Medical and Rehabilitation Innovations Neuroendocrine Screening and Hormone Replacement Therapy in Trauma Related Acquired Brain Injury

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1 Medical and Rehabilitation Innovations Neuroendocrine Screening and Hormone Replacement Therapy in Trauma Related Acquired Brain Injury

2 BACKGROUND Trauma related acquired brain injury (ABI) is known to cause a number of secondary effects to the brain including neuroendocrine dysfunctions. Pituitary hormonal disruptions after ABI have been well described in medical literature but with variable prevalence rates of deficiency ranging from 25% to 69% depending upon the definitions and laboratory screening used. A review article in 2007 noted prevalence of anterior hypopituitarism following ABI being 27.5% and posterior hypopituitarism being 26% in the acute phase, while in the longer term survivors of ABI had a prevalence of 6.9%. 1 Interestingly, there is a lack of consensus around the criteria defining pituitary deficiency in ABI patients, as well as best practice recommendations regarding neuroendocrine hormone replacement therapies. It is also important to note that there is no clear delineation as to what degree of endocrine changes in ABI is adaptive and functional versus maladaptive and detrimental during the recovery period. Furthermore, the generally accepted threshold for normal cutoff values for endocrine laboratory tests are based upon a healthy, mainly middle aged, normal weight population. 1 The debate remains about whether screening and treating neuroendocrine dysfunctions in ABI leads to measurable improvements in cognitive, behavioral and physical functions that enable optimal neurological and neurobehavioral recovery. Although a number of studies have looked at the incidence and prevalence of neuroendocrine dysfunctions following ABI, the number of Class I research studies looking at functional outcome benefits from hormonal replacement therapies in ABI have been very minimal, 2 especially with gonadal and growth hormones. Hence, it is unclear whether hormone replacement is as beneficial for ABI patients as it is for those patients from other non-traumatic causes of hypopituitarism. LITERATURE SUMMARY The following summarizes the current conclusions from the medical literature to date. 1. Studies suggest that acute disturbances of hypothalamic-pituitary-gonadal (HPG) axis are noted soon after ABI, but the majority recover normal HPG axis function within one year from injury. Deficiencies were more likely with LH/FSH; followed by growth hormone (GH); then adrenal insufficiency with low ACTH; and the least common being TSH due to less common pituitary-thyroid axis disturbance. Diabetes Insipidus (DI) was not associated with the presence of anterior hypopituitarism. 1,3 2. Opiates and cytokines from inflammatory cascade induced by ABI also lower testosterone levels 3 ; while other commonly prescribed medications, including phenytoin, carbamazepine, heparin, NSAIDs, and dopamine agonists affect thyroid function. 3. Provocative testing was more sensitive and specific in identifying GH deficiency and ACTH deficiency. TSH tends to fall following injury and rise with recovery, and measuring thyroid hormone levels during the acute period after ABI has not proven useful. 3 2 Paradigm Outcomes, Proprietary

3 4. In the acute phase of ABI, the diagnosis of adrenal insufficiency and diabetes insipidus should not be missed because it is life threatening and requires replacement therapy. In the ICU setting, replacement with thyroid hormone or GH therapy has not been clearly beneficial, while at 3 months post-injury, thyroid deficits should be treated. 2,3 5. Syndrome of Panhypopituitarism is associated with hypothermia, hypotension, hypoglycemia and hyponatremia. Providers should remain vigilant for symptoms of this rare but life threatening syndrome and screen and treat it acutely. 6. Replacement of other neuroendocrine deficits can restore normal growth hormone response to GH provocative testing A study of GH replacement therapy on ABI patients post one year of injury showed no difference between treated and placebo groups on most of the neuropsychological and functional measures. Some differential improvement was noted with finger tapping with dominant hand, WAIS III processing speed index, Wisconsin card sorting test, and California verbal learning test at 6 months and 12 months of GH replacement therapy. Interestingly, this study did not show improvements with the Community Integration Questionnaire (CIQ), a quality of life measure. The study intimated some potential benefit of GH replacement therapy, but acknowledged the limitation of the small sample size. 4 PARADIGM OUTCOMES POSITION Neuroendocrine dysfunctions are commonly associated with ABI and the endocrine changes that occur during the acute period seem to progress and recover during a one year time frame. To ensure identification of those ABI patients with chronic hypopituitarism that can impact the overall functional recovery of patients, Paradigm Outcomes supports the following neuroendocrine screening and treatment procedures specifically for our ABI patients. Neuroendocrine Screening Procedure 1. Candidate Criteria for screening (any presence of the following) a. Moderate and severe ABI patients by GCS criteria (score of 3-12) b. ABI patients with basilar skull fracture, facial fractures, diffuse brain swelling or edema, significantly elevated ICP, prolonged period of hypotension and/or hypoxia within 24 hours post injury c. MRI or CT Abnormalities in the area of Sella Turcica (location of Pituitary gland) d. Clinical symptoms consistent with chronic hypopituitarism 2. Acute period screening (within 30 days post injury) a. Cortisol level in am (within first 7days post-injury) b. Urine diuresis monitoring c. Serum Sodium and Osmolality & Urine Osmolality (if DI or SIADH suspected) 3. Post-acute period screening a. 3-6 months post-injury i. Serum Cortisol in am ii. Cosyntropin stimulation test (if acute period cortisol level < 12 mcg/dl) 3 Paradigm Outcomes, Proprietary

4 iii. TSH, free T3, free T4 iv. Insulin like growth factor (IGF-1) v. If clinically symptomatic: 1. Follicle stimulating hormone (FSH), Luteinizing hormone (LH) 2. Testosterone (male) or Estradiol (female) 3. Prolactin vi. If in vegetative state (VS), would defer steps iv-v b. 12 months post-injury i. Serum Cortisol in am (if abnormal level during prior testing) ii. Urinary free cortisol (if abnormal serum cortisol level during acute period) iii. Insulin like growth factor (IGF-1) iv. Glucagon Stimulation Testing (GTT) v. If clinically symptomatic or previously with low levels: 1. Follicle stimulating hormone (FSH), Luteinizing hormone (LH) 2. Testosterone (male) or Estradiol (female) 3. Prolactin 4. TSH, free T3, free T4 vi. If in a vegetative state, would defer steps iii-v Neuroendocrine Hormone Replacement Therapy General approach: Hormone replacement therapy (HRT) must be instituted for Diabetes Insipidus (DI) and Secondary Adrenal Insufficiency from ABI. Acute Panhypopituitarism requires hormonal replacement therapy for DI, Secondary Adrenal Insufficiency and hypothyroidism. Chronic Panhypopituitarism and multiple endocrine deficits at one year post ABI, HRT be continued for DI and Secondary Adrenal Insufficiency. Replacement therapy to be implemented for hypothyroidism. In Chronic Panhypopituitarism and multiple endocrine deficits at one year post ABI, consider benefits of hypogonadism therapy and GH replacement as related to given patient s clinical symptoms (consultation with an endocrinologist required). Case-by-case approach: Isolated hypogonadism and growth hormone deficiency at one year post ABI requires the consultation of an endocrinologist to determine the potential functional outcome improvement. Prior to initiation of HRT for hypogonadism and GH deficiency, the physical medicine and rehabilitation specialist and endocrinology specialist must collaborate to determine the appropriate outcome measure, as well as a therapy plan that combines HRT with rehabilitation modalities customized for each individual. The Paradigm Medical Director will review the treating physician s letter of medical necessity to ensure the appropriate consideration is given to contraindications, 4 Paradigm Outcomes, Proprietary

5 Summary outcome measures, therapy plan, and regularly scheduled follow-up timelines for monitoring treatment effectiveness. Neuroendocrine dysfunctions are common following ABI with higher risk of developing chronic hypopituitarism. Since symptoms of pituitary deficiencies and ABI sequelae can overlap, chronic hypopituitarism may be underdiagnosed in ABI patients. Help: Diabetes Insipidus and Secondary Adrenal Insufficiency are life threatening and require screening and immediate hormone replacement therapy during both acute and post-acute periods of TBI. Syndrome of Panhypopituitarism requires HRT for DI, adrenal insufficiency and hypothyroidism. Treatment of ABI induced secondary hypothyroidism during post-acute period is considered appropriate and beneficial. Hope: Extrapolating from published studies of non-abi associated endocrinopathies related to the benefits of HRT in growth hormone deficiency and gonadotropin deficiency, there are hopes that ABI induced pituitary deficiencies may benefit from aforementioned HRT leading to incremental cognitive, neurobehavioral and physical gains that can enhance the quality of life for ABI patients. Hype: GH and hypogonadism HRT will expedite and facilitate functional neurological and neurobehavioral recovery of ABI patients. ENDNOTES References 1. Schneider et al. Hypothalamopituitary Dysfunction Following Traumatic Brain Injury and Aneurysmal Subarachnoid Hemorrhage: A Systemic Review. JAMA. 2007; 208(12) E. Ghigo et al. Consensus guidelines on screening for hypopituitarism following traumatic brain injury. Brain Injury. 2005; 19 (9): Rothman et al. The Neuroendocrine Effects of Traumatic Brain Injury. J. Neuropsychiatry Clinical Neurosciences. 2007; 19: High et al. Effect of Growth Hormone Replacement therapy on Cognition after Traumatic Brain injury. Journal of Neurotrauma : Acknowledgements Special thanks Nancy Mann, MD, Brent Masel, MD, Elizabeth Sandel, MD, Alan Weintraub, MD, and Ross Zafonte, DO, for contributing to this paper, as well as the facilitators Chris Anderson, Laurie Anderson, Michael Choo, MD, and Steven Moskowitz, MD. 5 Paradigm Outcomes, Proprietary

6 2014. Paradigm Management Services, LLC ( Paradigm ). No part of this publication may be reproduced, transmitted, transcribed, shared, disseminated, summarized, stored in a retrieval system, adapted, or translated into any language in any form by any means without the written permission of Paradigm. Trademarks, service marks, products names, company names or logos of Paradigm are protected by trademark and other laws of the United States, as well as international conventions and the laws of other countries. 6 Paradigm Outcomes, Proprietary