D ISCUSSION

Our study indicates that LP is a safe technique to evaluate AD biomarkers in CSF. Most participants had no complications. Headache was the most frequent event, occurring in about a quarter of the subjects, but it was mild in most cases and required no treatment or only low doses of commonly-used analgesic drugs. The main factors associated with headache were younger age and the use of cutting-edge needles.

We also confirmed other interesting findings. First, we observed that patient positioning was not associated with the incidence of headache, but the sitting position was associated with headache of severe intensity. Accordingly, we would recommend the lying position as the first option to perform the procedure, especially in young patients, who are at higher risk of

headache. Second, as suggested in previous studies,^22,29 early mobilisation after LP was associated with a lower incidence of back pain and had no influence on the occurrence of headache. And third, we found that the volume of CSF extracted was not associated with the presence of complications.

Consistent with our results, most studies have estimated the frequency of PLPH as between 20 and 40%.15,20,23,24,30,31

A few have reported significantly lower frequencies,³² even below 5% in some cases.^19,21,26 This large variability could be explained by methodological differences. The first of these is that the definitions of PLPH differed across studies. Some groups required definite PLPH, fulfilling the IHS criteria,¹³ whereas others recorded the appearance of any kind of headache regardless of its characteristics. Second, different methods were used to record complications. Some authors recorded only those complications spontaneously reported by patients,¹⁹ while others, such as ourselves, interviewed the participants systematically after the procedure.^20,23,32 Lastly, there is great variability across studies regarding the age of participants and the technical aspects of the procedure. In this respect, studies in older patients,^19–21 and studies using pen-point needles23,24,26,30

have consistently found lower frequencies of headache.

As a consequence, pen-point needles have been proposed as the best choice in elective LP,^13,14,24 and more specifically in LP to determine AD biomarkers.^33,34 However, the use of this kind of needle could have other consequences. In our study, pen-point needles showed a trend towards a higher rate of visual haematic staining of CSF. We believe this is an important finding in this context because blood contamination of CSF could potentially alter the biomarker results.³⁵ To our knowledge, no previous large studies have compared the occurrence of haematic staining of CSF using different needle types. A smaller study

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another reported technical difficulties and a higher failure rate when pen-point needles were used, especially in patients with high body mass index.²⁵ In our series, haematic contamination was only observed at the beginning of the flow. It is unlikely that this interfered with the determination of biomarkers because we systematically discarded the first 1-2 ml of CSF until it was clear, and we centrifuged all samples after collection.

Nonetheless, this point should be taken into account when standardizing the needle type for analysis of AD biomarkers.

Finally, besides the technical aspects discussed, psychological factors might also play a role in the appearance of complications. This consideration would be supported by findings from the only double-blind study available to date on the incidence of headache after LP;³⁷ the author found that frequencies of headache in the diagnostic LP and in the sham LP groups were similar. Furthermore, in our study, participants who reported fearfulness before the procedure had a higher frequency of PLPH. As the IHS criteria for PLPH have not been validated, we cannot be certain that every headache fulfilling these criteria is due to CSF leakage after LP. Thus, tension-type headache or other types of headache related to psychological factors may be misdiagnosed as PLPH.

The main limitation of our study is the lack of randomization in the technical aspects of the procedure. Some of these aspects were intrinsically linked to the centres. The use of pen-point needles was limited to only one centre and conclusions about the type of needle should be taken with caution. Moreover, participants at the three memory units differed in age and clinical diagnosis. Those from CITA were mostly younger healthy volunteers, while those from the other two centres, HC and HSP, had a higher proportion of older patients with cognitive impairment. To overcome the possible biases that these differences between centres could have introduced, we used a multivariate analysis.

In conclusion, in this multicentre study we found that LP can be safely performed to study CSF biomarkers. Headache was the most common adverse effect, and it was associated with younger age and the use of cutting-edge needles. It was rarely severe, and we did not find other major complications. The risk of headache decreased significantly when pen-point needles were used, but the presence of haematic CSF and an increased difficulty in the procedure with the use of this needle are issues that should be addressed in future studies.