We set out to systematically evaluate all existing relevant data on the management of patients with nhSPCs to assist physicians with counselling of their patients regarding the role of surgery. We conducted a rigorous review of published literature and performed meta-analysis of a cohort of 294 surgically treated nhSPCs patients. As the current literature consists of case reports and retrospective series, this review is essentially a summary of all existing retrospective data relating to the management of nhSPCs.
We found that following surgery, 93% of 280 patients with nhSPCs experienced improvement of their symptoms. When only cases with resection are considered the improvement is 94%, while improvement rate is lower where fenestration only was performed (56%). There was remarkably little variation in the rates of improvement among the reported series. All inter-author variability was explained by the number of fenestrations (as opposed to resection) performed. (Supplementary Fig. 3 and Supplementary Table 9). Given the small number of cases treated by fenestration and the number of potential reasons why fenestration only was carried out/achieved in these specific cases, it is best to treat this observation as a hypothesis for future studies rather than a guideline to be used in a clinical practice.
Some authors attempted to objectivise their evaluation by introducing the Chicago Chiari Outcome Scale [7, 13, 28], the EORTC QLQ-C30  or their own bespoke symptom scoring [10, 12]. However, in most cases, the overall surgical outcome was mostly derived from clinical consultations when patients would be asked whether they are overall better or worse as a result of the operation. As much as these statements seem to express what really matters to patients, they are associated with a risk of bias stemming from patient reporting directly to the treating surgeon who in turn is recording these. Therefore, more objective measurements of quality of life need to be agreed upon and prospectively collected to provide more solid evidence regarding the benefit of surgery in the management of nhSPCs patients.
When considering each symptom individually, more than 85% of patients experienced improvement in most symptoms, with the exception of cognitive deficit, fatigue and sleep disturbance, which improved in 80%, 68% and 45% of patients, respectively (Supplementary Table 10). This is not surprising as the latter three symptoms have complex multifactorial underpinning. It is noteworthy that symptoms with perhaps the most tenuous etiological link to the pineal cyst, such as episodic loss of consciousness, seizures and psychiatric symptoms, improved in 97%, 100% and 100%, respectively. Headaches, the most common symptom, improved in 93% of patients. This has previously been shown in a systematic review focused on headaches .
Complications occurred in 17% the 280 surgically treated cases. Most of the impairment resulting from complications resolved by the last follow-up, while 10 patients (3.6%) experienced permanent adverse effects of surgery. One patient died post-operatively secondary to myocardial infarction . Although the mortality seems unrelated to the surgery itself, it is a stark reminder that any surgical intervention comes with risks of morbidity and mortality against which the decision to operate must always be carefully considered.
Comparable rates of improvement and complication rates following surgery were observed in adult and paediatric (< 18 years) patients (91% vs 96% and 16% vs 22% respectively). Similar results (96% improvement, N = 109) were reported in a systematic review of patients younger than 21 years by Choque-Velasquez et al. . This is not surprising as much of the data in this paper and the current study overlap, although different age definitions and methodologies were used. Ages of patients in this cohort were normally distributed with a mean and SD of 29.3 and 12.3, respectively (Fig. 7). Interestingly, the improvement rate of patients older than 55 years is lower than that of younger patients (OR = 0.11, 0.02–0.79, p. val = 0.01). This may suggest that other factors, such as perimenopausal changes, may play a role in the aetiology of at least some symptoms in this subset of patients. Interestingly, the complication rate may be lower in this age group (not significant but underpowered, 12% vs 17%).
The majority of resections were caried out using SCIT, while a few using OTT. There was no difference in outcomes in patients treated by either approach. The choice of approach was likely a matter of greater familiarity, but also individual anatomical considerations likely played a role . Based on the data from our meta-analysis, it seems that resection is more effective than fenestration (OR = 12.64; 3.07–52.01). Other means of surgical treatment of patients with nhSPC have been described. Davidson reports his experience with endoscopic management of 16 patients with ‘pineal cyst-associated aquaeductal stenosis’, where 10 of the patients had no ventriculomegaly so, technically, could be classed as nhSPCs . All these 10 cases were treated with endoscopic third ventriculostomy (ETV) and 7 of these patients improved (mean follow-up 10 months). Interestingly, Eide et al. treated 6 patients with insertion of ventriculoperitoneal shunt, but only one patient had improved .
There is very little published on conservative management of patients with nhSPCs, and the data assembled in this meta-analysis cohort (N = 80) are probably most informative on the subject. Despite, best non-surgical management symptoms did not improve in 87% and worsened in 13% of patients during a mean of 52 months of non-surgical management. These data are broadly accordant with the conservatively managed patients in the series by Eide et al.  and Majovsky et al. . In the former series (N = 66, mean follow-up 3 years), 11% improved, 14% were unchanged and 75% worsened while in the latter (N = 110, 6.5 years), 12% improved, 74% were stable and 16% worsened. Given the lack of strict prospectively adopted definitions of the conservative management, selection bias and other shortcomings, these cohorts are not suitable as direct controls for the surgical group. Importantly, before considering surgical management of patients with suspected nhSPCs, it is essential to exclude other causes of patients’ symptoms as highlighted in all published series (see also Fig. 2).
It is the authors’ experience that understanding the subtleties of presentation of patients with nhSPC is of crucial importance in the elicitation and recognition of all existing symptoms. Despite the retrospective nature of the input data and with its associated varying levels of detail about presenting symptoms—both between published studies and individual cases within each study—this metanalysis was fruitful in providing the most comprehensive description so far of the characteristics of nhSPC as a disease entity. This said, it is important to recognise that, overall, these data are reductive. Below, we briefly share our observations of the most common symptoms and clinical phenomena and suggest potential links to their aetiologies. As much as we hope that the reader may find this helpful, the validity of these observations needs to be explored in prospective studies.
Headaches are the most common and usually the dominant symptom, yet probably the least well understood. It is our experience that headaches associated with nhSPCs have often more than one component: one commonly described as constant dull pressure or fullness and the other ‘migrainous’. Indeed, not infrequently patients are treated for migraines with only partial or no success. As shown in this paper, female patients make up 80% of adult nhSPC patients, while only 65% of patients below 18 years of age. Like migraine headaches, headaches in nhSPC patients can be associated with the menstrual cycle. It is therefore likely that hormonal changes directly and/or through body fluid content and its redistribution play a role in the aetiology of headaches and other symptoms of nhSCP patients. Typically, the ‘non-migraine headaches’ resolve following surgery, while the ‘migraine headaches’ either also resolve or, if not, the frequency and duration of migraine attacks almost always abate.
Visual symptoms are often reported as blurred vision, double vision, delayed acquisition or binocular fusion of visual images after gaze change or simply as ‘tired’ and painful eyes. Prolonged work on a computer or frequent switching of gaze, such as driving a car, especially at night, can trigger headaches, vertigo and disorientation. Bedside eye examination is usually normal, although some limitations or discomfort on gazing upward is not uncommon. Some or all components of Parinaud’s syndrome can sometimes be demonstrated. Ophthalmological examination usually fails to demonstrate any additional abnormalities, but more specialised pursuit examinations are rarely carried out. These dorsal midbrain symptoms are likely a result of direct compression by the cyst.
Other symptoms. The tectum, especially the superior colliculus, is not only important in processing visual and auditory information, but is also a centre of multimodal sensory integration involving visual, auditory, vestibular and other somatic sensory information [5, 19, 25, 26, 35, 37,38,39, 41]. More recently, superior colliculi have also been linked with cognition [3, 22]. Indeed, ‘headache-visual’, ‘headache-visual-nausea/vomiting’, ‘headache-visual-vertigo/dizziness-neurology not otherwise specified’ were most common when combinations of two, three and four symptoms were considered (Fig. 4 and Supplementary Fig. 5). It is reasonable that visual and balance-associated symptoms, such as dizziness, vertigo, unsteady gait and nausea can be attributed to interference of the pineal cyst with tectal processing. It is also possible that other symptoms otherwise difficult to explain, such as sensory symptoms (e.g. ‘neurology_NOS’ in our series) and even some ‘psychiatric’ symptoms (e.g. multisensory dysfunction and dissociative disorders) could be explained by a similar mechanism . Presenting symptoms should not outright be dismissed on the basis of lack of understanding of their aetiology. In fact, given the improvement of ‘psychiatric symptoms’ following surgery in nearly 100% of patients in this relatively small cohort (Supplementary Table 10), one should keep an open yet critical mind. As pointed out by Majovsky et al. , certain symptoms are likely the result of ‘somatisation’, e.g. secondary to chronic headaches, sleep disturbance, difficulty with fulfilling personal and family, work and other wider social expectations. This can be further compounded by lack of effective treatment and consequent feeling of hopelessness.
Patients’ symptoms sometimes worsen during pregnancy, after gaining weight and are often worse in the morning. Some patients require an hour or more after getting up for their symptoms to subside sufficiently for them able to function. They often describe this as a ‘bad hangover’. These factors suggest CSF/venous aetiology. Interestingly, intracranial pressure (ICP) is generally not raised in patients with nhSPCs, and ICP monitoring studies are not routinely undertaken. Eide and colleagues studied overnight ICP parameters in 20 nhSPCs and compared them with that of 19 patients with chronic daily headaches (CDH), i.e. patient suspected of idiopathic intracranial hypertension without papilloedema . Both groups had relatively normal mean static ICP, while nhSPC patients had higher pulsatile ICP scores than CDH patients. Six were treated with a ventriculoperitoneal shunt (VPS) and 14 underwent resection of their pineal cyst . While none of the ICP parameters differed significantly between the VPS and resection groups, patients treated with resection enjoyed significantly greater improvement of symptoms. These results suggest that symptoms in most nhSPC patients are not determined by globally raised ICP, but more subtle and probably more localised effects of the pineal cyst; likely, a result of a combination of the direct compression of the tectal plate and crowding the quadrigeminal cistern, thus, preventing sufficiently effective opening of the aqueduct during systole as well as interfering with the deep venous flow during both, systole and diastole . Overall, the aetiology of the symptoms is not well understood, and this major shortcoming needs to be addressed in future studies.
Placebo effect is sometimes suggested as the reason behind the improvement of symptoms following surgery in patients with nhSPCs. It is true that undergoing brain surgery is a profound experience for patients, but placebo alone is unlikely to be effective in such a high proportion of patients (93%), and it is even less likely that the effect would persist at a mean of 34.6-month follow-up. The observation of poorer symptom control following cyst fenestration compared to resection (OR = 12.64, p = 0.0004) also argues against placebo, although it is not possible to rule out the influence of patient interpretation of their post-operative scans as ‘the cause of my problem is no longer there’ versus ‘it is still there’. Furthermore, despite the heterogeneity of cultural background, clinical practice and the level of detail in recording and reporting of clinical data, the review has uncovered remarkable concordance in the main baseline clinical characteristics and outcome between the included studies (see Figs. 4 and 5).
While this meta-analysis has been carried out with a great deal of scientific rigour, the results must be interpreted with caution. One must keep in mind the difference between internal validity, which depends on the quality of the analysis, and external validity, which is a function of the quality of the data.
The conclusions taken from the input data are internally valid, in that they describe properties of the dataset analysed in a scientifically rigorous fashion. However, their external validity (i.e. their applicability outside of this dataset, into the real world) is limited by the quality of the data from which they originate. Given that the input data are derived from case reports and retrospective, single-surgeon cohort studies, they are inherently associated with several of limitations. These include (1) Incompleteness and heterogeneity of data collection and reporting. This applies especially to the publication bias but also the inevitable lapses in detection and recording of post-operative complications. We tried to mitigate the publication bias, i.e. a greater likelihood of reporting cases with favourable outcome, by only considering consecutive series when calculating safety and efficacy. Despite of this, it is likely that the rate of long-term complications is underestimated. (2) Lack of objective definition of symptoms and outcome measure. This is further compounded by a potential bias related to patients reporting outcome to their treating surgeons and the treating surgeons recording these outcomes in the majority of cases. (3) Lack of appropriate control of conservatively managed cohort.
Future work needs to address these limitations by defining, objectivising and standardising assessment of presentation and outcome, both in terms of symptom and quality of life. In addition, systematic mapping and evaluation of non-surgical treatment needs to be caried out. Prospective studies with these carefully defined clinical data points will provide an important knowledge base for recognising patients with nhSPCs and estimation of the likelihood for improvement of each symptoms and overall quality of life of each patient at individual level. Authors of this study are proposing the formation of an international registry for this purpose. A randomised controlled trial of conservative versus surgical treatment would provide ultimate answers regarding the safety and efficacy of surgical treatment of nhSPCs. Design and execution of such as trial is associated with numerous potential challenges, including the reluctance of patients to be randomised, selection criteria for participating centres etc. Lastly, although several hypotheses about the link between PCs and symptoms have been put forward, there is very little scientific evidence to back or disprove these. Employment and thoughtful analysis of the existing and novel imaging techniques, computerised ICP measurements and, possibly, intraluminal venous pressure studies as well as systematic translation of the results of animal neuro-physiology to humans will be required to fill these knowledge gaps. This will enhance the objectivity and accuracy of assessment, selection of appropriate treatment and, ultimately, contribute to improvement of quality of life of patients.