Documenti di Didattica
Documenti di Professioni
Documenti di Cultura
Genevieve Sirois MD, Jo-Anne Aubut BA, Lilia Golverk MD, Robert
Teasell MD FRCPC, T. Arnold Bayley, MD, FRCPC, Mark Bayley
MD, FRCPC
1
Table of Contents
2
9.6 Treatment ................................................................................. 33
9.6.1 When to Begin Treatment Post ABI ................................................... 33
9.6.3 Immediate Hormone Replacement Therapy (HRT) ........................... 33
9.6.4 Gonadal Steroid Therapy .................................................................... 33
9.6.4.1 Androgen Replacement in Men or Testosterone Therapy ............... 33
9.6.4.2 Estrogen Replacement in Women ................................................... 34
9.6.5 Growth Hormone Replacement Therapy ........................................... 34
9.6.6 Replacement Therapy for SIADH........................................................ 34
9.6.6.1 Conivaptan Hydrochloride ................................................................ 34
9.6.7 Treatment of Diabetes Insipidus ........................................................ 34
9.6.7.1 Desmopressin (DDAVP) .................................................................. 34
9.6.8 Secondary Adrenal Insufficiency ....................................................... 35
9.6.8.1 Hydrocortisone ................................................................................. 35
9.6.9 Summary of Treatment........................................................................ 35
3
List of Common Abbreviations
4
Table Directory
Figure 9.1 Pituitary Gland: Normal Condition and Post Traumatic Condition
5
Key Points
Reducing the fluid intake of patients has been shown to be effective in treating
SIADH post ABI.
Insulin-like Growth Factor I (IGF-I) given post injury has been found to improve
outcomes in ABI patients; however, there is a limited amount of research
available.
Evidence has shown that an ABI can affect gonadropic function; however there
is very little evidence regarding possible treatments post injury.
6
9 ± Neuroendocrine Disorders Following Acquired Brain
Injury
9.1 History and Epidemiology
Neuroendocrine disorders, primarily hypopituitarism, was first diagnosed by the
German researcher Cyran in 1918 (Benvenga, 2005; Lieberman et al., 2001;
Makulski et al., 2008). Until recently damage to the hypothalamus and pituitary
gland following trauma was often not diagnosed until the post mortem
examination (Yuan & Wade, 1991). Recent research indicates neuroendocrine
disorders vary post traumatic brain injury (TBI) (Sandel et al., 2007) and what
was once thought to be a rare occurrence is now increasingly diagnosed
(Bondanelli et al., 2005; Ghigo et al., 2005; Benvenga, 2005). In the early
¶VWKHLQFLGHQFHRIK\SRSLWXLWDULVPSRVWLQMXU\ZDVWKRXJKWWREH
however, the rate has recently been quoted between 20 and 70% (Sirois, 2009,
Makulski et al., 2008). In a recent review of the literature, Schneider et al. (2007)
found the pooled prevalence of hypopituitarism was 27% post TBI and 47% post
stroke. In a study by Lieberman et al. (2001), the prevalence of neuroendocrine
dysfunction among study participants was found to be high. The pituitary gland is
most often affected with dysfunction occurring at the hypothalamic stalk or
pituitary level.
Blood and urine analysis are the most common means used to diagnose
neuroendocrine disorders. Disorders can be seen in the early days post injury,
while the patient is still in the acute stage of recovery, or in the later subacute
stage. Overall, neuroendocrine abnormalities, hypopituitarism and growth
hormone deficiencies are common among those with TBI, especially those who
have sustained moderate to severe injuries (Popovic et al., 2005).
Figure 9.1 shows the pituitary gland Figure 9.1 Pituitary Gland: Normal Condition and Post
under normal conditions (9.1a and b) Traumatic Condition
and how it can suffer injury during
and following a traumatic injury
(9.1c).
7
Table 9.1 Clinical Presentation of Hypopituitarism
Fatigue,
Sleep Disturbance
Decreased muscle mass, increased fat mass,
Reduced exercise tolerance and muscle strength,
Amenorrhea, decreased libido, erectile dysfunction,
Decreased cognitive function, concentration, memory,
Mood disturbances, depression, irritability,
Social isolation, decreased quality of life.
Neuroendocrine disorders post TBI result from specific injuries to those areas
that regulate physiological functions in various regions of the brain, specifically
injuries along the hypothalamic-pituitary axis (Sandel et al., 2007). Symptoms
will vary depending on the area of the brain that has been affected by the injury.
Current research suggests that anyone who suffers a brain injury (whether the
result of a stroke or a traumatic brain injury) and has a GCS between 3 and 12
should be tested for hormonal disorders or deficiencies (Behan et al., 2008).
Some discretion needs to take place in those patients with the most severe
disability (vegetative state) (Sesmilo et al., 2007). Individuals at greatest risk for
post-traumatic hypopituitarism (PTHP) are those who have sustained a diffuse
axonal injury, a basal skull fracture, or who were older at the time of injury.
Length of stay in ICU, longer hospitalization and a prolonged loss of
consciousness may also play a role in the development of hypopituitarism (Klose
et al., 2007).
In the acute phase, very early hormonal alterations may reflect adaptive
responses to injury and critical illness and are not necessarily associated with
long-term PTHP. Various studies have shown that the majority of patients with
low grade or isolated deficiencies recover during the first 6 months post injury
and tend to have a much better prognosis than those who do not recover
(Bondanelli et al., 2004; Aimaretti et al., 2005; Aimaretti et al., 2004). In one
study, 5.5% of patients who showed no signs of PTHP deficiencies at 3 months
did so later at 12 months. The same study showed that 13.3 % of patients who
demonstrated isolated deficiencies at 3 months developed multiple deficiencies
at 12 months (Aimaretti et al., 2005). Growth hormone deficiency has been
shown to be the most common deficit (Bondanelli et al., 2004; Aimaretti et al.,
2005)
Due to the nature of its features and the delay of its presentation, hypopituitarism
may be missed following a stroke or an ABI (Schneider et al., 2007); thus, the
diagnosis of hypopituitarism following an ABI remains a challenge. Some of the
key indicators, such as low serum-like growth factor, may already be low in older
patients due to normal aging. Studies looking at this issue to date indicate TBI
severity, as measured by the GCS or EEGs, is not an accurate indicator of the
likelihood of developing hypopituitarism. There is however, a trend to show an
association with TBI severity (Sirois 2009).
8
9.1.2 Association with Severity
There is as of yet no clear association of the development of PTHP with the
severity of TBI, the type of accident or the type of injury. Although it has been
shown by several researchers that PTHP patients had significantly lower GCS
than unaffected survivors (Sirois, 2009, Bondanelli et al., 2001; Klose et al.,
2007); this has not been a consistent finding (Aimaretti et al., 2005; Bondanelli et
al., 2007). The incidence of skull fractures and neurosurgical procedures has
been reported to be similar in patients with hypopituitarism when compared to
those with normal pituitary function (Bondanelli et al., 2007).
Benvenga et al. (2000) have noted that hypopituitarism post TBI is primarily a
disorder seen much more often with male survivors between the ages of 11 and
39 years. This is likely related to the fact that greater number of younger males
tend to sustain head injuries more often. Currently there is no evidence that
specific types of head injuries are more likely to lead to hypopituitarism (Ghigo et
al., 2005). Due to the life threatening consequences associated with pituitary
dysfunction, it represents a negative prognostic factor (Benvenga et al., 2000).
9
ruptured. Diabetes insipidus often occurs as the result of inflammation and
edema around the posterior pituitary gland; however, this has been shown to
improve with time (Behan et al., 2008).
10
Table 9.5 Isolated and Multiple Pituitary Axes Affected (%)
Post traumatic phase 1 axis (single deficiency) 2 or more (multiple
deficiencies)
Acute 48% 28%
3 months 6.5% 6.5%
12 months 4.3% 6.5%
The pituitary gland is connected to the hypothalamus through the pituitary stalk
and controls both homeostasis and endocrine function.
The anterior lobe contains glandular cells which Figure 19.2 Diagram of Hypothalamic-Pituitary
Axis
secrete hormones into circulation. It is
controlled by the hypothalamus through the
vascular portal system. The posterior lobe
contains the axons and nerve terminals of neurons
which have their cell bodies in the hypothalamus.
These hormones serve to regulate endocrine systems in other areas of the body
and are under control of hypothalamic releasing factors.
11
Thyrotropic releasing hormone Æ thyroid hormone release
LHRH/GnRH Æ FSH and LH release
Corticotropic releasing hormone Æ ACTH release
Prolactin releasing factor (PRF) and throtropin-releasing hormone (TRH)
Æ prolactin
The posterior lobe is responsible for the secretion and storage of 2 hormones:
Vasopressin (or antidiuretic hormone (ADH)) promotes water retention in
the kidneys, which allows for concentration of urine.
Oxytocin allows for milk let down in the breast and causes uterine
contractions during labour.
The following table (Table 9.7) lists those hormones that are released by both the
anterior or posterior pituitary glands and WKHERG\¶VUHVSRQVHWRWKLV
12
Hormone (ACTH)
13
and often mimic the neuropsychological sequelae of TBI. It is therefore
reasonable to consider performing baseline hormonal evaluation in more severe
TBI or SAH patients. Early post injury the most important anterior hormones to
screen may be thyroid, growth and Adrenocorticoid axes as these will lead more
quickly to symptoms that may affect recovery although baseline testing of all
hormones allow more easy clinical follow-up.
Because hypotituitarism can evolve over time post injury, it is important to begin
screening as soon as possible. In the acute stage, due to its life threatening
potential, screening for adrenal insufficiency is important (Bernard et al., 2006).
During this stage of recovery, cortisol levels of less than 7.2ug/dL may indicate
adrenal insufficiency. Treatment should also be considered and initiated in those
cases where hyponatremia, hypotension and hypoglycaemia are present and
cortisol levels are between 7.2 and 18ug/dL (Schneider et al., 2007). For those
who have extended stays in the ICU and increased intracranial pressure, diffuse
axonal injury, or basal skull fractures assessing pituitary function may be
necessary and should be considered. While in the acute stage of recovery it is
not necessary to assess growth, gonadal or thyroid hormones as there is no
evidence to suggest supplementation of these hormones during this phase is
beneficial (Schneider et al., 2007; Ghigo et al., 2005); however, during the post
recovery stage, at 3 and 6 months, a clinical assessment for hypopituitarism
should be completed (Powner & Boccalandro, 2008; Powner et al., 2006;
Schneider et al., 2006). This is especially important if any of the following are
noted: loss of secondary hair, impaired sexual function, weight changes,
polydipsia, or amenorrhea.
14
For mild TBI it has been suggested to test only patients who spend more than 24
hours in hospital, who have an abnormal CT scan, or who initially have
symptoms suggesting post-traumatic hypopituitarism.
Hormonal screening should include 0900 AM serum cortisol, fT3, fT4, TSH, FSH,
LH, testosterone in men and E2 in women, prolactin, and IGF-I. In patients with
polyuria or suspected diabetes insipidus, urine density, sodium and plasma
osmolality should also be evaluated. Low IGF-I levels strongly predict severe
growth hormone deficiency (in the absence of malnutrition). Normal IGF-I levels
may be found in patients with growth hormone deficiency; therefore, provocative
tests are necessary in patients with another identified pituitary hormone deficit.
Provocative testing is recommended if IGF-I levels are below the 25th percentile
of age related normal limits (Ghigo et al., 2005).
Figure 9.4 Screening for hypopituitarism based on severity of head injury (Estes & Urban,
2005; Sirois, 2009)
Head Injury
(TBI/SAH)
If Symptoms Develop
9.4.4 Neuroimaging
In a recent review of the literature, Makulski et al. (2008) concluded that
magnetic resonance imaging (MRI) is the preferred imaging technique for the
pituitary gland as it can readily distinguish between the anterior and posterior
lobes. An MRI allows for both visualization of structural abnormalities and indirect
imaging of the blood supply. The most common pathological findings are
haemorrhage of the hypothalamus and posterior lobe and infarction of the
anterior lobe of the pituitary (Makulski et al., 2008; Maiya et al., 2008). While
15
widely regarded as the best imaging technique, MRI may still fail to show
pathological abnormalities in some patients with post traumatic hypopituitarism
(Makulski et al., 2008).
16
Adrenocortical insufficiency is confirmed with a serum cortisol <500 nmol/l (18
lg/dl). Standard ACTH tests should be done 4 weeks at the earliest after pituitary
surgery (Auernhammer & Vlotides, 2007).
Metyrapone
Metyrapone has been shown to block the last step in the biochemical pathway
from cholesterol to cortisol, leading to a reduction in serum cortisol, an increase
of ACTH secretion and an increase of cortisol precursors such as 11b-
deoxycortisol. The peak serum 11b-deoxycortisol levels in healthy people range
between 195 nmol/l to 760 nmol/l. During the test, serum 11-deoxycortisol may
increase to >200 nmol to exclude adrenal insufficiency. Another variant of the
test is WKHµµPXOWLSOHGRVHPHW\UDSRQHWHVW¶¶UHTXLUHRWKHUGLDJQRVWLFFXW-offs of
serum 11-deoxycortisol levels. In order to sustain this multi-step testing patients
must be hospitalized. Metyrapone may cause gastrointestinal upset and may
lead to adrenal insufficiency (Auernhammer & Vlotides, 2007). Currently this test
is considered only if other tests are inconclusive.
17
Short ACTH stimulation test 250 µg recombinant human ACTH and serum cortisol, given
intravenously. The responses are assessed at 0, 30 and 60 min.
Table 9.10 Hormone Delivery and the Effects of Insufficiency (Makulski et al., 2008) p.326
Pituitary
Anterior pituitary
Somatotrophs Lactotrophs Gonadotrophs Thyrotrophs Corticotrophs
Targets
Musculoskeletal Mammary gland Gonads and Thyroid gland Adrenal gland
System Ovaries
Symptoms of Insufficiency
abdominal fat lactation facial wrinkles dry skin, depression,
LDL secretion of weight, anxiety,
estrogen and depression, fatigue,
progesterone fatigue & apathy,
muscle cognitive nausea,
mass, libido deficits vomiting, & under
vigor, fertility, stress,
concentratio pubic hair & Ļcold tolerance hypoglycemia
HDL axillary hair & heart rate hyponatremia
ĻZHLJKWVWUHQJWK
& skin color
Posterior Pituitary
Oxytocin Vasopressin
Targets
Mammary gland and Uterus Kidney and Arterioles
Symptoms of Insufficiency
lactation & uterine contractions blood pressure & water retention
18
an acute TBI are disorders of salt and water balance resulting in inappropriate
secretions of antidiuretic hormone (SIADH), hyponatremia and diabetes insipidus
(DI). Abnormalities of antidiuretic hormone represent one of the most common
endocrine disturbances that occur in patients following a TBI (Powner et al.,
2006).
Individual Studies
Table 9.11 Syndrome of Inappropriate Secretion of ADH (SIADH) Post TBI
Author/Year/
Country/ Study
Methods Outcome
design/PEDro
and D&B Score
Doczi et al., N=84 1808 patient charts were During the first week post injury, of the
(1982) reviewed. Only patients with 84 pts who developed SIADH 8.2% had
Hungary evidence of syndrome of a moderate to severe TBI. 41 patients
Chart Audit inappropriate secretion of developed symptoms of SIADH but these
antidiuretic hormone (SIADH) symptoms resolved themselves in a few
were included. Patients were days and did not require drastic fluid
given 400 to 500 ml of 5% restriction. The remaining 43 patients
dextrose in half-normal sodium developed severe SIADH and required
chloride solution every 8 hours. fluid restriction.
SIADH was diagnosed when the
following symptoms were present:
serum sodium below 134
mmol/litre, serum osmolality
below 280 mosm/kg, urine
sodium (24hrs) above
30mmol/litre and urine osmolality
higher than serum osmolality.
Born et al., N=109 Patients with severe TBI Six of the 36 patients were diagnosed 3
(1985) were included in the study and of to 4 day post injury with SIADH, the
Belgium these 36 (or 33%) developed remaining 30 were diagnosed 7 to 19
Case series hyponatremia according the lab days post injury. For those diagnosed
definition of SIADH. 5% glucose several days post injury, serum sodium
in a 0.45% saline solution at the values indicated moderate or severe
rate of 50mL/h was intravenously syndromes.
19
fed to patients during the 3 days
post injury.
Discussion
In a review of 1808 ABI patients conducted by Doczi et al.(1982), the authors
reported 84 patients developed SIADH, with the majority of these patients
suffering a moderate (n=60) to severe (n=19) head injury. Of the 84 patients, 43
ZHUHIRXQGWRKDYHGHYHORSHGVHYHUH6,$'+3DWLHQWV¶ZHUHGLDJQRVHGZLWK
elevated intracranial pressure resulting from suspected brain edema, and each
required strict fluid restriction. In this group of patients, serum sodium levels
were found to be below 125 mmol/litre and each had an osmolality below 270
mosm/kg. Deterioration of the original injury and the development of
complications can result in a delay in the diagnosis of SIADH.
In another study, conducted by Born et al. (1985), of the 36 patients who were
diagnosed with a severe ABI, all developed signs of SIADH. Six were diagnosed
within 4 days of injury (early syndrome), while in the remaining patients SIADH
became noticeable 7 or more days (late syndrome) post injury. The authors also
noted that 33% of patients who underwent surgery showed signs of SIADH.
Authors suggested limiting fluid intake (250 to 500 ml per 24 hours) to resolve
symptoms.
Conclusion
Results from two studies found those who had sustained a severe ABI
were more likely to develop symptoms of SIADH. In both studies the
authors suggested restricting fluid intake to assist in the resolution of
symptoms.
9.5.1.3 Hyponatremia
Hyponatremia, defined as serum sodium concentration less than 136 mmol/L
(Gross, 2008) may result from SIADH or cerebral salt wasting. Prevalence rates
for severe hyponatremia among the ABI population have been found to range
from 2.3% to 36.6% (Chang et al., 2008). Symptoms of hyponatremia include
lethargy, coma, or seizures. Recommendations for the treatment of
hyponatremia, resulting from SIADH, include limiting daily fluid intake. The death
rate for those diagnosed with hyponatremia is 60% higher than for patients who
do not have it.
20
Individual Studies
21
this hyponatremia was noted as sodium
levels once again were found to be
121mEq/dl. Cerebral salt wasting was
established and the patient was treated with
saline both intravenously and orally. The
situation began to resolve itself within a few
days.
Chang et al., N=1 A 48 year old male Patient was treated with hypertonic saline
(2008) patient suffered a rapid (3%NaCl) and fluid restriction. Sodium levels
China drop in serum sodium improved gradually.
Case Study levels.
Discussion
Zhang et al. (2008), looked at the development of central hyponatremia in a
group of ABI patients (n=68; GCS scores were 3-15) and a group of non-ABI
patients (n=24). Blood osmotic pressure was only found to be significantly
different between those with a mild or moderate ABI compared to those with a
severe TBI. Test results showed urine osmotic pressure was significantly
different (p<0.01) between the ABI group and the non-ABI group. No significant
differences were noted within the 3 ABI groups. Blood sodium levels between the
ABI group and the non-ABI group were found to be significantly different with the
ABI group having lower sodium (Na+) concentrations in their blood than the non-
ABI group (p<0.02). Within the ABI group, the majority of patients (n=25) who
had sustained a severe TBI were diagnosed with hyponatremia and were found
to have a significantly lower Na+ than those in the mild to moderate ABI groups
(p<0.05) (Zhang et al., 2008).
Moro et al. (2007) conducted a review of 298 patient files and found 50 patients
presented with signs of hyponatremia. Those diagnosed with hyponatremia were
found to have worse outcomes, longer stays in hospital and most were
diagnosed within the first 3 days of injury. Treatment included sodium
supplementation therapy, which was effective for 37 patients. The remaining 13
patients received sodium supplementation therapy and sodium retention therapy
with hydrocortisone. The administration of the hydrocortisone allowed the serum
sodium levels to reach the normal range within 3 days as sodium excretion was
reduced as was urine volume.
Zafonte and Mann (1997) and Chang et al. (2008) each published case studies
where hyponatremia was present. Zafonte and Mann (1997) noted that the
SDWLHQW¶VVRGLXPOHYHOKDGGHFUHDVHGWRP(JG/VKHKDGORVWZHLJKWand
was clinically dehydrated. The patient was treated intravenously with normal
saline and oral salt supplementation. $QLPSURYHPHQWZDVIRXQGLQWKHSDWLHQW¶V
serum sodium levels within days.
22
and after 3 more episodes of hyponatremia, sodium levels increased and
stabilized.
Individual Studies
23
neurosurgical intensive care; that of the control group (40lcal/kg/day).
however those in the treatment During the 14 day period of the
group also received insulin-like intervention, the WUHDWPHQWJURXS¶V
growth factor-I for 14 days. The nitrogen intake decreased significantly
following were monitored: energy compared to the control group
expenditure (MEE), nitrogen, (p<0.0002). Again when looking at
weight, serum IGFI concentrations weight gain and weight lost, those in the
and glucose. Glasgow Coma Score control group were found to have had a
(GCS) were evaluated daily during weight loss of approximately 3 lbs, while
the study and Glasgow Outcome the treatment group were found to have
Scores (GOS) were taken at day had a weight gain of approximately 2 lbs.
15, 28 and 6 months post injury. Glucose concentrations were also higher
among the control group. Serum IGF-I
concentration which were low for all
patients were elevated for all in the
treatment group but only 6 control
patients were found to have the serum
IGF-I levels increased at the end of the
study. The treatment group were able to
elevate their IGF-I levels in about 4 days
compared to 11 days for the control
group.
PEDro = Physiotherapy Evidence Database rating scale score (Moseley et al., 2002).
D&B = Downs and Black (1998) quality assessment scale score.
Discussion
In an RCT, Hatton et al. (1997) randomized patients with GCS 5-7 initially to
placebo or to the treatment group that received insulin-like growth factor-I (IGH-
I) administered as 5 mg rhIGF-I/1ml citrate/NaCL, pH6 via a continuous
intravenous infusion within the first 72 hours that continued for 14 days. Both the
control and treatment group were provided with nutritional support. In total 5
patients died during the study: 2 were in the treatment group and 3 were in the
control group. Study results indicate those in the treatment group gained weight
even though they had a lower caloric intake and higher energy expenditure. The
control group lost weight and were found to have greater nitrogen outputs and
daily glucose concentrations. Nitrogen intake during week 2 was significantly less
in the treatment group (p=0.002) when compared to the control group. Nitrogen
output was greater in the control group over the two week study period,
compared to the treatment group. Glucose concentrations were also higher in the
control group, when compared to the treatment group during the study period.
GOS improved, from poor to good, for 8 of the remaining 11 patients in the
treatment group. In the control group, the Glasgow Outcome Scale improved in
only 3 patients.
Hadjizacharia et al. (2008), in a study of 436 head injured patients, found 15.4%
(n=67) developed diabetes insipidus. Onset of diabetes insipidus for most
patients occurred within the first few days of admission to acute care (mean =1.2
days), with treatment beginning on average of 1.6 days post diagnosis. There
was a significantly higher incidence of complications in the DI group when
compared to the remaining group (p=0.016). Those at greatest risk for
24
developing DI were those whose GCS was </=8. Those in the DI group were also
found to have a higher mortality rate.
Agha et al. (2005) found 13 out of 50 ABI patients developed DI within the first 11
days post injury. It was also noted that these patients had a lower GCS score
than those who did not develop DI. Diabetes insipidus was treated with
desmopressin, subcutaneously at first and then orally. Six months post injury
only 4 of the 13 patients were found to have persistent DI. At the 12 month, 3
patients were still being treated for DI. When accessing patient outcomes, using
the GOS, 5 of the 13 with DI had Glasgow Outcome scores between 1 and 3.
Conclusion
Results of the studies indicate that DI is associated with lower GCS, lower
GOS and a higher mortality rate.
There is Level 2 evidence suggesting IGF-I given post ABI may improve
clinical outcomes in patients diagnosed with DI.
Insulin-like Growth Factor I (IGF-I) given post injury has been found to
improve outcomes in ABI patients; however, there is a limited amount of
research available.
Bondanelli et al. (2007) noted that anterior hypopituitarism occurred in 26% of the
TBI patients in their study. All were approximately, 6 months to one-year post
injury. These results compared well to previous studies which noted anterior
hypoituitarism occurred in about one-third of those who were 5 years post injury
(Aimaretti et al., 2005; Agha & Thompson, 2006). Results also indicated that the
LH-FSH and GH axes were directly related to the high occurrence of isolated
deficiencies (Bondanelli et al., 2007). Furthermore, complete hypopituitarism was
detected in only 1.4% of the 72 participants in the study. Study authors also
found that pituitary dysfunction did not appear to be related to the GCS which
was noted in several previous studies.
25
In a systematic review, Urban et al. (2005) concluded that regardless of the
severity of injury, APH deficiencies (including GH deficiency) in those who had
had a TBI were more common than originally thought. Difficulties in diagnosis
arise because these hormonal deficiencies can produce physical and
psychological symptoms which mimic symptoms generally associated with other
brain trauma pathology. Urban et al. (2005) noted that the consequences of
these hormonal abnormalities can be significant; for instance, hypopituitarism
can increase the risk of ischemic heart disease and even a shortened life span.
The following studies monitored the function of the APD in individuals with an
ABI.
Individual Studies
Schneider et N=78 All patients underwent First evaluation (3 months post injury):
al., (2006) hormonal and clinical 44 of the 78 patients showed signs of
Germany assessments at 3.5 months impairment of at least one pituitary axis.
post injury and again at 13 15 had hypocortisolism
months post injury. Patients In 6 secondary hypothyroidism was found
underwent a CT scan, and Those with impaired GH secretion were
hormone measurements were found to be older and had higher BMIs, and
taken. GCS, modified Rankin lower IGF-I levels.
scale scores, BMIs were Second evaluation (12 months post injury):
recorded for all patients. 36% continued to have hormonal
disturbances.
Those with hypopituitarism were older than
those not diagnosed with hypopituitarism.
Modified Rankin Scale scores were higher
among those with hypogonadal.
Schneider et N=78 Patients who had Testing at both time periods indicated that
al., (2008) sustained a TBI participated in greater diffuse axonal injury was associated
Germany the following study. All were 14 with a higher prevalence of hypopituitarism.
(follow-up to weeks post injury and were Hypogonadism was more frequent for those
previous assessed again at 13 months whose TBI resulted in transient diabetes
study) post injury. Patients underwent insipidus, or whose injury was the associated
a CT scan, and hormone with polytrauma and/or hypoxia. t.
measurements were taken
Agha et al., N=104 Patients with a An anterior pituitary hormone deficiency was
2004 moderate to severe TBI ranging found in 29 of the 102 patients studied. 10.7%
Ireland in age from 15 to 65 yrs were were found to be GH deficient, with 8.8%
included. All underwent thyroid having severe GH deficiencies. Those found to
testing 17 months post injury be GH deficient also had a higher body mass
index. 12 patients (of which 10 were men) had
gonadotropin deficiency. This deficiency did not
appear to be associated with gender, BMI,
GCS, CT scan results, cerebral edema or mass
evacuations; however, it did appear to be
26
associated with age.
Tranriverdi N=104 Patients with mild No significant differences were noted between
et al., 2007 (n=49), moderate (n=24), and the age, TSH, cortisol, ACTH, FSH, LH, IGF-I,
Spain severe (n=31) TBIs were GH and free testosterone levels between the
included. Hormonal testing was groups. Based on prolactin levels 19 of 97
conducted post injury. patients had hyperprolactinemia. GCS were
negatively correlated with prolactin levels (r=-
0.26, p=0.01), positively correlated with cortisol
levels (r=0.20, p=0.04), cortisol levels were
positively correlated with ACTH levels (r=0.42,
p=0.0001). In males testosterone levels were
positively correlated to GCS (r=0.25), p=0.04).
When looking at deaths (n=20), these were
related to age and GCS. Pituitary hormone
deficiencies were noted: TSH deficiencies in
3.8%, gonadotropin in 40%, ACTH deficiency
in 8.8% of the patients.
Tranriverdi N=52 All patients underwent GH levels decreased between T1 and T2, At 1
et al., 2006 basal hormonal testing with in yr post injury, those who were GH deficient
Spain the first 24 hours of admission were found to be older. IGF-I levels were also
to acute care and were found to be lower than the levels found in
revaluated 12 months later. patients who were GH sufficient. GH
Various hormonal assessments deficiencies were not originally detected in 7 of
were conducted the 13 patients diagnosed with the problem.
ACTH deficiencies were found in approximately
19% of patients in total. In the initial ACTH
screening, deficiencies were noted in 5 patients
but at the end of one year, deficiencies were
noted in 10. Four of the original 5 had
recovered, while 9 were newly diagnosed.
Tranriverdi N=30 All patients involved with Basal hormone levels were measured at 1 yr
et al., 2008 the study had sustained a TBI post injury (T1) and again at the third yr post
Spain through either traffic accidents injury (T2), with no significant differences
(follow-up to or falls. The majority of patients noted. The total testosterone and free
2006 study) (n=19) were found to have mild testosterone levels were significantly different
injuries and the remaining 11 from T1 to T2. Total testosterone levels were
SDWLHQWV¶LQjuries were found to lowered in patients with a severe TBI
be moderate or severe. All compared to those with a mild or moderate
underwent various hormonal TBI.
testing.
Cernak et N=31 Individuals were divided Changes in hormonal levels were more
al., (1999) into 3 groups: group 1 mild TBIs profound in those who had sustained a severe
Yugoslavia (n=8) with no significant injury. TSH levels were elevated in those who
neurological deficits; group 2 had sustained a mild TBI for the first 3 days
severe TBIs (n=10) who had following an injury. Those with severe injuries
sustained severe injuries due to TSH levels remained low for the first 7 days
a GSW to the head; group 3, 13 following the injury. T3 levels remained low in
indirect neurotrauma patients. those with a severe TBI for the entire time of
Patients were then compared to the study (7 days). T4 levels appeared to be
a group of normal subjects unchanged in all groups regardless of the level
(n=10). Blood level of of injury. Serum cortisol levels were also
testosterone, thyroid stimulating elevated for those with TBIs.
hormone (TSH), total
triiodothyronine (T3), throxine
(T4), and serum cortisol were
taken on all patients.
27
Discussion
Study results reported Schneider et al. (2006; 2008), found that 56% of the 78
TBI patients who participated, had a least one pituitary axis impairment. Overall,
no significant differences were noted when looking at GCS, modified Rankin
scores, BMI, and age between those with and without hypopituitarism. Those
with impaired GH secretion were found to be older and had higher BMIs, and
lower IGF-I levels. Twelve months post injury fewer patients were affected, but
several new cases were diagnosed.
Agha et al. (2004) in one of the largest studies of individuals (n=102) with a
moderate to severe TBI found a high prevalence of undiagnosed hypopituitarism.
More than a quarter of study subjects were found to have a large amount of
undiagnosed anterior hormone deficiency. Those who were GH-deficient had a
significantly higher body mass index (p=0.003) and lower IGF-I concentrations
(p<0.001) than GH-sufficient patients. No relationship was found between the
GCS, age and other pituitary hormone abnormalities and deficiencies of the GH
or ACTH (p > 0.05) (Agha et al., 2004).
Cernak et al. (1999) found changes in hormonal levels were affected by the level
of injury a patient had sustained. Those with severe injuries were diagnosed with
greater hormonal changes. In patients with a mild TBI TSH levels were elevated
for the first 3 days following an injury; however, in patients with a severe injury
TSH levels remained low for the first 7 days following the injury. T3 levels
remained low in those with a severe TBI throughout the study; however, T4 levels
appeared to be unchanged in all groups regardless of the level of injury.
28
Conclusion
Studies have shown that those who suffer from moderate to severe TBIs
are at greater risk for developing hormonal deficiencies. This may lead to a
poorer outcome following a TBI as hypopituitarism has been shown to
negatively influence recovery.
Individual Study
Lieberman et al., N=70 Adults (both males and GCS were available for only 38
(2001) females) who had sustained a subjects, of which 32 were diagnosed
USA TBI participated in the following with a severe TBI. Seven of the 48
Cohort study. Routine endocrine patients (14.6%) who underwent
testing was performed on all glucagon stimulation testing were
participants. Included in these found to be GH deficient. In the 7
tests were TSH, free T4, (FT4), diagnosed with GHD, IGF-I levels were
PRL and IGF-I, and a short also lower than the remaining 41
corticotropin stimulation test patients. In 2 of 69 patients, free T 4 and
(ACTH). Testosterone levels TSH levels were well below the lower
were measured in male patients limit of normal. 6 subjects with normal
and a menstrual history was TSH, had low FT4, and in those with
taken in female patients. When normal FT4, 7 and low TSH. In almost
possible GCS were recorded. half of all subjects (n=32) basal
29
morning cortisol levels were below
normal.
Discussion
Leiberman et al. (2001), examined at the prevalence of neuroendocrine disorders
in those who had sustained a TBI and noted that GHD was diagnosed in 7 of the
48 patients tested. To diagnose GHD deficiencies the authors used glucagon and
L-dopa stimulation tests as the majority of patients were diagnosed with a severe
TBI. Further testing (IGH-I testing) was also conducted confirming the presence
of GHD in these 7 patients. Of the initial 70 patients who participated, early
morning cortisol levels were lower in 46%. In 15 patients, blood work revealed
TSH or FT4 levels were below the normal range. Overall, 36 patients had a single
abnormal axis, while 12 were diagnosed with two abnormalities. The remaining
22 patients were found to have no abnormalities (Lieberman et al., 2001). Given
these abnormalities can impair recovery, the study authors recommended the
routine testing of TBI patients.
30
Table 9.17 Presentation of Gonadotropine Deficiency
Testosterone and estrogen/progesterone
Hypogonadism - oligomenorrhea, amenorrhea, infertility, sexual dysfunction, decreased libido
Muscle atrophy, osteoporosis, loss of hair
Reduced tolerance to exercise
Decreased memory and cognitive performance
Individual Studies
Table 9.18 Gonadotropic Dysfunction Post ABI
Author/Year
Country/ Study
Methods Outcome
Design
Kleindienst et N=71 Both male and female Gonadotropic dysfunction was noted in
al., (2009) patients ranging in age from 18 to both males and females. Gonadotropic
Germany 87 participated in the current study. insufficiency was noted in 9 of the 71
Prospective Various blood samples and urine patients upon admission to hospital; 17
samples were collected from each patients on day three, and 13 patients
participant. Glasgow Outcome on day seven.
Scores (GOS) were used to assess
patients at 6 month follow-up
Lee et al., N= 21 Male patients were recruited Testosterone levels in all 21 patients
(1994) to participate in the study. GCS, the were adversely affected by the head
China Disability Rating Scale (DRS) and trauma. Fourteen men were found to
Prospective the Rancho Los Amigos Cognitive have abnormally low serum
Behavioural Scale (RLACBS) were concentration of testosterone, 7 were
used to assess all participants. found to be toward the lower end of the
Individuals had diffuse or focal brain normal range. GCS scores and results
injuries. Testosterone, follicle from the DRS and RLACBS were not
stimulating hormone (FSH) and correlated to serum concentrations of
luteinizing hormone (LH) levels testosterone FSH or LH.
were assessed for all participants
Discussion
Two studies have examined the development of hypogonadism post ABI.
Kleindienst et al. (2009) reported gonadotropic dysfunction was found in both
genders. Deficiencies were noted in 13% of patients upon admission to hospital.
20 more patients were diagnosed with a deficiency within the first week post
injury. Study results also indicated that those who had sustained more severe
injuries had either lower testosterone levels or luteinising hormone levels. In an
earlier study, Lee et al. (1994) found similar results. In their study of males who
had sustained a TBI, all were found to have altered levels of testosterone post
injury. Fourteen of the twenty-one participants had an abnormally low serum
concentration of testosterone, while the remaining 7 had levels towards the lower
end of the normal range.
31
Evidence has shown that an ABI can affect gonadotropic function;
however, there is very little evidence suggesting possible treatments post
ABI.
9.5.2.3 Hyper/Hypoprolactinemia
Hyperprolactinemia has been shown to be present in more than half of ABI
patients in the early acute phase and it is believed that symptoms may be
present in 30% of patients diagnosed with hyperprolactinemia (Bondanelli et al.,
2005). Kilimann et al. (2007) found males had higher levels of prolactin than
females and more males were found to have hyperprolactinema than females. Of
note, all patients with hyperprolactinemia also either had an infection, were
hypoglycemic, or were on dopamine antagonists, GABA agonists, opiates or
central catecholamine depletors. All of these medications are known to increase
prolactin levels.
32
Table 9.20 Clinical Presentation of TSH Deficiency
Fatigue, anemia,
Paleness, cold intolerance,
Muscle atrophy/cramps,
Weight gain, depression,
Loss of outer 1/3 of eyebrow, coarse hair,
Coarse voice, macroglossia,
Pre-orbital oedema
Bradycardia,
Constipation
Neuropsychiatric disorders (hallucinations, delirium)
9.6 Treatment
9.6.1 When to Begin Treatment Post ABI
To date there is no relevant data or guidelines on when to treat, how to treat or
what medication to administer. It has been suggested that testing should begin
immediately for those individuals who have been diagnosed with a moderate or
severe ABI (Estes & Urban, 2005), and are no longer in a coma or vegetative
state. Those who sustain diffuse axonal injuries (DAI) resulting from a MVA may
be at even greater risk, regardless of the severity of injury, due to the rotational
forces which the brain is subjected to (Estes & Urban, 2005). It is reasonable to
repeat screening at a minimum 6 and 12 months post injury and again at 18 and
24 months post injury in those who had a severe injury or early diabetes
insipidus.
Conditions that require immediate treatment are ACTH, ADH, TSH and
panhypopituitarism. GHD as been shown to improve with time and may improve
as other deficiencies improve; therefore, it is not necessary to begin treatments
the moment it is diagnosed particularly if it is an isolated incidence. Also
treatment in the acute phase is not recommended for GHD as there appears to
be no benefit (Sirois, 2009). For those who sustain a mTBI and a GH deficiency
has been noted during regular blood work, but no other symptoms have
appeared, it is suggested waiting 3 years post trauma to begin treatment to see if
the condition will reverse itself. If possible, when there is clear indication of
anterior or posterior pituitary dysfunction consulting an endocrinologist is strongly
recommended (Estes & Urban, 2005).
33
2001). Often GHD escapes detection for months or year post injury. Symptoms
of growth hormone deficiency include fatigue, decreased muscle mass,
osteoporosis, exercise intolerance, dyslipidemia and truncal obesity as well as a
number of cognitive deficits and a poorer quality of life (see table 9.15)
(Schneider et al. 2007; Sandel et al. 2006).
34
9.6.8 Secondary Adrenal Insufficiency
9.6.8.1 Hydrocortisone
Moro and colleagues found that the administration of hydrocortisone was
beneficial in reducing the amount of sodium excretion in a small group of patients
with a TBI (Moro et al., 2007). Although the risk of adverse effects appears to be
low, when administering hydrocortisone, more research is needed.
Table 9.21 Endocrine Treatments Post ABI (Mitchell & Owens, 1996)
Condition Treatment Dosage
Hormone Replacement Somatropin 0.06 mg/kg subcutaneous or
Therapy (HRT) intramuscular (3x/wk)
Hypogonadism Testosterone therapy Implants
(males) Oral test therapy
Intramuscular therapy
Transdermal patches
Intramuscular injection
9.7 Conclusions
Neuroendocrine dysfunction post ABI is more frequent than initially thought. The
prevalence varies considerably among studies and this may reflect the
inaccuracy of actual testing methods. Neuroendocrine disorders often result in a
variety of symptoms such as: temperature lability, appetite disturbances,
decreased muscle mass, sleep disturbances, decreased hair, decreased libido,
and disorders of fluid regulation, or hypertension (Sirois, 2009). With the
exception of diabetes inspidus other neuroendocrine disorders remain under
35
reported and under diagnosed. Testing should be done while the patient is in
acute care for ACTH and ADH deficiencies and then during the next 12 months
for the remaining hormones. Although TSH is not a frequent deficit in the TBI
patient GH, ACTH and LH/FSH are. Failure to diagnose these dysfunctions could
LPSDFWWKHLQGLYLGXDO¶VUHFRYHU\SURFHVVDQGLPSDFWWKHLURYHUDOOTXDOLW\RIOLIH
36
Conclusions
1. Results from both studies found that those who had sustained a
severe ABI were more likely to develop symptoms of SIADH. In both
studies the authors suggested restricting fluid intake to assist in
resolving of symptoms.
4. Studies have shown that those who suffer from moderate to severe
TBIs are at greater risk for developing hormonal deficiencies. This
may lead to a poorer outcome following a TBI as hypopituitarism has
been shown to negatively influence recovery.
37
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