Advance modern medicine with clinical case reports

The evidence-based health care places randomized clinical trial (RCT) at the top of the hierarchy for clinical evidence, while case reports are at the bottom (1,2). RCT is meant for the evaluation of medical interventions in which there is uncertainty about a benefit that is in itself not striking. RCT is costly and time intensive, often limit scientists and clinicians to examining a few limited variables, and can fail to demonstrate the richness of individual patient characteristics. Given the unpredictable nature of medicine, a patient may present in an unusual way, have a strange new pathology, or react to a medical intervention in a manner not seen before. The publication of these novelties as case reports is a fundamental way of conveying medical knowledge. Throughout history there have been famous case studies that shaped the way we view health and disease.

Case reports, including a single case report, two case reports, or a case series (greater than two reported cases), have a time-honored tradition. From Hippocrates (460 B.C. to 370 B.C.), and even arguably further back since the papyrus records of ancient Egyptian medicine (c. 1600 B.C.) to modern day, physicians described interesting cases involving all specialties (3). Published case reports describe important scientific observations that are missed or undetected in clinical trials, and provide individual clinical insights. A case report of Kaposi’s sarcoma in a young homosexual man is the seminal observation to the finding of acquired immune deficiency syndrome (4). In 1817 James Parkinson reported an article with the title “An essay on the shaking palsy”, which lead to the discovery of the disease carrying the author’s name (Parkinson’s disease) (5). Case reports linked the anorexic agents, fenfluramine and dexfenfluramine, with primary pulmonary hypertension and subsequently initiated trials that investigated the mechanism and incidence of this adverse effect, finally lead to their withdrawal from the market (6,7). One recent example is the publication of a case series during the outbreak of Shiga-toxin producing Escherichia coli, a type of enterohemorrhagic E. coli, in Germany in mid-2011 (8). Hemolytic-uremic syndrome is a severe condition commonly associated with Escherichia coli. It is characterized by hemolytic anemia, thrombocytopenia, acute renal failure, and is often deadly. At the start of the outbreak, a timely case series reported dramatic resolution of symptoms of Escherichia coli associated hemolytic-uremic syndrome after treatment with monoclonal antibody Eculizumab (9). This case series led to the rapid adoption of Eculizumab as a treatment option. In 1985, the American Medical Association reprinted 51 papers from the Journal of the American Medical Association that had significantly changed the science and practice of medicine during the 150 years of the organization’s existence. Five of these papers were case reports (10).

Case reports the following functions (11).

• Descriptions of new diseases: a series of cases can bring a potentially new disease to the attention of the medical public (12). The commonest variety is a further subdivision and refinement of existing entities (12). Although the AIDS virus may be over one hundred years old in central Africa, the disease was recognized only when it spread internationally. The recognition was by clinicians who were startled by the ‘total immunodeficiency’ in patients with no apparent reason for immunodeficiency of that type and severity (13).
• Study of mechanisms: clues to etiology can be derived from case reports. The first clues about tobacco smoking and lung cancer came from surgical patient series in the 1920s and 1930s; formal case-control and cohort studies came only decades later (14). A new form of thrombophilia was detected via the clotting abnormality in one family; it proved to be the most widespread genetic cause of thrombosis (15,16). Most of the recent progress in genetics, e.g., the elucidation of the genetics of cystic fibrosis or of sickle cell anaemia is also rooted in earlier case studies (17).
• Device new therapies: sometimes the effect of a drug is too strong against the background knowledge of usual prognosis of a patient’s disease. That happened with a new therapy for chloroquine poisoning (mechanical ventilation and diazepam plus adrenaline). Ten of eleven patients survived a dose of chloroquine (5 g or more) that was quite securely known to be lethal (18). Case reports can also give clues about new indications for old drugs. Mood improvement on a tuberculostatic drug led to new antidepressants; and decreased serum cholesterol was observed in schizophrenia patients treated with niacin (19).
• Recognition of side effects: side effects are sometimes detected because they produce diseases that were previously non-existent or unrecognized, for example, the eosinophilia myalgia syndrome, specific forms of valvulopathy with slimming drugs, or retrolental fibroplasia. At other times a known disease develops in unusual and unexpected circumstances: a young woman developing venous thrombosis without any precipitating factors in the first weeks of taking oral contraceptives (11). The unexpected sudden deaths during or immediately after intravenous infusion of high dosages of an anti-emetic domperidone. A few such deaths were reported independently by physicians who saw no reason for the sudden intractable arrhythmias in their patients. The intravenous form was withdrawn from the market (20).
• Education: case histories like the lesson of the clinicopathological conference ‘do not make the same mistake as I did’; when a series of cases with an unfavourable outcome is collected to see whether that outcome might have been prevented (2,11).

Charlton and Walston suggested that the use of case series might be formalized (21). After the proposal of a new theory, one might go back to review existing cases, either from the published work or from medical practice, to see whether they fit the new theory or not. In the case of our own example, by using an MR-based intervertebral disc degeneration grading system to study a cohort of 163 healthy men (mean age, 73.5 years ±4.3) and 196 healthy women (mean age, 73.2 years ±4.1), we found that elderly female subjects had more severe disc degeneration than male subjects at all lumbar levels (22). This contradicts the general perception that men are more susceptible to disc degeneration than are women a due to increased mechanical stress and physical injury. We further reviewed the published literature and found that indeed both autopsy and MRI showed in young and middle-aged subjects, disc degeneration was observed in men in the second decade of life, occurring at an earlier age than in women; the severity of aged matched disc degeneration was also greater in men (23,24). However, in a radiographic study of subjects 55 years and older, de Schepper et al. (25) reported disc space narrowing was more prevalent in women than men. Based on additional literature review we proposed that relative deficiency estrogen due to menopause accelerates disc degeneration, though female discs tend to have initial milder disc degeneration during young and middle age, this trend is reversed in elderly subjects, with interception occurred around the age of menopause (26). Our further epidemiological studies provided additional supportive evidences (27). In a recent example, Koene et al.’s paper tries to reconstruct the natural disease course and genotype-phenotype correlations in Complex I deficiency with four new cases and 126 case reports from literature (28).

Which cases are worthwhile to be reported is a tricky question. With the increased use of evidence-based health care, new standards are expected of case reports. Case reports must be authentic cases and have some educational value along with representing at least an incremental advance in the field. Rarity of a condition usually meets the criterion of worthiness, but few have the opportunity to describe something that is completely new. Be wary of to boast it is the "first" to describe a particular phenomenon, since even the most thorough searches often fail to reveal all instances of similar cases. Also consider presenting a case if it increases awareness of a condition, suggests the proper diagnostic strategy, or demonstrates a more cost-effective approach to management. Alternatively, a case can be presented because it represents an unusual presentation of a relatively common condition. Cases that shed new light on the possible pathogenesis of a disease or an adverse effect, increase the awareness of an unusual condition, describe a rare presentation of a common condition, or identify innovative treatment and diagnostic strategies are valuable additions to the medical literature. While it is important to contribute something unique, but not if it depends on some trivial variation from previously presented cases. For example, if it is known that a certain cancer widely metastasizes, it is not worthwhile to report each new site. Similarly, drug reactions often merit a case report, but not if it is simply a report of a drug in a class whose other members are known to cause the same reaction.

Usually a case report should include the following sections (29,30):

• Title: The title is a summary of the abstract and should convince the reader that the topic is relevant.
• Abstract: key information should be summarized in the abstract as this is the part readers will likely to pay full attention.
• Introduction: the introduction should be followed by an explanation of why the case report is novel or merits review, and also mention how rare the case is.
• Case description: this is one of the most integral sections. The case should be described in a concise and chronological order. One should usually begin with the primary complaint, then significant family, occupational, and other social history along with any significant medications taken or allergies, followed by the physical examination, starting with the vital signs presented at the examination, along with pertinent laboratory and radiological investigations and results. There should be enough detail for the reader to establish his or her own conclusions about the validity. A case report that contains detailed and relevant patient information allows the reader with a different clinical expertise to uncover idiosyncracies that are not detected or described by the author and stimulates further inquiry and commentary. The patient’s progress and outcome should be described. In the meantime be sensitive to patient confidentiality.
• Discussion and recommendation: the discussion section aims to compare the case report with the published literature; summarize the essential features of the report. It is essential that the author’s preparation for writing the manuscript include a good review of the literature. All the references cited should be critically evaluated. Review articles should not be used as good references. A table listing the pertinent facts of the cases detected from the literature review is a good method for providing extensive, detailed data in an interpretable form.

Keeping in mind the limitations of the case report, the author must be careful not to make firm judgments and sweeping recommendations based on speculation, or on limited information. Pocock and Hughes described why randomized trials that are stopped prematurely because of extremely high benefit will more often than not be on a ‘random high’; the direction of the effect is true, the magnitude is indeed large, but there is the possibility that in this particular instance mere chance added an extra benefit (31). In the next trial the effect will still be there, but may be much less than in the trial that was stopped prematurely (regression to the mean phenomenon) (31). The same caution also applies for side effects. The report that OKT3 antibody treatment in a series of transplantation patients induced a surprising number of lymphoreticular disorders early in therapy contained truth, but the magnitude of the effect reflected ‘bad luck’ in these patients (32).

Before submitting a case report, it is worthwhile to refer to the Case Report Check Sheet described by Green and Johnson (Table S1) (29).

Table S1 Case report check sheet
Full table

RCT aims for confirmatory end and a final quantification, but offer little scientific novelty. It is the ‘discovery’ aspect, both scientific and educational, that makes case reports and series great fun to present. Sir William Osler, known by many as the Father of modern medicine, once stated that physicians should “always note and record the unusual. Publish it. Place it on permanent record as a short, concise note. Such communications are always of value” (33).

Disclosure: The author declares no conflict of interest.

References

1. Martyn C. Case reports, case series and systematic reviews. QJM 2002;95:197-8. [PubMed]
2. Vandenbroucke JP. Observational research and evidence-based medicine: What should we teach young physicians? J Clin Epidemiol 1998;51:467-72. [PubMed]
3. Garrison FH. An Introduction to the History of Medicine. 4th edition. Philadelphia: W. B. Saunders, 1929.
4. Gottlieb GJ, Ragaz A, Vogel JV, Friedman-Kien A, Rywlin AM, Weiner EA, Ackerman AB. A preliminary communication on extensively disseminated Kaposi's sarcoma in young homosexual men. Am J Dermatopathol 1981;3:111-4. [PubMed]
5. Goetz CG. The history of Parkinson’s disease: early clinical descriptions and neurological therapies. Cold Spring Harb Perspect Med 2011;1:a008862. [PubMed]
6. Douglas JG, Munro JF, Kitchin AH, Muir AL, Proudfoot AT. Pulmonary hypertension and fenfluramine. Br Med J (Clin Res Ed) 1981;283:881-3. [PubMed]
7. Atanassoff PG, Weiss BM, Schmid ER, Tornic M. Pulmonary hypertension and dexfenfluramine. Lancet 1992;339:436. [PubMed]
8. Frank C, Werber D, Cramer JP, Askar M, Faber M, an der Heiden M, Bernard H, Fruth A, Prager R, Spode A, Wadl M, Zoufaly A, Jordan S, Kemper MJ, Follin P, Müller L, King LA, Rosner B, Buchholz U, Stark K, Krause G; HUS Investigation Team. Epidemic profile of Shiga-toxin-producing Escherichia coli O104:H4 outbreak in Germany. N Engl J Med 2011;365:1771-80. [PubMed]
9. Lapeyraque AL, Malina M, Fremeaux-Bacchi V, Boppel T, Kirschfink M, Oualha M, Proulx F, Clermont MJ, Le Deist F, Niaudet P, Schaefer F. Eculizumab in severe Shiga-toxin-associated HUS. N Engl J Med 2011;364:2561-3. [PubMed]
10. American Medical Association. 51 landmark articles in medicine. Chicago: American Medical Association, 1985
11. Vandenbroucke JP. Case reports in an evidence-based world. J R Soc Med 1999;92:159-63. [PubMed]
12. Rise and fall of diseases. Lancet 1993;341:151-2. [PubMed]
13. Gottlieb MS. Discovering AIDS. Epidemiology 1998;9:365-7. [PubMed]
14. Doll R. Uncovering the effects of smoking: historical perspective. Stat Methods Med Res 1998;7:87-117. [PubMed]
15. Dahlbäck B, Carlsson M, Svensson PJ. Familial thrombophilia due to a previously unrecognized mechanism characterized by poor anticoagulant response to activated protein C: prediction of a cofactor to activated protein C. Proc Natl Acad Sci U S A 1993;90:1004-8. [PubMed]
16. Bertina RM, Koeleman BP, Koster T, Rosendaal FR, Dirven RJ, de Ronde H, van der Velden PA, Reitsma PH. Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature 1994;369:64-7. [PubMed]
17. Vandenbroucke JP. Clinical investigation in the 20th century: the ascendancy of numerical reasoning. Lancet 1998;352 Suppl 2:SII12-6. [PubMed]
18. Riou B, Barriot P, Rimailho A, Baud FJ. Treatment of severe chloroquine poisoning. N Engl J Med 1988;318:1-6. [PubMed]
19. Goodwin JS. The empirical basis for the discovery of new therapies. Perspect Biol Med 1991;35:20-36. [PubMed]
20. Joss RA, Goldhirsch A, Brunner KW, Galeazzi RL. Sudden death in cancer patient on high-dose domperidone. Lancet 1982;1:1019. [PubMed]
21. Charlton BG, Walston F. Individual case studies in clinical research. J Eval Clin Pract 1998;4:147-55. [PubMed]
22. Wang YX, Griffith JF, Ma HT, Kwok AW, Leung JC, Yeung DK, Ahuja AT, Leung PC. Relationship between gender, bone mineral density, and disc degeneration in the lumbar spine: a study in elderly subjects using an eight-level MRI-based disc degeneration grading system. Osteoporos Int 2011;22:91-6. [PubMed]
23. Miller JA, Schmatz C, Schultz AB. Lumbar disc degeneration: correlation with age, sex, and spine level in 600 autopsy specimens. Spine (Phila Pa 1976) 1988;13:173-8. [PubMed]
24. Takatalo J, Karppinen J, Niinimäki J, Taimela S, Näyhä S, Järvelin MR, Kyllönen E, Tervonen O. Prevalence of degenerative imaging findings in lumbar magnetic resonance imaging among young adults. Spine (Phila Pa 1976) 2009;34:1716-21. [PubMed]
25. de Schepper EI, Damen J, van Meurs JB, Ginai AZ, Popham M, Hofman A, Koes BW, Bierma-Zeinstra SM. The association between lumbar disc degeneration and low back pain: the influence of age, gender, and individual radiographic features. Spine (Phila Pa 1976) 2010;35:531-6. [PubMed]
26. Wang YX, Griffith JF. Effect of menopause on lumbar disk degeneration: potential etiology. Radiology 2010;257:318-20. [PubMed]
27. Wang YX, Griffith JF, Zeng XJ, Deng M, Kwok AW, Leung JC, Ahuja AT, Kwok T, Leung PC. Prevalence and sex difference of lumbar disc space narrowing in elderly chinese men and women: osteoporotic fractures in men (Hong Kong) and osteoporotic fractures in women (Hong Kong) studies. Arthritis Rheum 2013;65:1004-10. [PubMed]
28. Koene S, Rodenburg RJ, van der Knaap MS, Willemsen MA, Sperl W, Laugel V, Ostergaard E, Tarnopolsky M, Martin MA, Nesbitt V, Fletcher J, Edvardson S, Procaccio V, Slama A, van den Heuvel LP, Smeitink JA. Natural disease course and genotype-phenotype correlations in Complex I deficiency caused by nuclear gene defects: what we learned from 130 cases. J Inherit Metab Dis 2012;35:737-47. [PubMed]
29. Green BN, Johnson CD. How to write a case report for publication. J Chiropr Med 2006;5:72-82. [PubMed]
30. Cohen H. How to write a patient case report. Am J Health Syst Pharm 2006;63:1888-92. [PubMed]
31. Pocock SJ, Hughes MD. Practical problems in interim analyses, with particular regard to estimation. Control Clin Trials 1989;10:209S-221S. [PubMed]
32. Swinnen LJ, Costanzo-Nordin MR, Fisher SG, O’Sullivan EJ, Johnson MR, Heroux AL, Dizikes GJ, Pifarre R, Fisher RI. Increased incidence of lymphoproliferative disorder after immunosuppression with the monoclonal antibody OKT3 in cardiac-transplant recipients. N Engl J Med 1990;323:1723-8. [PubMed]
33. Osler W. eds. The Quotable Osler. Philadelphia: American College of Physicians, 2003.