A Clinical Vignette

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HISTORY AND PHYSICAL EXAMINATION A 42-year-old male with no significant past medical history presented to a brain injury clinic with a 10-year history of persistent fatigue, cognitive slowing, mood disturbance, and generalized anxiety. Symptoms began after a motor vehicle collision at age 32 that resulted in a moderate traumatic brain injury (TBI) with subarachnoid hemorrhage. He was hospitalized for 3 days without surgical intervention and discharged with outpatient follow-up. He completed 4 weeks of physical/occupational therapy and 12 weeks of speech-language therapy. Despite initially resuming daily activities, he struggled to return to his job as a registered nurse due to worsening attention, memory, motivation, and mood stability. He ultimately withdrew from work and remained unemployed for 8 years. He was followed by psychiatry, diagnosed with major depressive disorder (MDD) and generalized anxiety disorder (GAD), and treated with selective serotonin reuptake inhibitors, valproic acid, lithium, and serotonin-norepinephrine reuptake inhibitors, with minimal benefit. At presentation, he was taking escitalopram (20 mg daily). His condition was considered treatment resistant after inadequate response to multiple antidepressants from different classes. Psychotherapy was the only intervention that provided meaningful benefit. On examination, he was alert and oriented. Height was 6 feet with a body mass index of 26.5 kg/m2 and increased truncal body fat. Neurological examination was normal: intact cranial nerves II to XII, strength 5/5 in bilateral upper and lower extremities, deep tendon reflexes 2+ throughout, and sensation intact to light touch with no abnormalities. Given his long-standing neuropsychiatric symptoms after TBI and a normal neurological examination, what additional causes should be considered? DIFFERENTIAL DIAGNOSES The patient’s presentation is consistent with several possible etiologies. Primary psychiatric conditions, including the patient’s documented MDD and GAD, cause fatigue, impaired concentration, and mood disturbance. Neuroendocrine dysfunction, particularly growth hormone deficiency (GHD), testosterone deficiency, adrenocorticotropic deficiency, and hypothyroidism, is increasingly recognized after TBI and may mimic psychiatric conditions if unaddressed.1,2 Persistent post-concussive symptoms (PPCS) refer to a constellation of symptoms, often considered within the broader spectrum of post‑TBI sequelae, that include headache, fatigue, sleep disturbance, slowed thinking, irritability, and mood changes, which are common after TBI but persist beyond the expected recovery period.3 Although most frequently associated with mild TBI, PPCS and post-TBI sequelae can develop after TBI of any severity.4 Symptoms may overlap with psychiatric conditions and persist beyond 1 year, causing significant functional impairment.3 Additional etiologies included sleep disorders such as obstructive sleep apnea, which are common after TBI and contribute to fatigue, cognitive impairment, and mood symptoms;5 post-traumatic epilepsy, which can present with subtle cognitive or behavioral changes without overt seizures;6 and, less likely, neurodegenerative disease, given his age and stable neurological function.7 What testing could help identify treatable causes of long-term neuropsychiatric symptoms after TBI? DIAGNOSTIC RESULTS To identify treatable contributors, the patient underwent neurocognitive and psychiatric screening, which demonstrated severe depression on the Patient Health Questionnaire-9 (PHQ-9, score 20, reference range 0 to 27), severe anxiety on the Generalized Anxiety Disorder-7 (GAD-7, score 21, reference range 0 to 21), and mild cognitive impairment on the Montreal Cognitive Assessment (MoCA, score 25/30). A sleep study was unremarkable, and detailed neuropsychological testing was deferred pending initial evaluation. A comprehensive laboratory panel was obtained (Table 1). Significant findings (in bold) included low insulin-like growth factor 1 (IGF-1), measured at 50 ng/mL (repeat 48 ng/mL) with z-scores of –1.9 and –2.0, respectively, and hypogonadal testosterone levels of 100 ng/dL (repeat 120 ng/dL). A glucagon stimulation test (GST) demonstrated a peak GH of 0.5 ng/mL, diagnostic of GHD given the low IGF-1 and high pre-test probability (ie, IGF-1 z-score < 0).8 Luteinizing hormone (LH) and follicle-stimulating hormone (FSH) were low-normal. TABLE 1 - Comprehensive laboratory evaluation Test Initial Result Repeat Result Reference Range Interpretation Complete blood count Unremarkable — — Normal Complete metabolic panel Unremarkable — — Normal Thyroid-stimulating hormone 3.173 µIU/mL — 0.55-4.78 Normal Thyroxine 5.1 µg/dL — 4.5-12 Normal Morning cortisol 10.24 µg/dL — 5.27–22.45 Normal Prolactin 7.8 ng/mL — 2-18 Normal IGF-1 50 ng/mL 48 ng/mL 52-328 Low Total morning testosterone 100 ng/dL 120 ng/dL 250-1100 Low FSH 1.92 mIU/mL — 1.6-8 Low-normal LH 1.71 mIU/mL — 1.7-8.6 Low-normal Peak GH on GST 0.5 ng/mL — >3 ng/mL Diagnostic for GHD Bold values indicate The patient has a low IGF-1 and a GST that meet diagnostic criteria for GHD. The patient also has two low morning testosterone levels with low-normal FSH and LH, consistent with testosterone deficiency. Magnetic resonance imaging (MRI) of the brain and pituitary gland (Fig. 1), with and without contrast, was unremarkable.FIGURE 1: Sagittal T1-weighted MRI demonstrating a normal pituitary gland with preserved size, contour, and infundibular morphology. No mass lesion or structural abnormality is identified.Home 72-hour electroencephalography (EEG) was unremarkable with no epileptiform discharges or sharp waves. Together, these findings confirmed adult-onset GHD and testosterone deficiency likely secondary to post-traumatic hypopituitarism. Alternative causes of adult hypopituitarism include pituitary tumors, inflammatory disease, central nervous system infections, vascular insults, and rare congenital conditions. However, hypopituitarism is uncommon in the general adult population,9 whereas post-TBI hypopituitarism has been reported in a significant proportion of patients with chronic TBI.2 The patient’s moderate TBI, absence of other risk factors, symptom timeline, and normal MRI supported TBI as the most likely etiology. What is the appropriate management strategy for hormone deficiencies in patients with prior TBI? MANAGEMENT AND OUTCOME Testosterone replacement was started first using 1% transdermal gel, 50 mg daily. After testosterone optimization, growth hormone therapy was initiated at 0.2 mg subcutaneously daily. Over 12 months, the patient experienced marked improvement in fatigue, cognition, and mood, and tapered off psychiatric medications under supervision. His MoCA score improved to 29/30 six months after initiating hormone replacement therapy. Most notably, he returned to work as a nurse. He demonstrated excellent adherence without side effects or adverse events. He continues to be followed in the brain injury clinic for ongoing management. At 24-month follow-up, IGF-1 and testosterone levels remained normalized. DISCUSSION This case highlights the importance of recognizing neuroendocrine dysfunction in patients with persistent neuropsychiatric symptoms after TBI. Chronic anterior hypopituitarism, particularly GHD and gonadotropin deficiencies, occurs in 10% to 63% of individuals post-TBI and is frequently underdiagnosed due to overlapping psychiatric and cognitive symptoms.1,2 Given the persistence of symptoms, we considered a broad differential. This directed our diagnostic workup, which included MRI of the brain and pituitary to evaluate for structural pathology; EEG to rule out subclinical seizures; and a sleep study to exclude common post-TBI sleep disorders known to worsen fatigue and cognition. Comprehensive laboratory evaluation, emphasizing pituitary function due to its known association with TBI, identified the endocrine abnormalities responsible for hi

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