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Abstract

Background

A lumbar puncture constitutes an important diagnostic procedure in the evaluation of idiopathic intracranial hypertension. Chronic overflow of cerebrospinal fluid into the sheaths of the olfactory nerves appears to be related to olfactory impairment in these patients. Here, we asked whether cerebrospinal fluid drainage in idiopathic intracranial hypertension patients improves olfactory function.

Methods

Fourteen idiopathic intracranial hypertension patients and 14 neurologic control patients were investigated before and after lumbar puncture using the extended Sniffin’ Sticks procedure. We assessed odor threshold, discrimination, and identification. In idiopathic intracranial hypertension patients, cerebrospinal fluid was drained until cerebrospinal fluid pressure had normalized. In addition, a third group of 14 healthy controls participated in the two smell tests at similar intervals.

Results

Relative to healthy controls, threshold, discrimination, and identification composite scores before lumbar puncture were significantly lower in idiopathic intracranial hypertension patients and also in neurologic controls. Following lumbar puncture, threshold, discrimination, and identification scores for neurologic controls remained unchanged whereas idiopathic intracranial hypertension patients showed robust improvement on the composite score as well as on all three subscores (all changes: p < 0.003), quickly regaining olfactory function in the normal range. Cerebrospinal fluid opening pressure was significantly correlated with improvement in threshold, discrimination, and identification score upon cerebrospinal fluid drainage (r = 0.609, p = 0.021).

Conclusion

Olfactory impairment is an important, yet underappreciated, clinical feature of idiopathic intracranial hypertension. Lowering of increased intracranial pressure improves hyposmia. Our findings shed new light on the pathophysiology of cerebrospinal fluid circulation in idiopathic intracranial hypertension.

Keywords

Hyposmia idiopathic intracranial hypertension olfactory dysfunction pseudotumor cerebri Sniffin’ sticks cerebrospinal fluid

Introduction

Idiopathic intracranial hypertension (IIH) is a disorder that preferentially affects overweight or obese women of childbearing age (1,2). Clinical complaints include headache, vision loss, pulsatile tinnitus, and binocular horizontal diplopia (1,3,4). A definitive diagnosis of IIH is based on the presence of the following signs and symptoms: Papilledema; unremarkable neurologic evaluation except for cranial nerve abnormalities; normal brain anatomy on CT or MRI; normal CSF composition but increased opening pressure on LP. Besides the visual problems that frequently accompany papilledema, sixth cranial nerve dysfunction may also occur (2).

A number of recent studies have drawn attention to the fact that IIH patients may also experience hyposmia, which is typically characterized by an increase in olfactory threshold (5,6). Indeed, the prevalence of impaired smell is similar to the prevalence of other major symptoms associated with IIH (1,5). This observation is clinically relevant because the sense of smell plays a critical role in regulating food intake and dietary choices, detecting hazards, guiding social interactions, and influencing emotional states (7 –9). The sense of smell in humans does not seem to be inferior to the sense of smell in other mammalian species, and an impairment in olfaction may have far-reaching consequences (10,11).

Many patients with IIH experience a transient improvement in their headache symptoms after LP. However, being highly subjective, this improvement is difficult to measure (2,12). Based on prior research in the field, assessing olfaction may also hold promise for evaluating disease activity in IIH (5,6,13 –15). Building on a previous case report by our group (13), we here set out to test the pre-specified hypothesis that a reduction in intracranial pressure (ICP) through LP leads to improved olfaction.

Methods

Participants

IIH was diagnosed according to the modified Dandy criteria (2). Patients with a secondary pseudotumor cerebri syndrome were not eligible for inclusion. The neurologic control group consisted primarily of patients with an unclear headache presentation. Where a diagnostic lumbar puncture was indicated, the patient was offered enrolment into the study. As far as possible, IIH patients and healthy controls were matched for age, sex, smoking status, and body mass index (BMI).

Olfactory testing

Patients with olfactory disturbances attributable to any other causes (e.g. infectious, traumatic, allergic, tumor-related, side effects of medications) were excluded by a careful clinical examination and history. Smoking status was recorded. Orthonasal olfaction was examined using the “Sniffin’ Sticks” smell test (Burghart Messtechnik GmbH, Wedel, Germany). Briefly, the “Sniffin’ Sticks” procedure consists of three subtests for odor threshold (T), odor discrimination (D), and odor identification (I). The test is reliable and easy to perform (16). Patients were tested in a comfortable seated position. Great care was taken to ensure that the interval between the lumbar puncture and the second smell test was similar in IIH patients and neurologic controls. Olfactory testing was performed by HK and NB, who were both unaware of the results of LP at the time of olfactory testing. Study participants were only informed of the results of olfactory testing after the second smell test had been completed. Age-adjusted normative data for the “Sniffin’ Sticks” procedure were used (17,18).

MR imaging (MRI)

All IIH patients underwent 1.5-T brain MRI including MR angiography (Siemens Magnetom Avanto, Siemens AG, Erlangen, Germany). To further characterize IIH patients, we measured the distension of the optic nerve sheath (ONS) as described in detail previously (19). In brief, in addition to the circularly polarized head coil, a loop surface coil (7 cm diameter) was placed over the eye with worse vision. For the evaluation of the optic nerve (ON) and the optic nerve sheath (ONS), a coronal turbo spin echo (TSE) sequence was used (repetition time [TR] 6960 msec, echo time [TE] 99 msec, field of view [FOV] 85 × 85 mm², matrix size 256 × 256 [in plane resolution 0.332 × 0.332 mm²], slice thickness 2 mm and acquisition time [TA] 7 min 20 s). ONS diameter was measured on coronal T2w images perpendicular to the ON in the slice with the maximum ONS diameter. MRIs were evaluated by a neuroradiologist and a neurologist (EW, JH) in a blinded fashion.

Standard protocol approvals, registrations, and patient consents

Eligible patients were 18 years or older and gave written informed consent prior to any study-specific procedures. Approval for the study was obtained from the institutional ethics committee. The study was conducted at the Charité University Medical Center from April 2015 to September 2018.

Statistical analyses

All statistical analyses were performed using IBM SPSS Statistics 23 (SPSS Inc., Chicago, IL, USA). Descriptive statistics were used to summarize characteristics of study groups. Group differences in socio-demographic variables, time intervals (i.e. time between the two smell tests, time between LP and the second smell test) were examined using the chi-square test for categorical variables (sex, smoking status), the Mann-Whitney U test for non-normally distributed variables (BMI, time intervals), and the Student’s t-test for normally distributed variables (age). Repeated measures mixed-model ANOVAs were used to compare olfactory function before and after LP depending on the group factor. We conducted four separate analyses with the composite TDI score as well as with the three subscores (i.e. T, D, I) as dependent variables. The normality assumption of dependent variables was tested by Kolmogorov-Smirnov test as well as by visual inspection of the Q-Q-plots. According to this approach, the dependent variables such as composite TDI score and the three subscores (i.e. T, D, I) can be considered normally or almost normally distributed. The two measurement points were defined as within-subject factor and the three study groups were entered as between-subject factor. As the IIH patient group and the neurologic control group differed significantly in BMI, BMI was entered as a covariate in the models. Finally, Pearson correlation analysis was used to investigate the relation between CSF pressure and olfaction. The level of significance was set at p < 0.05 (two-tailed).

Results

Fourteen patients with IIH, 14 neurologic control patients, and 14 healthy participants matched to the IIH patients for age, sex, and BMI were enrolled into the study. Time since onset of IIH was 9.6 months (median: 5.5 months, range 0–60 months). Socio-demographic variables of study participants are summarized in Table 1.

Table 1.

Socio-demographic and clinical characteristics of study subjects.

	IIH patients	Neurologic controls	Healthy controls
N	14	14	14
Sex (number of females)	10	8	8
Age (years)	33.5/36.9 (11.5)	46/46 (12.6)	39/40.5 (11.3)
BMI (kg/m²)	34.5/36.4 (9.5)	24.5/25.3 (4.0)	36.9/37.9 (6.8)
Time since onset of IIH (months)	5.5/9.6 (9.7)	n.a.	n.a.
Optic nerve sheath diameter (in mm)	5.3/5.5 (0.8)	n.a.	n.a.
Number of smokers	5	5	5

BMI: body mass index; CSF: cerebrospinal fluid; IIH: idiopathic intracranial hypertension; n.a.: not applicable.

Note: For age, BMI, time since onset of IIH, and CSF opening pressure, median/mean and standard deviation (in brackets) are reported. As shown by chi-square test (sex, smoking status), Mann-Whitney U test for non-normally distributed variables (BMI), and Student’s t-test (age), the neurological controls differed significantly from the IIH patients and the healthy controls in BMI (both p < 0.001 while no other group differences occurred (all other p > 0.05).

Patients in the neurologic control group had the following diagnoses: Tension-type headache (n = 3); ischemic stroke (n = 2); migraine with aura (n = 1); cluster headache (n = 1); vestibular neuritis (n = 1); polyneuropathy (n = 1); primary progressive multiple sclerosis (n = 1); follow-up LP at 6 months after treatment for viral meningitis (n = 1); autoimmune encephalitis (n = 1); optic neuritis (n = 1); venous sinus thrombosis (n = 1). None of the neurologic control patients exhibited substantially increased intracranial pressure. There were no significant differences in the distribution of age, sex, or smoking status across groups (all p > 0.05). BMI in neurologic controls was significantly lower relative to both IIH patients and healthy study participants (both p < 0.001). Information regarding the LP is summarized in Table 2.

Table 2.

Olfactory assessment and CSF pressure in IIH patients.

Patient	Composite TDI score (T,D,I subscores) at T1	Optic nerve sheath diameter (mm)	CSF opening pressure (cm)	CSF drained (ml)	CSF closing pressure (cm)	Composite TDI score (T,D,I subscores) at T2
1	27 (5/10/12)	4.9	50	15	15	41 (11/14/16)
2	35 (9/13/13)	4.5	28	18	12	41 (10/16/15)
3	23 (4/11/8)	6.9	43	20	10,5	25 (3/9/13)
4	28 (2/11/15)	6.4	30	25	8	35 (6/14/15)
5	31 (7/13/11)	5.8	26	30	15	33 (6/15/12)
6	34 (7/13/14)	5	27	30	5	39 (9/14/16)
7	35 (7/15/13)	6.3	23	10	15	38 (10/14/14)
8	32 (4/14/14)	5.7	26	12	8	32 (5/14/13)
9	31 (5/12/14)	4.9	17*	10	10	36 (6/15/15)
10	32 (5/14/13)	6.4	25	16	11,5	38 (7/16/15)
11	30 (5/11/14)	5	31	25	11	35 (7/15/13)
12	24 (1/11/12)	4.7	43	23	17	35 (9/13/13)
13	28 (10/9/9)	4.9	27	25	9	33 (11/12/10)
14	33 (10/11/12)	5.6	28	17	15	39 (12/14/13)

The table provides the individual results of all IIH patients investigated here. Olfactory function was assessed at T1 and T2 as described in the main text. The composite TDI score consists of three subscores (T, odor threshold; D, odor discrimination; I, odor identification). CSF, cerebrospinal fluid; IIH, idiopathic intracranial hypertension; LP, lumbar puncture.

This patient had been diagnosed with IIH four months earlier. A previous LP performed one month before this LP had yielded a CSF opening pressure of 32 cm. The patient had then been started on acetazolamide 250 mg b.d. Upon enrolment into the study, the patient again reported headache symptoms similar to those that had accompanied the initial manifestation of IIH. Moreover, please note that MRI investigation revealed an increased optic nerve sheath diameter. Taken together, the patient’s presentation was most consistent with IIH.

The interval between the first (T1) and the second smell test (T2) did not differ significantly between IIH patients and healthy study participants (p > 0.05). Due to practical issues, this interval was somewhat reduced in neurologic controls compared to the IIH group (p = 0.044). However, more importantly, the length of time between LP and the second smell test was similar in IIH patients and neurologic controls (p > 0.05).

Based on normative data accounting for age and sex, 43% of IIH patients, 29% of neurologic control patients, but only 7% of the healthy control participants were categorized as hyposmic at baseline. Hyposmia was defined as a reduced olfactory function below the 10th percentile of a normal population of the same sex and age (11,18). Furthermore, 86% of IIH patients, 64% of neurologic control patients, and 21% of healthy participants displayed below-average olfactory function.

Although only 21% (n = 3) of IIH patients had been aware of their olfactory loss, all IIH patients reported meaningful improvement on LP. Upon retesting, the proportion of patients with hyposmia had decreased to 7% in the IIH group, while 21% of neurologic control patients and 7% of healthy controls still displayed hyposmia. An increase in TDI score of 5.5 points or more is associated with a relevant improvement in olfactory function that is perceived as such by the majority of patients (20). While 43% (n = 6) of IIH patients achieved such robust improvement, none of the neurologic control patients and none of the healthy participants reached this cutoff value.

Figure 1 illustrates the results of olfactory testing. We performed four separate analyses with the composite TDI score (Figure 1(a)) as well as with each of the three subscores (Figure 1(b)–(d)) as dependent variables. All four analyses revealed significant interaction effects of time × group (see Figure 1). Furthermore, pairwise comparisons demonstrated that the composite TDI score and the T subscore of both IIH patients and neurologic controls was lower than that of the healthy study participants at baseline (all comparisons, p < 0.002). Moreover, IIH patients also showed impaired olfactory function on the D subscore compared to healthy controls (p = 0.029). The composite TDI score did not change significantly from T1 to T2 in either neurologic controls (p = 0.772) or healthy study participants (p = 0.369). The same was true for all three subscores (all comparisons, p > 0.05). By contrast, IIH patients improved on all scores (all changes: p < 0.003, $η_{p}^{2}$ > 0.22) with the composite TDI score demonstrating a robust effect of $η_{p}^{2}$ = 0.51 (p < 0.001). Interestingly, higher CSF opening pressure was associated with greater improvement in olfactory function in the IIH group (composite TDI score, r = 0.609, p = 0.021; subscores, T: r = 0.509, p = 0.063; D: r = 0.011, p = 0.971; I: r = 0.557, p = 0.038) but not in the neurologic control group (all p > 0.3). The effect size of the correlation between CSF opening pressure and improvement in olfactory function assessed with the TDI composite score remained virtually unchanged in the IIH group when age and BMI were controlled for using partial correlation (r = 0.603, p = 0.038).

Figure 1.

Repeated assessment in olfactory performance. Olfactory function was assessed at T1 and T2 as described in the main text. The F-statistics refer to the significant interaction effect (time × group) that was observed for the composite TDI score (a) and for all subscores ((b)–(d)). Results for pairwise comparisons are given in the text. Error bars indicate standard errors of the mean (SE).

Discussion

To our knowledge, this is the first prospective study of IIH patients to explore changes in olfactory perception following CSF drainage. The major results of our study are that: (1) after CSF removal, IIH patients evidence a rapid improvement in smell function within, on average, less than a day; (2) this effect appears specific to IIH patients and was not observed in neurologic control patients with a similar degree of hyposmia; (3) in IIH patients, increased CSF opening pressure is related to improvement in olfaction upon CSF drainage (Table 3).

Table 3.

CSF drainage and time to olfactory testing.

	IIH patients	Neurologic controls	Healthy controls
CSF opening pressure (cm)	27.5/30.3 (8.9)	15.5/16.3 (3.0) n.d.	n.d.
CSF drained (ml)	19.0/19.7 (6.8)	3–5	n.d.
CSF closing pressure (cm)	11.3/11.6 (3.5)	n.d.	n.d.
Time between smell tests (h)	49.8/57.8 (33.2)	29.0/33.6 (13.1)	66/60.1 (14.6)
Time between LP and the second smell test (h)	17.5/18.1 (3.8)	16.5/14.3 (8.3)	n.a.

BMI: body mass index; CSF: cerebrospinal fluid; IIH: idiopathic intracranial hypertension; LP: lumbar puncture; n.a.: not applicable; n.d.: not determined.

Results are reported as median/mean and standard deviation (in brackets).

The present study reinforces the fact that olfactory impairment is a common feature of IIH. A large majority of patients in our IIH sample displayed below-average olfactory function. Moreover, 43% of IIH patients suffered from hyposmia. Interestingly, at least initially, most of our IIH patients were unaware of their reduced olfactory function. Prior research suggests that this lack of awareness seems to be the rule rather than the exception in patients with IIH (5,6,14).

We here show that, after LP, IIH patients regained olfactory function to a level similar to that of age- and sex-matched healthy controls. This is also the first report suggesting that olfactory function in IIH patients may be restored within a matter of hours following a reduction in CSF pressure through LP. From this, it may be inferred that the IIH-related smell disorder is generally treatable and possibly directly related to elevated CSF pressure. Further, our results suggest that lowering of elevated CSF opening pressure plays a role in normalizing olfactory function, meaning that especially those IIH patients with highly elevated CSF opening pressure show improvement in smell function. Interestingly, this association between CSF pressure and symptom improvement in IIH appears to be relatively specific to olfactory dysfunction. For example, a recent study of therapeutic LP for headache in IIH did not find a relationship between CSF opening pressure and headache response after CSF (21). However, this may not be surprising because intracranial hypotension, which may occur after LP, may, in turn, cause headache symptoms (12). A number of limitations should be noted. In particular, it should be considered that headache symptoms may conceivably impinge on olfactory performance. It might therefore be worthwhile for future studies of IIH patients to explore both headache symptoms and olfactory performance in relation to each other as well as to CSF pressure. Another unexpected observation of this study was that odor discrimination and odor identification improved in parallel with increased threshold scores. Odor discrimination and odor identification are usually attributed to central rather than peripheral impairments, although the debate on this continues (6,22). Finally, it should be acknowledged that, in this study, we did not collect a detailed smoking history.

Neurologic control patients did not show significant improvement in olfactory performance after LP. We chose to include this particular group in this investigation in an attempt to gauge a potential effect of the LP procedure as such on olfaction. However, the relatively small amount of CSF removed as part of routine diagnostic LP (usually between 3 and 5 ml) may not have fully mirrored the consequences of the removal of much larger volumes of CSF during therapeutic LP in IIH patients. To address this criticism, future studies may wish to include patients suffering from normal pressure hydrocephalus (NPH) as the neurologic control group, because diagnostic LP in NPH patients usually also entails the removal of large amounts of CSF. The relatively low TDI scores observed in our neurologic control patients highlight the fact that, albeit quite prevalent, especially in neurodegenerative disorders (23,24), olfactory symptoms in neurologic patients may generally deserve more attention than has hitherto been accorded to them. Interestingly, emerging evidence seems to indicate that, besides classical neurodegenerative disorders, other neurologic disorders such as multiple sclerosis and autoimmune encephalitis may also lead to hyposmia (25,26). Also, the validity of the Sniffin’ Sticks procedure needs further investigation in groups other than healthy controls. The association between advancing age and reduced olfactory capacity is well established (17,18). However, according to the normative data published by Oleszkiewicz et al. (18), less than 2 points on the TDI can be explained by age differences. It should also be noted that there were no statistically significant age differences between the three groups, although the difference between the IIH and neurologic control group showed a tendency to significance.

To summarize, neither healthy participants nor neurologic controls showed improved olfactory performance on the second smell test. With the important qualifications made above, our results support the idea that the significant improvement in olfactory function observed in IIH patients after LP is relatively peculiar to IIH and not due to learning effects or other effects of LP besides removal of CSF. In line with our findings, head-down tilt, which promotes headward fluid shifting and increased intracranial pressure, has been shown to aggravate olfactory impairment in IIH (6). We note, however, that it is quite probable that the effect of CSF removal extends beyond lowering CSF pressure. For example, it has been suggested that the effect of a single spinal tap on CSF pressure may only last for hours in certain patients (27). It is therefore likely that our finding may also be due to second-order functional effects (28).

Our study suggests that, in the treatment of IIH patients, olfactory testing should be considered as an additional element for monitoring disease activity. The main result; that is, the change in composite TDI score in the IIH group over time as well as the changes in all subscores, showed comparatively large effect sizes. IIH patients improved on all scores (all changes: p < 0.003, $η_{p}^{2}$ > 0.22) with the composite TDI score demonstrating a large effect of $η_{p}^{2}$ = 0.51 (p < 0.001). These p-values would survive a correction for multiple comparisons. Taken together, this consistent pattern of results is in accordance with our hypothesis and the likelihood of type 1 error appears to be rather low. Moreover, a post-hoc power analysis using G*Power (29) showed that, with our sample size of n = 42 divided into three groups and two measurements (intercorrelated about r = 0.70), we were able to detect time × group effects of about η²= 0.035 with an α of 0.05 and a power of 0.80; that is, small to moderate effects.

Our findings have implications for the pathophysiology of smell dysfunction in IIH. Most importantly, from a clinical perspective, our results indicate that, at least in the patients investigated here, long-term structural changes are not a pre-requisite for IIH-related hyposmia. Although the olfactory system possesses a high capacity for structural regeneration, the cellular mechanisms involved (e.g. neuroblast migration, neurogenesis) would require a time frame of weeks to months instead of hours (30,31). More to the point, it has been speculated that chronic overflow of CSF along the sheath of the olfactory bulb may underlie hyposmia in IIH. An analogous mechanism is believed to account for the dysfunction of other cranial nerves in the disorder (32). By eroding the cribriform plate, chronic overflow of CSF may even lead to spontaneous CSF rhinorrhea, another not uncommon symptom of IIH (33). LP may possibly counteract pressure-induced axoplasmic stasis (34). Kapoor and co-workers proposed that a dysfunction of the extensive lymphatic network around the olfactory nerves might be causally linked to IIH (35). The exciting recent discoveries of the glymphatic and lymphatic systems of the brain have since led to a refined hypothesis of IIH centering on the congestion of veno-glymphatic connections (32).

Clinical implications

Olfactory impairment is an important, yet underappreciated, clinical feature of IIH.

After CSF removal, IIH patients experience a rapid improvement in smell function within, on average, less than a day. This effect appears specific to IIH patients and was not observed in neurologic control patients with a similar degree of hyposmia. In IIH patients, increased CSF opening pressure is related to improvement in olfaction upon CSF drainage.

Our findings shed new light on the pathophysiology of CSF circulation in IIH.

Footnotes

Author contributions

HK had full access to all data in this study and takes responsibility for the integrity of the data and the accuracy of analyses. Study concept and design: JH, LH, GK, HK. Acquisition, analysis and interpretation of data: All authors. Drafting of the manuscript: All authors. Approval of version to be published: All authors. Critical revision of the manuscript for important intellectual content: All authors. Statistical analysis: NB, SE, GK, HK. Administrative, technical or material support: NB, FS, JH, EW, LH. Study supervision: JH, EW, LH, HK.

Data sharing statement

Data used in this manuscript will be made available to qualified health care professionals in accordance with Partners Human Research Committee policies.

Declaration of conflicting interests

The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: JH has consulted for and/or serves on advisory boards for Allergan, Autonomic Technologies Inc. (ATI), Chordate Medical AB, Eli Lilly, Hormosan Pharma, Novartis and Teva. He received honoraria for speaking from Allergan, Autonomic Technologies Inc. (ATI), Chordate Medical AB, Novartis and Teva. These activities are unrelated to the content of this manuscript. LH received personal compensation for speaking from Biogen, Novartis, Genzyme, Teva, Merck, Euroimmun, Roche, Boehringer Ingelheim, Pfizer and Bayer. He also received honoraria for participation in advisory boards from Novartis, Roche, Genzyme, and Teva as well as travel support to congresses by Novartis, Biogen, Genzyme, and Teva. These activities are unrelated to the content of this manuscript. HK received personal compensation for speaking from Biogen, Novartis, Genzyme, Teva, Merck, Mylan, and Bayer. He also received honoraria for participation in advisory boards from Novartis, Roche, Genzyme, and Teva as well as travel support to congresses by Novartis, Genzyme, and Teva. These activities are unrelated to the content of this manuscript. All other authors declared no potential conflicts of interest regarding this manuscript.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Research ethics and patient consent

Approval for the study was obtained from the institutional ethics committee of the Charité University Hospital. All participants gave written informed consent prior to any study-specific procedures.

ORCID iD

Jan Hoffmann

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Lumbar puncture rapidly improves olfaction in patients with idiopathic intracranial hypertension: A cohort study

Abstract

Background

Methods

Results

Conclusion

Keywords

Introduction

Methods

Participants

Olfactory testing

MR imaging (MRI)

Standard protocol approvals, registrations, and patient consents

Statistical analyses

Results

Discussion

Clinical implications

Footnotes

Author contributions

Data sharing statement

Declaration of conflicting interests

Funding

Research ethics and patient consent

ORCID iD

References