Tamara L. Wexler, MD, PhD, Chantel T. Debert, MD MSc FRCPC, Walter M. High, Jr., PhD, Brent E. Masel, MD, Alina Nico West, MD, PhD, Kevin C.J. Yuen, MD
CASE DISCUSSION
Experts from different disciplines were invited to provide their perspectives on a case. The responses highlight the different perspectives that may exist regarding post-TBI pituitary deficiencies and their importance in post-TBI health and quality of life, and the importance of clinical judgement and multidisciplinary collaboration and communication.
Further information on this topic from the perspectives of Neurology (p. 36), Physiatry (p. 28), Neuropsychology (p. 32), Pediatric Endocrinology (p. 22), and Adult Endocrinology (pp. 10 and 28) can be found in this journal edition. Military cases are thought to be sufficiently distinct that commentary was not included on this
non-military case; a full perspective and review on pituitary sequelae on TBI in Veterans is provided on page 16.
Case
A 28 yo female with a series of concussions sustained during soccer (most recently 6 months ago) presents at your office, noting that she is not recovering as she did from prior concussions. She has had trouble focusing and recalling words and events, and her productivity at her government job has declined due to difficulty sustaining work for more than several hours. She was told all testing was normal, but her speech and cognitive processing seem slower to her family and partner. On exam, she also describes new loss of libido and menstrual irregularity since the recent concussion; she ascribed these to stress, as she has also felt more anxious than usual. She has stopped playing soccer or exercising due to fatigue.
Perspectives
Brent Masel, Neurology: This young lady has had multiple concussions and has not recovered from her last blow 6 months ago. She now has cognitive and executive functioning issues. She has anxiety, altered menses, and extreme fatigue. Although the “work up” has been negative, unfortunately, “work ups” frequently lack a neuroendocrine evaluation.
Chantel T. Debert, Physiatry: This athlete has sustained multiple concussions in the past, recovering from each in the appropriate time period. However, following the most recent concussion, she has a protracted and halted recovery. The lack of consistent improvement, cognitive difficulties, altered libido and menses irregularities should cue the neurorehabilitation specialist that a deeper look into neuroendocrine abnormalities is warranted.
Walter High, Neuropsychology: A person can score well within the normal range for any given neuropsychological test and still be experiencing a significant decrement in their pre-injury cognitive performance. It is difficult to estimate expected pre-injury performance with precision without pre-injury testing which is rarely
available. Even if testing were available, performance on any given test can vary day-to-day, or year-to-year.
Decrements in functioning due to either concussion or growth hormone deficiency are often relatively small and difficult to detect because they fall within the same range as test-retest or inter-subject variability. The net result is that the person experiencing the decrement in cognitive function feels like they are having a ‘bad’
or ‘sluggish’ day, every day. This may be especially noticeable for persons working in cognitively demanding jobs or studies where even
a small decrement in performance may result in greater difficulty or even inability to complete a given task.
Case
The patient is referred to an endocrinologist. Initial screening tests (8a morning fasting cortisol, TSH and free T4,* estradiol with LH/FSH/prolactin,* and IGF-1*) appear normal, with the IGF-1 level in the lower part of the normal range.
Perspectives
Kevin Yuen, Endocrinology: Based on her history and symptomatology, a full neuroendocrine work up is recommended. If there are any non-GH pituitary hormone deficiencies detected, these deficiencies should be optimally replaced first before re-screening this patient again for possible GH deficiency with a serum
IGF-I measurement. If her serum IGF-I level continues to be low or low-normal together with the presence of symptoms, then GH
stimulation testing either with a GST or an ITT is recommended.
The GST is generally the preferred test because it does not require direct and close medical supervision and can be performed in an office setting, unlike the ITT. Libido issues are difficult to ascertain regarding cause and in the context of a patient with possible TBI-induced hypopituitarism, tend to be related to secondary hypogonadism or the injury itself rather than GHD.
B. Masel, Neurology: In this scenario, we will assume that her imaging and pituitary axis testing are normal, and her IGF-1 is low normal. Based on what you will read (p. 36), you would agree that the most likely diagnosis is BIAFAC, and she should be referred to an Endocrinologist for provocative (and definitive) testing of the
GH axis. If she is “lucky”, her testing will be abnormal and she can be started on growth hormone replacement which may markedly improve her symptoms.
Case
The endocrinologist, aware that normal-range IGF-1 levels can be seen in the presence of failed provocative testing for growth hormone deficiency (GHD), ordered a glucagon stimulation test (GST). Peak GH on the test was 2.9 mg/mL in this patient with normal weight (BMI 23 kg/m2).
Perspectives
K. Yuen, Endocrinology: The cut-offs for GST for diagnosing adult GHD are as follows:
- peak GH ≤ 3.0 mg/L in normal-weight (BMI < 25 kg/m2) patients
- peak GH ≤ 3.0 mg/L in overweight (BMI 25-30 kg/m2) patients
with a high pre-test probability - peak GH ≤ 1.0 mg/L in overweight (BMI 25-30 kg/m2) patients
with a low pre-test probability - peak GH ≤ 1.0 mg/L in obese (BMI > 30 kg/m2) patients If the patient instead had a BMI that is < 25 kg/m2 with a GH peak of 3 mg/L, then the patient, as per guidelines, is not GH deficient. This is because several GST studies have shown that BMI inversely correlated with peak GH levels. In addition, I would put this patient at low pre-test probability based on an IGF-I in the lower half of normal range and no other pituitary hormone deficiencies.
B. Masel, Neurology: Indeed, her peak GH level is 2.9, and she would be considered GH deficient and appropriate for therapy. However, what if her peak was 3.5? Abnormal is less than 3 according to most guidelines.
In view of her clear BIAFAC symptomatology, many physicians who treat people with this problem would consider her to be GH insufficient, as many patients with a peak between 3 and 10 do indeed respond to GH replacement. The Endocrinologist will most likely have to do some convincing to get the insurance company to
pay—but with perseverance, it can be accomplished. Although treatment is life-long and can be expensive, most likely she will see improvement and possibly resolution in her symptoms. Using a phrase we hear from many patients after starting treatment, she may be able to say: “I got my life back”.
W. High, Neuropsychology: The expected decrement in cognitive performance from concussion falls within the same range as the expected decrement associated with growth hormone deficiency.
Therefore, the cognitive effects from growth hormone deficiency can be easily confounded with the effects of concussion. The symptom of increased fatigue due to growth hormone deficiency or concussion may be similarly confounded. Increased fatigue and decrements in cognitive performance are probably interrelated.
Case
If the case were identical other than age, with the patient presenting at age 15, how might the evaluation and treatment differ?
Nico West, Pediatric Critical Care: Considering the patient’s age and pubertal status, endocrinology and/or adolescent Ob/Gyn referrals would be appropriate regarding her menstrual irregularities. Neurology, clinical psychology or neuropsychology (depending on availability) could be consulted regarding her neurocognitive deficits, slowed speech, and increased anxiety. Brain imaging may be indicated preliminarily for neurocognitive and neuropsychological
changes. If this patient is referred to endocrinology, auxological measurements, her past medical and concussion history (especially timing of concussions related to age and pubertal status), and physical examination would determine if growth hormone testing is warranted.
* TSH = thyroid-stimulating hormone, produced by the pituitary; T4 = thyroxine, produced by the thyroid gland; LH = luteinizing hormone, produced by the pituitary; FSH = follicle-stimulating hormone, produced by the pituitary; IGF-1 = insulin-like growth factor-1, produced by the liver in response to growth hormone.
Author Bios
Tamara L. Wexler, MD, PhD, a neuroendocrinologist, is a Clinical Professor in the Department of Rehabilitation Medicine at NYU, and Adjunct Professor in the Division of Endocrinology, Diabetes, and Metabolism at the University of Pennsylvania. See full bio on page 7.
Chantel T. Debert, MD, MSc, FRCPC, is an associate professor and clinician scientist in the Department of Clinical Neurosciences, division of physical medicine and rehabilitation and member of the Hotchkiss brain Institute at the University of Calgary. See full bio on page 31.
Brent E. Masel, MD, is a Board Certified Neurologist, Clinical Professor of Neurology at UTMB and Executive VP for Medical Affairs at the Centre for Neuro Skills. See full bio on page 38.
Walter M. High, Jr., PhD, is a neuropsychologist currently in private practice in New Mexico. See full bio on page 35.
Kevin C.J. Yuen, MD, is a Professor of Medicine at the University of Arizona College of Medicine and Creighton School of Medicine, and Medical Director of the Barrow Pituitary Center at the Barrow Neurological Institute in Phoenix, AZ. See full bio on page 15.
Alina Nico West, MD, PhD, is an Assistant Professor of Pediatrics and Clinical Researcher at the University of Tennessee Health Science Center (UTHSC) in the Division of Pediatric Critical Care Medicine in Memphis, Tennessee, USA. See full bio on page 26