Screening for Hypopituitarism in Traumatic Brain injury Patients

ABSTRACT

Background: Post traumatic hypopituitarism (PTHP) is one of the leading cause of disability and morbidity amongst the patients who suffer from an event of traumatic brain injury. The main reason regarding the prevalence of this hypopituitarism is because not adequate protocols and pathways exists for the screening and evaluation of a patient who suffers from a trauma to the head. Thus, many a times this pituitary hormone deficiency is missed to picked up as the symptomatic presentation of fatigues, decreased GCS, lethargy can be confused to post-concussion syndrome or neurological signs due to trauma to the brain. Also, though we know about this syndrome and it has been defined quite a few years ago, the data available is not enough to understand and comprehend the aetiology and the course of presentation of post-traumatic hypopituitarism. It is very essential to know what screening tests should be conducted to reach the diagnosis and at what intervals of time. Also, if there is outline of which patients are at high risk of developing post-traumatic hypopituitarism after a trauma to the head, it would make it better to screen those patients specifically instead of all patients who have had a traumatic brain injury. Management of this deficiency is by hormone replacement which helps solve the deficiency of the hormone and improves the quality of life of the individual from the consequences of hormone deficiency after a traumatic brain injury (TBI).

Methods: The aim of presenting this dissertation was to discuss about the incidence and prevalence of post-traumatic hypopituitarism and the importance of formulating a pathway for screening. By researching and exploring the various articles and literature available in reference to the effects of traumatic brain injury causing dysfunction of the pituitary and presenting with hormone deficiency, 5 article have been discussed and critically analysed in this dissertation

Results: From overlooking the 5 articles discussed we can summarize that pituitary dysfunction is a significant risk in patient with a history of traumatic brain injury (p<0.001) and this risk keeps on increasing over the period of time seen in article 1 for a 5 year follow up.in the acute phase it is observed that there is a deficiency of growth hormone level which decrease through the days and cortisol which is the highest immediately after the traumatic event and increases later.

It has also been observed that pituitary hormone deficiency my manifest in the post-acute phase (3 months) and may normalise in due course of time sometimes new deficiencies occurring after the post-acute phase. The most common deficiency seen is growth hormone deficiency which may improve or persist in the patients over the period of 12 months as seen in Article 3. Also observed is hypo gonadotrophic hypogonadism in patients with follow up at 6 months or more in Article 4.

Conclusion: Thus, it can be said that a trauma to the brain is significantly associated with changed in the pituitary functioning and deficiency of the hormones. It is very essential to have a well outlined pathway for evaluation of post-traumatic hypopituitarism after the event and as follow up. Prompt diagnosis and management with hormone replacement help decrease the mortality and morbidity caused by this disorder and increase the quality of life of the patient who has suffered a traumatic brain injury.

Table of Contents

INTRODUCTION

BACKGROUND

METHODS

Research Strategy

Inclusion & Exclusion Criteria

REVIEW OF ARTICLES

Article 1 – Endocrine dysfunction following a traumatic brain injury: a 5 year follow up nationwide – based study

Article 2 – Prevalence of anterior pituitary insufficiency 3 and 12 months after traumatic brain injury

Article 3 – High Risk of Hypopituitarism after Traumatic Brain Injury: A Prospective Investigation of Anterior Pituitary Function in the Acute Phase and 12 Months after Trauma

Article 4 – Incidence of Pituitary Dysfunction following Traumatic Brain Injury: A Prospective Study from a Regional Neurosurgical Centre

Article 5 – Neuroendocrine Dysfunction in Acute Phase of Moderate-to- Severe Traumatic Brain Injury – A Prospective Study

DISCUSSION

CONCLUSION

REFERENCES

INTRODUCTION

Hypopituitarism is a clinical condition defined by the partial or complete deficiency of the pituitary hormones in the body (1). This syndrome may develop due to under secretion of the hormones secreted by the pituitary, hypothalamus or the structures surrounding it. Most common deficiency seen is in the anterior pituitary hormone secretion (2) and the presentation and symptoms depend on which hormone is deficient and can be either the anterior or pituitary hormone. Quite commonly the symptoms of anterior hormone deficiencies are overlapped and masked because of the clinical presentation of traumatic brain injury and these patients are not subjected to any screening and investigations for pituitary deficiencies (3) unless there is an overt presentation of diabetes insipidus as there is no specific protocol for routine investigation for pituitary hormone levels.

There are various causes which lead to hypopituitarism like pituitary adenoma, other intrasellar tumours, inflammatory or infectious disorder to the pituitary, surgical removal of the gland, radiation induced destruction, traumatic brain injury, subarachnoid haemorrhage, post-partum pituitary necrosis.

Any form of injury to the head either by a fall, motor vehicle accident or direct damage to the head due to any projectile force might injure the pituitary stalk or the hypothalamus. It is noticed that this sort of traumatic brain injury might precipitate hypopituitarism in the course of time or immediately after the event.

It has been found that Traumatic brain injury is a commonest cause of death and disability in young adults living in developed countries. It has been observed that traumatic brain injury affects about 33 – 50 % of its survivors with partial or total abnormality in the functions of the pituitary hormones (4) and is a major part of the burden of disability in the population.  Quite a few studies have showed that hypopituitarism is the commonest complication of head injury with a prevalence of 25% among the patients studied after the injury for months to years. (5)

The abnormality of post-traumatic endocrinopathy was noticed and reported by a German researcher Cyran in 1918 (6)(7)(8) (9) and was thought to be a rare complication (10).

Anterior pituitary insufficiency, most common presentation of hypopituitarism was first reported by Simmonds and hence is known as Simmonds disease (11). Later as more studies were reported a varied incidence of pituitary deficiency was seen ranging from 2% to 90% (3) (8) (12) (13).

Multiple articles have suggested the requirement for screening of TBI patients presenting with non-specific symptoms of lethargy, depression, fatigue at 3 month and 12 month intervals post the event for post-traumatic endocrinopathy (14) (15) (16) (17)

It is said that the hypophyseal vessels are very vulnerable to the shearing traumatic force, raised intracranial pressures and fractures at the base of the skull which may lead to either pituitary ischemia or haemorrhage causing pituitary dysfunction (4).

Multiple factors influence the prevalence of hypopituitarism after a traumatic brain injury like the duration of time between the injury and assessment of the pituitary function, the severity of the head injury, the tests done for assessment of the pituitary function vary between studies (18). It has been observed that persistent pituitary insufficiency is most commonly seen after severe traumatic brain injury (19) (20).

A complete assessment of the hypothalamic- pituitary axis is inclusive of specialized neuroendocrine evaluation which consists of basal hormonal levels, stimulation tests which help in reaching the diagnoses as compared to random hormone level testing.

While, we do see patients recovering from hypopituitarism after a traumatic brain injury within 3 to 6 months, several of them continue to suffer from symptoms of fatigue, depression, anxiety, sexual dysfunction, cognitive impairment which affect their functioning and quality of life (21). Amongst the survivors and increase in disability with a decrease in the quality of life is observed in patients having combined or isolated growth hormone deficiency (22) (23) although it has also been stated that neuropsychological and quality of life deficits is more frequently associated with intracranial haemorrhage in comparison to hypopituitarism (24)

Thus, it is of prime importance to implement screening for neuroendocrine dysfunction and the post traumatic hypopituitarism after a traumatic brain injury to help in identification and early management of the hormonal deficiencies.

The treatment of this post traumatic hypopituitarism by replacement of the hormones deficiencies will provide an approach to decrease the morbidity of the phenomena and help in recovery & rehabilitation of patient after a traumatic brain injury (5).

BACKGROUND

In the present today, we see around a million cases of head injury in the A&E every year and it is a concern that the complications of post traumatic hypopituitarism are under diagnosed due to presentation of symptoms after discharge or after a few months (25).

Various studies have stated that 20 to 30 percent of the 135,000 patients who suffer from serious head injury, also experience damage to the pituitary gland situated below the brain (26) (27). There are probably 18,000 to 30,000 cases of PTHP in UK every year.

Post traumatic Hypopituitarism (PTHP) is seen when the pituitary gland has incurred an injury to the head which may be either due to a motor vehicle accident, a fall, or a trivial blow to the head. The gland is responsible for producing hormones and their regulation for maintaining the immune system, the thyroid functioning, the growth, puberty, sex drive and fertility of and individual. The presentation depends on the degree of injury and the hormones effected but manifests with lethargy, fatigue, weakness, depression, loss of sex drive and infertility.

Patients are often misdiagnosed as chronic fatigue syndrome or fibromyalgia, which fails to respond in 70 % of the cases to the treatment offered for the above stated disorder (27) (28).

The key to the treatment is lifelong replacement of the deficient hormone which has excellent effectiveness in reversal of the symptoms and a leading towards a healthy existence.

Post traumatic Hypopituitarism was known since around 90 years back during those times it was a very rare occurrence. The current clinical evidence provided by the various studies and reviews points towards  the fact that a traumatic brain injury might  have a frequent association with hypothalamus pituitary dysfunction either immediately after the injury or developing in the prospective coming months being one of the major reason for delayed recovery from the head injury or consequences ranging from  disabilities to long term cognitive, behavioural , psychological and social difficulties (29) It mostly presents as isolated hormone deficiency and rarely as complete pituitary failure.  More commonly it starts with a gonadotropin and somatotropin deficiency and later may manifest with corticotropin and thyrotropin deficiency (29) (30).

It is quite difficult to predict when post traumatic hypopituitarism may develop after the traumatic brain injury and how long it may exist and whether it may reverse back or not. Some cases of hypopituitarism developing several years later have also been seen (31).

Hence it is of prime importance to evaluate the pituitary function after the event of traumatic brain injury and long term follow up, irrespective of the severity of the head injury and basal hormone level at the time of injury. Replacing the hormones in these patients provides an excellent opportunity in improving the outcome and quality of life of these patients. (29)

The reason behind picking this topic for dissertation was because despite the data available to us today about the prevalence of post traumatic hypopituitarism (PTHP), the current NICE guidelines for head injury make no reference to post traumatic hypopituitarism. Hence there is no warning for the patient nor is there a protocol for follow up on this condition in the patient post the event of head injury.

NICE claims that PTHP is not an acute occurrence but a late complication of the head injury and guidelines are only made for acute care. Despite this it is known that pituitary complications during the acute stage can be life threatening or resulting in persistent disability. This can all be avoided or minimized if there is early and prompt detection with timely treatment intervention (32).

Chris Thompson, Professor of Endocrinology in Beaumont Hospital, Dublin has said that 30 % of the patients who were followed at 7 – 14 days after the traumatic brain injury event (33) were found to have suboptimal pituitary function (34), also a detailed evaluation of 100 patients with traumatic brain injury during their hospital stay showed a suboptimal cortisol in 80 % of the patients (35). There is a significant consequence to acute pituitary injury which manifests as hypoglycaemia, hyponatremia, hypotension (36).

METHODS

Research Strategy

Literature research form the main foundation while drafting a dissertation. The preliminary step is the formulate the question using the PICO model.

Patient/Population and /or Problem

Intervention

Comparison/ Control

Outcome

A list of words and synonyms in each category were written down. For problem words like “post traumatic hypopituitarism”, ” traumatic brain injury”, “head injury”, “brain insult” were used. For intervention “neuroendocrine screening”, “diagnostic tests”, “hormonal evaluation” were written down. Similarly, for outcomes words such as “hypopituitarism”, “neuroendocrine dysfunction”, ” hormonal disorders”, “pituitary deficiency” were used.

The research was done at the PUBMED database first using the single words and then combine and refining the research with Boolean operators OR & AND. The results of the search led to multiple articles out of which 5 articles were selected and reviewed. A few of the selected articles were reviews of other articles and so the studies done in these articles was selected for further re- viewing.

Inclusion & Exclusion Criteria

Well defined inclusion criteria were outlined for the identification of articles.

1. Studies that included patients admitted with history for traumatic head injury
2. Adult Patients (17 years or above)
3. Articles published in English
4. Human Studies

The exclusion criteria were as follows:

1. Patient having hormonal disorders before the traumatic brain injury event or being treated for them prior to TBI
2. Article more than 15 years earlier

After re-viewing the data of each article, each of them was critically analysed to understand the study so that the important conclusions of the study could be understood as well as the limitations identified. Each article was reviewed and critically analysed using the CASP tools for critical appraisal for an article – http://www.casp-uk.net/casp-tools-checklists  (37)

REVIEW OF ARTICLES

Article 1 – Endocrine dysfunction following a traumatic brain injury: a 5 year follow up nationwide – based study.

Wei-Hsun Yang, Pau-Chung Chen, Ting-Chung Wang, Ting-Yu Kuo, Chun-Yu Cheng & Yao-Hsu Yang

Data Review Article #1

It is a study down in Taiwan on patients registered in the Health Insurance database. A cohort study was performed with a follow up at 1 year and 5 year after traumatic brain injury on patients registered in National Health Insurance Research database which is formed by the National Health Research Institutes, Taiwan. The aim of this study was to analyse the long-term effect of developing Post traumatic hypopituitarism (PTHP) after and event of traumatic brain injury.

Among the 1,000,000 patients who were randomly selected from the database between the years 1996 – 2009, 38,710 patients had a diagnosis of Traumatic Brain Injury.

These patients formed the cohort for the study group and the other group was formed matching people based on gender, age, diabetes, hypertension, urbanization level & income.

The traumatic brain injury group had 31,389 people, and non- traumatic brain injury group had 125,556 people. Hence the final analysis was done for a total of 156,945 people.

Inclusion Criteria for this study was the TBI cohort of people who were enrolled in the study and had a follow up till 2009 or until death of the patient. Exclusion criteria was comprised of i) patients who had abnormal endocrine functions within 3 months of the event {158 patients} ii) patients who were diagnosed with brain disease/tumour/stroke prior to the event {4515 patients} iii) missing patients {17} iv) error in patient details {1}.

The Kaplan Meier method was used to calculate the survival curve and the Log Rank test to detect difference in those survival curves.

The outcome of the study is discussed in two stages that is at 1 year and 5 year follow up. Patients in traumatic brain injury group had a higher risk of developing endocrine dysfunction and pituitary disorders at the 1 year follow up in comparison to the non-TBI group. Also, there is increased association of pituitary dysfunction with skull fractures in comparison to head injury and intra cranial haemorrhage.

At 5 year follow up significant association between post traumatic endocrine dysfunction and traumatic brain injury continued. But, that between the skull fracture and endocrine dysfunction was no longer significant. A new association between ICH and pituitary dysfunction came into picture at the 5 year follow up which is stronger than the 1 year follow up association with skull fractures. Incidence of Post traumatic endocrinopathies and pituitary dysfunction with traumatic brain injury have increased consistently through the follow up period.

Conclusion from this study after the follow up over the 5 years is such that all patients with an event of traumatic brain injury should have a long-term monitoring of pituitary functions as there is a delayed effect seen post the head injury event in an individual.

Critical Analysis Article #1

For the purpose of this study the National Insurance Database (NHIRD) was used which provided registration files & original re-imbursement claims which is maintained by the National Health Research Institute.

The NHRI extracted 1 million randomly sampled representative data from the data provided in the register and created a Longitudinal Health Insurance Database in 2005 which is representative of all beneficiaries.

The stated study includes patients who suffered from a traumatic brain injury during the period between 1996 to 2009. The medical records of the traumatic brain injury cohort were evaluated and scrutinized along with a follow up of these patients till end of 2009 or their death. The patients included in the traumatic brain injury cohort has a well-documented diagnosis by International Classification of Disease 9^th Revision, clinical modification.

Patients who were diagnosed with endocrine disorder, stroke, brain tumour before the event were excluded from this study. Also, subject with data error or missing data were not included in the cohort for this study. The non- traumatic brain injury cohort was matched to the traumatic brain injury cohort and a ratio of 1:4 was fixed. Overall 156,945 insured subjects (31,389 matched sets) was included in the final analysis.

The conclusion which was to be evaluated through this study was the risk of developing common endocrinopathy or pituitary dysfunction after a TBI and the incidence and prevalence at 1 year & 5 year follow up. This would help validate the concept that a traumatic brain injury has an increased risk of resulting in an endocrine or pituitary dysfunction.

The study was part retrospective (until 2005) and part prospective (2005 onwards) maintaining strict confidentiality guidelines in accordance with regulations for personal electronic board at the Chang Gung Memorial Hospital.

On critical analysis of this article a few limitations in this study were observed: –

1. There are no clear informative details of the diagnostic tests performed on the patients for evaluation and follow up, whether it was a blood test, basal hormonal level, stimulation test or any imaging. It is unclear how a diagnosis of endocrine or pituitary dysfunction was reached.
2.  It is very difficult to diagnose a hormonal dysfunction at the onset of the event as nonspecific symptoms of headache, dizziness and extremity weakness may also be as a result of head injury.
3. Low GCS – Glasgow coma scale is likely to be due to the head injury and it is quite difficult to assess if the decreased levels of consciousness are resulting due to hormonal disarray.
4. Also, no data is available which might help in detailing the severity of the head injury of the patient (for example coma scale during ICU stay)

As a culmination of the study, it is seen that patients with a TBI had a higher risk of developing an endocrinopathy & pituitary dysfunction at 1 year and 5 year follow up.

Endocrinopathy [ 0.4% in TBI group, p <0.001, HR- 1.49]

Pituitary dysfunction [ 0.1% in TBI group, p<0.001, HR- 2.06]

Skull Bone fracture is more significantly associated with pituitary dysfunction at 1 year follow up. Intracranial Haemorrhage is more strongly associated with pituitary dysfunction than skull bone fractures at 5 year follow up.

Hence, long term monitoring of patients who have had an event of traumatic brain injury is recommended to diagnose any endocrine and pituitary dysfunction arising which can be managed by hormone replacement therapy.

Article 2 – Prevalence of anterior pituitary insufficiency 3 and 12 months after traumatic brain injury

H J Schneider, M Schneider, B Saller, S Petersenn, M Uhr, B Husemann, F von Rosen and G K Stalla

Data Review Article # 2

It has come to notice that many cross-sectional study highlight the high prevalence of Hypopituitarism after traumatic brain injury but there are no longitudinal studies done on the time of presentation of PTHP and a possibility of reversibility of the dysfunction.

The aim to conduct and follow this study over the period of 12 months is to provide time for manifestation of signs and symptoms or reversibility of any abnormalities in the pituitary function which may occur after the traumatic brain injury.

A prospective longitudinal diagnostic study was conducted with the aim to sidestep the non-specific abnormalities which might present in the early phase and to evaluate the prevalence of pituitary dysfunction in the early & chronic phase. Pituitary testing along with clinical judgement at 3 months & 12 months formed the standard. Pituitary testing included basal hormone measurements along with stimulation tests like GHRH + arginine test, Short ACTH test.

The study group included 78 patients with an event of TBI ranging from grade I to Grade III and the non- TBI group consisted of 38 people who were healthy subjects matched with the above group in age, sex and BMI. The study group of TBI were patients from Rehabilitation Unit of Neurologic Clinic, Germany.

Inclusion Criteria for this study comprised if i) Traumatic Brain Injury Grades I to III assessed by the Glasgow Coma Scale ii) Age of the subject between 18 years to 65 years iii) Body Mass Index between 17 kg/m2 to 30 kg/m2. Exclusion Criteria was detailed as i) Glucocorticoid treatment within the 3 weeks or Growth Hormone treatment within 12 months prior to the first evaluation for this study ii) Any history of cranial radiation iii) Patient presenting with pre-existing pituitary disorder iv) Any patient having sever cardiac, renal or hepatic disease v) A case of sepsis vi) History of substance abuse.

All the assessment of the pituitary hormones was performed in the early phase, acute and chronic phase. Visit 1 (acute) was at 3 month +/- 2 weeks after the TBI event. Visit 2 chronic) was at 12 months +/- 4 weeks after the trauma. Stimulation tests were performed on all the subjects at the first visit but only repeated on patients at the second visit in patients who had an abnormal basal or stimulation tests at the first visit.

The conclusion seen on assessing this study and following it through the year is summarized as – at 3 months showed 44 patients with impairment seen in at least one pituitary axis (corticotropic & somatotropic) whereas 8 patients with combined impairment of 2 axes. There was no difference observed in the pituitary dysfunction based on the initial GCS, Modified Rankin scale, Age, BMI & presence of hyperprolactinaemia, but low GCS was a prominent feature in patient who developed hypogonadism.

At 12 months- 36% hormonal disturbances in all axes except somatotropic axis, two axes were impaired in 3 patients out of which 2 patients remained deficient in gonadotropic + somatotropic axis as on the first visit. An additional patient who had a decreased growth hormone on stimulation test at the first visit became deficient in cortisol at the second visit.

Hence, it was observed that initial discrepancy in the Gonadotropic, Corticotropic and Thyrotrophic axes mostly is resolved after 12 months but the deficiency in the somatotrophic axis persists constant. New deficiency in Gonadotropic & Corticotropic axes may occur at 12 months’ visit. It is of prime importance that all patient with a traumatic brain injury should have an evaluation of the pituitary functioning disregardful of the severity of the trauma to the brain.

Critical Analysis Article # 2

This article is a prospective longitudinal diagnostic study, performed to evaluate the occurrence of post traumatic hypopituitarism in an individual patient who has had an even of trauma to the head and was followed up at 3 month and 12 month intervals post the event. Two groups were studied, one had 78 patients from the Rehabilitation Unit of Neurology Clinic, Germany and the other group consisted of 38 healthy individuals matched for age, sex, BMI with the earlier group.

Hormonal evaluation was performed on these subjects on 2 visits at 3 month and 12 month. Test done included stimulation tests like GHRH + Arginine, short ACTH and basal hormone level (fasting IGF-1, TSH, FT4, FT3, LH, FSH, PRL, Testosterone in males, Oestrogen in females) along with clinical assessment based on Modified Rankin Scale and severity of TBI based on Glasgow Comma Scale. The outcome from this study would be beneficial in detailing the necessity of having a protocol of pituitary function assessment in a patient post traumatic brain injury.

The data collected was displayed in terms of mean +/-standard deviation. The evaluate the significance between the groups unpaired 2 tailed student t test was used, and paired student t test was used for assessing any changes within the group. Co-relation was gauged with Spearman’s co-relation co-efficient. The difference of proportions between the patient and control group was calculated by the Fischer’s exact test. Receiver operating analysis (ROC) was calculated to test predictive value of stimulated & basal hormone assessment.

Results obtained from the study show that at the 3-month visit, comment could only be made for 77 patients from the study group as 1 person refused to get tested for stimulation tests. 44 patients showed deficiency in at least one pituitary axis, 15 patients had hypocortisolism, 6 patients had secondary hypothyroidism and 7 patients had negative stimulated growth hormone response. [ one sided p = 0.19] 8 patients had combined impairment of 2 axes in varying proportion. Prolactin was elevated in 9 patients out of which 7 were on drugs which elevated prolactin levels. No commendable difference was observed in patient irrespective of the pituitary dysfunction in terms of age, sex, BMI, prevalence of elevate prolactin. However, in patients who developed hypogonadism an initial low GCS and a higher Modified Rankin Scale was observed in comparison to eugonadal subjects.

The results at the second visit at 12 months, only 70 patient data were accessible as the rest 8 refused to be re tested. Among these patients and increase of BMI was observed in 1.69+/-1.98 [ p<0.001] and a decrease in the modified Rankin scale in 0.69+/-1.03 [ p<0.001] in comparison to the first visit. Stimulation tests were only performed on 32 patients as the other either refused the testing or had normal basal hormonal levels at the first visit testing. Thus these 38 remining patients only basal hormone evaluation in the second visit. This make it very difficult to comment on the hormonal disturbances in the corticotropic and somatotropic axis without the aid of the stimulation tests. 36 % patients still showed some hormonal disturbances but the prevalence of disorder was comparatively lower in all axes except the somatotropic axis during the second visit.

Limitation observed in this study was that subject who had normal basal hormones in the 3-month visit had no stimulation test either at 3 month or later. They were regarded as normal, also some patients at their 12 month follow up refused to have stimulation test and only underwent basal hormone evaluation. All this makes it difficult to analyse and comment of the data and does not provide a proper understanding of the dynamic changes to the various pituitary hormones and their functioning.

As a result of performing this prospective longitudinal study it was found that there was a high prevalence of hypogonadism & hypocortisolism at 3-month stage which streamlined to a normal level during follow up later in most but not all cases. Impairment of the growth hormone levels remained constant even at 12 month follow up. Thyrotrophic Axis was the least affected axis. New deficiencies were noted in the gonadotropic and corticotropic axis in the later follow up, providing proof and evidence that it is essential to retest each axis even if the earlier test have been in the normal range.

Despite all this information, it yet unclear what is the predisposing factor for post traumatic hypopituitarism. Severity of TBI does not have a significant association with hypopituitarism. Therefore, more detailed evaluation is of importance to formulate various protocols and methods to outline the evaluation of a patient with traumatic brain injury in terms of the clinical condition & status and explore the predictors and factors of post traumatic hypopituitarism.

Article 3 – High Risk of Hypopituitarism after Traumatic Brain Injury: A Prospective Investigation of Anterior Pituitary Function in the Acute Phase and 12 Months after Trauma

Fatih Tanriverdi, Hakan Senyurek, Kursad Unluhizarci, Ahmet Selcuklu, Felipe F. Casanueva, and Fahrettin Kelestimur

Data Review Article # 3

This is a prospective study, conducted in Spain with the intention to look at i) the prevalence of anterior pituitary hormone deficiencies manifesting after an event of trauma to the brain in the acute phase and at 12 month follow up ii) if the severity if the trauma has any association with the basal hormone levels measured iii) if the hormonal disorders present at the event in acute phase was due to stress or pituitary dysfunction and was there a possibility of the initial hormone disorder being a predictor of the mid-term hormonal status for the individual. The study was performed by selecting the TBI group of patients which had 52 patients who were admitted to the Neurosurgery Intensive Care (NICU) and had an assessment of their pituitary functions at 24 hours of admission and then at 12 month follow up. Glasgow Coma Scale formed a part of the evaluation on admission in NICU along with basal hormonal level at 24 hours’ post admission.

This study included patients who had suffered a traumatic brain injury and were admitted to the Neurosurgery Intensive Care Unit with varying severity of head injury which was validated by the GCS measurements. Trauma to the brain could be in form of a motor vehicle accident, fall or any other reasons. Patients were excluded from this study if they were on any hormone replacement therapy.

At the 12-month re-evaluation, the basal hormone level was measured as before but also ACTH was confirmed by a low dose ACTH stimulation test and Growth Hormone was evaluated by GHRH + GH releasing peptide GHRP-6 in all patients. In the acute phase, it was observed that the severity of TBI had no change in the basal hormone levels. A positive correlation was seen between total testosterone & GCS levels [ r = 0.46, p = 0.003]. On the other hand, Prolactin had a negative correlation with GCS [r = -0.34, p = 0.01]. Cortisol levels positively co-related with ACTH levels [ r = 0.32, p = 0.03].

On comparison between the hormone level in the acute phase and 12 months it was noticed that FT4, PRL, LH, free testosterone, ACTH had no significant difference amongst the mean hormonal levels but a there is a valid increase in TSH, FT3, FSH, IGF-1 and total testosterone [p <0.05] and noticeable decrease in the GH and cortisol [p <0.05] 12 months after the event.

In the 12 month follow up it was observed 17 patients developed GH deficiency, 9 out of which did not have any GH deficiency in the acute phase. 13 patients had ACTH deficiency out of which 10 had the stimulation test and were accepted as being ACTH deficient. Out of these 10 patients, 9 had a basal cortisol during the acute phase and 2 of them had no anterior pituitary deficiency. During the 12 month follow up significant decrease was observed in FSH/LH level [p<0.0001] and a non-significant increase in ACTH [p = 0.175] and GH [p = 0.163]. Pituitary Hormone deficiency recovered in 30 patients (57.7%) at 1 year, but at the same time new onset pituitary dysfunction was observed in 27 patients (51.9%).

Therefore, it can be put in a nut shell that transient hormonal changes are seen in the acute phase after the traumatic brain injury which can be due to stress related release of inflammatory mediators or pituitary deficiency. But that is not a predictor of the hormonal status at 1 year. It can be safely concluded that it is important to assess the pituitary function after a TBI not only after the even but also as a long term follow up regardless of the severity of the head injury.

Critical Analysis Article #3

In this study conducted in Spain, a prospective observational study was done with the desire to assess and comment on the prevalence of anterior pituitary hormone deficiencies which manifest after an event of TBI in the early acute phase and a follow up at 12 months & also, if the deficiency of the hormones in the early phase could be prognosticator for the status of the pituitary function in the later follow up period.

Patient who were admitted in the neurosurgery intensive care unit (NICU) were the subject group in this study. 52 post TBI patients were included who had evaluations of the pituitary function and assessment in terms of GCS with clinical status at 24 hours’ post admission into the unit and later repeated at 12 month follow up.

The basal hormone levels which were used as objective measurements included FT3, FT4, TSH, Prolactin, Cortisol, ACTH, FSH, LH, IGF-1, Growth Hormone, Total and free testosterone in males, oestradiol in females along with their menstrual history. The deficiency of the hormones was defined in terms of an objective measurement of a level below the designated normal levels for each hormone.

At the 12 month re assessment was done as basal hormone evaluations for Gonadotropins & Thyroid functions, but ACTH deficiency was confirmed based on a low dose ACTH stimulation test. Similarly, Growth hormone deficiency was proved after the results of GHRH + GHRH releasing peptide 6.

Statistical analysis was performed on the data gathered and put forward as Mean +/- Standard deviation. Unpaired t test was used to compare the normally distributed values between the 2 variables. If there was no normal distribution between more than 2 variables Kruskal-Wallis test and Dunn test was completed for post hoc analysis. Chi square tests was done to correlate the percentage data. A value of p<0.05 was considered significant. To assess the significant co relation between the chosen variables in the study Pearson’s Co-relation Analysis was used.

The conclusion obtained from this study during the acute (early) phase suggests there no significant changes are observed in the basal hormone levels co relating to the severity of the brain injury. A significant positive association was observed between the GCS levels and total testosterone levels, whereas Prolactin was negatively co-related with GCS levels.

No major changes were observed between the mean hormone level between the acute phase & 12 month follow up for certain hormones like free T4, prolactin, LH, free testosterone and ACTH but, there was an increase seen in TSH, free T3, FSH, IGF-1 and total testosterone[p<0.05]. Similarly, there was decrease in cortisol levels and growth hormone level at 12 month follow up[p<0.05].

3 patients out of 52 had TSH deficiency, 20 patients out of 48 had gonadotropin deficiency, 5 patients out of 51 had ACTH deficiency and 10 patients out of 49 had GH deficiency. Also, it was observed that in all 26 patients had at least deficiency of 1 pituitary hormone out of which 17 had isolated hormone deficiency & 9 patients had combined hormone deficiencies. None of the patients presented with pan hypopituitarism during the early phase.

At the 12 month re assessment 17 patients had GH deficiency out of which 13 patients had isolated GH deficiency and the other 4 had another hormone deficiency in addition to it. Out of there 17, 9 patients did not have any pituitary deficiency observed during the acute phase.

13 patients from the group of 52 had ACTH deficiency seen on basal hormone evaluation which was later tested by the stimulation test. Only 10 were ACTH deficient with having isolated deficiency.

Out of these 10 patients 9 patients had a normal cortisol reading in the acute phase of >7 ug/dl and 2 patients had no anterior pituitary deficiency. A decrease in level of FSH and LH were observed to be significant [p<0.001] and non-significant rise in ACTH [p = 0.175]and GH [p = 0.163]. Pituitary Hormone Deficiency recovered in 30 patients (57.7%) at 1 year follow up, but new onset pituitary hormone deficiency manifested in 27 patients (51.9%) during that same period of time.

Limitations of this study which was observed that in the early phase there was non-availability of data of gonadotropin levels for 4 patients, cortisol for 1 patient and IGF-1 for 3 patients. Hence there is a discrepancy in the number of subjects evaluated in each axis at early phase and 12 month follow up. Also, no stimulation tests were performed during the early phase for cortisol and GH and thus it is difficult to comment of the results when comparing the result at the 12 month follow up with the evaluation done at 24 hours’ post admission.

It is a great idea to conduct a study which helps put forward the status of the hormone in the acute phase and then comparing it later phase evaluation at 12 month outlining transitory hormonal changes which might either be present at the acute phase which might resolve later or there might be a commencement of hormone deficiency which may manifest in a long term follow up. Also, it is concluded that IGF-1 levels of lower than 84 ng/ml in acute phase has a predictive value for GH deficiency at 12 month.

Amongst all the pituitary deficiency GH deficiency is most common with a high incidence at 12 months. Thus, concluded that screening of patients with TBI should be performed irrespective of the severity of brain injury and followed up over time.

Article 4 – Incidence of Pituitary Dysfunction following Traumatic Brain Injury: A Prospective Study from a Regional Neurosurgical Centre

Seyed Alireza Alavi, Chin Lik Tan, David K. Menon, Helen L. Simpson & Peter J. Hutchinson

Data Review Article # 4

Post traumatic hypopituitarism (PTHP) after a traumatic brain injury is gaining more recognition yet, the exact prevalence & incidence remains not so clearly specified. In this prospective study done at a regional neurosurgical centre in Cambridge the incidence of PTHP was explored amongst a group of TBI patients who were considered to be at risk of PTHP. This was achieved by conducting the study dividing the study group into 2 cohorts and assessing the pituitary function in each group.

Serial Cohort – comprised of patients who were admitted to the Neuro Critical Care Unit. 58 consecutive patients were the part of this cohort which had assessment at 2 points – first at 7 days or less after the trauma, during the admission and second 6 months after the TBI. Cross – Sectional Cohort which consisted 47 patients evaluated at the Neurotrauma clinic 6 months of more after the event of trauma. They either had their traumatic event before the visited this clinic or were referred to this clinic by other centres. They were evaluated if they were symptomatic and presenting with symptoms of fatigue, low tolerance for stress, loss of appetite, loss of libido, erectile dysfunction in males and oligomenorrhea in females. A small fraction from the two cohorts was reassessed for Growth Hormone Deficiency at 12 month after the TBI.

Patients included in this study were from the patients admitted at the Neurosurgical Unit, Addenbrroke Hospital, Cambridge UK. They were recruited and followed up between Aug 2009 to Jan 2012 ranging in age from 16 years to 65 years. All of them had an abnormal CT Scan finding post the traumatic brain injury in terms of contusion, haemorrhage – subdural, intracranial, extradural, diffuse axonal injury, intra & extra axial lesions, subarachnoid haemorrhage and skull fracture including base of skull fracture.

The only exclusion group to these patients in the study was any patient who had a pre-existing pituitary dysfunction.

Results of this study in the acute phase proved that pituitary functioning evaluated during the acute phase cannot predict long term hormonal status of the individual.

10 patients who had normal cortisol in the early phase manifested with cortisol deficiency at 6 months. Out of the 6 patients who have initially presented with decreased cortisol in acute phase only 1 patient had persistent low levels and 2 of them recovered the cortisol abnormality but went to the develop deficiency in another pituitary axis. In the patients assessed at Neurotrauma clinic, since the evaluation was done at presentation to the clinic – 21.3% i.e. 10 patients out of the 47 in the group has abnormal levels of hormones in at least 1 axis. 2 patients from the random 22 patients chosen for evaluation of Growth Hormone at 12 month showed GH deficiency along with hypogonadotropic hypogonadism and intact HPA axis.

It is further discussed the importance of diagnosing PTHP and differentiating it from post-concussion syndrome. Also, an individual suffering from PTHP has a negative effect on body composition, metabolic profile & quality of life thus requiring prompt diagnosis and therapy with hormone replacement. Parameters for evaluation of patients at risk of PTHP after a TBI should be outlined so that identification of those at high risk can be offered immediately and as a long term follow up. We can safely sum up that PTHP is a common occurrence in patients admitted in the NICU and are the reason of increased morbidity encountered on patients who are followed up after a TBI event.

Critical Analysis Article # 4

The prospective study conducted in the regional neurosurgical centre in Cambridge, UK with the aim to explore the incidence of PTHP in a patient who at high risk after a traumatic brain injury. A total of 105 patients divided into two cohorts have been studied. Serial Cohort consists of 58 consecutive patients admitted to the Neuro Intensive Critical Care Unit who have evaluation in 2 phases. First one within 7 days’ post trauma event where the serum cortisol level of the patient is checked and if found low the patient further undergoes a short synacthen test. Second phase was at 6 months post TBI where 38 of the patients in acute phase who had an assessment then were re-evaluated with the following tests of FT4, TSH, 9 am cortisol, LH/FSH, testosterone in males and oestradiol E2 in females. Cross sectional Cohort consisted of 47 patients attending the Neurotrauma clinic for follow up at 6 months or more post the event of trauma to the brain.

The follow up was based symptomatic presentation manifesting post TBI. These patients were not offered the cortisol level test in acute phase as there were either referred and had their primary treatment in another hospital. They underwent the similar list of hormonal tests to the 6 month follow up in serial cohort with and addition of Urea & Electrolyte levels. 22 patients randomly chosen (9 from serial cohort & 13 from cross sectional cohort) had an evaluation of their pituitary functioning at 12-month post TBI with glucagon stimulation test and IGF1 to detect any growth hormone deficiency. Patients who were found to have GH deficiency were sked to fill a questionnaire (quality of life assessment of growth hormone deficiency in adults) to help in the identification of patients who require GH replacement for their deficiency. The feedback of the questionnaire is evaluated based of certain criteria one of them being – answer Yes to 11 or more questions out of the 25 questions provided. Growth hormone replacement when offered to these patient is re-evaluated after 9 months with the same questionnaire. An improvement of more than 7 points validated lifelong therapy of growth hormone.

When looking at the results obtained from the Serial cohort 10.3% (6/58) had deficiency in the hypothalamus-pituitary-adrenal axis in the acute phase whereas in the cross-sectional cohort 21.3% (10/47) manifested with and abnormal reading in at least 1 axis at the 6 month or more post TBI where hypogonadotropic hypogonadism is the most common deficiency. The Growth Hormone assessment done at 12 months from the 22 patients randomly chosen showed 9.1% (2/22) GH deficiency associated with hypogonadotropic hypogonadism.

Limitations observed in this study is that it does not consider all patients with traumatic brain injury. The cohort consists of patient which are thought to be at high risk of developing PTHP. Also, there is no clarity to the risk factors which were selected in defining the at-risk group. They have discussed quite a few probabilities of what would constitute to be the high-risk group but it is not clearly outlined. In the serial cohort only the cortisol assessment was done in the acute phase, so when the other hormones were evaluated at the 6 month follow up there was no available values to compare and comment on. It was assumed that the deficiency of cortisol level was of prime importance in the acute phase and none other pituitary hormone was assessed then. In the cross-sectional cohort, the only data available it at the assessment done at the clinic which is 6 or more months post traumatic, hence again no comment can be made with regards to the change is hormones through the follow up and there is no baseline level available at the time of the traumatic event. This makes it difficult to evaluate if the hormonal disturbances have recovered or remained static or if there is a new onset observed.

Growth Hormone assessment was done in a select few people from the 2 cohorts at 12 months and made it difficult to look at any positive significant co-relation with the other pituitary hormones.

Accurate diagnosis of post traumatic hypopituitarism after the traumatic brain injury is of prime necessity not only to reduce morbidity but also improving the quality of life and providing rehabilitation to patients who have had a traumatic event. This it is of main concern to clearly specify the group of patients with TBI who are at high risk to develop PTHP. Also, evaluation in early phase and long term around 6 months is essential as any recovery or new onset deficiency after this time period is not common. In all it can be concluded that PTHP is cause of a significant morbidity in patients admitted in Neuro Critical Care Unit with Traumatic Brain Injury and timely detection management of the disorder is a requisite.

Article 5 – Neuroendocrine Dysfunction in Acute Phase of Moderate-to- Severe Traumatic Brain Injury – A Prospective Study

K. L. Prasanna, R. S. Mittal, & Ashok Gandhi

Data Review Article # 5

This is the first prospective screening study organised and performed at a single centre in India with the objective to assess and analyse the pituitary function in moderate to severe cases of traumatic brain injury. This was evaluated during the acute phase at Day 1 and Day 7 after the traumatic event.

The primary objective of this study was to determine the prevalence of deficiencies in the pituitary hormones in the acute phase after the event of traumatic brain injury in cases with moderate to severe head injury and conclude if there is an existing co-relation between the severity of head injury, pressure effects and Glasgow coma scale outcome with the resultant hormonal status of the individual. For the study purpose, 100 consecutive patients who were admitted with moderate to severe traumatic brain injury to Neurosurgery Unit in SMS Medical College, Jaipur- India were the study group. The patients were admitted between August 2012 and November 2013. Inclusion parameters were a GCS < 13 and age more than 17 years’ age. Patients were excluded on basis of a GCS >13 and age <17 years age, any history of endocrinal disorders or extra cranial injury or metabolic disorders.

The assessment of these post traumatic patient consisted of clinical evaluation, non-contrast CT scan Head and basal hormone level. The clinical status of the patient was indicator of the severity of traumatic brain injury which was assessed by the Glasgow coma scale done on the patient on admission. A score of 15 – 13 was considered mild injury, 9- 12 moderate and less than 9 severe head injury.          CT Scan of Head was helpful to look for various cause of pressure effects like midline shift > 5 mm or basal cistern obliteration. Basal hormone evaluation was done within 24 hours of admission which included FT3, FT4, TSH, GH, Cortisol, Prolactin and the same tests were repeated on Day 7 amongst the patients who survived. The outcome was judged based on the Glasgow Outcome Scale, a score of 4-5 was a good outcome and 1,2,3 was bad outcome group.

The most common hormone to show a decrease in their levels was Growth Hormone which was of highest value on day 7 as compared to day 1. Whereas, Cortisol was found to increase with the maximum value on day 1. It can thus be said significant changes were noticed in the decreasing trend of FT4 level along with reaching near normal levels of cortisol from the initially high level evident on day 1. Also, patients who presented with severe traumatic brain injury with pressure effects and were amongst the bad outcome group in the Glasgow Outcome Scale had an abnormal hormonal status in comparison to patients who had moderate traumatic brain injury with no pressure effects and belonged to a good outcome group in the Glasgow Outcome Scale.

Thus, this study reported a positive correlation and significance between pituitary dysfunction and severe traumatic brain injury during the acute phase. Since the management is simply providing the patient with hormone replacement, identification of post traumatic hypopituitarism offers an opportunity of not only decreasing morbidity but also for rehabilitation and improving the standard of life of the patient.

Critical Analysis Article # 5

A prospective study conducted in India and submitted in 2015, screening patients with moderate to severe traumatic brain injury for prevalence of pituitary dysfunction and its co-relation to the severity of brain injury, pressure effect and Glasgow Outcome Scale.

100 consecutive patients who were admitted to the department of neurosurgery in SMS Medical College, Jaipur India with moderate to severe traumatic brain injury based on the Glasgow Coma Scale assessment on admission were selected to be the study cohort. Along with the GCS assessment for clinical status of the patient, they also had a non-contrast CT Head to diagnose any pressure effects and basal hormone levels done within 24 hours of admission on day 1 and repeated on day 7. Normal range values for the hormones evaluated was clearly specified and the outcome was measured by the Glasgow Outcome scale outlining the good outcome and bad outcome group.

The normally distributed values in this study amongst the two variables was compared by the unpaired t test. Chi square test was used to compare percentages with a p<0.05 considered as significant. Pearson’s correlation analysis was used to determine if a significant correlation existed between the variables. Amongst the 100 patients, 52% of them had moderate head injury and 49% had severe head injury, 66% had pressure effect on CT Scan and 34 % had no pressure effect, 68% had a good outcome on Glasgow outcome scale and 32% had a poor outcome. 6 patients died during the course of admission before the day 7 assessment.

In the moderate to severe traumatic brain injury the hormonal status can be summed up as, a decrease in growth hormone levels from day 1 to day 7 (28% to 48.93%) with a maximum at day 7 whereas, an increase in cortisol level (38% to 21.27%), maximum on day 1 in comparison to day 7 with a statistical significant p<0.005. A low T3 syndrome was also seen (day 1- 22% & day 7- 10.63%) along with low prolactin level (day 1 – 6% & day 7 – 4.25%). Therefore, the tendency of decrease in T4 values along with a normalisation with the decreasing values of cortisol is observed. Also, if was seen that a positive significance existed between the hormone levels and severe traumatic brain injury with pressure effects and bad outcome in the Glasgow outcome scale as compared to moderate traumatic injury with no pressure effects and a good outcome assessment.

Majority of the studies done are retrospective, hence a prospective screening study is a good way to evaluate the changes in the pituitary hormone functioning in acute phase in the patient with traumatic brain injury. The subjects were well chosen with clear definition to the criteria for choosing patients with moderate to severe traumatic brain injury outlined by the Glasgow Coma Scale. There was a complete assessment in all axis clinical status, radiological imaging and basal hormone level. Though, it is to be though that the GH deficiency seen in acute phase could be further evaluated with a stimulation test. Also, since this is a study concentrating on the acute phase it is very difficult to comment if there is a reversal in the hormone level in a long-term situation whether they normalise or remain stagnant.

This study puts forward the significance of post traumatic hypopituitarism and hence pituitary function assessment after a traumatic brain injury. Hormone replacement & rehabilitation helps to reduce morbidity in the society and provides a good quality of life. It is helpful if assessments are considered as a protocol for all patients with moderate to severe head injury thus improving the clinical outcome.

DISCUSSION

It had been observed that traumatic brain injury is one of the most common cause of morbidity & mortality in developed countries (38) (39) (40) (41). Post traumatic hypopituitarism has been talked about and identified since around 90 years (6) but was considered a rare occurrence (10) as the data for the incidence and prevalence was limited through case reports and case series (42) (43). Most prospective follow up studies were performed from 2000 onwards to assess the prevalence of pituitary dysfunction in the patients targeting the long term follow up of these patients post traumatic brain injury (3) (8) (44) (45) (46) (47) (48) (49) (50). Post traumatic Hypopituitarism is found to affect all grades of severity of brain injury and it is very difficult to arrive at a diagnosis as there is an overlap in the presentation of symptoms to differentiate it from post-concussion syndrome (4).

To better understand the response of pituitary functioning to a traumatic event to the brain it seems to be essential to evaluate and compare the hormone levels and functioning of pituitary gland at various time interval after the traumatic brain injury event. Broadly, it can be divided acute phase and long term follow up. Acute phase is the time duration immediately following the traumatic brain injury which can be at day 1 within the 24 hours of admission to the hospital. Long term follow up comprises of a re investigation at 3 months, 6 months or 12 months. One of the studies discussed here had a follow up at 5 years as it was thought that there is a necessity to establish the co relation between the traumatic brain injury and post traumatic endocrinopathy having new cases or prevalence of disease in people who were diagnosed in the early phase (51). The reason that it is important to have a follow up studies is because it is essential to establish whether the pituitary hormone deficiencies which may be seen in the early phase are sustained at follow up stages or if there is new emergence patter of deficiencies at the follow up which were not a part of the results obtained in the early phase investigation. Some studies do state that the hormone levels in a patient with traumatic brain injury reach a steady and permanent status after and approximate period of 6 – 12 months (52).

Though it has also been seen that a long term follow up, may provide to be useful to assess the pituitary hormone deficiencies (52) and their ongoing association, with emergence of new association in hormone levels in cases with intracranial haemorrhage. In the articles discussed here the duration specified for the acute phase investigation vary from day 1 within 24 hours of admission (53) (54) where as some studies have the initial investigation done on day 7 (52).

Though in Article 5(54) the first point of investigation was at day 1 the repeat evaluations were done on day 7 to assess whether there is any change pituitary hormone level through the 7 days as the results on day 1 could also be influenced by the stress of the injury. In article 4 (52) it was concluded that each pituitary hormone is effected in different way by the traumatic brain injury. Growth hormone and Gonadotrophin deficiency is the most common deficiency observed in the individual. Thus, reviewing the studies and analysing them proves to be useful to outline that deficiency in the pituitary hormone level whether it is independent of the acute reaction of the body to traumatic brain injury which could be a manifestation of a response to the stress of the injury. All this knowledge about the varying changes in the pituitary hormone level through various time interval is helpful while drafting a protocol for assessment of patients who have sustained a traumatic brain injury.

Gathering information from all the various studies done on this subject it can be summarised that yet there are no clear outlines which will help demarcate the group of patients with traumatic brain injury who should have a screening of their pituitary function. The fraction of patients which sustains any kind of trauma to head is huge and it is not feasible to perform tests for everyone. Hence it is essential to have guidelines to help us know which patients have a high probability of developing post traumatic hypopituitarism and should have screening and assessment for the same.

In 2005, a group of experts drafted a consensus statement (17) in view of increasing the awareness of the group of patients at risk of post traumatic hypopituitarism, the outcomes related to the deficiency and prognosis of the patient with the disorder. As stated in this statement all patient with traumatic brain injury who were hospitalised and presented with hyponatremia or hypotension underwent screening with routine basal hormone testing and re-evaluation at 3 month and 12 month follow up regardless of the severity of the head injury. Patients who were found to have and abnormality in any of the pituitary hormone level were then put through a complete set of tests for complete evaluation of the pituitary axis.

CONCLUSION

Reviewing the various studies and data available on this topic we can conclude that Post Traumatic Hypopituitarism forms a major contributor to the burden of healthcare. It is essential to recognise the importance of identifying and treating it (50). In an ideal situation, the best way to manage this would be to perform a multi-centre study for the purpose of outlining the prevalence and incidence of cases with post traumatic hypopituitarism (52). It apparent that doing this would be difficult to execute.

It might be helpful if a survey and audit is conducted and data collected from patients with traumatic brain injury with varying degree of severity of head injury. This input can be used to formulate a pathway for management of a patient with traumatic brain injury. The pathway should include details on the screening and evaluation of patients with traumatic event causing head injury in terms of i) outlining the group pf patient at risk of post-traumatic hypopituitarism, ii) the tests which should be used for assessment of pituitary functioning iii) the time intervals when the assessment should be performed for follow up.

A prompt diagnosis and management of an individual who has suffered a traumatic brain injury and has developed post traumatic hypopituitarism by hormone replacement decreased the morbidity and disability of the patient and improves the quality of life of the patient. There is rapid improvement in the prognosis of the patient and thus assessment and screening all patients with traumatic brain injury for pituitary deficiency is of prime importance.

12 questions to help you make sense of cohort study

How to use this appraisal tool

Three broad issues need to be considered when appraising a cohort study:

Are the results of the study valid? (Section A)

What are the results? (Section B)

Will the results help locally? (Section C)

The 12 questions on the following pages are designed to help you think about these issues systematically. The first two questions are screening questions and can be answered quickly. If the answer to both is “yes”, it is worth proceeding with the remaining questions.

There is some degree of overlap between the questions, you are asked to record a “yes”, “no” or “can’t tell” to most of the questions. A number of italicised prompts are given after each question. These are designed to remind you why the question is important. Record your reasons for your answers in the spaces provided.

These checklists were designed to be used as educational pedagogic tools, as part of a workshop setting, therefore we do not suggest a scoring system. The core CASP checklists (randomised controlled trial & systematic review) were based on JAMA ‘Users’ guides to the medical literature 1994 (adapted from Guyatt GH, Sackett DL, and Cook DJ), and piloted with health care practitioners.

For each new checklist a group of experts were assembled to develop and pilot the checklist and the workshop format with which it would be used. Over the years overall adjustments have been made to the format, but a recent survey of checklist users reiterated that the basic format continues to be useful and appropriate.

(A) Are the results of the study valid?

Screening Questions

1. Did the study address a clearly focused issue? Yes Can’t tell No

HINT: A question can be ‘focused’ In terms of

• The population studied
• The risk factors studied
• The outcomes considered
• Is it clear whether the study tried to detect a beneficial or harmful effect?

2. Was the cohort recruited in anacceptableway? Yes            Can’t tell           No

HINT: Look for selection bias which might compromise the generalisability of the findings:

• Was the cohort representative of a defined population?
• Was there something special about the cohort?
• Was everybody included who should have been included?

Is it worth continuing?

Detailed questions

3. Was the exposure accurately measured to minimise bias?                                  Yes    Can’t tell  No              

HINT: Look for measurement or classification bias:

• Did they use subjective or objective measurements?
• Do the measurements truly reflect what you want them to (have they been validated)?
• Were all the subjects classified into exposure groups using the same procedure.

4. Was the outcome accurately measured to minimise bias?               Yes           Can’t tell               No

HINT: Look for measurement or classification bias:

• Did they use subjective or objective measurements?
• Do the measures truly reflect what you want them to (have they been validated)?
• Has a reliable system been established for detecting all the cases (for measuring disease occurrence)?
• Were the measurement methods similar in the different groups?
• Were the subjects and/or the outcome assessor blinded to exposure (does this matter)?

5. (a) Have the authors identifiedallimportant confoundingfactors?

Yes         Can’t tell    No  

List the ones you think might be important, that the author missed.

(b) Have they taken account of the confounding factors in the design and/or analysis?

Yes      Can’ttell      No  

HINT: Look for restriction in design, and techniques e.g. modelling, stratified-, regression-, or sensitivity analysis to correct, control or adjust for confounding factors.

6. (a) Was the follow up of subjects complete enough?   Yes   Can’t tell   No

(b) Was the follow up of subjects long enough?                Yes   Can’t tell  No 

HINT: Consider

The good or bad effects should have had long enough to reveal themselves

The persons that are lost to follow-up may have different outcomes than those available for assessment

In an open or dynamic cohort, was there anything special about the outcome of the people leaving, or the exposure of the people entering the cohort?

(B) What are the results?

7. What are the results of this study?

HINT: Consider

• What are the bottom line results?
• Have they reported the rate or the proportion between the exposed/unexposed, the ratio/the rate difference?
• How strong is the association between exposure and outcome (RR,)?
• What is the absolute risk reduction (ARR)?

8. How precise are the results?

HINT: Look for the range of the confidence intervals, if given.

9. Do you believe the results?

Yes       Can’t tell        No

HINT: Consider

• Big effect is hard to ignore!
• Can it be due to bias, chance or confounding?
• Are the design and methods of this study sufficiently flawed to make the results unreliable?
• Bradford Hills criteria (e.g. time sequence, dose-response gradient)

(C) Will the results help locally?

10. Can the results be applied to the local population?

Yes       Can’t tell     No

HINT: Consider whether

A cohort study was the appropriate method to answer this question

The subjects covered in this study could be sufficiently different from your population to cause concern

Your local setting is likely to differ much from that of the study

You can quantify the local benefits and harms.

11. Do the results of this study fit with other available evidence?

Yes   Can’t tell  No 

12. What are the implications of this study for practice?

HINT: Consider

• One observational study rarely provides sufficiently robust evidence to recommend changes to clinical practice or within health policy decision making
• For certain questions, observational studies provide the only evidence
• Recommendations from observational studies are always stronger when supported by other evidence

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