Low Tri-Iodothyronine Syndrome in Neurosurgical Patients: A Systematic Review of Literature

Accepted Manuscript Low tri-iodothyronine syndrome in neurosurgical patients: a systematic review of literature Adomas Bunevicius, MD, PhD, Timothy Smith, MD, PhD, Edward R. Laws, MD PII:

S1878-8750(16)30559-9

DOI:

10.1016/j.wneu.2016.07.035

Reference:

WNEU 4328

To appear in:

World Neurosurgery

Received Date: 27 May 2016 Revised Date:

10 July 2016

Accepted Date: 11 July 2016

Please cite this article as: Bunevicius A, Smith T, Laws ER, Low tri-iodothyronine syndrome in neurosurgical patients: a systematic review of literature, World Neurosurgery (2016), doi: 10.1016/ j.wneu.2016.07.035. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT 1 Title page Low tri-iodothyronine syndrome in neurosurgical patients: a systematic review of literature Adomas Bunevicius, MD, PhD 1,2 Timothy Smith, MD, PhD 3 Edward R. Laws, MD3 Department of Neurosurgery, Lithuanian University of Health Sciences, Kaunas, Lithuania

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Neuroscience Institute, Lithuanian University of Health Sciences, Kaunas, Lithuania

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Department of Neurosurgery, Brigham and Women’s Hospital, Boston, Massachusetts, USA

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Financial support: Preparation of this paper was supported by the Research Council of Lithuania (grant

Corresponding author: Adomas Bunevicius, M.D., Ph.D. Institute of Neurosciences,

Eiveniu g. 2, LT-50009, Kaunas, Lithuania

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Lithuanian University of Health Sciences,

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number: MIP-044/2015).

E-mail: [email protected]

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Phone: (+370 37) 326984

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Fax: (+370 37) 331767

Keywords: brain tumor; hydrocephalus; neurosurgery; thyroid; traumatic brain injury; tri-iodothyronine; subarachnoid hemorrhage

ACCEPTED MANUSCRIPT 2 Highlights: Low T3 syndrome is a common complication in neurosurgical patients.

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Reduced T3 concentrations mirror greater disease severity.

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Patients with reduced T3 concentrations are at increased risk for poor outcomes.

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It is unclear whether or how the Low T3 syndrome should be treated.

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ACCEPTED MANUSCRIPT 3 Abstract Background. Intracranial neurosurgical disorders are important causes of mortality and disability worldwide. The Low tri-iodothyronine (T3) syndrome is a common complication in critically ill patients and is associated with a poor prognosis. Methods. We performed a systematic review of clinical studies

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analyzing the prevalence of the Low T3 syndrome and the association of serum T3 concentrations with disease severity and outcomes in patients with traumatic brain injury (TBI), hydrocephalus, aneurysmal subarachnoid hemorrhage (SAH) and brain tumors. Results. The greatest prevalence rate of the Low T3 syndrome was reported in severe TBI patients (up to 67%), followed by patients with brain tumors (54%),

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aneurysmal SAH (up to 43%) and hydrocephalus (33%). A lower than normal serum T3 concentration was associated with greater disease severity, worse health status, complicated clinical course and worse hospital discharge outcomes for TBI, aneurysmal SAH and brain tumor patients. Lower T3 concentrations

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were also associated with greater long-term mortality and increased disability in TBI and aneurysmal SAH patients. Conclusions. The Low T3 syndrome is a common complication in patients suffering from intracranial neurosurgical disorders and is associated with greater disease severity, complicated clinical course, and with greater mortality and handicap rates. However, it remains unclear if the Low T3 syndrome can impact the findings of currently available clinical prognostic models and if management of

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the Low T3 syndrome can improve outcomes in neurosurgical patients.

ACCEPTED MANUSCRIPT 4 Introduction Disorders of the central nervous system are common causes of mortality and disability worldwide.1 Neurosurgical treatment plays an important role in the management of certain brain disorders, such as traumatic brain injury (TBI), hydrocephalus, intracranial aneurysms and brain tumors.

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The mortality rate in severe TBI victims is approximately 40% 2 and up to half the survivors remain disabled.3 Aneurysmal SAH is the third most common cause of stroke, and is associated with a high mortality rate and risk for severe complications, such as vasospasm, that can subsequently contribute to poor functional outcomes.4 Certain brain tumors, such as glioblastoma, remain incurable diseases with a

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grim prognosis despite radical surgical tumor resection and combined adjuvant therapies.5 Hydrocephalus is the most common disorder treated by pediatric neurosurgeons, and can develop as a result of numerous congenital or acquired causes,. It is associated with increased risk for functional and cognitive disability.6

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Accurate patient outcome prognostication is important for treatment decision guidance, improving patient outcomes and optimized use of available healthcare resources. However, despite significant research efforts allocated towards identification of reliable and readily available prognostic biomarkers, prognostication of neurosurgical patients is based mainly on clinical disease characteristics. The ideal prognostic biomarker should accurately reflect disease severity and patient prognosis, be readily available across laboratories, be related to underlying biological abnormalities and be modifiable by appropriate

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treatment.

Towards this end, it is well established that alterations of the hypothalamic-pituitary-thyroid (HPT) axis are common complications in patients suffering from critical illnesses, including disorders of the central nervous system (CNS).7,8 Briefly, activation of the HPT axis is regulated by the thyrotropin

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releasing hormone (TRH) that, in turn, is synthesized in the periventricular nucleus of the hypothalamus and travels via the hypophyseal portal system to the anterior pituitary gland. Here it stimulates release of the thyroid stimulating hormone (TSH) that is released into the systemic circulation and activates the

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thyroid gland to release thyroxin (T4) and tri-iodothyronine (T3) hormones. Approximately 80% of the thyroid gland output is T4, which is a less metabolically active thyroid gland hormone and is converted into more metabolically active T3 via 5’-monodeiodination that is mediated by type 1 (D1) and type 2 (D2) deiodinase enzymes.9 Type 3 deiodinase (D3) deactivates thyroid hormones via T4 to reverse T3 (rT3) conversion and T3 to diiodothyronine conversion. Thyroid gland hormones are actively transported across the blood-brain barrier and blood-cerebrospinal fluid (CSF) barrier, and into glial and neuronal cells by thyroid hormone transporter systems, such as organic anion transporter protein 1c1 and monocarboxylate transporter 8 (MCT8).10 Importantly, the brain is capable of regulating tissue thyroid hormone concentration by employing deiodinase enzymes, because D2 is expressed is glial cells while D3

ACCEPTED MANUSCRIPT 5 is present in neurons 9. Once in the cell, T3 binds to cytoplasmic thyroid hormone receptors (TR) that subsequently binds to thyroid hormone response elements, which are present in promoter regions of T3 responsive genes, and regulate T3-responsive gene transcription.11,12 Non-genomic actions of thyroid gland hormones do not require nuclear binding and include guidance of neuronal migration, participation

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in brain connectivity and synaptic plasticity, among other actions 12. It is well described that normal functioning of the HPT-axis and TRs are critical for normal brain development and maintenance.13 Spatially and temporally different, and thyroid hormone-dependent changes of neuronal and glial TR expression following brain injury were previously described.14,15 For

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example, it was demonstrated that microglia cells and astrocytes residing within an ischemic infarct core preferentially expressed nuclear TRα1 and TRβ, while penumbral neurons expressed mainly TRα1.14 Furthermore, administration of thyroxin in an intraventricular hemorrhage animal model was associated

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with adaptive changes of thyroid hormone signaling (transient increase of TRα and delayed suppression of TRβ expression) and metabolism (reduced D3 expression) that was accompanied by accelerated structural and functional recovery of injured brain.15 Together, these findings suggest that the brain is capable to adaptively regulate local thyroid metabolism and signaling when facing injury, in order to promote survival of injured brain tissue and post-ischemic remodeling.

The most commonly described pattern of impaired HPT-axis functioning in critical illness

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encompasses reduced serum T3 concentrations in the presence of normal TSH concentrations. This pattern of HPT-axis dysfunction is coined the Low T3 syndrome (or non-thyroidal illness syndrome or euthyroid sick syndrome). Other common features of the Low T3 syndrome are elevation of the reversed T3 serum concentrations with or without reduction of T4 serum concentrations. Development of the Low

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T3 syndrome in critical illness is attributed both to impaired central regulation of the HPT-axis functioning, such as reduced hypothalamic TRH secretion, and impaired thyroid hormone peripheral metabolism, thyroid hormone receptor binding and transportation in peripheral tissues.16,17 For a detailed

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discussion describing biological mechanisms underlying the development of the Low T3 syndrome in critical illness please see a review paper by Warner and Beckett.18 It is well defined that the Low T3 syndrome is a common complication among patients suffering from severe somatic and psychiatric disorders, and it correlates with greater disease severity, and is associated with increased mortality and handicap rates.7,8,19,20 An accumulating body of evidence suggests that the Low T3 syndrome is a common complication in patients suffering from CNS disorders, and can have important prognostic and therapeutic implications. To the best of our knowledge, however, there are no studies systematically reviewing the prevalence rate and clinical significance of the Low T3 syndrome in patients suffering from intracranial neurosurgical disorders.

ACCEPTED MANUSCRIPT 6 The goal of the present study was to systematically review clinical studies analyzing the prevalence of the Low T3 syndrome and the association of serum T3 concentrations with disease severity and outcomes in patients with TBI, hydrocephalus, ruptured intracranial aneurysms and brain tumors.

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Methods A systematic literature review was conducted on November 30, 2015 aimed at identifying studies that evaluated the prevalence of the Low T3 syndrome and association of serum T3 concentration with disease severity and outcomes of patients diagnosed with TBI, hydrocephalus, aneurysmal SAH and brain tumors. Articles for review were identified from PubMed by using the following keywords: “thyroid” or

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“tri-iodothyronine” and "traumatic brain injury", “TBI”, "brain tumor", “glioma”, “meningioma”,

“subarachnoid hemorrhage” and “intracranial aneurysm”. There were no restrictions regarding year of publication; however, only papers performed in humans and with their abstract or full-text written in

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English were analyzed. Review papers and case reports were excluded from the analysis. Identified papers were also reviewed for other relevant studies.

An initial literature search was performed by reviewing titles and abstracts of papers and relevant full-text articles were extracted for finals analyses. Full-text articles of selected studies were reviewed for year and country of publication, study inclusion criteria, study design, number of patients studied, definition of the Low T3 syndrome, prevalence of the Low T3 syndrome, associations of the Low T3

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syndrome and serum T3 concentrations with disease severity and patient outcomes. Studies reporting T3 serum concentrations only, but not reporting their association with disease severity and/or outcomes were excluded, as were studies evaluating an association other HPT axis hormone serum concentrations (e.g.,

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Results

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T4) with disease severity and/or outcomes.

A total of 367 articles were identified during the database search (Figure 1). During a screening

process 286 articles were excluded because they were irrelevant to TBI, aneurysmal SAH, hydrocephalus or brain tumor patients. Eighty-one articles were selected for full text review; however, 56 articles were excluded because they did not evaluate serum T3 concentrations (n=25) or were not original research reports (n=31). The remaining 25 articles were included in the final analysis.

Traumatic brain injury

ACCEPTED MANUSCRIPT 7 We identified 15 studies that investigated an association of serum T3 concentrations with TBI severity and/or outcomes (Table 1). Patient sample size varied across studies ranging from 15 21 to 198 22 patients. Studies were heterogeneous in terms of patient inclusion criteria and TBI severity and outcome assessment. The majority of studies were performed in the acute phase of TBI (n=13), included adult

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patients (n=13) and considered patients with severe TBI only (n=5). Healthy control group comparison was included in four studies.

The prevalence of the Low T3 syndrome was reported in five studies and ranged from 24% in a sample of patients with mild to severe TBI 23 to 67% in patients with severe TBI.24 T3 serum

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concentrations fell within the first week after the injury followed by increasing concentrations during the recovery phase.23,25-28 Relative to healthy controls, TBI patients had lower serum T3 concentrations during acute 21,29,30 and remote 31 phases of TBI.

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Findings regarding an association of serum T3 concentrations with disease severity were mixed, and largely depended on patient selection as a function of TBI severity. Namely, in patients with severe TBI, lower serum T3 concentrations were associated with a lower admission Glasgow Coma Scale (GCS) score 24,32, greater vasopressor doses, greater intracranial pressure (ICP)32 and greater serum neuronal specific enolase (NSE) serum concentrations.33 Studies that considered TBI patients across the spectrum of TBI severity also found that serum T3 concentrations decreased with increasing TBI severity 23,28,34;

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however, some authors did not find an association between T3 concentrations and TBI severity.29,35 Lower serum T3 concentrations were associated with greater mortality rates 24,36, decreased discharge

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functional status 28 and decreased long term functional outcomes.25,26

Aneurysmal subarachnoid hemorrhage

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The clinical significance of serum T3 concentrations was investigated in five studies that included 204 patients with aneurysmal SAH (Table 2). In all studies serum T3 levels were assessed within the first 72 hours after ictus and one study performed daily assessment of serum T3 levels during the first 7 days post-ictus.37 The prevalence rate of the low T3 syndrome ranged from 14% 38 to 43% 39. Serum total T3 levels were lower in SAH patients relative to the control group of patients with spine disorders 40 and there was a reduction of T3 serum levels within 7 days after aneurysm rupture.37 The association of lower serum T3 levels with greater disease severity and unfavorable outcomes was documented in two studies 36,37, while one study did not find an association of T3 concentrations with disease severity and outcomes.39 In a study from Denmark, a lower mean 7-day T3 concentration was

ACCEPTED MANUSCRIPT 8 associated with a higher admission World Federation of Neurological Surgeons (WFNS) score (r=-0.58), a trend for higher Fisher grade (p=0.13), with a complicated clinical course (defined as prolonged unconsciousness), severe complications, permanent neurological deficit or death, and with poor 6-month functional outcome.37 Furthermore, the authors of the latter study also documented a gradual decrease of

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serum T3 levels throughout the hospitalization period in patients with a complicated clinical course, while patients with an uncomplicated clinical course demonstrated fluctuations of serum T3 concentrations throughout a 7 day study period. Another study in 59 patients with acute aneurysmal SAH also found that lower blood T3 levels correlated with greater disease severity, early clinical deterioration, a higher

incidence of vasospasm and poorer disease outcomes.36 On the other hand, a study from Italy did not find

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significant correlation of T3 levels with score on the Fisher scale, Hunt-Hess scale, GCS or in-hospital

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complications.39

Brain tumors

Three studies evaluated T3 concentrations in patients with an established brain tumor diagnosis 21,41,42

(Table 3). All studies were performed in heterogenous patient samples in terms of histological brain

tumor diagnosis with study sample sizes ranging from 10 patients 41 to 90 patients.42 The prevalence rate of the Low T3 syndrome was 38% before and 54% after neurosurgery.42 Brain tumor patients had lower

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T3 concentrations relative to healthy control subjects.21,41 Furthermore, tissue T3 concentrations were lower in brain tumor relative to healthy brain tissue.21 The association of serum T3 concentrations with disease severity and outcomes was reported by

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one group, and showed that the Low T3 syndrome was associated with increased odds for elevated depressive and anxiety symptom severity and poor hospital discharge outcomes, independent of patient

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age, gender, disease severity and histological diagnosis.42

Hydrocephalus

We identified two studies that investigated serum T3 concentrations in a total of 35 patients

undergoing endoscopic third ventriculostomy (ETV) for hydrocephalus attributed to various organic lesions 43,44 (Table 4). We did not find studies evaluating thyroid hormone profile in patients selected for shunting procedures. The prevalence rate of the Low T3 syndrome before ETV surgery was 14% in patients with aqueductal stenosis 43. The prevalence rate of the postoperative Low T3 syndrome ranged from 0 in

ACCEPTED MANUSCRIPT 9 patients 17.6 months following ETV for aqueductal stenosis 43 to 33% in patients 20 months following ETV for tumor (n=3), IVH (n=1), myelomeningocele (n=1) and aqueductal stenosis (n=1).44 Association

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T3 concentrations with disease severity or outcome were not addressed in the reviews studied.

Discussion

The Low T3 syndrome is a common complication in patients with intracranial neurosurgical disorders with reported point-prevalence rates being the highest among patients with severe TBI, followed

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by aneurysmal SAH, brain tumors and hydrocephalus. Lower serum T3 concentrations are associated with greater disease severity, impaired health status, complicated clinical course and worse hospital discharge in TBI, aneurysmal SAH and brain tumor patients. Lower T3 concentrations are also associated

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with greater long-term mortality and more disability of TBI and aneurysmal SAH patients. The greatest point-prevalence rate of the low T3 syndrome was reported in patients with severe TBI (67% in severe TBI patients) 24

23 22 21 20 19 18

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, followed by patients undergoing elective brain tumor

surgery (54%) , aneurysmal SAH patients (43%) 39 and post-ETV hydrocephalus patients (33%) 44. Mean serum T3 concentrations were significantly lower in aneurysmal SAH, TBI and brain tumor patients relative to healthy control subjects. The prevalence rate of the Low T3 syndrome in neurosurgical

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patients corresponds to previously reported point-prevalence rates of the Low T3 syndrome among other populations of critically ill patients, including patients with sepsis (63%),45 polytrauma (33%) 46 and acute myocardial infarction (31%).47 The Low T3 syndrome should be distinguished from other HPT-axis disorders, such as untreated primary hypothyroidism and thyrotoxicosis, which are substantially rarer

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conditions in the setting of critical illness 48. Primary hypothyroidism is associated with high serum TSH accompanied by low serum T4 concentrations, while thyrotoxicosis is associated with low TSH and high T4/T3concentrations. However, changes of thyroid hormone metabolism in critical illness can mask the

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diagnosis of previously undiagnosed thyroid gland disorders. For example, in critically ill patients with previously undiagnosed primary hypothyroidism high TSH concentrations can be suppressed to normal range, while T3 and T4 concentrations remain low. 49 Nevertheless, high prevalence rates of the Low T3 syndrome in neurosurgical patients indicate that healthcare providers should be suspicious for this complication. However, it remains unclear whether assessment for the Low T3 syndrome has clinically significant implications for an improved prognosis in this patient population. Therefore, routine assessment of the thyroid hormone profile for the Low T3 syndrome screening or diagnostic purposes cannot be recommended at this time. Further studies should address whether such a diagnostic intervention can alter the treatment plan and improve patient prognosis.

ACCEPTED MANUSCRIPT 10 Lower serum T3 concentrations were associated with greater disease severity and with a more complicated clinical course among patients with TBI, aneurysmal SAH and brain tumors. In TBI patients, lower serum T3 concentrations were associated with greater clinical TBI severity and with greater brain damage.24,32 23,28,34 In addition, lower T3 levels correlated with greater serum levels of NSE 33 that is 78-

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kDa dimeric γ-isoenzyme of the glycolytic enzyme enolase localized predominately in the cytoplasm of neurons and is upregulated to maintain homeostasis following axonal damage and has been shown to correlate with mortality and unfavorable outcomes of TBI patients.50 Studies that included TBI patients across the spectrum of TBI severity also found that serum T3 concentrations decreased with increasing TBI severity; however, others did not find an association between T3 concentrations and TBI severity.29,35

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In aneurysmal SAH patients, lower T3 concentrations were associated with an impaired neurological status, a complicated clinical course and clinical deterioration.36 37 These findings imply that the Low T3

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syndrome can be considered as a surrogate biomarker of disease severity and brain damage in neurosurgical patients. The Low T3 syndrome was associated with greater mortality and disability rates among patients with TBI 28, aneurysmal SAH 36,37, and following elective brain tumor surgery.42 These findings suggest that the Low T3 syndrome can potentially be employed for patient prognostication, and patients with the Low T3 syndrome should be considered at elevated risk for death and disability. However, it should be noted that studies investigating whether the Low T3 syndrome can predict patient outcomes independently from well-established clinical prognostic markers are lacking. Furthermore, there

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are no studies considering whether the inclusion of the Low T3 syndrome in currently used prognostic models can improve patient risk stratification. For example, brain tumor patients with the Low T3 syndrome before and after neurosurgery were at up to 8-fold increased risk for disability at discharge (Glasgow outcome scale score <4), and this association was independent of age, gender, preoperative

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functional status, previous brain tumor treatment, histological diagnosis of brain tumor, and mental distress before surgery.42 Further studies should attempt to elucidate whether Low T3 can serve as an independent prognostic biomarker, and whether it can improve the accuracy of currently available

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prognostic models of patients suffering from neurosurgical disorders. Mental disorders and their symptoms, behavioural problems and cognitive impairments are

common complications in patients with brain tumors,51 hydrocephalus following TBI 52 and aneurysmal SAH.53 Mental disorders and their symptoms are associated with impaired health-related quality of life 54 and are associated with shorter survival in brain tumor patients,55 suggesting that identification and adequate management of mental distress is important for improving quality of life and prognosis of neurosurgical patients. Normal HPT-axis functioning is critical for brain functioning, and low T3 concentrations put patients at elevated risk for mood disorders and cognitive impairment.20,56,57 However, only one reviewed study found that lower T3 concentrations were associated with greater

ACCEPTED MANUSCRIPT 11 depressive/anxiety in brain tumor patients.42 Thus, future studies should attempt to investigate the association of the Low T3 syndrome with more subtle cognitive and functional outcomes among neurosurgical patients. An increasing body of evidence from studies in animal models suggests that thyroid hormones are

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neuroprotective in the setting of traumatic brain insult (Table 5). For example, a study in a controlled cortical impact model in mice found that T3 administration was associated with reduced neuro-

inflammation and enhanced neurotrophic factor expression that translated into improved motor and cognitive recovery and reduced lesion volume.58 Other studies in cryo-injury TBI models and

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hippocampal slices of injured brain have documented that T4 administration improved neuronal and glial cell survival, promoted regeneration of injured neurons and enhanced neurotrophic factor expression.59,60 Neuroprotective actions of thyroid hormone were also shown in brain ischemia animal models 19. Taken

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together these findings strongly suggest that thyroid hormones are neuroprotective and promote survival of injured brain in the laboratory environment. However, it remains unclear whether neuroprotective actions of thyroid hormones can translate to the clinical setting.

There remains an ongoing debate in the literature as to whether the Low T3 syndrome should be 48

treated. There have been a few attempts to treat the low T3 syndrome in burn injury patients 61 and in patients with sepsis 62, however, these studies provided disappointing results, as thyroid hormone

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administration did not improve patient outcomes. On the other hand, others found that T3 administration improved cardiac functioning in patients undergoing coronary artery bypass graft surgery 63 and in heart failure patients.64 There is evidence to suggest that thyroid hormone administration can improve the prognosis of brain tumor patients. Two studies have documented improved survival of high-grade glioma

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patients treated with T3, presumably due to increased tumor radiosensitivity. Specifically, Yung and colleagues have reported median survival of 60 weeks in patients who received surgery, radiation therapy and high dose T3 therapy (between 500 and 1000 µg daily) when compared to a median survival of 32

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weeks in patients who were treated with surgery and irradiation only.65 Survival benefits of T3 administration were subsequently confirmed in an independent study from Puerto Rico in 80 high-grade glioma patients treated using surgical tumor removal, irradiation therapy and T3 (daily doses ranged between 200 and 400 µg).66 It should be noted that both studies included euthyroid patients, thus it remains unclear if the management of brain tumor patients diagnosed with the Low T3 syndrome can also improve patient outcomes. It is well established that thyroid hormone replacement therapy can improve cognitive functioning and mood symptoms.56,67 Ma and colleagues have recently carried out a placebocontrolled randomized clinical trial in 22 patients within 12 months after aneurysmal SAH who suffered cognitive dysfunction (Montreal Cognitive Assessment score <25) and hypothyroidism (elevated TSH

ACCEPTED MANUSCRIPT 12 and normal thyroid hormone concentrations).68 Their patients were randomly assigned to a placebo group or to 8 to 12 weeks of oral levothyroxine (initial dosage of 25µg with maintenance dose of 25‑100 µg/day) therapy until normalization of serum TSH levels. Levothyroxine therapy was associated with improvement in visuospatial/executive function, naming, attention, language, delayed recall, orientation

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and total scores, suggesting beneficial cognitive effects of thyroid hormone replacement therapy. We did not find studies investigating clinical benefits of thyroid hormone replacement therapy in patients with TBI and hydrocephalus. Based on the well documented association of the Low T3 syndrome with poor outcomes in neurosurgical patients, documented neuroprotective actions of thyroid hormone in laboratory settings, and findings showing beneficial effects of thyroid hormone administration in patients with brain

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tumors and aneurysmal SAH, we believe that further studies should investigate whether treatment of the Low T3 syndrome can improve the prognosis and patient-oriented outcomes of neurosurgical patients.

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A limitation of the current paper that the reviewed studies were heterogeneous in terms of patient selection, disease severity and study design should be acknowledged when considering our pooled conclusions. Specifically, the number included studies and patient sample sizes in each study included were highly variable across neurosurgical conditions considered for the review, therefore the strength of evidence for the prevalence of the Low T3 syndrome and its clinical significance should interpreted with caution across the reviewed neurosurgical conditions. Also, the included studies were heterogeneous in terms of disease characteristics for patients with TBI (severe and mild), brain tumors (various histological

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diagnoses considered together) and hydrocephalus (aqueduct stenosis and other causes). Furthermore, thyroid hormone serum concentrations were measured using different assays and at different laboratories, both free and total T3 serum concentrations were not evaluated by all studies, and the prevalence rate of the Low T3 syndrome was reported in 12/25 studies. The prevalence rate of the Low T3 syndrome and,

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consequentially, the clinical prognostic value of T3 concentrations should be interpreted in the context of assessment timing and disease severity, because functioning of the HPT-axis fluctuates during the course

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of severe illness and is associated with disease severity. Finally, inclusion of papers limited to at least an abstract in English is another limitation of the present review.

Conclusions

The Low T3 syndrome is a common complication in patients with intracranial neurosurgical

disorders. The Low T3 prevalence rates are the greatest among patients with severe TBI, followed by aneurysmal SAH, brain tumors and hydrocephalus. Lower serum T3 concentrations are associated with greater disease severity, complicated clinical courses and poor prognosis in TBI, aneurysmal SAH and brain tumor patients, and with greater long-term mortality and handicap rates in TBI and aneurysmal SAH

ACCEPTED MANUSCRIPT 13 patients. However, it remains unclear whether neurosurgical patients should be evaluated for the Low T3 syndrome, as it remains largely unclear if assessment of the Low T3 syndrome can improve accuracy of currently available prognostic models. Also, it is unknown whether the management of the Low T3 syndrome can improve outcomes in selected neurosurgical patients. Studies investigating treatment of the

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Low T3 syndrome designed to improve outcomes in neurosurgical patients are warranted.

Acknowledgment

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This study was supported by the Research Council of Lithuania (grant number: MIP-044/2015).

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Table 1. Studies evaluating T3 serum concentrations in patients with traumatic brain injury. Study patients n (male) / age

Assessment timing and TBI severity

Prevalence of low T3 syndrome

Major findings

Within 24 hours and 4 days after severe TBI (GCS≤8 and CPP≥10 mmHg) Severe TBI

25% (day 1) and 60% (day 4) *

Free T3 levels decreased from day 1 to day 4 post TBI. Day 4 free T3 levels correlated with 3-month GOS, but not with GCS, ISS, Marshall grade, ICP or CPP. Free T3 was an independent predictor of unfavorable 3-month outcomes.

Within 24 hours of admission for severe TBI (GCS≤8) Days 0, 3 and 7 after severe TBI (GCS≤8)

67%*

24%, 40% and 28% and 5% on admission, day-3, day-7 and follow-up * Not reported

RI PT

Reference / Country

27

/ Russia

56 / -

19

/ Iran

72 / -

21

/ USA

37 (27) / 9.3±4.7

/ Germany

71 (57) / mean age 53 years

Days 0-7 and >24 months after mild/moderate/se vere TBI

/ Greece

59 (47) / 34 years

On days 0, 6 and 12 after admission

22

57% (day 3) *

AC C

18

41% (low T3) and 23% (low T3 and T4) *

M AN U

45 (30) / 35.7 ± 2.2 years

T3 correlated positively with GCS in low T3 patients 39% of low T3 patients and 63% of low T3/T4 patients had poor outcomes. Low T3 and T3/T4 received higher vasopressor doses and low T3/T4 patients had higher ICP. Low T3 patients had lower admission GCS scores. Low T3 was not associated with greater mortality rate.

TE D

/ Sweden

EP

20

SC

Acute phase

Total T3 concentrations reduced from day 0 to day 3 and then increased on day 7. Total T3 concentrations were not different between good/poor 6-month outcomes. 94% patients with “good” outcomes and 58% patients with “poor” outcomes had normal T3 values. Total T3 levels were lower in patients ventilated for >24h. Total T3 levels were lower with increasing TBI severity. Total T3 levels normalized in 95% of patients at follow-up.

Free T3 concentrations decreased on days 6 and 12 relative to day 0.

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24

/ Denmark

46 (33) / median 36, range from 19 – 65

30

/ Turkey

104 (78) / 38.8 ± 15.3

28

/ Russia

32 (27) / range from 11 to 55]

3 to 25 days after severe TBI (GCS<8)

Not reported

/ Yugoslavia

31 / military TBI

Not reported

16

/ Germany

15 (9) / 36.2± 13.8 years

25

/ Austria

21 (16) /

Days 1, 2, 3, 5, 7 after mild closed (GCS 13-15; n=8); extensive penetrating (GCS 4-6; n=10) and blast (n=13) military TBI Within 2 days after TBI and in patients with other somatic disorders and healthy controls From 2 to >60

Not reported

Free T3 concentrations not different as a function of TBI severity Mean free T3 concentrations were below reference range in moderate and severe TBI patients. Free T3 levels did not correlate with GCS score and were not different in survivors vs. non-survivors In diffuse axonal injury, total T3 increased and free T3 decreased on day 1 before emergence from coma and free T3 increased on 1-3 post-coma days. In contusions, subdural and epidural hematoma patients, total T3 decreased until 4-6 post-coma days. Total and free T3 levels correlated negatively with NSE levels There was a more significant decrease of free and total T3 in non-survivors relative to survivors. In mild injury, T3 levels were elevated on days 1, 5 and 7. In severe penetrating injury, T3 declined over the 7 days post-trauma. In blast injury, T3 initially declined and increased to above normal levels between days 5 and 7 post-trauma

SC

RI PT

Total T3 concentrations of TBI patients were lower than in healthy controls at baseline, 3 and 6 months post-injury. TBI severity not associated with total T3 concentrations.

TE D

EP

AC C

29

Not reported

M AN U

for severe TBI (GCS≤8) 0-12 days, 3, 6, 12 months after mild/moderate/se vere TBI and healthy controls Within 24 hours of admission for mild/moderate/se vere TBI

No reported

T3 levels were lower in TBI patients relative to healthy controls

Not reported

Relative to controls, total T3 levels were lower in acute TBI with GCS scores lower

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or greater than 6, and higher in patients with traumatic apallic syndrome lasting >60 days

On admission and 4 days after mild/moderate/se vere TBI

Not reported

T3 fell significantly within 24 hours after injury. T3 levels correlated with GCS. Patients who died or remained vegetative had 30-50% lower T3 values than patients with good recovery. Prevalence of low T3 levels was 72% and 23% in patients with poor and good discharge outcomes, respectively.

RI PT

/ USA

days after TBI and control group

SC

23

mean age of 30.5 years 66 (51) / median age 25 years

Remote phase 198 (112)/ children

TBI severity did not correlate with FT3 concentrations. Most severe TBI cases had lower free FT3 concentrations.

M AN U

6.5±3.2 years None A after TBI sustained within 5 years of life 26 / Hungary 26 (17) / 30.6±8.3 months Not reported 11.47 after TBI and ±0.75 years controls * – T3 concentrations below the reference range. / USA

Total T3 levels were lower in patients relative to controls.

TE D

17

AC C

EP

CPP, cerebral perfusion pressure; GCS, Glasgow Coma scale; T3, tri-iodothyronine; T4, thyroxin; TBI, traumatic brain injury; ICP, intracranial pressure;

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Table 2. Studies evaluating T3 serum concentrations in patients with aneurysmal subarachnoid hemorrhage.

/ Italy

35

/ Brasil

60 (26) / 52.3±15.7 years 30 (9) / 41.7±11.4 years

Within 72 hours after spontaneous SAH Within 24 hours of ictus before intervention and control group (spine disorders) Within 24 hours of ictus and before intervention Aneurysmal SAH

/ Brasil

31

/ Russia

35 (12) / 51.9±13.3 years

59 (37) / range from 21 -64 years * – T3 concentrations below reference range

14% *

Not reported

EP

33

Clinical significance

RI PT

34

Prevalence of low T3 syndrome In 51% of measurements, and 50% of patients had average total T3 concentrations below the reference range * 43% (53% in females and 31% in males) * 40%*

Lower T3 concentrations were associated with greater WFNS grade and trend for more blood on CT. Lower T3 concentrations were associated with complicated clinical course and worse 6-month outcome

SC

Diagnosis/ assessment setting Within 24 h after aneurysmal SAH and for 7 days afterwards

M AN U

Study patients n (male) / age 20 (7) / 58.4± 12.8 years

TE D

Reference / Country 32 / Sweden

T3 was not associated with disease severity, clinical course or outcome. Total T3 levels were lower in SAH patients relative to the control group

Not investigated

Lower blood T3 levels correlated with greater disease severity, early clinical deterioration, greater degree of vasospasm and worse disease outcome

AC C

CT, computed tomography; T3, tri-iodothyronine; WFNS, World Federation of Neurological Surgeons.

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Table 3. Studies evaluating T3 serum concentrations in patients with brain tumors.

36

/ Croatia

Prevalence of low T3 syndrome

Major findings

Various histological diagnoses / Before and next day after BT surgery

38% before and 54% after surgery * Not reported

Preoperative and postoperative low T3 syndrome predicted poorer discharge outcome, and preoperative low T3 syndrome increased risk for elevated preoperative depressive symptoms independently of demographic factors and clinical status. Serum total and free T3 concentrations were lower in brain tumor patients vs. the control group. CSF free T3 concentrations were lower in brain tumor patients relative to serum concentrations in both groups.

Hospitalized patients with various histological diagnoses (8 gliomas) and control group (age and sex matched volunteers) 16 / Germany 21 (9) / Various histological 50.1±12.5 diagnoses, during years anesthesia before surgery and control group (healthy controls) * – T3 concentrations below reference range

AC C

EP

CSF, cerebrospinal fluid; T3, tri-iodothyronine.

Not reported

TE D

10 / -

RI PT

/ Lithuania

Diagnosis/ assessment setting

SC

37

Study patients n (male) / age 90 (26) / 55.1 ± 13.9 years

M AN U

Reference / Country

Serum total T3 concentrations were lower in brain tumor patients relative to controls. Tissue T3 levels were lower in brain tumor samples relative to healthy brain.

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Table 4. Studies evaluating T3 serum concentrations in patients with hydrocephalus.

Before and after ETV for aqueductal stenosis 39 / Germany mean 25 months [3 months – 5 years] after ETV for various causes * – T3 concentrations below reference range

Prevalence of low T3 syndrome 14% before and 0% after surgery *

Major findings

33%*

Association with disease severity/outcome not studied. 2/6 (33%) of low T3 patients had failed outcomes.

AC C

EP

TE D

ETV, endoscopic third ventriculostomy; T3, tri-iodothyronine.

RI PT

Assessment setting

Association with disease severity/outcome not studied

SC

Study patients n (male) / age 15 (10) / range from 2 months to 18 years 20 (11) / mean 4 years

M AN U

Reference / Country 38 / India

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Table 5. Neuroprotective actions of thyroid hormones in traumatic brain injury animal models. Traumatic brain injury

Thyroid hormone

model

administration dose and route,

Effects of thyroid hormones

and timing Crupi et al.

Controlled cortical

T3 (1.2µg/100g body weight, i.p.)

Improved motor and cognitive recovery, reduced lesion

impact in adult mice

1h after TBI

volume.

SC

(2013)

50

RI PT

Author (year)

Modulation of cytoplasmic-nuclear shuttling of nuclear

M AN U

factor-κB (NF-κB), reduced TUNEL(+) apoptotic

neurons and Bax induction. Enhanced BDNF and GDNF expression

Shulga et al. (2009)

51

Hippocampal slices of 8-

1 µmol/l of T4

9 day old mice lesioned

Increased neuronal (NeuN intensity) and glial cell

Cryo-injury in mice

Regeneration of injured neurons and restoration of K-Cl cotransporter

T4 (1 mg/g body weight)

Increase in GFAP/BrdU-positive cells and distinct

EP

(2005)

52

subcutaneously on

increase in marker positive cells for mature

the 1st, 3rd and 5th day after

oligodendrocytes (CNPase, PLP)

AC C

Tatsumi et al.

survival (Hoechst staining).

TE D

between CA3 and CA1 using a razor blade

Higher BDNF expression.

surgery

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Figure 1. Study selection flow diagram.

RI PT

Records identified through search strategy (n=367) Excluded during screening process (n=286)

M AN U

Full-text articles excluded with reasons: T3 not evaluated (n=25) Review paper (n=28) Letter to Editor (n=2) Case report (n=1)

AC C

EP

TE D

Studies included in qualitative analysis (n=25)

SC

Full-text articles assessed for eligibility (n=81)

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Abbreviations: CNS, central nervous system; CSF, cerebrospinal fluid;

RI PT

ETV, endoscopic third ventriculostomy GCS, Glasgow Coma Scale; HPT, hypothalamic-pituitary-thyroid;

SC

MCT8, monocarboxylate transporter 8; NSE, neuronal specific enolase;

SAH, subarachnoid hemorrhage; T3, ri-iodothyronine; T4, thyroxin;

TE D

TBI, traumatic brain injury;

M AN U

rT3, reverse T3;

TR, thyroid hormone receptors;

TRH, thyrotropin releasing hormone;

AC C

EP

WFNS, World Federation of Neurological Surgeons;