Review

Technological advances and changing indications for lumbar

puncture in neurological disorders
Joost M Costerus, Matthijs C Brouwer, Diederik van de Beek

Lancet Neurol 2018; 17: 268–78 Technological advances have changed the indications for and the way in which lumbar puncture is done. Suspected
Department of Neurology, CNS infection remains the most common indication for lumbar puncture, but new molecular techniques have
Academic Medical Center, broadened CSF analysis indications, such as the determination of neuronal autoantibodies in autoimmune
University of Amsterdam,
encephalitis. New screening techniques have increased sensitvity for pathogen detection and can be used to identify
Amsterdam Neuroscience,
Amsterdam, Netherlands pathogens that were previously unknown to cause CNS infections. Evidence suggests that potential treatments for
(J M Costerus MD, neurodegenerative diseases, such as Alzheimer’s disease, will rely on early detection of the disease with the use of
M C Brouwer MD, CSF biomarkers. In addition to being used as a diagnostic tool, lumbar puncture can also be used to administer
Prof D van de Beek MD)
intrathecal treatments as shown by studies of antisense oligonucleotides in patients with spinal muscular atrophy.
Correspondence to:
Lumbar puncture is generally a safe procedure but complications can occur, ranging from minor (eg, back pain) to
Prof Diederik van de Beek,
Department of Neurology, potentially devastating (eg, cerebral herniation). Evidence that an atraumatic needle tip design reduces complications
Academic Medical Center, of lumbar puncture is compelling, and reinforces the need to change clinical practice.
University of Amsterdam,
Amsterdam Neuroscience,
1100DD Amsterdam,
Introduction diagnosis of various neurological inflammatory
Netherlands Lumbar puncture is imperative to diagnose many diseases—eg, autoimmune encephalitis,6 acute trans­
d.vandebeek@amc.uva.nl neurological diseases. The procedure is reasonably easy verse myelitis,12 Guillain-Barré syndrome,13 and primary
to do and highly available, even in resource-limited CNS vasculitis.14 In patients with suspected subarachnoid
settings.1 Principal indications for diagnostic lumbar haemorrhage and non-conclusive results from neuro­
puncture are a suspected CNS infection and imaging, the presence of CSF haemoglobin breakdown
measurement of the CSF opening pressure, but it is also products is crucial for clinical management decisions.15
used in the differential diagnosis of subarachnoid In suspected lepto­meningeal metastases, cytology and
haemorrhage, CNS autoimmune disease, neoplastic flow cytometry of CSF can confirm the diagnosis.3 One
meningeal disease, and dementia.2 retrospective study16 including 326 patients who
Over the past 10 years, technological advances have underwent elective diagnostic lumbar puncture in an
decreased the necessity of CSF examination for some academic hospital (Iowa City, IA, USA) showed that the
diseases—eg, improved neuroimaging techniques in procedure was successful in 264 patients (81%), and high
cases of leptomeningeal metastasis3 and the introduction body-mass index was identified as the most predictive
of imaging-guided stereotactic aspiration of brain factor for an unsuccessful procedure (p<0·0001). Lumbar
abscess.4 However, new laboratory techniques have puncture was regarded as successful if quantifiable CSF
broadened indications for CSF examination in other was obtained.16
diseases—eg, biomarkers of neurodegenerative diseases,5 Lumbar puncture can itself be used therapeutically—
neuronal autoantibodies in autoimmune encephalitis,6 eg, in patients with cryptococcal meningitis and acute
and discovery of previously unidentified pathogens by communicating hydrocephalus, the procedure directly
sequencing.7 Intrathecal delivery of antisense relieves headache as a result of lowering of CSF
oligonucleotides or other treatments can be used in pressure.17,18 In an obser­vational cohort study19 including
patients with previously untreatable neurodegenerative 248 patients with HIV-associated cryptococcal meningitis,
disease.8 Also, technological advances in lumbar therapeutic lumbar punctures were associated with a
puncture are continuously taking place, with new 69% relative improve­ment in survival. Lumbar puncture
findings from many randomised controlled studies on is essential in the diagnosis of idiopathic intracranial
the use of atraumatic lumbar puncture needles9 and the hypertension because the diagnostic criteria include a
emergence of ultrasound and x-ray guidance.10 raised CSF opening pressure (>25 cm H2O) and normal
In this Review, we summarise indications for lumbar CSF composition.20 In hydrocephalus with normal CSF
puncture, describe clinical applications and contra­ opening pressure, the CSF tap test can be done by
indications, and discuss technological advances in removal of 30–50 mL CSF to predict efficacy of CSF
lumbar puncture, CSF diagnostics, and the use of catheter placement.21 In a prospective case series22
biomarkers. We propose some practical guidance for including 115 patients with idiopathic normal pressure
lumbar puncture and the interpretation of CSF analysis hydrocephalus, the tap test had a positive predictive value
and discuss ongoing developments in the field. of 88% and a negative predictive value of 18% for clinical
improvement after catheter placement.
Clinical applications Lumbar puncture can also be used to deliver
CNS infection remains the major indication for treatment—eg, intrathecal injection of nusinersen, an
diagnostic lumbar puncture.2,11 CSF analysis can aid antisense oligonucleotide that increases the amount of

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 Review

functional survival motor neuron protein, which is

Panel 1: Contraindications for lumbar puncture
Relative contraindications
• Platelet count 20–40 × 10⁹/L27*
• Thienopyridines therapy28†
Absolute contraindications
• Non-communicating obstructive hydrocephalus29
• Uncorrected bleeding diathesis28
• Anticoagulant therapy28
• Platelet count <20 × 10⁹/L27
• Spinal stenosis or 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 × 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 temporary cessation (1 week) of thienopyridine therapy is advised.32
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 double-
blind 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

A Subdural empyema B Cervical spinal stenosis

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 (green
arrows) 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) Cervical spinal stenosis with
myelopathy contraindicates lumbar puncture, which can elicit spinal coning.

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 Review

Contraindications Spinal cord compression is also a contraindication for

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).29 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 com­
pression of vital brain structures (figure 1).4,33
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 Diseases34 recom­
mends doing cranial CT before lumbar puncture
in patients with new-onset seizures, a severe immuno­
compromised state, focal neurological deficits, or a
moderate-to-severe impairment of consciousness defined
as a score less than 10 on the Glasgow Coma Scale. This
guideline34 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.
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 myelo­
meningocele, 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 analysis35 of lumbar punctures in
440 children with cancer reported no complications in
the 272 lumbar punctures done in 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 study28
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

Before lumbar puncture

A B C

23 hours after lumbar puncture

D E F

Figure 2: Generalised oedema on cranial CT before and after lumbar 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 5 mm CT showing increase of oedema, complete obliteration of basal cisterns, and cerebral
herniation through the foramen magnum (E,F). CT=computerised tomography.

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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 recom­
mendations for regional anaesthesia of the European
Society of Anaesthesiology,36 which were mainly based on
pharmacokinetics of the described drugs.
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
study41 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 (odds ratio 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
having a diagnosis of mild cognitive impairment or
dementia were protective against back pain after lumbar
puncture in this study. A meta-analysis9 of randomised
controlled trials showed that nerve root irritation, defined
as pain radiating to lower limbs following lumbar
puncture, occurred in 164 (11%) of the 1496 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.42 The
reported incidence varies from 1% to 50%9 and is
associated with patient factors such as young age,41,43
female sex,44 low body-mass index,43,45 and a medical history
of headache,41 as well as technical factors such as doing the
puncture in a sitting position,43 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 24  903 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
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Review
Panel 2: Case study
A 48-year-old woman with hypertension was admitted to the emergency department
with coma and seizures. She had a 2-day history of headache, nausea, and fever, and
neurological examination showed a minimal Glasgow Coma Scale score (E1M1V1).
Treatment was started with intravenous antibiotics and dexamethasone. Cranial CT
showed generalised oedema, causing brain shift, with partial obliteration of basal cisterns
and hydrocephalus. A lumbar puncture revealed 2500 leucocytes per µL and cultures grew
Streptococcus pneumoniae, suggesting a diagnosis of bacterial meningitis. 1 h after lumbar
puncture, the patient was found to have wide and non-reactive pupils. A new cranial CT
showed increased cerebral oedema with complete obliteration of basal cisterns and
cerebral herniation through the foramen magnum (figure 2). At day 2 after admission,
supportive care was withdrawn and the patient died. It remains unclear whether her
cerebral herniation was caused by the fulminant meningitis, by direct consequence of
lumbar puncture, or both.
Discontinuation interval Laboratory test
Coumarin derivatives 3–7 days (can be reversed for International normalised ratio <1·4
immediate lumbar puncture)
Novel oral anticoagulants 48 h (depending on renal function) None
Unfractioned heparin 4h Activated partial thromboplastin
time (<1·5 × reference value)
Low molecular weight 24 h None
heparin
Profylactic low molecular None None
weight heparin
Aspirin None None
Clopidogrel 7 days None
Ticlopidine 10 days None
Prasugrel 10 days None
Ticagrelor 5 days None
These proposed intervals are based on the recommendations of the European Society of Anaesthesiology36
Table 1: Proposed intervals of discontinuation of anticoagulant therapy before lumbar puncture.
they were aware of the benefit of atraumatic needles on
incidence of postdural puncture headache, only 12 (16%)
were routinely using them.46 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 (8%) patients.
Postdural puncture headache can be treated
conservatively with analgesics combined with bed rest
since pain is exacerbated by sitting and standing.47
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.47 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.48 An observer-blind randomised controlled
study49 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%)
 Review

Frequency (%) Study characteristics Participants (N) Limitations

Back pain 15% Meta-analysis of studies of atraumatic vs 5431 Meta-analysis of randomised controlled trials; observational
(range 2–61%) conventional needles9 studies were excluded; the majority of patients underwent
lumbar puncture for spinal anaesthesia
Nerve root 11% Meta-analysis of studies of atraumatic vs 1496 Meta-analysis of randomised controlled trials; observational
irritation (range 2–40%) conventional needles9 studies were excluded; the majority of patients underwent
lumbar puncture for spinal anaesthesia
Postdural 7% Meta-analysis of studies of atraumatic vs 24 903 Meta-analysis of randomised controlled trials; observational
puncture (range 1–50%)* conventional needles9 studies were excluded; the majority of patients underwent
headache lumbar puncture for spinal anaesthesia
Cerebral 3–7% Meta-analysis of clinical characteristics and 1030 patients with brain abscess; 296 patients with No prospective data; risk depends on indication for
herniation outcome in patients with brain abscess;37 community-acquired bacterial meningitis lumbar puncture
retrospective study of characteristics of adults
with acute bacterial meningitis38
Bacterial <0·1% Case series and case reports39 179 patients with dural puncture-related meningitis No prospective data; no cohort studies; majority of
meningitis evidence is from epidural anaesthesia
Spinal Unknown Case reports27 18 patients with platelet count 1–63 × 10⁹/L and three No prospective data; no cohort studies
haematoma patients with normal platelet count >140 × 10⁹/L
Cerebral Unknown Case reports40 52 patients with lumbar puncture for spinal No prospective data; no cohort studies
venous sinus anaesthesia or for diagnostic purpose
thrombosis

*The meta-analysis9 on the safety of atraumatic needles found an incidence of 4·2% in the atraumatic needle group and 11·0% in the conventional needle group. The overall incidence in the meta-analysis was 7%.

Table 2: Most common complications of lumbar puncture

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.49
A blood patch is generally considered after 5 days of
conservative therapy without sufficient improvement.49,50
Cerebral herniation following lumbar puncture is a rare
complication. In a meta-analysis37 of 1030 patients with
brain abscess, which can cause brain shift contraindicating
lumbar puncture, clinical deterioration attributed to
lumbar puncture was reported in 76 (7%) patients. In a
retrospective study38 in 296 adults with community-acquired
bacterial menin­ gitis, autopsies were available for 27 of
40 patients who died shortly after lumbar puncture,
showing cerebral herniation in eight (3%) of these patients.
See Online for appendix 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 sinus
thrombosis. Estimated incidence of bacterial meningitis
after lumbar puncture is less than 0·1%.51 Possible causes
include contamination of the puncture site by skin
bacteria or aerosolised mouth commensals from medical
personnel,39 with the most common reported causative
organisms being Streptococcus salivarius and viridans
streptococci.39 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,27 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 2014.52 Cerebral venous sinus 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 sinus thrombosis in patients with
prothrombotic diseases, such as factor V Leiden mutation
or protein C deficiency.40
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 H₂O.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 H₂O.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, erythro­

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phages, and elevated CSF ferritin concentrations can be
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.33 PCR has emerged as gold
standard for detection of viruses58 and is also increasingly
used for detection of bacteria.33 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 CSF lactate for the diagnosis of bacterial
meningitis decreases in patients pretreated with
antibiotics.59,60 Therefore, increased CSF lactate con­
centrations 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
a 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
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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 haematological 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 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.94 Such untargeted
profiling can be used not only to study fundamental
biological processes but also for early diagnosis,
monitoring of therapy, and personalised medicine.94 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.95 With continued development, CSF bio­
markers are likely to offer clinical utility.96
 Review
CSF biomarker
Alzheimer’s disease Aβ42, t-tau, p-tau5
Motor neuron diseases PNfH, NfL74–77
Multiple sclerosis IgG, IgA, or IgM synthesis, IgG index or IL-4 correlation, oligoclonal
bands, CD2778,79,80
Lyme neuroborreliosis CXCL1381
Human African trypanosomiasis CXCL10, CXCL8, H-FABP, neopterin, 5-hydroxytryptophan82,83
Parkinsonian syndromes NfL, sAPP-α, α-synuclein, Aβ42, Aβ4084–86
Syndromes associated with sAPP-β, NfL, YKL-4087
frontotemporal lobe degeneration
Huntington’s disease NfL88
Neurosarcoidosis Soluble IL-2 receptor89
Narcolepsy* Hypocretin-190
Prion diseases* 14-3-3 protein91
Serine deficiency disorders* Serine92
Cerebral folate deficiency* 5-methyltetrahydrofolate93
Aβ42=amyloid β 1-42. Aβ40=amyloid β 1-40. t-tau=total tau. p-tau=phosphorylated tau. PNfH=phosphorylated
neurofilament heavy chain. NfL=neurofilament light protein. YKL-40=chitinase-3-like 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.
Table 3: CSF diagnostic or prognostic biomarkers for neurological disease
A meta-analysis5 of 231 studies on Alzheimer’s disease
biomarkers, comprising 15 699 patients and 13 018 con­
trols, showed that several biomarkers were strongly
associated with the disease, including CSF total-tau,
phosphorylated-tau, and amyloid β 1-42 (Aβ42).
Commercial immunoassays on biomarkers of
neurodegeneration have been developed and are being
validated to standardise analytical methods and improve
diagnostic accuracy.97 In a cohort study87 of 159 patients
with clinical syndromes of frontotemporal lobar degen­
eration (frontotemporal dementia, primary progressive
aphasia, progressive supranuclear palsy, or corticobasal
syndrome), 72 patients with Alzheimer’s disease
dementia, and 76 cognitively healthy controls, con­
centrations 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 concen­
trations 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.87
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 study84 in 160 patients with
parkinsonian syndromes and 30 healthy controls found a
role for CSF neurofilament light protein, soluble amyloid
274 www.thelancet.com/neurology Vol 17 March 2018
precursor protein α, and α-synuclein concentrations in
predicting diagnosis of Parkinson’s disease versus
atypical parkinsonian syndromes. A prospective
observational study85 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.86 A retro­spective analysis88 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.88
Several CSF biomarker candidates (diagnostic and
prognostic) have been proposed for amyo­trophic lateral
sclerosis and primary lateral sclerosis, and the most
promising candidate biomarkers are phosphorylated
neurofilament heavy chain and neuro­ filament light
chain, which have been found to be increased in patients
with motor neuron diseases compared with healthy
controls and disease mimics in multiple cohort
studies.74–77 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 study78 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 sclerosis98 but can also be seen in
other autoimmune diseases such as neurosarcoidosis.79 In
a prospective cohort study80 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 multiple sclerosis
during follow-up, limiting the potential clinical use of this
biomarker on an individual patient level.80

Disease-related patterns of IgG, IgA, and IgM synthesis
in CSF combined with clinical and other laboratory
parameters have been described in the diagnostic work-
up of multiple sclerosis, CNS lymphoma, CNS
tuberculosis, and Lyme neurobor­ reliosis.81 Cohort
studies82–83 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.83
In a cohort study89 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%.89 However, CSF
concentrations of soluble IL-2 receptor of more than
150 pg/mL did not discriminate between neuro­
sarcoidosis and infectious menin­gitis.89 These findings
need to be replicated in 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 1,90 14-3-3 protein
in prion diseases,91 serine in serine deficiency disorders,92
and 5-methyltetrahydrofolate in cerebral folate
deficiency.93 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.94 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
www.thelancet.com/neurology Vol 17 March 2018 275
Review
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-effective­
ness studies, are needed before their implementation in
routine clinical practice. Matrix-assisted laser desorption
or ionisation time-of-flight mass spectrometry (MALDI-
TOF 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 micro-
organisms 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 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 intra­
thecal treatment. The efficacy of intrathecal treatment
with nusinersen in patients with spinal muscular atrophy
is promising and the design of new splice-switching
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 randomised placebo-controlled trial of
IONIS-HTTRx, an intra­ thecally delivered anti­ sense
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
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
 Review
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-Barré 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.
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.31,36
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.
Contributors
All authors contributed to writing and editing this Review, and all
authors gave final approval for submission.
Declaration of interest
We declare no competing interests.
Acknowledgments
MCB is supported by the Netherlands Organisation for Health Research
and Development (ZonMw, NWO-Vidi-Grant [917.17.308]). DvdB is
funded by the Netherlands Organisation for Health Research and
Development (ZonMW, NWO-Vidi-Grant [016.116.358]) and the
European Research Council (ERC Starting Grant).
276 www.thelancet.com/neurology Vol 17 March 2018
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