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Pitfalls in the diagnosis of meningitis in neonatesand young infants: the role of lumbar puncture

Luca Bedetti, Lucia Marrozzini, Alessandro Baraldi, Elisabetta Spezia,Lorenzo Iughetti, Laura Lucaccioni & Alberto Berardi

To cite this article: Luca Bedetti, Lucia Marrozzini, Alessandro Baraldi, Elisabetta Spezia, LorenzoIughetti, Laura Lucaccioni & Alberto Berardi (2018): Pitfalls in the diagnosis of meningitis inneonates and young infants: the role of lumbar puncture, The Journal of Maternal-Fetal & NeonatalMedicine, DOI: 10.1080/14767058.2018.1481031

To link to this article: https://doi.org/10.1080/14767058.2018.1481031

Accepted author version posted online: 23May 2018.

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Pitfalls in the diagnosis of meningitis in neonatesand young infants: the role of lumbar puncture

Luca Bedetti, MDa; Lucia Marrozzini, MDa; Alessandro Baraldi, MDa; ElisabettaSpezia, MDa; Lorenzo Iughetti, MDa,b; Laura Lucaccioni, MDc; Alberto Berardi MDc;

Affiliations:a Scuola di Specializzazione in Pediatria, Università di Modena e Reggio Emilia, Modena, Italyb Unità Operativa di Pediatria, Dipartimento di Scienze Mediche e Chirurgiche Materno-Infantili edell’Adulto, Azienda Ospedaliero-Universitaria Policlinico, Modena; Italyc Unità Operativa di Terapia Intensiva Neonatale, Dipartimento di Scienze Mediche e ChirurgicheMaterno-Infantili e dell’Adulto, Azienda Ospedaliero-Universitaria Policlinico, Modena; Italy

Correspondence to:Luca Bedetti, Scuola di Specializzazione in Pediatria, Università di Modena eReggio Emilia, Modena, Italy, Via del Pozzo, 71 - 41124 Modena (MO), ItalyPhone: +39 347 3667447. e-mail: luca.bedetti87@gmail.com

Keywords: meningitis, infections, neonate, young infant, paediatric practice

Running head: Lumbar puncture in neonates and young infants

Contributors All authors made substantive intellectual contributions to the published study andapproved the final manuscript as submitted.

Funding None declared

Competing interests None declared

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Abstract

Meningitis occurs frequently in neonates and can lead to a number of acute, severe complications andlong-termdisabilities. An early diagnosis of neonatal meningitis is essential to reduce mortality andto improve outcomes. Initial clinical signs of meningitis are often subtle and frequently overlap withthose of sepsis, and current haematologic tests do not distinguish sepsis from meningitis. Thus, lumbarpuncture remains the gold standard for the diagnosis of meningitis in infants, and this procedure isrecommended in clinical guidelines. Nevertheless, in clinical practice, lumbar puncture is frequentlydeferred or omitted due to concerns regarding hypothetical adverse events or limited experience ofthe performer. Future studies should assess whether a combination of clinical findings and selecthaematological tests at disease onset can identify those neonates with the highest risk of meningitiswho should undergo lumbar puncture. Furthermore, clinicians should be convinced that the actualbenefits of an early diagnosis of meningitis far outweigh the hypothetical risks associated with lumbarpuncture.

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INTRODUCTION

Neonates and young infants (0-90 days) are the most susceptible to infections; sepsis and meningitis

occur more frequently during the first month of life than during later periods1. Sepsis can be classified

as early onset sepsis (EOS), presenting from birth to day 3 and reflecting vertical transmission, or

as late onset sepsis (LOS), from day 4 to 89, mostly reflecting horizontal transmission2. The main

mechanism of meningitis development is primary bacteraemia with secondary spread to the central

nervous system; for this reason, meningitis frequently overlaps with sepsis in neonates.

Incidence rates of neonatal meningitis are lower in high-income countries than in low-income

countries (0.3 vs 0.8-6.1/1000 live births),3 partly due to the decline in early onset meningitis

because of widespread intrapartum antibiotic prophylaxis for preventing group B streptococcus

EOS4,5. Nevertheless, group B streptococcus remains a leading cause of both sepsis and meningitis

in high-income countries2,6.

Neonatal meningitis can cause a number of acute, severe complications (seizure,

stroke, intracerebral thrombosis, haemorrhage and brain abscess)7 and long-

termdisabilities(neurodevelopmental or sensory neural impairment)8. An early diagnosis of neonatal

meningitis is essential for correct therapy and to reduce mortality and complications.

Lumbar puncture (LP) is currently the best way to confirm the diagnosis3. However, the indications

for LP vary across studies1,9. Clinicians are sometimes reluctant to perform an LP, potentially

because of concerns regarding the potential risks of adverse events during the procedure (i.e.,

hypoxia or bradycardia) or further complications (see below). However, these potential risks, even

if they are real, have not been precisely defined in large prospective studies, particularly with

regard to neonates of younger gestational age. Perhaps because of these uncertainties, the rate of

performing an LP seems to vary across gestational ages, and rates of LP are lower in neonates of

younger gestational age10,11.

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WHEN TO SUSPECT MENINGITIS IN INFANTS WITH SEPSIS

Clinical signs

The diagnosis of meningitis remains challenging because the initial signs are often subtle and overlap

with those of sepsis. The suspicion of meningitis is greater in the presence of seizures, irritability,

fever, bulging fontanel, abnormal consciousness, hypotonia and tremors12.

Signs of meningitis may also vary according to birth weight. Crebs and Costa13 compared clinical

signs in 34 neonates with birth weights <2500 g and in 53 neonates with birth weights >2500 g and

found that apnoea (20.6%), jaundice (17.6%) and abdominal distension (23.5%) were predominant in

neonates <2500 g, whereas irritability (45.3%), seizures (41.5%) and bulging fontanel (30.2%) were

the most frequent clinical findings in neonates >2500 g.

Laboratory tests

Attempts have been made to identify blood indicators to rule out meningitis in sick infants.

However, none of the currently available tests are sufficiently accurate to exclude bacterial

meningitis without performing an LP.

C-reactive protein (CRP). A retrospective cohort study including 97 new-borns with culture-

negative EOS14 evaluatedthe immature-to-total neutrophil (I/T) ratio, CRP at 12 and 24 hours, and

LP. CRP >40 mg/L and an I/T ratio >0.3 had poor sensitivity (70-73% and 18-70%, respectively)

and specificity (28-45% and 63-76%, respectively) for confirming meningitis. The authors

concluded that these are not valid screening tests for diagnosing meningitis in patients with culture-

negative EOS.

Procalcitonin (PCT). ThePCT assay is currently an excellent laboratory test for diagnosing serious

bacterial infections in young infants. The diagnostic value of PCT >0.3 ng/ml (specificity 78%,

sensitivity 90%) is greater than that of CRP >20 mg/L (specificity 75%, sensitivity 75%)15.

Unfortunately, no studies have compared PCT levels in septic neonates with and without meningitis.

White blood cell (WBC) count. Total WBC count has little value in the diagnosis of neonatal

meningitis16. Bonsu17 demonstrated that no WBC count intervals or cut-off points are sufficiently

accurate to guide the decision to perform an LP; otherwise, there is a risk of missing a substantial

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proportion of meningitis cases. Martinez18 found that in young infants with fever without a source,

haematological tests (leukocyte count, absolute neutrophil count, CRP and/or PCT levels) were

performed in 92% of 21- to 90-day-old infants who appeared well, whereas 19% of these infants

underwent an LP. LP was more likely to be performed in infants with abnormal blood tests than in

infants with entirely normal blood tests (29% vs 14%). However, no infants had confirmed bacterial

meningitis, suggesting that the decision to perform an LP should not be based on laboratory test results

only.

Blood culture (BC). In daily practice, someone performs an LP on the basis of BC results. By studying

90 cases of EOS, Berardi10 found that an LP was performed in only 32% of neonates; furthermore, LP

was performed even less often among new-borns with birth weights <1500 g (13% of cases).Stoll19

retrospectively evaluated >9000 very low birth weight (VLBW) neonates with suspected late onset

meningitis and found that LP was more likely to be performed in infants with a positive BC than

in those with a sterile BC (66% vs 34%). Notably, meningitis was more likely in neonates with a

positive BC than in those with a sterile BC (7.2% vs 1.5%, p<.001), but ~1/3 of those with meningitis

had a sterile BC. False negative BC results are frequent (due to insufficient blood samples), whereas

meningitis may occur in some (up to ~50%) neonates with a sterile BC16,20. Therefore, if an LP is

performed on the basis of BC results, cases of meningitis can be missed, and the diagnosis is delayed

until the BC results are available21. Because antibiotics are frequently given at disease presentation,

these drugs could inhibit the growth of pathogens in cerebral spinal fluid (CSF) culture.

Meningitis and CSF parameters. Normal CSF white cell count and glucose levels are similar in

preterm and full-term neonates, while CSF protein values are significantly higher in preterm neonates

and decrease with age (table 1)22. It is controversial whether the diagnosis of meningitis can entirely

rely on CSF parameters; in fact, no single CSF value can confirm the diagnosis. CSF parameters vary

widely among neonates with bacterial meningitis (ranges: WBC count, 0 to 15900/mm3; glucose, 0 to

199 md/dL; protein, 41 to 1964 mg/dL). WBC count <8/mm3 has the highest sensitivity (97%), while

CSF glucose value <20 mg/dl has the highest specificity (98%)15.

CSF culture: CSF culture is the gold standard for confirming bacterial meningitis and identifying

the pathogen23. However, antibiotic treatment is frequently initiated before performing an LP, which

affects CSF parameters. Children pre-treated for 12 hours had lower rates of positive CSF cultures

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(84% vs 58%), higher CSF glucose levels (median, 29 mg/dl vs 49 mg/dl), and lower CSF protein

levels (median, 174 mg/dl vs 121 mg/dl) than non-pre-treated children. In contrast, CSF Gram-positive

rates and CSF WBC count are not affected by antibiotics24.

Meningitis and bacterial polymerase chain reaction. Compared to standard cultures, molecular

methods have increased sensitivity for diagnosing bacterial meningitis (78.1 vs 90.6%)25, and

polymerase chain reaction is useful for diagnosing group B streptococcal meningitis in neonates and

young infants26. Molecular methods yield results more rapidly than BC, and they have a role when

antibiotics are given before LP27.

Meningitis and cytokine levels. Ye28 studied cytokine levels in blood and CSF and the blood/CSF

ratio in children younger than 10 years with bacterial meningitis and children with viral encephalitis,

epilepsy, febrile seizures or no complications/diseases. CSF WBC count had low sensitivity (70%)

and good specificity (93%), while CSF IL-6 levels >38.2 pg/mL had 100% sensitivity and 91.0%

specificity. The combination of CSF IL-6 and the CSF/blood IL-6 ratio had the best sensitivity

(100%) and specificity (97%) in discriminating bacterial meningitis. Data concerning neonates are

unavailable.

Meningitis and ultrasound diagnosis

Spinal ultrasound could improve the diagnosis and follow-up of neonatal meningitis. Echogenicity

and trabeculations have high specificity (100%) and low sensitivity (59%) for the diagnosis of

meningitis29, whereas pulsation of the spinal cord and nerve roots has good specificity (85%) and

moderate sensitivity (76%). The authors suggest that spinal ultrasound follow-up could be used to

monitor disease severity and treatment efficacy without the need for additional invasive procedures.

LUMBAR PUNCTURE

When to perform LP: selective or universal approach?

The gold standard for confirming bacterial meningitis is a positive CSF culture30. Delaying treatment

until signs and symptoms of meningitis are obvious carries the risk of preventable mortality, whereas

treating neonates with antibiotics presumptively on the basis of subtle signs or risk factors alone results

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in overtreatment31. Some clinicians may choose to perform LPs in the sepsis workups for all neonates

but are sometimes forced to defer the procedure in cases of critical clinical conditions.

Performing an LP in infants younger than 90 days of age is challenging for physicians, and the

variability in performing LP is well documented1.9. Patrick32 found that full-term new-borns in

teaching and children’s hospitals and those in urban areas were significantly more likely to undergo

LP for suspected EOS than new-borns in rural areas and non-teaching hospitals. These results indicate

inconsistent application of available clinical guidelines.

It is controversial whether LP should be performed with a universal or a selective approach in

suspected EOS and LOS. At the Kaplan Medical Centre33, a selective approach was applied in VLBW

infants with suspected LOS. The decision to perform am LP was made by an experienced senior

physician who considered the clinical state evaluation and presence of risk factors. LP was performed

in 71% of suspected LOS cases, and meningitis was diagnosed in 1.4% of infants. An analysis of the

rates of complications at 18 months of age between infants who did or did not undergo LP did not

show significant differences, with no evidence of missed or partially treated meningitis. Even if this

selective strategy seems safe and advisable, it is poorly standardized and susceptible to individual

interpretation. In contrast, LP in asymptomatic neonates at risk for EOS is not recommended34.

LP in young infants with respiratory distress syndrome or urinary tract infections

None of 203 new-born infants less than 24 hours old investigated for respiratory distress syndrome

had a positive CSF culture35. Weiss36 came to similar results in a study of preterm infants with

respiratory signs on the first day of life: 4 of 374 patients had a positive CSF culture, and only one

had a negative BC. Thus, the authors concluded that infants with isolated respiratory signs deserve

a selective approach regarding undergoing an LP, and an abnormal neurological examination should

be considered. More recent data from Stefanski37 showed that the incidence of meningitis in children

younger than 1 year of age with bronchiolitis was zero.

Urinary tract infection in infants younger than 90 days of age is rarely associated with meningitis; thus,

routine LP is not recommended in this population. Viullermine38 studied 75 infants with a urinary tract

infection, and none had coexisting culture-proven meningitis. Positive urinalysis has a high negative

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predictive value for meningitis (98.2%) in infants 30 to 90 days of age39, but it probably needs further

investigation in neonates.

How to perform LP

LP in young infants is sometimes difficult to perform; however, experienced clinicians40 and, in our

experience, nurses who maintain the baby in the best position may have a higher success rate. A

successful LP should avoid blood contamination to obtain reliable CSF parameters. A minimum of

30 drops (1.5 ml) is required to perform all routine laboratory tests (CSF parameters and viral and

bacterial cultures).

Local anaesthetics should be administered to reduce pain, and sedation with benzodiazepine (usually

midazolam) is sometime required41.

LP can be performed in at least four positions (Figure1)42. Oncel43 found that the sitting position with

flexed legs (and abdominal compression) provides the widest interspinous spaces, thereby increasing

the LP success rate in neonates. However, an early study44 evaluated hypoxemia during LP in neonates

aged 0-24 hours (mean gestational age, 34 weeks) in three positions (sitting without abdominal

compression and lateral with or without abdominal compression) and found that mean transcutaneous

PO2 was significantly lower during LP in the lateral position with abdominal compression; therefore,

positions in which the legs do not compress the abdomen are recommended for LP. On the basis of

these conflicting results, it is difficult to suggest the best position for performing LP. Furthermore,

the correct site to tap can be found by palpating from the superior iliac crest to the midline, reaching

the L3-L4 or L4-L5 interspaces. Recent trials suggest that ultrasound assistance may minimize the

number of attempts45.

Indications to perform LP

“Too sick to tap” and “risk of complications” are cited daily in neonatal units as reasons to defer LP19,

and in our experience, an additional reason is “the baby was too well to suspect meningitis”. According

to NICE guidelines46, every child and young person with suspected meningitis should undergo an LP

unless any contraindications are present.

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In addition, US guidelines34 recommend that “LP can be deferred in any infant who is critically ill or

who is likely to have cardiovascular or respiratory compromise during the procedure”, but LP should

be performed in young infants with suspected sepsis unless meningitis can be excluded clinically17,34.

LP should be performed in neonates who can safely undergo the procedure; have a positive BC and

abnormal laboratory markers and clinical signs; and do not respond to antimicrobial therapy34. LP

seems to be mandatory in febrile neonates aged less than 21 days who do not appear well18.

However, clinical guidelines do not provide indications for every situation, and the decision whether

to perform LP is often left to clinicians.

LP contraindications and complications

Unfortunately, most contraindications and complications of LP (table 2) are from studies carried out

in paediatric patients, with limited data regarding neonates. Stoll et al. found no change in the risk of

death among VLBW infants who underwent LP (10% vs 10%)19, whereas mortality was significantly

increased in neonates with confirmed meningitis (23%) compared to those without meningitis (9%,

p .001). A fearful complication is brain herniation resulting from different pressures between the

cranial and spinal compartments47. However, it is unknown whether these paediatric complications

occur at the same (or perhaps lower) rates in neonates.

Traumatic and unsuccessful LP

LP may fail after a traumatic tap or when the CSF volume is insufficient. Nigrovic found that

factors associated with failure were younger age, inability to palpate and visualize the lumbar

spinous processes, limited clinician experience, no use of local anaesthetics and troubled patients48. A

retrospective review carried out in an Academic level-4 NICU49 confirmed that 75% of LPs performed

by residents were traumatic (>1,000 red blood cells/mm3). Glatstein50 studied infants younger than

2 years of age and found that the rates of traumatic LP (defined as >400 red blood cells/mm3) were

26.2% and 12.5% in the sitting and lying positions, respectively. The rates of unsuccessful LP (failure

to obtain CSF) were 24% after a single LP and 50% after multiple attempts; traumatic LP was not

affected by the duration of the procedure or, in contrast to the results reported by Nigrovic48, by

physician experience or sedative use.

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Ultrasonographic support is under study, but more data are necessary to recommend its widespread

use51,52. Neal40 found that the rates of first successful LP in infants under six months of age were 58%

and 31% with and without bedside spine ultrasonography, respectively; these rates increased to 75%

and 44%, respectively, after three attempts.

CONCLUSIONS

Currently, LP remains essential to confirm meningitis, but further data are welcome to reinforce the

concept that the actual benefits of an early meningitis diagnosis far outweigh the hypothetical risks

associated with LP. In the future, a combination of clinical findings and select laboratory tests upon

disease presentation could help identify neonates with the highest risk of meningitis and those who

should undergo an LP.

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51. Marin JR. Ultrasonography for Infant Lumbar Puncture: Time to Pop the Champagne? AnnEmerg Med 2017;69:620-621. DOI: 10.1016/j.annemergmed.2016.11.018

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Table 1. CSF findings in preterm and term infants in Neonatal Intensive Care Unit.

JUST A

CCEPTED

Value Preterm Infants

Term Infants

≤ 7 days > 7 days all ≤ 7 days > 7 days all

CSF WBC, cells/µL

All infants

Median (IQR) 3 (1-7) 3 (1-4) 3 (1-6) 3 (1-6) 2 (1-4) 3 (1-6)

95th percentile 18 12 16 23 32 26

Antibiotic-unexposed

95th percentile 17 10 11 31 53 32

CFS protein, mg/dL

All infants

Median (IQR) 116(93-138)

93 (69-122) 104(79-131)

78 (60-100) 57 (42-77) 74 (54-96)

95th percentile 213 203 203 137 158 137

Antibiotic-unexposed

95th percentile 195 136 195 136 284 136

CSF glucose, mg/dL

JUST A

CCEPTED

All infants

Median (IQR) 53 (43-65) 47 (40-58) 49 (42-62) 50 (44-56) 52 (45-64) 51 (44-57)

5th percentile 33 33 33 35 38 36

Antibiotic-unexposed

5th percentile 33 35 33 33 33 33

Adapted from “Cerebrospinal fluid reference ranges in term and preterm infants in the neonatalintensive care unit”22. CSF, cerebral spinal fluid; IQR, interquartile range.

Table 2. Contraindications and complications of LP

Controindications53

• Haemodinamical instability

• Severe respiratory distress syndrome

• Increased intracranial pressure

• Underlying coagulopathies

• Skin infection on the site of the tap

• Status epilepticus

• Abnormal anatomy of spinal cord

• Spinal Epidural Abscess

Complications

Common54:

• Headache

• Mild local pain at the puncture site

Rare41,47,54:

• epidural, subdural or subarachnoidhaemorrhage

• Osteomyelitis

• epidural abscess or discitis

• bleeding

• backache transient dysaesthesia

• brain herniation

JUST A

CCEPTED

Table 2. Contraindications and complications of LP

Controindications53

• Haemodinamical instability

• Severe respiratory distress syndrome

• Increased intracranial pressure

• Underlying coagulopathies

• Skin infection on the site of the tap

• Status epilepticus

• Abnormal anatomy of spinal cord

• Spinal Epidural Abscess

Complications

Common54:

• Headache

• Mild local pain at the puncture site

Rare41,47,54:

• epidural, subdural or subarachnoidhaemorrhage

• Osteomyelitis

• epidural abscess or discitis

• bleeding

• backache transient dysaesthesia

• brain herniation

JUST A

CCEPTED

JUST A

CCEPTED