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Head circumference: The forgotten tool for hydrocephalus management. A reference interval study in the Spanish population
Clinical Neurology and Neurosurgery 115 (2013) 2382–2387
Contents lists available at ScienceDirect
Clinical Neurology and Neurosurgery journal homepage: www.elsevier.com/locate/clineuro
Head circumference: The forgotten tool for hydrocephalus management. A reference interval study in the Spanish population Maria A. Poca a,b,∗ , Francisco R. Martínez-Ricarte a,b , Mireia Portabella c , Ramon Torné a,b , Maria L. Fuertes c , Pilar González-Tartiere b , Juan Sahuquillo a,b a
Department of Neurosurgery, Vall d’Hebron University Hospital and Vall d’Hebron Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain Neurosurgery and Neurotraumatology Research Unit, Vall d’Hebron University Hospital and Vall d’Hebron Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain c Emergency Trauma Department, Vall d’Hebron University Hospital and Vall d’Hebron Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain b
a r t i c l e
i n f o
Article history: Received 14 April 2013 Received in revised form 30 July 2013 Accepted 1 September 2013 Available online 7 September 2013 Keywords: Head circumference Macrocephaly Microcephaly Spanish people Reference interval
a b s t r a c t Introduction: In children, deviations from the normal range of head circumference (HC) have traditionally been related with CSF dynamics abnormalities. In adults, this neglected parameter is helpful in the diagnosis and understanding of the pathophysiology of some CSF abnormalities. It has been demonstrated that HC is related to height. Because humans have increased in stature dramatically during the last 50 years, pediatric charts for head growth physiology and normal HC values in adults should be reevaluated. Objectives: The main aim of the present study was to assess HC in a series of 270 normal healthy Spanish adults and to determine any differences between sexes and age groups. A secondary aim was to discuss the relevance of this parameter in the management of hydrocephalus in adult people. Methods: HC measurements were taken using a measuring tape placed over the greatest frontal and occipital protuberances. The reference interval and the upper and lower thresholds for HC were calculated by 3 different methods: normal distribution, the non-parametrical percentile method, and the “robust method”. Results: The results were consistent and showed that Spanish adult men with a HC greater than 60 cm, and Spanish adult women with a HC greater than 58 cm should be considered macrocephalic. Microcephaly should be considered when HC is 53.6 cm in men and 51.3 cm in women. Adult age groups of either sex do not present any statistically significant differences in HC. Conclusions: HC obtained in Spanish adult people are greater than those reported in the classical Nellhaus graphs in both men and women aged 18. These findings should be considered in the management of hydrocephalus in adults today. © 2013 Elsevier B.V. All rights reserved.
1. Introduction The measurement of head circumference (HC) is an easy, non-invasive, and inexpensive way to screen for developmental, neurological, and genetic disorders. It is included routinely in the physical examination of infants and children. In infants, rapid increases in head size suggest the presence of hydrocephalus, while microcephaly can be associated with structural brain abnormalities or genetic syndromes [1–3]. In adults, the diagnosis of hydrocephalus associated with macrocephaly suggests that the cause of this process occurred before the complete closure of sutures and
∗ Corresponding author at: Department of Neurosurgery, Vall d’Hebron University Hospital, Passeig Vall d’Hebron 119-129, 08035 Barcelona, Spain. Tel.: +34 3 489 35 14; fax: +34 3 489 35 13. E-mail addresses: [email protected], [email protected] (M.A. Poca). 0303-8467/$ – see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.clineuro.2013.09.001
fontanels [4–9], while microcephaly may be a pathogenic mechanism in pathologies such as idiopathic intracranial hypertension [10]. In the literature there are many articles on the physiology of head growth. However, the pivotal paper of Nellhaus in 1968 [11] continues to be the main reference used in Spain today. This author pooled results and variances from 14 reports on HC published in the literature up to 1948, and drew the classical graphs of mean increments in HC from birth to 18 years (mean ± SD in cm and inches) for both sexes. The graphs show how the two-thirds of total head growth from full-term birth to adulthood normally take place during the first 24 months of life and that in all ages the HC of boys is approximately 0.9 cm larger than that of girls [11]. At 18 years, 98% of head growth has occurred. Nellhaus also stressed that there were no significant racial, national, or geographic differences in HC [11]. The Nellhaus graphs, however, may be inappropriate for use today. Humans have increased in stature dramatically during the
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last 50 years [12] and several authors have demonstrated that HC is related to height [13,14]. In 1992, Bushby et al. collected data on HC, height, and age in 159 British adult men and 195 women aged between 17 and 83 years. The results of these authors showed that the mean HC of a subject of average height (170 cm for men and 165 cm for women) is above the 98th percentile at age 18 on the Nellhaus graphs [14]. Additionally, Japanese studies have demonstrated that the standards for HC differ from country to country and from generation to generation [15]. These findings support the idea that old pediatric charts and HC values considered normal for adults must be reevaluated. The main aim of the present study was to assess HC in a series of normal healthy Spanish adults and to determine whether differences between sexes and age groups are present. A secondary aim was to discuss the relevance of this parameter in the management of hydrocephalus in adult people. 2. Materials and methods 2.1. Patient selection. Inclusion and exclusion criteria Maximal HC assessment was carried out on a prospective cohort of 307 patients who were consecutively evaluated due to a mild traumatic brain injury (mTBI) in the emergency room of the Trauma Hospital at Vall d’Hebron University Hospital in Barcelona, Spain, from July 2004 to December 2011. To minimize heterogeneity and ethnic influences that may affect morphometric parameters such as height and thus HC, only Spaniards whose family had no known history of immigration to Spain were included in this study to obtain a sample that was geographically representative of the country. Additional inclusion criteria were as follows: (1) age equal or greater than 17 years, (2) mTBI with no loss of consciousness, (3) normal neurological examination results and Glasgow coma scale score of 15, (4) normal CT scans, (5) subjects who were born fullterm with normal neurodevelopment, (6) no previous history of neurological or psychiatric pathology, (7) no previous history of TBI, (8) no previous history of alcoholism or drug addiction, and (9) willingness to participate in the study. Patients with cranial contusion that might have hampered HC measurements and those who did not meet the inclusion criteria were excluded. Informed consent for all aspects of the study was obtained from each patient. 2.2. Computed tomography scan studies Brain computed tomography (CT) was performed in all patients using a helicoidal CT scan (Philips Mx8000; FOV de 300 mm; 120 kV and 300 mAS) following the methodology proposed by the European Brain Injury Consortium: 3-mm slices, parallel to the canto-meatal line, from the skull base to the vertex, with a cutting distance of 5 mm in the posterior fossa and 10 mm in the supratentorial compartment. 2.3. Head circumference assessment All HC measurements were taken by the neurosurgeon evaluating the patient or by the nurse in charge of the neurotraumatology unit using the methodology described by Nellhaus in 1968 [11]. A measuring tape is placed over the greatest frontal (usually in the glabela, or supraorbital protuberance) and occipital (inion) protuberances (Fig. 1). 2.4. Intraobserver and interobserver reliability Interobserver agreement and intraexaminer reliability of HC measurements were tested by 2 of the authors (MAP and FRMR) using two-way mixed intraclass correlation coefficients (ICC) with a 95% confidence interval (CI) on repeated measurements. The
Fig. 1. Occipitofrontal head circumference measurement in an adult woman. Note that the tape is placed in the most prominent frontal and occipital protuberances.
measurements were taken in 56 subjects using a strip of white, laminated, unmarked paper. This method has been shown to be superior to the use of measuring tapes in performing this kind of reliability study [16]. High intrarater agreement (rater 1: ICC = 0.99; rater 2: ICC = 0.96) and interobserver agreement (ICC = 0.98, 95% CI 0.97–0.99) were found. 2.5. Statistical analysis All descriptive statistics were analyzed and summarized using the SigmaPlot package for Windows (Version 11.0, Systat Software, Inc., Germany). The assumption that data were normally distributed was tested using the Shapiro–Wilk test. In normally distributed data, the mean ± standard deviation (SD) was used to summarize the variables. In skewed samples, the median and the interquartile range (IQR) were used. To calculate the reference interval and the upper threshold for HC we also used the following 2 additional distribution-free methods: (1) the non-parametrical percentile method (percentiles: 2.5 and 97.5), and (2) the “robust method” described in the National Committee on Clinical Laboratory Standards (NCCLS) and Clinical and Laboratory Standards Institute (CLSI) guidelines C28-A2 and C28-A3 for estimating percentiles and their 90% confidence intervals (CI). In these guidelines, percentiles are calculated as the observations corresponding to rank r = p*(n + 1). In addition, the CLSI guidelines [17] were followed for the 90% CI of the reference limits and conservative CI were calculated using integer ranks. In both methods, we used MedCalc version 12.2 (MedCalc Software, Mariakerke, Belgium) to calculate reference intervals. Differences between 2 independent samples were analyzed using the Mann–Whitney Rank Sum Test. The Kruskal–Wallis oneway analysis of variance on ranks test was used to compare HC in patients with different ages. Statistical significance was considered when p ≤ 0.05. Data were presented graphically using box-andwhisker plots. 3. Results Of the 307 patients assessed, 37 were not included in the study due to nationality other than Spanish (n = 14), age below 17 years (n = 5), incorrectly taken measurements (n = 6), and data loss (n = 12). The final sample included 270 subjects, 129 men (mean age 40.8 ± 19.2 years, median 34, IQR of 31 [24–55], minimum 17, maximum 89) and 141 women (mean age 48.9 ± 23.8 years, median 46, IQR of 45.3 [27–72.3], minimum 17, maximum 100).
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Fig. 2. Histograms of head circumference measurements in men (top) and women (bottom).
The mean HC of the complete sample (n = 270) was 56 ± 2 cm (CI of mean: 0.234); the median was 56 cm with an IQR of 2 cm (55–57). Minimum and maximum values were 51 cm and 60.5 cm respectively. In men, the mean HC was 57.07 ± 1.6 cm (CI of mean: 0.286), with a median value of 57 cm, an IQR of 2 cm (56–58) and minimum and maximum values of 53 cm and 60.5 cm, respectively. For women, the mean HC was 55.02 ± 1.7 cm (CI of mean: 0.282), with a median value of 55 cm, an IQR of 2 cm (54–56) and minimum and maximum values of 51 cm and 59 cm respectively (Figs. 2 and 3). The double-sided 95% reference interval for upper thresholds for men and women, using a method based on normal distribution, were 60.28 cm (90% CI: 59.87–60.69) and 58.34 cm (90% CI: 57.94–58.75), respectively. The upper thresholds for men and women using the non-parametrical percentile method (percentile 97.5) were 60 cm (90% CI: 60–60.50) and 58 cm (90% CI: 58–59), respectively. Differences between males and females were statistically significant (U = 3567.0, p < 0.001). When the robust method described in the CLSI guidelines was used, upper thresholds for men and women were 60.36 cm (90% CI: 59.95–60.77) and 58.52 cm (90% CI: 58.14–58.96) respectively. The 3 methods were consistent in identifying an upper threshold of 60 cm for men and 58 cm for women (Table 1). Lower thresholds for men and women using the 3 methods are summarized in Table 1. The 3 methods were consistent in identifying a lower threshold of 53.6 cm for men and 51.3 cm for women (Table 1).
When patients were distributed by age, no differences were found in HC between patient groups (17–30, 31–40, 41–60, 61–80, and 80–100 years) in either men (H = 5.720, p = 0.221) or women (H = 1.437, p = 0.838) (Figs. 4 and 5).
Fig. 3. Box-plot graph showing additional statistical data of head circumference in men and women. Values are significantly different between groups (U = 3567.0, p < 0.001).
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Table 1 Upper and lower threshold limits for head circumference in Spanish adult people. Method used
Normal distribution (mean ± 2SD) Non-parametrical percentile method (2.5 and 97.5 percentiles) Robust method as described in the CLSI guidelines
Upper threshold
Lower threshold
Men
Women
Men
Women
60.28 cmCI: 59.87–60.69 60 cm CI: 60.00–60.50
58.34 cmCI: 57.94–58.75 58 cm CI: 58.00–59.00
53.85 cmCI: 53.44–54.27 53.63 cmCI: 53.00–54.00
51.70 cmCI: 51.29–52.11 51.28 cmCI: 51.00–52.00
60.36 cmCI: 59.95–60.77
58.52 cmCI: 58.14–58.96
53.83 cmCI: 53.43–54.22
51.79 cmCI: 51.35–52.26
SD: standard deviation; CI: 90% confidence interval; CLSI: Clinical and Laboratory Standards Institute.
relevant medical history, or abnormalities in neuroimaging studies. To avoid possible differences due to the inclusion of subjects from other countries or ethnic groups, the nutritional or developmental aspects of which may affect height and therefore HC, among other factors, our study was limited to Caucasian patients of Spanish origin who reported no known history of immigration to Spain. The results obtained are therefore relevant to this particular group only and cannot be generalized to other groups. A further important aspect of our study is that the results obtained were consistent when analyzed independently with 3 different statistical methods. Our findings are very similar to those reported by Bushby et al. [14] in British adults in 1992. These results suggest that the contemporary human head circumference is larger than that of people born during the first half of the 20th century, at least in adults. Our data, however, did not show an overall increase in HC for younger patients. In the present series Spanish men were shown to have larger heads than Spanish women, but in both cases there were no statistically significant differences in HC between age groups, A future study including height, body mass index, and HC measurements may be able to clarify this point. Fig. 4. Head circumference (HC) in men distributed by age. There are no statistically significant differences between groups (H = 5.720, p = 0.221).
4.1. Cranial development and normal head circumference in adults 4. Discussion Head circumference in Spanish adults has been observed to be greater than our estimations based on the classical Nellhaus values in both men and women. It is particularly relevant that we assessed only normal healthy adults with no neurological symptoms,
Fig. 5. Head circumference (HC) in women distributed by age. There are no statistically significant differences between groups (H = 1.437, p = 0.838).
Human craniofacial morphology is very complex, being controlled by genetic, environmental, mechanical, and epigenetic factors. Measurement of the maximal occipito-frontal HC provides a simple and reproducible measurement of head size that correlates closely with brain volume [18,19]. The most dramatic increase in brain volume occurs in the last 3 months of fetal life and during the first 2 years after birth. Concomitantly, the skull follows the volumetric increase in the cerebral hemispheres, mostly by passive adaptation. Cranial development is also influenced by molecular mechanisms related mainly with the dura mater and sutures [20]. HC increases by 33% between the ages of 2 and 18 years, with the greatest growth (19%) occurring between 2 and 8 years of age. At the age of 18, development of the calvaria is nearly complete [11]. Less than 2% of all HC growth occurs after the age of 18, and this consists largely of an increase in skull and scalp thickness [21–23]. Macrocephaly and microcephaly are defined by HC measurements 2 standard deviations above or below the mean in any age group. Apart from the influences of brain development and molecular mechanisms related with the dura mater, periosteum, and sutures, the final head size depends on sex, nutrition, and other body parameters such as height, among others [2]. Although Nellhaus stressed that there were no significant racial, national, or geographic differences in HC [11], posterior studies have put in doubt this idea [15,24]. Ishikawa et al. [15] demonstrated that the heads of Japanese people were smaller up to the age of 10 years and larger beyond that age when compared to those in the Nellhaus composite graphs. The
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heads of children of both sexes in the Japanese study were smaller than those of children born in the United Kingdom in the same period, but they were considerably larger than those of children born in Japan more than 50 years ago [15]. At present, a systematic review including studies published from January 1990 up to the present time is being conducted to compare mean head sizes for different nations and ethnic groups with international mean values reported by the World Health Organization to elucidate if HC varies between different nations or ethnic groups around the world [24]. In the Nellhaus graphs using data extracted from studies published between 1933 and 1965, the 98th and the 2nd percentiles for HC for a man aged 18 years are 58.6 cm and 53.3 cm respectively, and for a woman aged 18 years 57.7 cm and 52.1 cm, respectively [11]. Currently, in Spanish adults, these values have been calculated to be 60 cm (90% CI: 60–60.5) and 53.63 cm (90% CI: 53.00 to 54.00) in men, and 58 cm (90% CI: 58–59) and 51.28 cm (90% CI: 51.00 to 52.00) in women. When comparing our results with those of Nellhaus, there are greater discrepancies in men than in women. 4.2. Indications of assessing head circumference. Clinical applicability Measurement of occipito-frontal HC is an integral part of most pediatric and many other medical examinations. It is often of particular importance in making a diagnosis in dysmorphic children with developmental delay, possibly associated with microcephaly or macrocephaly. Many of these conditions are inherited and therefore accurate assessment and counseling of relatives should include measurement of HC in the child and his or her parents and siblings. The assessment of HC in parents is especially important in the investigation of cases in which abnormal HC is the only finding, given that in up to 50% of cases, variations of normality in head size is familial [25]. HC assessment is also important in adults with certain neurological pathologies. Hydrocephalus associated with severe ventriculomegaly and macrocephaly may be caused in the early stages of life, although symptoms may occur during adulthood [6–9]. The presentation of this syndrome may be very similar to “normal pressure” hydrocephalus (Hakim and Adams syndrome), however, the prognosis may be worse [5], with less improvement and a greater rate of complications. At the same time, some studies suggest that 1 of the pathogenic mechanisms of pseudotumor cerebri – also known as benign intracranial hypertension or idiopathic intracranial hypertension (IIH) may be a smaller cranial size. This theory has been used to justify the use of alternative surgical techniques aimed at producing an expansion of the internal cranial space [10]. This technique may be used as part of the multidisciplinary management approach in the treatment of refractory IIH. 4.3. Study limitations The most relevant limitation of the present study is that HC was measured without other body measurements, such as weight, height, and body mass index. A second limitation is that although all patients were assessed in the same center, measurements were taken by different individuals. However, the reliability of HC measurements has been studied by our group and other authors, and a high concordance in both intra- and inter-examiner measurements was confirmed. Johnson et al. [26] studied the intra- and inter-examiner reliability of anthropometric measurements in 50 full-term infants showing that 98–100% of the observed differences in HC were less than 1 cm. Very similar results were found in our study, which used white, laminated, unmarked paper strips.
5. Conclusions According to our data, Spanish adult men with HCs greater than 60 cm, and Spanish adult women with HCs greater than 58 cm should be considered macrocephalic. These values are greater than those reported in the classical Nellhaus graphs in both men and women aged 18. In these same groups, microcephaly should be considered when HC is less than 53.6 cm and 51.3 cm, respectively. In adulthood (>17 years), the HC of Spanish individuals remains constant. These findings should be considered in the management of hydrocephalus in adults today. Conflict of interest The authors declare that they have no conflict of interest. Acknowledgments The authors gratefully acknowledge Sabrina Voss for editorial ˜ (M.D.), R. Lastra (M.D.), assistance and the collaboration of J.D. Anez and O. Mestres (R.N.) in collecting data from some patients. This study was supported in part by Grant 07/0681 from the Fondo de Investigación Sanitaria (FIS) given to Dr. M.A. Poca. References [1] Cowie VA. Microcephaly: a review of genetic implications in its causation. J Ment Defic Res 1987;31:229–33. [2] Ivanovic DM, Leiva BP, Perez HT, Olivares MG, Diaz NS, Urrutia MS, et al. Head size and intelligence, learning, nutritional status and brain development. Head, IQ, learning, nutrition and brain. Neuropsychologia 2004;42:1118–31. [3] Coronado R, Giraldo J, Macaya A, Roig M. Head circumference growth function as a marker of neurological impairment in a cohort of microcephalic infants and children. Neuropediatrics 2012;43:271–4. [4] Sahuquillo J, Poca MA, Chasampi A, Molins A, Rovira A, Gabas E, et al. Adult chronic hydrocephalus (normal pressure hydrocephalus) and macrocephaly. Neurocirugia 1991;2:344–53. [5] Oi S, Shimoda M, Shibata M, Honda Y, Togo K, Shinoda M, et al. Pathophysiology of long-standing overt ventriculomegaly in adults. J Neurosurg 2000;92:933–40. [6] Fukuhara T, Luciano MG. Clinical features of late-onset idiopathic aqueductal stenosis. Surg Neurol 2001;55:132–6. [7] Wilson RK, Williams MA. Evidence that congenital hydrocephalus is a precursor to idiopathic normal pressure hydrocephalus in only a subset of patients. J Neurol Neurosurg Psychiatry 2007;78:508–11. [8] Krefft TA, Graff-Radford NR, Lucas JA, Mortimer JA. Normal pressure hydrocephalus and large head size. Alzheimer Dis Assoc Disord 2004;18:35–7. [9] Cowan JA, McGirt MJ, Woodworth G, Rigamonti D, Williams MA. The syndrome of hydrocephalus in young and middle-aged adults (SHYMA). Neurol Res 2005;27:540–7. [10] Ellis JA, Anderson RC, O’Hanlon J, Goodman RR, Feldstein NA, Ghatan S. Internal cranial expansion surgery for the treatment of refractory idiopathic intracranial hypertension. J Neurosurg Pediatr 2012;10:14–20. [11] Nellhaus G. Head circumference from birth to eighteen years. Practical composite international and interracial graphs. Pediatrics 1968;41:106–14. [12] Ogden CL, Fryar CD, Carroll MD, Flegal KM. Mean body weight, height, and body mass index, United States 1960–2002. Advance data from vital and health statistics. Maryland: National Center for Health Statistics; 2004. [13] Bale SJ, Amos CI, Parry DM, Bale AE. Relationship between head circumference and height in normal adults and in the nevoid basal cell carcinoma syndrome and neurofibromatosis type I. Am J Med Genet 1991;40:206–10. [14] Bushby KM, Cole T, Matthews JN, Goodship JA. Centiles for adult head circumference. Arch Dis Child 1992;67:1286–7. [15] Ishikawa T, Furuyama M, Ishikawa M, Ogawa J, Wada Y. Growth in head circumference from birth to fifteen years of age in Japan. Acta Paediatr Scand 1987;76:824–8. [16] Sutter K, Engstrom JL, Johnson TS, Kavanaugh K, Ifft DL. Reliability of head circumference measurements in preterm infants. Pediatr Nurs 1997;23:485–90. [17] Clinical Laboratory Standards Institute. Defining, establishing, and verifying reference intervals in the clinical laboratory: approved guideline. CLSI document C28-A3. 3rd ed. Wayne, PA: Clinical Laboratory Standards Institute; 2008. [18] Bray PF, Shields WD, Wolcott GJ, Madsen JA. Occipitofrontal head circumference: an accurate measure of intracranial volume. J Pediatr 1969;75:303–5. [19] Bartholomeusz HH, Courchesne E, Karns CM. Relationship between head circumference and brain volume in healthy normal toddlers, children, and adults. Neuropediatrics 2002;33:239–41.
M.A. Poca et al. / Clinical Neurology and Neurosurgery 115 (2013) 2382–2387 [20] Coussens AK, Wilkinson CR, Hughes IP, Morris CP, van DA, Anderson PJ, et al. Unravelling the molecular control of calvarial suture fusion in children with craniosynostosis. BMC Genom 2007;8:458. [21] Roche AF. Increase in cranial thickness during growth. Hum Biol 1953;25:81–92. [22] Young RW. Age changes in the thickness of the scalp in white males. Hum Biol 1959;31:74–9. [23] Baer MJ, Harris JE. A commentary on the growth of the human brain and skull. Am J Phys Anthrop 1969;30:39–44.
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[24] Natale V, Rajagopalan A. A comparison of human head circumference and the WHO MGRS growth standards: a systematic review. PROSPERO 2013; 2013. CRD42013003675. http://www.crd.york.ac.uk/PROSPERO/display record asp?ID=CRD42013003675 [accessed 14.04.13]. [25] Weaver DD, Christian JC. Familial variation of head size and adjustment for parental head circumference. J Pediatr 1980;96:990–4. [26] Johnson TS, Engstrom JL, Gelhar DK. Intra- and interexaminer reliability of anthropometric measurements of term infants. J Pediatr Gastroenterol Nutr 1997;24:497–505.
Contents lists available at ScienceDirect
Clinical Neurology and Neurosurgery journal homepage: www.elsevier.com/locate/clineuro
Head circumference: The forgotten tool for hydrocephalus management. A reference interval study in the Spanish population Maria A. Poca a,b,∗ , Francisco R. Martínez-Ricarte a,b , Mireia Portabella c , Ramon Torné a,b , Maria L. Fuertes c , Pilar González-Tartiere b , Juan Sahuquillo a,b a
Department of Neurosurgery, Vall d’Hebron University Hospital and Vall d’Hebron Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain Neurosurgery and Neurotraumatology Research Unit, Vall d’Hebron University Hospital and Vall d’Hebron Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain c Emergency Trauma Department, Vall d’Hebron University Hospital and Vall d’Hebron Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain b
a r t i c l e
i n f o
Article history: Received 14 April 2013 Received in revised form 30 July 2013 Accepted 1 September 2013 Available online 7 September 2013 Keywords: Head circumference Macrocephaly Microcephaly Spanish people Reference interval
a b s t r a c t Introduction: In children, deviations from the normal range of head circumference (HC) have traditionally been related with CSF dynamics abnormalities. In adults, this neglected parameter is helpful in the diagnosis and understanding of the pathophysiology of some CSF abnormalities. It has been demonstrated that HC is related to height. Because humans have increased in stature dramatically during the last 50 years, pediatric charts for head growth physiology and normal HC values in adults should be reevaluated. Objectives: The main aim of the present study was to assess HC in a series of 270 normal healthy Spanish adults and to determine any differences between sexes and age groups. A secondary aim was to discuss the relevance of this parameter in the management of hydrocephalus in adult people. Methods: HC measurements were taken using a measuring tape placed over the greatest frontal and occipital protuberances. The reference interval and the upper and lower thresholds for HC were calculated by 3 different methods: normal distribution, the non-parametrical percentile method, and the “robust method”. Results: The results were consistent and showed that Spanish adult men with a HC greater than 60 cm, and Spanish adult women with a HC greater than 58 cm should be considered macrocephalic. Microcephaly should be considered when HC is 53.6 cm in men and 51.3 cm in women. Adult age groups of either sex do not present any statistically significant differences in HC. Conclusions: HC obtained in Spanish adult people are greater than those reported in the classical Nellhaus graphs in both men and women aged 18. These findings should be considered in the management of hydrocephalus in adults today. © 2013 Elsevier B.V. All rights reserved.
1. Introduction The measurement of head circumference (HC) is an easy, non-invasive, and inexpensive way to screen for developmental, neurological, and genetic disorders. It is included routinely in the physical examination of infants and children. In infants, rapid increases in head size suggest the presence of hydrocephalus, while microcephaly can be associated with structural brain abnormalities or genetic syndromes [1–3]. In adults, the diagnosis of hydrocephalus associated with macrocephaly suggests that the cause of this process occurred before the complete closure of sutures and
∗ Corresponding author at: Department of Neurosurgery, Vall d’Hebron University Hospital, Passeig Vall d’Hebron 119-129, 08035 Barcelona, Spain. Tel.: +34 3 489 35 14; fax: +34 3 489 35 13. E-mail addresses: [email protected], [email protected] (M.A. Poca). 0303-8467/$ – see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.clineuro.2013.09.001
fontanels [4–9], while microcephaly may be a pathogenic mechanism in pathologies such as idiopathic intracranial hypertension [10]. In the literature there are many articles on the physiology of head growth. However, the pivotal paper of Nellhaus in 1968 [11] continues to be the main reference used in Spain today. This author pooled results and variances from 14 reports on HC published in the literature up to 1948, and drew the classical graphs of mean increments in HC from birth to 18 years (mean ± SD in cm and inches) for both sexes. The graphs show how the two-thirds of total head growth from full-term birth to adulthood normally take place during the first 24 months of life and that in all ages the HC of boys is approximately 0.9 cm larger than that of girls [11]. At 18 years, 98% of head growth has occurred. Nellhaus also stressed that there were no significant racial, national, or geographic differences in HC [11]. The Nellhaus graphs, however, may be inappropriate for use today. Humans have increased in stature dramatically during the
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last 50 years [12] and several authors have demonstrated that HC is related to height [13,14]. In 1992, Bushby et al. collected data on HC, height, and age in 159 British adult men and 195 women aged between 17 and 83 years. The results of these authors showed that the mean HC of a subject of average height (170 cm for men and 165 cm for women) is above the 98th percentile at age 18 on the Nellhaus graphs [14]. Additionally, Japanese studies have demonstrated that the standards for HC differ from country to country and from generation to generation [15]. These findings support the idea that old pediatric charts and HC values considered normal for adults must be reevaluated. The main aim of the present study was to assess HC in a series of normal healthy Spanish adults and to determine whether differences between sexes and age groups are present. A secondary aim was to discuss the relevance of this parameter in the management of hydrocephalus in adult people. 2. Materials and methods 2.1. Patient selection. Inclusion and exclusion criteria Maximal HC assessment was carried out on a prospective cohort of 307 patients who were consecutively evaluated due to a mild traumatic brain injury (mTBI) in the emergency room of the Trauma Hospital at Vall d’Hebron University Hospital in Barcelona, Spain, from July 2004 to December 2011. To minimize heterogeneity and ethnic influences that may affect morphometric parameters such as height and thus HC, only Spaniards whose family had no known history of immigration to Spain were included in this study to obtain a sample that was geographically representative of the country. Additional inclusion criteria were as follows: (1) age equal or greater than 17 years, (2) mTBI with no loss of consciousness, (3) normal neurological examination results and Glasgow coma scale score of 15, (4) normal CT scans, (5) subjects who were born fullterm with normal neurodevelopment, (6) no previous history of neurological or psychiatric pathology, (7) no previous history of TBI, (8) no previous history of alcoholism or drug addiction, and (9) willingness to participate in the study. Patients with cranial contusion that might have hampered HC measurements and those who did not meet the inclusion criteria were excluded. Informed consent for all aspects of the study was obtained from each patient. 2.2. Computed tomography scan studies Brain computed tomography (CT) was performed in all patients using a helicoidal CT scan (Philips Mx8000; FOV de 300 mm; 120 kV and 300 mAS) following the methodology proposed by the European Brain Injury Consortium: 3-mm slices, parallel to the canto-meatal line, from the skull base to the vertex, with a cutting distance of 5 mm in the posterior fossa and 10 mm in the supratentorial compartment. 2.3. Head circumference assessment All HC measurements were taken by the neurosurgeon evaluating the patient or by the nurse in charge of the neurotraumatology unit using the methodology described by Nellhaus in 1968 [11]. A measuring tape is placed over the greatest frontal (usually in the glabela, or supraorbital protuberance) and occipital (inion) protuberances (Fig. 1). 2.4. Intraobserver and interobserver reliability Interobserver agreement and intraexaminer reliability of HC measurements were tested by 2 of the authors (MAP and FRMR) using two-way mixed intraclass correlation coefficients (ICC) with a 95% confidence interval (CI) on repeated measurements. The
Fig. 1. Occipitofrontal head circumference measurement in an adult woman. Note that the tape is placed in the most prominent frontal and occipital protuberances.
measurements were taken in 56 subjects using a strip of white, laminated, unmarked paper. This method has been shown to be superior to the use of measuring tapes in performing this kind of reliability study [16]. High intrarater agreement (rater 1: ICC = 0.99; rater 2: ICC = 0.96) and interobserver agreement (ICC = 0.98, 95% CI 0.97–0.99) were found. 2.5. Statistical analysis All descriptive statistics were analyzed and summarized using the SigmaPlot package for Windows (Version 11.0, Systat Software, Inc., Germany). The assumption that data were normally distributed was tested using the Shapiro–Wilk test. In normally distributed data, the mean ± standard deviation (SD) was used to summarize the variables. In skewed samples, the median and the interquartile range (IQR) were used. To calculate the reference interval and the upper threshold for HC we also used the following 2 additional distribution-free methods: (1) the non-parametrical percentile method (percentiles: 2.5 and 97.5), and (2) the “robust method” described in the National Committee on Clinical Laboratory Standards (NCCLS) and Clinical and Laboratory Standards Institute (CLSI) guidelines C28-A2 and C28-A3 for estimating percentiles and their 90% confidence intervals (CI). In these guidelines, percentiles are calculated as the observations corresponding to rank r = p*(n + 1). In addition, the CLSI guidelines [17] were followed for the 90% CI of the reference limits and conservative CI were calculated using integer ranks. In both methods, we used MedCalc version 12.2 (MedCalc Software, Mariakerke, Belgium) to calculate reference intervals. Differences between 2 independent samples were analyzed using the Mann–Whitney Rank Sum Test. The Kruskal–Wallis oneway analysis of variance on ranks test was used to compare HC in patients with different ages. Statistical significance was considered when p ≤ 0.05. Data were presented graphically using box-andwhisker plots. 3. Results Of the 307 patients assessed, 37 were not included in the study due to nationality other than Spanish (n = 14), age below 17 years (n = 5), incorrectly taken measurements (n = 6), and data loss (n = 12). The final sample included 270 subjects, 129 men (mean age 40.8 ± 19.2 years, median 34, IQR of 31 [24–55], minimum 17, maximum 89) and 141 women (mean age 48.9 ± 23.8 years, median 46, IQR of 45.3 [27–72.3], minimum 17, maximum 100).
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Fig. 2. Histograms of head circumference measurements in men (top) and women (bottom).
The mean HC of the complete sample (n = 270) was 56 ± 2 cm (CI of mean: 0.234); the median was 56 cm with an IQR of 2 cm (55–57). Minimum and maximum values were 51 cm and 60.5 cm respectively. In men, the mean HC was 57.07 ± 1.6 cm (CI of mean: 0.286), with a median value of 57 cm, an IQR of 2 cm (56–58) and minimum and maximum values of 53 cm and 60.5 cm, respectively. For women, the mean HC was 55.02 ± 1.7 cm (CI of mean: 0.282), with a median value of 55 cm, an IQR of 2 cm (54–56) and minimum and maximum values of 51 cm and 59 cm respectively (Figs. 2 and 3). The double-sided 95% reference interval for upper thresholds for men and women, using a method based on normal distribution, were 60.28 cm (90% CI: 59.87–60.69) and 58.34 cm (90% CI: 57.94–58.75), respectively. The upper thresholds for men and women using the non-parametrical percentile method (percentile 97.5) were 60 cm (90% CI: 60–60.50) and 58 cm (90% CI: 58–59), respectively. Differences between males and females were statistically significant (U = 3567.0, p < 0.001). When the robust method described in the CLSI guidelines was used, upper thresholds for men and women were 60.36 cm (90% CI: 59.95–60.77) and 58.52 cm (90% CI: 58.14–58.96) respectively. The 3 methods were consistent in identifying an upper threshold of 60 cm for men and 58 cm for women (Table 1). Lower thresholds for men and women using the 3 methods are summarized in Table 1. The 3 methods were consistent in identifying a lower threshold of 53.6 cm for men and 51.3 cm for women (Table 1).
When patients were distributed by age, no differences were found in HC between patient groups (17–30, 31–40, 41–60, 61–80, and 80–100 years) in either men (H = 5.720, p = 0.221) or women (H = 1.437, p = 0.838) (Figs. 4 and 5).
Fig. 3. Box-plot graph showing additional statistical data of head circumference in men and women. Values are significantly different between groups (U = 3567.0, p < 0.001).
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Table 1 Upper and lower threshold limits for head circumference in Spanish adult people. Method used
Normal distribution (mean ± 2SD) Non-parametrical percentile method (2.5 and 97.5 percentiles) Robust method as described in the CLSI guidelines
Upper threshold
Lower threshold
Men
Women
Men
Women
60.28 cmCI: 59.87–60.69 60 cm CI: 60.00–60.50
58.34 cmCI: 57.94–58.75 58 cm CI: 58.00–59.00
53.85 cmCI: 53.44–54.27 53.63 cmCI: 53.00–54.00
51.70 cmCI: 51.29–52.11 51.28 cmCI: 51.00–52.00
60.36 cmCI: 59.95–60.77
58.52 cmCI: 58.14–58.96
53.83 cmCI: 53.43–54.22
51.79 cmCI: 51.35–52.26
SD: standard deviation; CI: 90% confidence interval; CLSI: Clinical and Laboratory Standards Institute.
relevant medical history, or abnormalities in neuroimaging studies. To avoid possible differences due to the inclusion of subjects from other countries or ethnic groups, the nutritional or developmental aspects of which may affect height and therefore HC, among other factors, our study was limited to Caucasian patients of Spanish origin who reported no known history of immigration to Spain. The results obtained are therefore relevant to this particular group only and cannot be generalized to other groups. A further important aspect of our study is that the results obtained were consistent when analyzed independently with 3 different statistical methods. Our findings are very similar to those reported by Bushby et al. [14] in British adults in 1992. These results suggest that the contemporary human head circumference is larger than that of people born during the first half of the 20th century, at least in adults. Our data, however, did not show an overall increase in HC for younger patients. In the present series Spanish men were shown to have larger heads than Spanish women, but in both cases there were no statistically significant differences in HC between age groups, A future study including height, body mass index, and HC measurements may be able to clarify this point. Fig. 4. Head circumference (HC) in men distributed by age. There are no statistically significant differences between groups (H = 5.720, p = 0.221).
4.1. Cranial development and normal head circumference in adults 4. Discussion Head circumference in Spanish adults has been observed to be greater than our estimations based on the classical Nellhaus values in both men and women. It is particularly relevant that we assessed only normal healthy adults with no neurological symptoms,
Fig. 5. Head circumference (HC) in women distributed by age. There are no statistically significant differences between groups (H = 1.437, p = 0.838).
Human craniofacial morphology is very complex, being controlled by genetic, environmental, mechanical, and epigenetic factors. Measurement of the maximal occipito-frontal HC provides a simple and reproducible measurement of head size that correlates closely with brain volume [18,19]. The most dramatic increase in brain volume occurs in the last 3 months of fetal life and during the first 2 years after birth. Concomitantly, the skull follows the volumetric increase in the cerebral hemispheres, mostly by passive adaptation. Cranial development is also influenced by molecular mechanisms related mainly with the dura mater and sutures [20]. HC increases by 33% between the ages of 2 and 18 years, with the greatest growth (19%) occurring between 2 and 8 years of age. At the age of 18, development of the calvaria is nearly complete [11]. Less than 2% of all HC growth occurs after the age of 18, and this consists largely of an increase in skull and scalp thickness [21–23]. Macrocephaly and microcephaly are defined by HC measurements 2 standard deviations above or below the mean in any age group. Apart from the influences of brain development and molecular mechanisms related with the dura mater, periosteum, and sutures, the final head size depends on sex, nutrition, and other body parameters such as height, among others [2]. Although Nellhaus stressed that there were no significant racial, national, or geographic differences in HC [11], posterior studies have put in doubt this idea [15,24]. Ishikawa et al. [15] demonstrated that the heads of Japanese people were smaller up to the age of 10 years and larger beyond that age when compared to those in the Nellhaus composite graphs. The
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heads of children of both sexes in the Japanese study were smaller than those of children born in the United Kingdom in the same period, but they were considerably larger than those of children born in Japan more than 50 years ago [15]. At present, a systematic review including studies published from January 1990 up to the present time is being conducted to compare mean head sizes for different nations and ethnic groups with international mean values reported by the World Health Organization to elucidate if HC varies between different nations or ethnic groups around the world [24]. In the Nellhaus graphs using data extracted from studies published between 1933 and 1965, the 98th and the 2nd percentiles for HC for a man aged 18 years are 58.6 cm and 53.3 cm respectively, and for a woman aged 18 years 57.7 cm and 52.1 cm, respectively [11]. Currently, in Spanish adults, these values have been calculated to be 60 cm (90% CI: 60–60.5) and 53.63 cm (90% CI: 53.00 to 54.00) in men, and 58 cm (90% CI: 58–59) and 51.28 cm (90% CI: 51.00 to 52.00) in women. When comparing our results with those of Nellhaus, there are greater discrepancies in men than in women. 4.2. Indications of assessing head circumference. Clinical applicability Measurement of occipito-frontal HC is an integral part of most pediatric and many other medical examinations. It is often of particular importance in making a diagnosis in dysmorphic children with developmental delay, possibly associated with microcephaly or macrocephaly. Many of these conditions are inherited and therefore accurate assessment and counseling of relatives should include measurement of HC in the child and his or her parents and siblings. The assessment of HC in parents is especially important in the investigation of cases in which abnormal HC is the only finding, given that in up to 50% of cases, variations of normality in head size is familial [25]. HC assessment is also important in adults with certain neurological pathologies. Hydrocephalus associated with severe ventriculomegaly and macrocephaly may be caused in the early stages of life, although symptoms may occur during adulthood [6–9]. The presentation of this syndrome may be very similar to “normal pressure” hydrocephalus (Hakim and Adams syndrome), however, the prognosis may be worse [5], with less improvement and a greater rate of complications. At the same time, some studies suggest that 1 of the pathogenic mechanisms of pseudotumor cerebri – also known as benign intracranial hypertension or idiopathic intracranial hypertension (IIH) may be a smaller cranial size. This theory has been used to justify the use of alternative surgical techniques aimed at producing an expansion of the internal cranial space [10]. This technique may be used as part of the multidisciplinary management approach in the treatment of refractory IIH. 4.3. Study limitations The most relevant limitation of the present study is that HC was measured without other body measurements, such as weight, height, and body mass index. A second limitation is that although all patients were assessed in the same center, measurements were taken by different individuals. However, the reliability of HC measurements has been studied by our group and other authors, and a high concordance in both intra- and inter-examiner measurements was confirmed. Johnson et al. [26] studied the intra- and inter-examiner reliability of anthropometric measurements in 50 full-term infants showing that 98–100% of the observed differences in HC were less than 1 cm. Very similar results were found in our study, which used white, laminated, unmarked paper strips.
5. Conclusions According to our data, Spanish adult men with HCs greater than 60 cm, and Spanish adult women with HCs greater than 58 cm should be considered macrocephalic. These values are greater than those reported in the classical Nellhaus graphs in both men and women aged 18. In these same groups, microcephaly should be considered when HC is less than 53.6 cm and 51.3 cm, respectively. In adulthood (>17 years), the HC of Spanish individuals remains constant. These findings should be considered in the management of hydrocephalus in adults today. Conflict of interest The authors declare that they have no conflict of interest. Acknowledgments The authors gratefully acknowledge Sabrina Voss for editorial ˜ (M.D.), R. Lastra (M.D.), assistance and the collaboration of J.D. Anez and O. Mestres (R.N.) in collecting data from some patients. This study was supported in part by Grant 07/0681 from the Fondo de Investigación Sanitaria (FIS) given to Dr. M.A. Poca. References [1] Cowie VA. Microcephaly: a review of genetic implications in its causation. J Ment Defic Res 1987;31:229–33. [2] Ivanovic DM, Leiva BP, Perez HT, Olivares MG, Diaz NS, Urrutia MS, et al. Head size and intelligence, learning, nutritional status and brain development. Head, IQ, learning, nutrition and brain. Neuropsychologia 2004;42:1118–31. [3] Coronado R, Giraldo J, Macaya A, Roig M. Head circumference growth function as a marker of neurological impairment in a cohort of microcephalic infants and children. Neuropediatrics 2012;43:271–4. [4] Sahuquillo J, Poca MA, Chasampi A, Molins A, Rovira A, Gabas E, et al. Adult chronic hydrocephalus (normal pressure hydrocephalus) and macrocephaly. Neurocirugia 1991;2:344–53. [5] Oi S, Shimoda M, Shibata M, Honda Y, Togo K, Shinoda M, et al. Pathophysiology of long-standing overt ventriculomegaly in adults. J Neurosurg 2000;92:933–40. [6] Fukuhara T, Luciano MG. Clinical features of late-onset idiopathic aqueductal stenosis. Surg Neurol 2001;55:132–6. [7] Wilson RK, Williams MA. Evidence that congenital hydrocephalus is a precursor to idiopathic normal pressure hydrocephalus in only a subset of patients. J Neurol Neurosurg Psychiatry 2007;78:508–11. [8] Krefft TA, Graff-Radford NR, Lucas JA, Mortimer JA. Normal pressure hydrocephalus and large head size. Alzheimer Dis Assoc Disord 2004;18:35–7. [9] Cowan JA, McGirt MJ, Woodworth G, Rigamonti D, Williams MA. The syndrome of hydrocephalus in young and middle-aged adults (SHYMA). Neurol Res 2005;27:540–7. [10] Ellis JA, Anderson RC, O’Hanlon J, Goodman RR, Feldstein NA, Ghatan S. Internal cranial expansion surgery for the treatment of refractory idiopathic intracranial hypertension. J Neurosurg Pediatr 2012;10:14–20. [11] Nellhaus G. Head circumference from birth to eighteen years. Practical composite international and interracial graphs. Pediatrics 1968;41:106–14. [12] Ogden CL, Fryar CD, Carroll MD, Flegal KM. Mean body weight, height, and body mass index, United States 1960–2002. Advance data from vital and health statistics. Maryland: National Center for Health Statistics; 2004. [13] Bale SJ, Amos CI, Parry DM, Bale AE. Relationship between head circumference and height in normal adults and in the nevoid basal cell carcinoma syndrome and neurofibromatosis type I. Am J Med Genet 1991;40:206–10. [14] Bushby KM, Cole T, Matthews JN, Goodship JA. Centiles for adult head circumference. Arch Dis Child 1992;67:1286–7. [15] Ishikawa T, Furuyama M, Ishikawa M, Ogawa J, Wada Y. Growth in head circumference from birth to fifteen years of age in Japan. Acta Paediatr Scand 1987;76:824–8. [16] Sutter K, Engstrom JL, Johnson TS, Kavanaugh K, Ifft DL. Reliability of head circumference measurements in preterm infants. Pediatr Nurs 1997;23:485–90. [17] Clinical Laboratory Standards Institute. Defining, establishing, and verifying reference intervals in the clinical laboratory: approved guideline. CLSI document C28-A3. 3rd ed. Wayne, PA: Clinical Laboratory Standards Institute; 2008. [18] Bray PF, Shields WD, Wolcott GJ, Madsen JA. Occipitofrontal head circumference: an accurate measure of intracranial volume. J Pediatr 1969;75:303–5. [19] Bartholomeusz HH, Courchesne E, Karns CM. Relationship between head circumference and brain volume in healthy normal toddlers, children, and adults. Neuropediatrics 2002;33:239–41.
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