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Five Is the Maximum Sample Size for Case Reports: Statistical Justification,
Epidemiologic Rationale, and Clinical Importance

Article  in  World Neurosurgery · May 2014

DOI: 10.1016/j.wneu.2014.05.014 · Source: PubMed

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diaphragma sellae through the opened sellar floor occurs
intraoperatively.
Nikolaos Gkekas, Panagiotis Primikiris, Nikolaos Georgakoulias
Department of Neurosurgery, Athens General Hospital G. Gennimatas,
Athens, Greece
To whom correspondence should be addressed: Nikolaos Gkekas, M.D.
[E-mail: nikolaosgkekasdr@yahoo.gr, nikosgkekasdr@hotmail.com]
Published online 13 May, 2014; http://dx.doi.org/10.1016/j.wneu.2014.07.001.
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51:1365-1372, 2002.
2. Couldwell WT, Kan P, Weiss MH: Simple closure following transphenoidal sur-
gery. Technical note. Neurosurg Focus 20:E11, 2006.
3. Mehta GU, Oldfield EH: Prevention of intraoperative cerebrospinal fluid leaks by
lumbar cerebrospinal fluid drainage during surgery for pituitary macroadenomas.
Clinical article. J Neurosurg 116:1299-1303, 2012.
4. Sade B, Mohr G, Frenkiel S: Management of intra-operative cerebrospinal fluid leak in
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5. Shiley SG, Limonadi F, Delashaw JB, Barnwell SL, Andersen PE, Hwang PH,
Wax MK: Incidence, etiology, and management of cerebrospinal fluid leaks
following trans-sphenoidal surgery. Laryngoscope 113:1283-1288, 2003.
Five Is the Maximum Sample Size for Case Reports: Statistical
Justification, Epidemiologic Rationale, and Clinical Importance
LETTER:
A tshifting
a time when scientific journals and research committees are
away from the case report and case series given their
low standing in the evidence-based ladder, these forms of research
remain ubiquitous in neurosurgical research. Perusing through
most neurosurgical journals, it takes no time for one to realize that
a bulk of the articles are case reports. Properly described case
reports can make a valuable contribution to medical research and
education (12). However, the label “case report” is sometimes
used inconsistently in regard to the sample size. In the most
simplified form, a case report is the smallest publishable unit in
the medical literature, whereas a case series is an aggregation of
several similar cases.
Although studies with one subject are usually reported as case
reports, some literature report studies with 11 (24) or 13 (27) pa-
tients as case reports. For example, an article titled “Pearl in
interhemispheric fissure: A rare phenomenon” presented 8 cases
of interhemispheric epidermoid cysts as a case report (3). Also,
some reviewers accept 3 cases to be a case series (14), whereas
others recommend at least 5 cases (1, 25). Some reviewers have
accepted a single case as a case series (2). A review of the literature
reveals that no clear-cut definitions exist for these types of studies
WORLD NEUROSURGERY 82 [5]: e657ee669, NOVEMBER 2014
CORRESPONDENCE
(1) with >30% of the articles with “case series” in their title having
<5 cases and >50% of “case series” labeled as a “case report”
having <5 cases (1).
This inconsistency in labeling causes an overlap between case
reports with case series and descriptive cohorts and impairs the
appropriate indexing and sorting of evidence. Nevertheless, the
number of patients per se does not indicate the required research
design for clinical trials have been performed even in a single
patient serving as a self control. Using this approach, rando-
mized controlled trials in a single patient (N of 1 clinical trial) were
used to define the best treatment for that patient (13). However,
the sample size is an important attribute and a distinguishing
factor of the case report design from case series and descriptive
cohorts.
Much has been written about what type of case is worthy of
reporting and publishing and the format or components of case
reports (9, 20), but the issue of sample size still has not been
adequately addressed. In the light of this lack, we reviewed the
literature to define this problem further to attempt to create a
comprehensive definition and compare and contrast case reports
and case series. In providing a statistical proof and an epidemi-
ologic justification for the maximum sample size to demarcate
true case reports from other study designs, it is our hope that we
will make these concepts clearer and guide the design of further
case reports and case series in neurosurgery in particular and
clinical medicine in general.
HYPOTHETICAL ILLUSTRATIVE CASE SCENARIO
What study designs best describe the following case scenario?
Dr. JJ has just designed a new technique for operating on suprasellar
meningiomas and wants to test the effectiveness of this new tech-
nique in terms of tumor resection, complications, and recurrence
rate. He applies this technique on 100 consecutive patients operated
upon in his hospital from 1995e2005 and follows these patients for
10 years. During the follow-up period, Dr. JJ notices a group of
3 patients with early tumor recurrence at 5 months of follow-up and 4
others at 1 year. A review of their pathologic report showed these
patients were subtype “Y” of aggressive meningiomas scantily
reported in literature.

Study design: case report (if reporting at 5 months follow-up;
sample size ¼ 3 cases)

Study design: case series (if reporting at 1 year follow-up;
sample size ¼ 7 cases)

Study design: descriptive cohort (if an investigator other than
Dr. JJ follows 100 patients to assess outcome)

Study design: uncontrolled intervention study (if Dr. JJ himself
follows 100 patients to assess outcome. Dr JJ is the “Allocator”
of the exposure (New Surgical Technique) as well as being the
“investigator.” No comparison groups are present for the
descriptive cohort study and uncontrolled intervention.)
www.WORLDNEUROSURGERY.org e659
CORRESPONDENCE
METHOD
Identification of Studies
We used PubMed to identify systematically articles that featured
“case report(s)” in the title that were published in 13 “pure
neurosurgical” journals with high impact factor (according to 2012
classification) (18) plus the Journal of Medical Case Reports. These
were selected because they are neurosurgical journals with a broad
readership, and their content and article types reflect material
commonly encountered in the neurosurgical literature. Journal of
Medical Case Reports is an open access online journal dedicated to
the publication of high-quality case reports and was included to
enable comparison with the neurosurgical journals. The search
strategy specified the journal name and required the words “case
report” and “case reports” in the title (2 separate searches). The
search included published articles from January 1, 2008, to
December 31, 2012, a period of 5 years.
Assessment of Studies
We reviewed the abstract of each article and the full text of ar-
ticles when there was an ambiguity in method from the abstract.
Titles and abstracts of the articles brought forth by this search
strategy were scanned to identify articles with descriptions of the
principal method as being “case report” or “case reports.” Only
articles with “case report(s)” in the title were included. “Mixed
journals” (neurosurgery þ neurology) were excluded. We calcu-
lated the proportion of articles labeled as “case reports” in the
title and noted the sample size of each article. Data were
analyzed using Stata 10.1 statistical software (StataCorp, College
Station, TX).
RESULTS
For the neurosurgical journals, most of the articles (817; 97.3%)
published as case reports had a sample size of 1 subject; 2 articles
had sample sizes of 11 and 13 (Table 1). For the Journal of Medical
Case Reports, 2031 articles (97.2%) had a sample size of 1 subject in
studies published as “case report,” whereas 56 articles (2.7%) had
a sample size of 2 (Table 2).
Sample Size Overlap
In a similar search using the MeSH term “case series” (Table 3),
for the 13 pure neurosurgical journals, 27 articles (54%) had a
Table 1. Number of Study Participants per Article Reported as
a Case Report (Neurosurgical Journals)
Number of Articles
Sample Size (Number of Subjects/Article) (N [ 840)
1 817 (97.26%)
2 16 (1.9%)
3 5 (0.6%)
11 1 (0.12%)
13 1 (0.12%)
e660 www.SCIENCEDIRECT.com
Table 2. Number of Individuals per Article Reported as a Case
Report (Journal of Medical Case Reports)
Number of Articles
Sample Size (Number of Subjects/Article) (N [ 2090)
1 2031 (97.2%)
2 56 (2.7%)
3 3 (1%)
sample size >10, whereas the sample size was <5 individuals per
article in 8 articles (16%). For the Journal of Medical Case Reports, 70
articles (78.7%) had a sample size of <5.
DISCUSSION
What Is a Case Report?
The case report has been defined as the most basic descriptive
study of individuals and is the smallest publishable unit in the
medical literature. It consists of a detailed report by 1 or more
medical professionals of the profile of a single patient or event (11,
14). Sample size is important in distinguishing case reports from
case series and descriptive cohorts. Our review showed that 16% of
articles published as case series had a sample size of <5 study
participants per article, whereas 2.7% of case reports had a sample
size >5. An overlap thus exists.
The current literature does not reveal any statistically justified and
universally agreed-on maximum sample size for case reports or a
minimum for case series. The following statistical argument on
the basis of standard error (SE) and confidence interval (CI) jus-
tifies a cutoff of 5 subjects as sample size maximum because below
this cutoff, summary statistics are characterized by a large SE,
wide CI, and less precision of effect size and statistically nonsig-
nificant probability values.
Statistical and Study Design Considerations
Two common types of statistical inferences in use are the CI (used
to estimate the population parameter, e.g., mean [m]) and test
Table 3. Number of Study Participants per Article Labeled as a
Case Series (Neurosurgical Journals)
Number of Study Subjects Frequency (Number
Per Article of Articles) Percentage
<5 8 16
4 3 6
3 3 6
2 2 4
5e10 15 30
>10 27 54
82 [5]: e657ee669, NOVEMBER 2014 WORLD NEUROSURGERY

Figure 1. Relationship between confidence level and sample size.
of significance (used to assess whether a hypothesis made about
a population parameter is true or not). When a study is con-
ducted, the sample data give us the “point estimate” whose pre-
cision is the “CI” (6, 7). The most commonly used CI in scientific
literature is the “95% CI” (read as the 95% confidence interval),
which means 95% of all possible samples will have a mean (x) or
effect size lying between 2 SDs from the point estimate. It means
there is a 95% chance that these limits will capture the true
population mean (m)—we are 95% confident that the right (true)
population means lies within these limits. However, this also
means there is a 5% chance of not having the mean within this
interval.
The margin of error indicates how accurate the estimate
or how close the CI pins down the true value of the param-
eter. Because the population SD (s) is constant, the SE
depends on and varies inversely with the sample size (n). A
large sample size implies a small SE, a small margin of
error, and high confidence (narrow confidence interval)
(Figure 1) (6, 7, 14).
Sample Size Justification for Case Reports. Consider a hypo-
thetical sample of 10 patients with a normal distribution of
cholesterol with SD ¼ 10 mg/dL. An iterative calculation of the
SE for an increasing sample size from 1e10 using the formula
SE ¼ SD/On gives results as in Figure 2.
WORLD NEUROSURGERY 82 [5]: e657ee669, NOVEMBER 2014
CORRESPONDENCE
The variance of the data, difference between the means, pro-
portions, and power of a study decide the sample size (n) needed for
a study. Finding a difference between 2 groups depends on the
standard error of the mean (SEM) of each of these groups. A risk
estimation based on only 5 patients is accompanied by a wide CI
and much uncertainty, and the generalizability of such a small
sample is questionable.
If data of a group of subjects are to be summarized statistically, a
minimum number of subjects is needed for it to be valid. The
SEM, which is used for comparisons, would be much larger for
a number of subjects 5 (Figure 2). The SEM equals the SD
(a marker of variation in the data) divided by the square root of the
sample size (Figure 1) (6, 7). A large SE implies a wide CI (less
precision of effect size) and statistically nonsignificant P values. It
is reasonable to set a cutoff of 5 for a case report and individual
cases reported separately. Above this cutoff of 5, the data can be
pooled and summarized.
Abu-Zidan et al. (1) suggested based on their “experience” that 5 is
the minimum reasonable number of independent subjects in a
group so as to combine data. Our statistical proof points to a
minimum of 6, not 5. Although some case series have been
published with 1, 2, and 3 cases (2, 14), Patterson et al. (21)
suggested that 5 cases should be the “lowest advised” number of a
case series. Nevertheless, although the number of patients is an
important criterion in defining case reports, the definition of other
www.WORLDNEUROSURGERY.org e661
CORRESPONDENCE
Figure 2. Statistical proof of sample size for case reports. [In consonance with the Transitive Law in mathematical logic
viz.: c a,b,c ˛ X: (aRb ^ bRc) / aRc]
research designs requires criteria beyond sample size, such as
sample selection criteria, directionality in which exposure and
outcome are investigated, and the timing of the study proper with
respect to the calendar times of exposure and outcome (15).
Tip of the Iceberg of Case Reports in Neurosurgical Literature
Table 4 illustrates the difficulties encountered in neurosurgical
literature in defining case reports. The case series in its simplest
form may be considered as a collection of individual case reports,
and the definition of the sample size is often left at the discretion
of journal editors. We have proven that a sample size of 5 should
be the cutoff, so the correct study types in Table 4 should be as
listed in column 3.
Although some authors still present “case reports” as “case series”
as is shown in Table 4 some literatures have set a cutoff to
differentiate between the 2 designs. Some authors accept 3 cases
to be a case series (14), whereas others recommend at least 5 cases
(1, 25). No maximum number of subjects is defined for case series,
although some literatures suggest 10 cases (4, 5, 10, 23). We
disagree with this concept because this does not make sense from
an epidemiologic perspective. A case series is not defined by its
e662 www.SCIENCEDIRECT.com
sample size, but rather its method of sampling, in contrast to a
case report.
In this regard, a case report is the smallest publishable unit in
the medical literature, whereas a case series is an aggregation of
several similar cases. A detailed guideline for preparing a case
report by DeBakey and DeBakey (9) expanded on a 5-section
format: introduction, description of the case, discussion, litera-
ture review, and summary/conclusions. Aside from their differ-
ences in number, the style of reporting each of these types is
also different (1). The importance in distinguishing between a
case series and a case report can be seen in a study such as that
by Aerts et al. (2) where a single case was presented as a case
series. In the evidence-based pyramid, case reports are level 5,
whereas case series are level 4. A systematic review or meta-
analysis of case reports can provide much more precise infor-
mation because detailed data of the cases are available, whereas
data about case series are usually presented already pooled or
summarized.
According to the latest version of the Dictionary of Epidemiology, a
case series is defined as “a collection of patients with common
82 [5]: e657ee669, NOVEMBER 2014 WORLD NEUROSURGERY
 CORRESPONDENCE

Table 4. Illustrative Examples of the Definition of Case Reports in Literature

Design Description and Methodologic
Study Title Explanation (From the Articles) Correct Study Type

A1—Atypical tumors of the facial
nerve: case series and review of the
literature (26)
A2—Cervical nerve injection:
computed tomography guidance with
IV contrast and extraforaminal needle
placement. Series of 7 consecutive
case reports (8)
B—Congenital brain tumors in a series
of seven patients (17)
“. A retrospective chart review was conducted for Case report
patients with tumors of the facial nerve that were
treated between 2008 and 2011. The authors present
a series of 4 patients with rare facial nerve tumors
..”
“The purpose of this study is to introduce a technique Case series
for cervical nerve injection that may decrease the
possibility for severe complications. This is a series
of case reports describing the technique and clinical
follow-up..”
“Congenital brain tumors are very rare. We review Case series
these tumors in patients younger than 2 months ..
Seven congenital brain tumors were diagnosed
during 5 years ..”

characteristics used to describe some clinical, pathophysiolog-
ical or operational aspects of a disease, treatment or diagnostic
procedures,” whereas a case report is a “detailed description of
a few patients or clinical cases with an unusual disease or
complication, uncommon combinations of diseases, and un-
usual or misleading semiology, cause or outcome” (22). The
PubMed MeSH database defines a case report as a clinical
presentation that may be followed by evaluative studies that
eventually lead to a diagnosis (16).
A case (from the Latin casus) can best be understood as a
happening, an event, or an occurrence. Some authors consider
the patient or person as the case. Strictly speaking, the disease
or the clinical phenomenon in question is the case (19). Case
reports usually contain pertinent, detailed but concise infor-
mation about the individual patients, including demographic
information and information on diagnosis, treatment, response
to treatment, and follow-up after treatment. In such studies,
there is an implicit comparison with what is usual or ordinary
in clinical practice (14).
For surgeons, the basic types of case reports stress on 1 or more
of 5 topics, as follows: 1) the unexpected, including a new asso-
ciation between a disease and symptoms, between previously
unrelated symptoms or findings, or involving a new disease or
syndrome; 2) a surprising event in the course of diagnosis or
treatment of a patient that may have wider implications; 3) events
that raise questions about the possible causes or of the typical
course of treatment of a disease or condition, particularly if there
is an increase or decrease in the occurrence of an adverse effect
resulting from a surgical procedure; 4) unique or rare features of a
disease that affected the surgical diagnosis or treatment; and 5)
exceptional or creative extensions or approaches to surgical
treatment (11).
A case report (also sometimes a shorter report that is published in
a journal’s “Brief Reports,” “Adverse Effects,” “How to Do It,”
“Clinical Notes,” “Letters,” or “Case Studies” section) usually
details 1 or a small set of specific and intrinsically educational
instances of the surgical treatment of a disease (20). A case
report, if prepared properly, is a valuable educational device to
describe an unusual clinical syndrome, association, reaction, or
treatment (9).
In the case scenario we presented earlier, 7 cases of the tumor
subtype were observed to recur at 1 year while the cohort of
100 patients was followed. This should be reported as a case
series of an unusual early recurrence of meningiomas (note:
most meningiomas are benign lesions that recur remotely). If
the investigator had done his assessment at 5 months, the 3
cases observed at this time should have been presented as a
case report.
If an investigator other than Dr. JJ is interested in studying the
outcome of these patients after surgery and follows them for 10
years, this is described as a descriptive cohort study. In contrast,
if Dr. JJ himself follows the 100 patients after having allocated
the exposure (his new surgical technique) to assess outcome, it
is an “uncontrolled intervention study.” Depending on sample
selection criteria, directionality in which exposure and outcome
are investigated, the timing of the study proper with respect to
the calendar times of exposure and outcome, and exposure

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CORRESPONDENCE
allocation, different study types can be described for the same
patients.
CONCLUSIONS AND RECOMMENDATIONS
The distinction between a case report and a case series should be
clear and uniform in the instructions to authors in different
journals. We strongly suggest a sample size maximum of 5 for the
reporting of case reports, and the cases should be reported indi-
vidually. Studies with a sample size >5 should have the effect size
pooled and presented as a case series if sampling is from outcome
to exposure, a cohort study if sampling is from exposure to
outcome, or the specific study type according to universally
accepted criteria. The case report is thus the basic structural and
functional unit of; and the smallest publishable unit in medical
research, consisting of one to a maximum five subjects, describing
in details; an atypical, an unusual, a unique, a rare, an unexpected
or surprising event(s); or an exceptional or creative approach to
diagnosis and treatment.
Researchers, reviewers, and end users need better training in
methods and terminology, and editors and reviewers should
scrutinize more carefully manuscripts claiming to be a “case
report.” This scrutiny would save the time of the authors and
editors and enhance the review process of medical journals as
some journals accept only a case series design but not a case
report.
ACKNOWLEDGEMENTS
I would like to express my special appreciation to my past teachers
of mathematics from primary through university for providing me
with the mental armamentarium that is serving as the foundation
for my scientific works.
I would also like to thank all of my friends especially Dr Julius
Ngu, Dr Lawrence Mbuagbaw for their critical comments during
the writing of this manuscript, as well as colleagues and teachers
who incented me to strive towards my goal. Worth mentioning
are: Prof. Filomena Valente (ESP, ULB, Belgium), the staff mem-
bers of the Department of Neurosurgery, Ain Shams University
and Nasser Institute Gamma Knife Center, Cairo, Egypt. Lastly my
sincerely thanks to His Excellency Dr. Mohamadou Labarang,
B.A., B.Sc., Ph.D (Ambassador of Cameroon to Egypt) and Pro-
fessor Madjid Samii, M.D., Ph.D. (WFNS Ambassador for Africa)
for supporting my training.
1-3 1
Ignatius Ngene Esene , Ali Kotb ,
Hossam ElHusseiny1
1
Department of Neurosurgery, Ain Shams University, Cairo, Egypt; 2Research Associate,
Gamma Knife Center, Nasser Institute, Cairo, Egypt; and 3Encyclopaedia Neurochirurgica,
Paris, France
To whom correspondence should be addressed: Ignatius Ngene Esene, M.D., M.Sc., M.P.H.
[E-mail: ignatiusesene@yahoo.co.uk, esenengene@yahoo.co.uk]
Published online 14 May, 2014; http://dx.doi.org/10.1016/j.wneu.2014.05.014.
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Hypocortisolism: An Underestimated Complication of
Subarachnoid Hemorrhage
LETTER:
W eregarding
read with great interest the article by Kronvall et al. (2)
pituitary dysfunction after aneurysmal subarach-
noid hemorrhage (SAH). The authors are to be commended for
their investigation of pituitary function during the acute phase of
SAH. The authors studied endocrine function in 51 patients at
5e10 days after SAH and at 3e6 months. The authors found an
overall prevalence of endocrine dysfunction of 37% during the
acute phase and of 27% at follow-up. The study concluded that
pituitary dysfunction may be associated with a higher risk of poor
outcome (2).
We would like to point out some methodologic concerns
regarding the prevalence of adrenal axis deficiency, which was
diagnosed in only 8% of the patients during the acute phase (2). It
is possible that the methodology of the study may have led to an
underestimation of the burden of hypocortisolism and its relative
risks. In particular, the blood sampling schedule that consisted of
a single assessment may have been a significant drawback. We
published a prospective study dealing with the prevalence of
hypocortisolism during the acute phase of SAH. Hypocortisolism
was defined according to international consensus statements:
random total cortisol of <10 mg/dL or D total serum cortisol of <9
mg/dL after 1 mg of corticotropin hormone (1, 5). We found a
prevalence of 42% in a series of noncomatose patients who un-
derwent cortisol blood sampling every day for the first 15 days after
SAH (3). In addition, we calculated the cortisol-time secretion
curve, which showed significant day-by-day variations with a peak
at day 5 and a minimum at day 8. The dynamic of secretion was
extremely variable, and the duration of hypocortisolism could be
episodic, lasting 48 hours (3). The finding that circadian cortisol
secretion is abnormal in half of patients with SAH supports our
conclusion (4). In the event of a single random sample, we would
have diagnosed hypocortisolism in only 0%e13% of our pa-
tients (3), a result that would have been in line with that of
Kronvall et al. (2).
Our suspicion of a substantial underestimation of the prevalence
of acute hypocortisolism is further strengthened by the fact that
the authors found a higher risk of hypocortisolism at follow-up
than in the acute phase and that most of the patients with
WORLD NEUROSURGERY 82 [5]: e657ee669, NOVEMBER 2014
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CORRESPONDENCE
hypocortisolism at follow-up were categorized as normal during
the acute phase. Considering that most pituitary dysfunctions are
transient, we would have expected the opposite pattern, provided
that all the cases of hypocortisolism were diagnosed during the
acute phase.
Although these methodologic observations regarding blood
sampling for cortisol assessment during the acute phase of SAH
may appear trivial or purely academic, they deserve clinical
attention in our opinion because hypocortisolism independently
increases the risk of poor outcome (3, 4), and the day-by-day
dynamic of cortisol secretion may reflect a dysfunction of the
hypothalamus and the risk of vasospasm (3). An underestimation
that affects a possible outcome determinant may significantly
impinge on the results of any multivariate analysis and the
conclusion of the study.
Luigi A. Lanterna1, Carlo Brembilla1, Paolo Gritti2
From the Departments of 1Neuroscience and Surgery of the Nervous System and
2
AnesthesiaeAnesthesia and Intensive Care IV, Papa Giovanni XXIII Hospital, Bergamo, Italy
To whom correspondence should be addressed: Luigi A Lanterna, M.D., Ph.D.
[E-mail: l.lanterna@gmail.com]
Published online 14 May, 2014; http://dx.doi.org/10.1016/j.wneu.2014.05.013.
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Hypertension and Intracranial Aneurysms: Association or
Causation?
LETTER:
T heaneurysmal
quest for a multivariate statistical model quantifying
rupture risk as a function of known variables is
ongoing. Intrinsic factors, such as size, location, and
morphology, as well as extrinsic factors, such as hypertension,
age, smoking, alcohol consumption, and ethnicity, have been
reported to affect rupture rate, with varying levels of evidence
(1, 3, 11). Among these, hypertension draws significant attention
from the medical community and continues to be studied to a
great extent in light of its high prevalence. Yet, its real impact on
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