easy way to guide antimicrobial therapy, whereas CSF culture is considered the gold standard for the diagnosis of bacterial meningitis.28 PCR has emerged as gold standard for detection of viruses58 and is also increasingly used for detection of bacteria.28 CSF lactate is produced by bacterial anaerobic metabolism or ischaemic brain tissue,59,60 and increased CSF lactate concentrations have been reported in patients with stroke, seizures, cerebral trauma, hypoglycaemic coma, or bacterial meningitis.59 Two meta-analyses59,60 on the diagnostic accuracy of CSF lactate in differentiating bacterial meningitis from aseptic meningitis included prospective and retrospective cross-sectional or case-control studies in adults and children. Both meta-analyses, including 1692 patients59 and 1885 patients,60 respectively, concluded that lactate is a good discriminator between bacterial and aseptic meningitis, but skewed shaped funnel plots indicated publication bias among studies included in both meta-analyses. Of note, the diagnostic accuracy of

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CSF lactate for the diagnosis of bacterial meningitis decreases in patients pretreated with antibiotics.59,60 Therefore, increased CSF lactate concentrations should raise the suspicion of bacterial meningitis, but the added value of the use of CSF lactate besides routine parameters such as CSF leucocyte count remains unclear.59,60 CSF procalcitonin concentrations were higher in patients with bacterial meningitis than in those with aseptic meningitis, but further studies are needed before procalcitonin could be recommended as routine test.61,62 Serological tests for detection of antigens or antibodies in CSF are important for the detection of various infectious diseases including cryptococcal meningitis,63 neurosyphilis,64 and Lyme neuroborreliosis.65 For diagnosis of Lyme neuroborreliosis an initial sensitive screening that detects Borrelia burgdorferi IgG and IgM antibodies is recommended, generally by ELISA, followed by a confirmatory immunoblot in the event of a positive or equivocal result because ELISA has relatively poor specificity.65 Calculating the CSF–serum ratio allows discrimination between specific intrathecal antibody production and passive transfer of antibodies through the blood–brain-barrier.65,66 The CSF–serum B burgdorferi antibody ratio is elevated in 70% of patients at onset of symptoms of Lyme neuroborreliosis and in almost 100% of patients after 6 weeks of symptom duration.65 The chemokine (C-X-C motif) ligand 13 (CXCL13) in CSF was found to be elevated in the majority of patients with early Lyme neuroborreliosis even before B burgdorferi antibodies were present and fell rapidly after antibiotic treatment.67–69 However, high CSF concentrations of CXCL13 were also found in patients with CNS lymphoma, tuberculous meningitis, or neurosyphilis, reducing its added value if any of these diseases are considered in the differential diagnosis.65 Detection of galactomannan in CSF is used to diagnose cerebral aspergillosis without the need for a cerebral biopsy.70

CSF cytology is used to detect malignant cells in suspected CNS lymphoma, leukaemia, leptomeningeal dissemination of metastatic tumours, and spread of primary brain tumours.3,71 A small case series of 94 patients suggest that flow cytometry is superior to cytology for the diagnosis of leptomeningeal metastases, but these results need further supportive evidence.72 Immunophenotyping by multiparameter flow cytometry of CSF cells can add to the diagnostic sensitivity in haematologic malignancies, such as primary CNS lymphoma.24

CSF neuronal autoantibody detection plays a central role in the diagnosis of autoimmune encephalitis.6 An increasing number of clinical syndromes—eg, anti-NMDA receptor encephalitis—associated with specific antibodies against neuronal cell-surface or synaptic proteins have been described in the past 10 years.6 In some patients, relevant antibodies might be only found in the CSF and not in serum.6 A retrospective study73 in 250 patients with anti-NMDA receptor encephalitis found that all patients had NMDA receptor antibodies in

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CSF but only 214 (86%) had antibodies in serum. Therefore, inclusion of both CSF and serum is recommended for neuronal antibody testing in suspected anti-NMDA encephalitis.6

CSF Biomarkers The study of molecular biomarkers in CSF constitutes an emerging field of neurological research, with many candidates being investigated (table 3). With new analytical methods, including metabolomic data analysis, virtually all molecules can be measured in CSF, providing a functional readout of cellular biochemistry.74 Such untargeted profiling can be used not only to study fundamental biological processes but also for early diagnosis, monitoring of therapy, and personalised medicine.74 In research settings, CSF biomarkers have good diagnostic accuracy on a group level for Alzheimer’s disease but are not yet recommended for routine diagnostic purposes on a patient level.75 With continued development, CSF biomarkers are likely to offer clinical utility.76

Table 3. CSF diagnostic or prognostic biomarkers for neurological disease.

CSF Biomarker 7 Alzheimer’s disease Aβ42, T-tau, P-tau5 Motor neuron disease pNfH, NfL83-86 Multiple Sclerosis IgG/ IgA/ IgM synthesis, IgG index, IgG index or IL-4 correlation, oligoclonal bands, CD2787,89,90 Lyme Neuroborreliosis CXCL1391 Human African trypanosomiasis CXCL10, CXCL8, H-FABP, neopterin, 5-hydroxytryptophan92,94 Parkinsonian syndromes NfL, sAPP-α, alpha-synuclein, Aβ42, Aβ4079-81 Syndromes associated with frontotemporal sAPP-β, NfL, YKL-4078 lobe degeneration Huntington’s disease NfL82 Neurosarcoidosis* Soluble IL-2 receptor95 Narcolepsy* Hypocretin-196 Prion diseases* 14-3-3 protein97 Serine deficiency disorders* Serine98 Cerebral folate deficiency* 5-methyltetrahydrofolate99 Aβ42= amyloid β 1-42. t-tau=total tau. p-tau=phosphorylated tau. PNfH=phosphorylated neurofilament heavy chain. NfL=neurofilament light protein. IL=interleukin. CXCL=chemokine (C-X-C motif) ligand. H-FABP=heart-type fatty acid binding protein. sAPP=soluble amyloid precursor protein. * Used in clinical practice.

A meta-analysis5 of 231 studies on Alzheimer’s disease biomarkers, comprising 15699 patients and 13018 controls, showed that several biomarkers were strongly associated with the disease, including CSF total-tau (t-tau), phosphorylated-tau (p-tau), and amyloid β

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1-42 (Aβ42). Commercial immunoassays on biomarkers of neurodegeneration have been developed and are being validated to standardise analytical methods and improve diagnostic accuracy.77 In a cohort study78 of 159 patients with clinical syndromes of frontotemporal lobar degeneration (frontotemporal dementia, primary progressive aphasia, progressive supranuclear palsy, or corticobasal syndrome), 72 patients with Alzheimer’s disease dementia, and 76 cognitively healthy controls, concentrations of soluble β fragment of amyloid precursor protein were significantly lower in all clinical syndromes associated with frontotemporal lobar degeneration than in healthy controls and patients with Alzheimer’s disease. CSF neurofilament light protein and YKL-40 concentrations were higher in the group of patients with clinical syndromes of frontotemporal lobar degeneration and in the Alzheimer’s disease group than in healthy controls.78 These findings indicate that neurofilament light protein, YKL-40, and soluble β fragment of amyloid precursor protein might help to increase the diagnostic certainty of frontotemporal lobar degeneration or to select candidates for clinical trials. Importantly, studies of prospective longitudinal diagnostic accuracy are needed to assess the added value of these biomarkers in the differential diagnosis of a cognitive disorder on an individual patient level before their routine clinical use.

A prospective cohort study79 in 160 patients with parkinsonian syndromes and 30 healthy controls found a role for CSF neurofilament light protein, soluble amyloid precursor protein α, and α-synuclein concentrations in predicting diagnosis of Parkinson’s disease versus atypical parkinsonian syndromes. A prospective observational study80 in 108 patients with Parkinson’s disease and 130 age-matched healthy controls found that low baseline CSF concentrations of Aβ42 and Aβ40 predicted decline in gait characteristics in the first 3 years following diagnosis, implicating underlying amyloid pathology. Evidence is inconclusive that neurofilament light protein concentration in CSF tracks disease progression in progressive supranuclear palsy over time.81 A retrospective analysis82 of 23 carriers of the CAG repeat expansions in the HTT gene leading to Huntington’s disease (three HTT mutation carriers with premanifest disease [Unified Huntington’s Disease Rating Scale diagnostic confidence scores <4] and 20 participants with manifest Huntington’s disease), and 14 healthy controls who all underwent CSF analysis showed that the median concentration of neurofilament light protein was significantly higher in the CSF of the mutation carriers than in healthy controls. Neurofilament light protein concentration in blood plasma might also be promising as a prognostic biomarker, but further evidence is needed.82

Several CSF (diagnostic and prognostic) biomarker candidates have been proposed for amyotrophic lateral sclerosis and primary lateral sclerosis, and the most promising candidate biomarkers are phosphorylated neurofilament heavy chain and neurofilament light chain,

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which have been found to be increased in patients with motor neuron disease compared with healthy controls and disease mimics in multiple cohort studies.83–86 Further multicentre studies are required to establish that measurement of these CSF biomarkers reduces the diagnostic delay in patients with motor neuron diseases and to provide evidence to support their use as a marker of disease progression.

IgG intrathecal synthesis, the IgG index, and the correlation between the IgG index and CSF interleukin (IL)-4 were identified as diagnostic biomarkers for multiple sclerosis in a prospective study87 in 64 patients presenting with symptoms suggestive of multiple sclerosis (in whom the diagnosis was subsequently confirmed) and 77 controls diagnosed with other neurological diseases. The presence of oligoclonal bands in CSF supports the diagnosis of multiple sclerosis88 but can also be seen in other autoimmune diseases such as neurosarcoidosis.89 In a prospective cohort study90 in 77 patients with a clinically isolated syndrome, high concentrations of soluble CD27 in CSF were associated with the diagnosis of multiple sclerosis during follow-up and a high relapse rate. However, soluble CD27 concentrations in CSF considerably overlapped between patients in the group with a monophasic clinically isolated syndrome and patients in the group who developed 7 multiple sclerosis during follow-up, limiting the potential clinical use of this biomarker on an individual patient level.90

Disease-related patterns of IgG, IgA, and IgM synthesis in CSF combined with clinical and other laboratory parameters have been described in the diagnostic workup of multiple sclerosis, CNS lymphoma, CNS tuberculosis, and Lyme neuroborreliosis.91 Cohort studies92–94 on Trypanosoma brucei gambiense infection (human African trypanosomiasis) suggest that CXCL10, CXCL8, heart-type fatty acid binding protein, neopterin, and 5-hydroxytryptophan are helpful biomarkers in staging of the disease; however, the added value is much lower when other inflammatory disorders are considered in the differential diagnosis. Furthermore, tests for T brucei gambiense infection should also be made available for use in resource- limited settings.94

In a cohort study95 of 88 patients (including 11 patients with neurosarcoidosis, 21 with multiple sclerosis, ten with CNS vasculitis, 22 with bacterial meningitis, 17 with viral meningitis or encephalitis, and seven with CNS tuberculosis), and 18 healthy controls, CSF soluble IL-2 receptor concentrations were determined with ELISA. This study found that CSF soluble IL-2 receptor concentrations of more than 150 pg/mL identified untreated patients with neurosarcoidosis with a sensitivity of 61% and specificity of 93%.95 However, CSF concentrations of soluble IL-2 receptor of more than 150 pg/mL did not discriminate neurosarcoidosis and infectious meningitis.95 These findings need to be replicated in

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multicentre prospective longitudinal diagnostic studies in patients with suspected neurosarcoidosis before this CSF biomarker is used in routine diagnostic work up.

CSF biomarkers used in routine clinical practice include hypocretin-1 in narcolepsy type 1,96 14-3-3 protein in prion diseases,97 serine in serine-deficiency disorders,98 and 5-methyltetrahydrofolate in cerebral folate deficiency.99 In neuromyelitis optica, detection of aquaporin-4 IgG antibodies (AQP4-IgG) is part of the diagnostic criteria.100 Although most patients with neuromyelitis optica have detectable serum antibodies, rare cases have been reported in whom AQP4-IgG was detected in CSF only.100 However, routine CSF testing of AQP4-IgG-seronegative patients is not recommended.100 CSF analysis of neurometabolites remains essential in the diagnosis of neurometabolic diseases (eg, glucose transporter type 1 deficiency syndrome), although next-generation sequencing has emerged as an important tool facilitating these diagnoses.101

Future Applications Although untargeted analysis of CSF through so-called omics approaches is only used in research settings, it will be of increasing importance in clinical practice in upcoming years, enabling personalised medicine.74 Early detection will be key to prevent or intervene in the early phase of neurological disorders and CSF diagnostic biomarkers are expected to play a central role. The potential of these new CSF analysis methods is enormous, but validation and prospective diagnostic studies are needed.

New methods in CSF microbial diagnostics are also moving to the forefront of clinical research. Multiplex PCR kits have been marketed as the new gold standard for the diagnosis of suspected CNS infections and can analyse DNA of up to 14 pathogens simultaneously.102 Current challenges of these kits are low specificity in clinical practice.103 Therefore, prospective studies of diagnostic accuracy of these kits, including cost-effectiveness studies, are needed before their implementation in routine clinical practice. Matrix-assisted laser desorption or ionisation time-of-flight mass spectrometry (MALDITOF MS) of CSF can detect pathogens on the basis of protein fragments released from the bacterial cell surface.104 MALDI-TOF MS requires only minutes to deliver a final result and its ability to identify microorganisms is not limited to prespecified targets.104 MALDI-TOF MS is a reliable alternative method for culture to identify bacteria in blood,104 and, in case reports,105,106 MALDI-TOF MS successfully identified the causative organism in CSF of patients with bacterial meningitis. Another technique that is not limited to prespecified targets is shotgun metagenomic sequencing of total DNA and RNA from host and pathogen. Shotgun metagenomic sequencing has successfully identified new and known viral pathogens in patients with encephalitis of

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unknown origin.107 For example, the technique identified a novel squirrel Bornavirus as the cause of fatal encephalitis in three squirrel breeders.108

Advances will also lead to renewed interest for intrathecal treatment. The efficacy of intrathecal treatment with nusinersen in patients with spinal muscular atrophy are promising and the design of new spliceswitching oligonucleotides targeting the CNS can create new indications for lumbar puncture, because oligonucleotides do not easily cross the blood–brain barrier.23,109 For example, a phase 1–2a randomized placebo-controlled trial of IONIS-HTTRx, an intrathecally delivered antisense oligonucleotide targeting the HTT gene in patients with early Huntington’s disease, has announced enrolment completion (NCT02519036). A phase 1 randomised placebo-controlled study on safety of IONIS- SOD1Rx, an intrathecally delivered antisense oligonucleotide targeting the SOD1 gene in patients with SOD1-related familial amyotrophic lateral sclerosis, is recruiting participants (NCT02623699). An experimental study in mice showed that a single intrathecal lentiviral gene delivery can lead to Schwann cell-specific expression in spinal roots extending to multiple peripheral nerves.110 This approach improved the phenotype of an inherited neuropathy mouse model and provided proof of principle for treating inherited 7 demyelinating neuropathies.110 Intrathecal gene therapy has showed promising results in experimental models of malignant leptomeningeal neoplasia,111 amyotrophic lateral sclerosis,112 and neurological manifestations of mucopolysaccharidoses.113

Conclusions Many advances have taken place in the field of CSF analysis ever since Heinrich Quincke did the first lumbar puncture more than a century ago. Lumbar puncture is generally a safe procedure but care should be taken in patients with coagulopathy or brain shift.31,35 A change of practice is needed with respect to use of atraumatic needles, which are easy to use and have lower rates of postdural puncture headache than conventional needles.9 CSF examination remains essential in the diagnosis of many CNS diseases, and technological advances such as determination of biomarkers and new techniques for pathogen discovery in CNS infections have changed the field of CSF diagnostics. CSF biomarker research will be imperative for early detection of neurodegenerative diseases. CSF genomics and metabolomics, and new intrathecal treatments, have expanded the use of CSF diagnostics and therapeutics although this work is still preliminary. Intrathecal treatment with oligonucleotides can now modify previously untreatable neurodegenerative diseases. The translation of these CSF biomarkers into clinical applications might enable personalised medicine in the near future, improving existing treatments and giving rise to future drug therapies.

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Search Strategy and Selection Criteria In addition to reviewing published practice guidelines and their reference lists, we searched PubMed and Cochrane Database electronic resources for published studies (from Jan 1, 2010, to Nov 2, 2017, in English) on the topics of lumbar puncture and CSF examination. Search terms included combinations of the Medical Subject Headings “spinal puncture”, “cerebrospinal fluid”, “bacterial meningitis”, “injections, spinal”, “normal pressure hydrocephalus”, “Alzheimer disease”, “encephalitis”, “vasculitis, central nervous system”, “Guillain-Barre syndrome”, “myelitis, transverse”, “practice guideline”, “lumbar vertebrae”, “central nervous system neoplasms”, “intracranial hypertension”, “hydrocephalus”, haemorrhage/prevention and control”, “postdural puncture headache”, “tonsillar herniation”, and “biomarkers/cerebrospinal fluid”. We also used references cited in the publications retrieved. Original research papers and, when appropriate, reviews were included. The final reference list was generated on the basis of relevance and originality with regard to the topics covered in this Review.

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60. Sakushima K, Hayashino Y, Kawaguchi T, Jackson JL, Fukuhara S. Diagnostic accuracy of cerebrospinal fluid lactate for differentiating bacterial meningitis from aseptic meningitis: a meta- analysis. J Infect 2011; 62: 255-62. 61. Li W, Sun X, Yuan F, et al. Diagnostic Accuracy of Cerebrospinal Fluid Procalcitonin in Bacterial Meningitis Patients with Empiric Antibiotic Pretreatment. J Clin Microbiol 2017; 55: 1193-204. 62. Vikse J, Henry BM, Roy J, Ramakrishnan PK, Tomaszewski KA, Walocha JA. The role of serum procalcitonin in the diagnosis of bacterial meningitis in adults: a systematic review and meta- analysis. Int J Infect Dis 2015; 38: 68-76. 63. Tan IL, Smith BR, von Geldern G, Mateen FJ, McArthur JC. HIV-associated opportunistic infections of the CNS. Lancet Neurol 2012; 11: 605-17. 64. Marra CM. Neurosyphilis. Continuum (Minneap Minn) 2015; 21: 1714-28. 65. Koedel U, Fingerle V, Pfister HW. Lyme neuroborreliosis-epidemiology, diagnosis and management. Nat Rev Neurol 2015; 11: 446-56. 66. Reiber H. Knowledge-base for interpretation of cerebrospinal fluid data patterns. Essentials in neurology and psychiatry. Arq Neuropsiquiatr 2016; 74: 501-12. 67. Schmidt C, Plate A, Angele B, et al. A prospective study on the role of CXCL13 in Lyme neuroborreliosis. Neurology 2011; 76: 1051-8. 68. Hytonen J, Kortela E, Waris M, Puustinen J, Salo J, Oksi J. CXCL13 and neopterin concentrations in cerebrospinal fluid of patients with Lyme neuroborreliosis and other diseases that cause neuroinflammation. J Neuroinflammation 2014; 11: 103. 69. Remy MM, Schobi N, Kottanattu L, Pfister S, Duppenthaler A, Suter-Riniker F. Cerebrospinal fluid CXCL13 as a diagnostic marker of neuroborreliosis in children: a retrospective case-control study. J Neuroinflammation 2017; 14: 173. 70. Chong GM, Maertens JA, Lagrou K, Driessen GJ, Cornelissen JJ, Rijnders BJ. Diagnostic Performance of Galactomannan Antigen Testing in Cerebrospinal Fluid. J Clin Microbiol 2016; 54: 428-31. 71. Scott BJ, Douglas VC, Tihan T, Rubenstein JL, Josephson SA. A systematic approach to the diagnosis of suspected central nervous system lymphoma. JAMA Neurol 2013; 70: 311-9. 72. Milojkovic Kerklaan B, Pluim D, Bol M, et al. EpCAM-based flow cytometry in cerebrospinal fluid greatly improves diagnostic accuracy of leptomeningeal metastases from epithelial tumors. Neuro Oncol 2016; 18: 855-62. 73. Gresa-Arribas N, Titulaer MJ, Torrents A, et al. Antibody titres at diagnosis and during follow-up of anti-NMDA receptor encephalitis: a retrospective study. Lancet Neurol 2014; 13: 167-77. 74. Patti GJ, Yanes O, Siuzdak G. Innovation: Metabolomics: the apogee of the omics trilogy. Nat Rev Mol Cell Biol 2012; 13: 263-9. 75. McKhann GM, Knopman DS, Chertkow H, et al. The diagnosis of dementia due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement 2011; 7: 263-9. 76. O’Bryant SE, Mielke MM, Rissman RA, et al. Blood-based biomarkers in Alzheimer disease: Current state of the science and a novel collaborative paradigm for advancing from discovery to clinic. Alzheimers Dement 2017; 13: 45-58. 77. van Waalwijk van Doorn LJC, Kulic L, Koel-Simmelink MJA, et al. Multicenter Analytical Validation of Abeta40 Immunoassays. Front Neurol 2017; 8: 310. 78. Alcolea D, Vilaplana E, Suarez-Calvet M, et al. CSF sAPPbeta, YKL-40, and neurofilament light in frontotemporal lobar degeneration. Neurology 2017; 89: 178-88.

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Supplementary Table

Supplementary Table 1. Cerebrospinal fluid examination and reference values.

Test Reference value Particulars Appearance Crystal clear Pressure < 28 cm water for children; <25cm water for adults1,2 Cells 0-5/ µL Cell differential None Determine predominant cells Protein <0·6g/l3 Lower protein concentration have been reported for younger patients3 CSF/ serum albumin quotient Upper range: age/25+83 Glucose 2·7-4·5 mmol/L (75% of blood glucose) 4 Glucose ratio CSF/ plasma 0·46-0·884 Spectrophotometry of haemoglobin Negative5 and bilirubin Ferritin <15 ng/ ml6 7 Siderophages/ erythrophages Absent6 Lactate <3·5 mmol/l4 Procalcitonin <0.5ng/ml7 Gram staining + culture Negative8 Polymerase Chain Reaction Negative9 Serology Negative10-12 Microscopy/ histopathology Variable Cytology/ flow cytology Variable13,14 MALDI-TOF MS (bacteria) Negative15 Immunophenotyping Variable16 Anti-neuronal antibodies Negative17

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References 1. Whiteley W, Al-Shahi R, Warlow CP, Zeidler M, Lueck CJ. CSF opening pressure: reference interval and the effect of body mass index. Neurology 2006; 67: 1690—1. 2. Avery RA, Shah SS, Licht DJ, et al. Reference range for cerebrospinal fluid opening pressure in children. The New England journal of medicine 2010; 363: 891—3. 3. Hegen H, Auer M, Zeileis A, Deisenhammer F. Upper reference limits for cerebrospinal fluid total protein and albumin quotient based on a large cohort of control patients: implications for increased clinical specificity. Clin Chem Lab Med 2016; 54: 285—92. 4. Leen WG, Willemsen MA, Wevers RA, Verbeek MM. Cerebrospinal fluid glucose and lactate: age- specific reference values and implications for clinical practice. PloS one 2012; 7: e42745. 5. Macdonald RL, Schweizer TA. Spontaneous subarachnoid haemorrhage. Lancet 2016. 6. Nagy K, Skagervik I, Tumani H, et al. Cerebrospinal fluid analyses for the diagnosis of subarachnoid haemorrhage and experience from a Swedish study. What method is preferable when diagnosing a subarachnoid haemorrhage? Clin Chem Lab Med 2013; 51: 2073-86. 7. Vikse J, Henry BM, Roy J, Ramakrishnan PK, Tomaszewski KA, Walocha JA. The role of serum procalcitonin in the diagnosis of bacterial meningitis in adults: a systematic review and meta- analysis. International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases 2015; 38: 68-76. 8. McGill F, Heyderman RS, Panagiotou S, Tunkel AR, Solomon T. Acute bacterial meningitis in adults. Lancet 2016. 9. Kleines M, Scheithauer S, Schiefer J, Hausler M. Clinical application of viral cerebrospinal fluid PCR testing for diagnosis of central nervous system disorders: a retrospective 11-year experience. Diagnostic microbiology and infectious disease 2014; 80: 207-15. 10. Marra CM. Neurosyphilis. Continuum 2015; 21: 1714—28. 11. Tan IL, Smith BR, von Geldern G, Mateen FJ, McArthur JC. HIV-associated opportunistic infections of the CNS. The Lancet Neurology 2012; 11: 605—17. 12. Koedel U, Pfister HW. Lyme neuroborreliosis. Current opinion in infectious diseases 2017; 30: 101-7. 13. Beauchesne P. Intrathecal chemotherapy for treatment of leptomeningeal dissemination of metastatic tumours. Lancet Oncol 2010; 11: 871—9. 14. Scott BJ, Douglas VC, Tihan T, Rubenstein JL, Josephson SA. A systematic approach to the diagnosis of suspected central nervous system lymphoma. JAMA Neurol 2013; 70: 311—9. 15. Angeletti S. Matrix assisted laser desorption time of flight mass spectrometry (MALDI-TOF MS) in clinical microbiology. J Microbiol Methods 2017; 138: 20-9. 16. Hoang-Xuan K, Bessell E, Bromberg J, et al. Diagnosis and treatment of primary CNS lymphoma in immunocompetent patients: guidelines from the European Association for Neuro-Oncology. Lancet Oncol 2015; 16: e322—32. 17. Graus F, Titulaer MJ, Balu R, et al. A clinical approach to diagnosis of autoimmune encephalitis. The Lancet Neurology 2016; 15: 391—404.

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