1446

With an estimated prevalence of ≈2%, subclinical hyper-thyroidism is common in the general population, vary-

ing in frequency with age, sex, and nutrition factors.1 It is associated with various cardiovascular effects and conditions, including a higher heart rate,2 an increase of left-ventricular mass,1 and atrial fibrillation (AF).3 Subclinical hyperthyroid-ism has further been shown to increase the risk for carotid plaques and prevalent stroke.4 Although subclinical hypo-thyroidism has been associated with favorable outcome after acute ischemic stroke,5,6 the effects of subclinical hyperthy-roidism on functional outcome have not been investigated. Therefore, we studied the effects of subclinical thyroid dys-function on functional outcome 3 months after acute ischemic stroke, considering euthyroid state as a reference.

MethodsStudy PopulationPatients were recruited through an observational single-center cohort study following Institutional Review Board approval by the medical faculty of the Ludwig-Maximilians- Universität-München. Inclusion criterion was an acute ischemic stroke defined by a new focal neu-rological deficit with a corresponding lesion on MR- or delayed computed tomography scan. Exclusion criteria were known thyroid disease, biochemically defined overt thyroid disease, time since symptom onset >72 hours, and use of thyroid-affecting medication. Patients received 72-hour ECG monitoring at baseline and 12-chan-nel ECG monitoring at follow-up.

Exposure MeasurementBlood samples were drawn between 6 and 9 am. Serum thyroid–stimulating hormone, free thyroxine (fT4), and free tri–iodothyronine

Background and Purpose—Subclinical hyperthyroidism is associated with adverse cardiovascular events, including stroke and atrial fibrillation. However, its impact on functional outcome after stroke remains unexplored.

Methods—A total of 165 consecutively recruited patients admitted for ischemic stroke were included in this observational prospective study. Blood samples were taken in the morning within 3 days after symptom onset, and patients were divided into the following 3 groups: subclinical hyperthyroidism (0.1< thyroid-stimulating hormone ≤0.44 μU/mL), subclinical hypothyroidism (2.5≤ thyroid-stimulating hormone <20 μU/mL), and euthyroid state (0.44< thyroid-stimulating hormone <2.5 μU/mL). Patients with overt thyroid dysfunction were excluded. Follow-up took place 3 months after stroke. Primary outcome was functional disability (modified Rankin Scale), and secondary outcome was level of dependency (Barthel Index). Ordinal logistic regression analysis was used to adjust for possible confounders. Variables previously reported to be affected by thyroid function, such as atrial fibrillation, total cholesterol, or body mass index, were included in an additional model.

Results—Nineteen patients (11.5%) had subclinical hyperthyroidism, and 23 patients (13.9%) had subclinical hypothyroidism. Patients with subclinical hyperthyroidism had a substantially increased risk of functional disability 3 months after stroke compared with subjects with euthyroid state (odds ratio, 2.63; 95% confidence interval, 1.02–6.82, adjusted for age, sex, smoking status, and time of blood sampling). The association remained significant, when including the baseline NIHSS, TIA, serum CRP, atrial fibrillation, body mass index, and total cholesterol as additional variables (odds ratio, 3.95; 95% confidence interval, 1.25–12.47), and was confirmed by the secondary outcome (Barthel Index: odds ratio, 9.12; 95% confidence interval, 2.08–39.89).

Conclusions—Subclinical hyperthyroidism is a risk factor for poor outcome 3 months after ischemic stroke. (Stroke. 2013;44:1446-1448.)

Key Words: acute ischemic stroke ■ functional outcome ■ subclinical thyroid dysfunction

Subclinical Hyperthyroidism Is a Risk Factor for Poor Functional Outcome After Ischemic Stroke

Frank Arne Wollenweber, MD*; Vera Zietemann, PhD*; Andreas Gschwendtner, MD; Christian Opherk, MD; Martin Dichgans, MD

Received January 18, 2013; accepted February 11, 2013.From the Institute for Stroke and Dementia Research (F.A.W., V.Z., A.G., C.O., M.D.), Department of Neurology (C.O.), Interdisciplinary Stroke

Center (C.O., M.D.), Klinikum der Universität München, Ludwig-Maximilians-University, Munich, Germany; and Munich Cluster for Systems Neurology (SyNergy), Munich, Germany (M.D.).

*Drs Wollenweber and Zietemann contributed equally to this work.The online-only Data Supplement is available with this article at http://stroke.ahajournals.org/lookup/suppl/doi:10.1161/STROKEAHA.

113.000833/-/DC1.Correspondence to Martin Dichgans, MD, Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-

University, Marchioninistr. 15, 81377 Munich, Germany. E-mail martin.dichgans@med.uni-muenchen.de© 2013 American Heart Association, Inc.

Stroke is available at http://stroke.ahajournals.org DOI: 10.1161/STROKEAHA.113.000833

2013

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Wollenweber et al Subclinical Hyperthyroidism and Functional Outcome 1447

(fT3) concentrations were quantified using a chemiluminescence-based immunoassay.7 Because clinical symptoms of mild thyroid dis-eases are nonspecific, thyroid state was biochemically defined using published criteria.5,8

OutcomeThe modified Rankin Scale measured 3 months after stroke was used as the primary functional outcome measure. The Barthel Index was used as a supporting measure to assess consistency in direction of effect.9

Statistical AnalysisAssociations between thyroid-stimulating hormone and functional outcomes were determined using ordinal logistic regression with eu-thyroid state as a reference.9 To avoid inappropriately small patient numbers within individual cells, modified Rankin Scale scores were categorized into 3 groups: 0 to 1, 2 to 3, and 4 to 6. Adjusted associa-tions were calculated to investigate confounding and direct effects. All analyses were 2-sided, conducted at a 0.05 level of significance, and carried out using SAS version 9.3. Detailed Methods are de-scribed in the online-only Data Supplement.

ResultsBaseline characteristics of the study population are shown in Table 1. Patients with subclinical hyperthyroidism had a lower body mass index and lower blood lipid levels compared with patients with euthyroid state. AF was more common in patients with subclinical hyperthyroidism and hypothyroidism compared with patients with euthyroid state.

Stroke recurrences occurred in 1 patient (5.3%) with sub-clinical hyperthyroidism, in 6 patients (4.9%) with euthyroid state, and in none of the patients with subclinical hypothy-roidism. One patient with subclinical hyperthyroidism and 4 patients with euthyroid state died during follow-up (Figure). Subclinical hyperthyroidism was associated with a signifi-cantly higher risk of poor functional outcome in both statistical models (Table 2). Subclinical hypothyroidism was associated with a lower risk of poor functional outcome, although the association was not significant (Table 2).

Table 1. Baseline Characteristics

Total (n=165)Subclinical Hyperthyroidism

(n=19)Euthyroid State

(n=123)Subclinical Hypothyroidism

(n=23)

TSH, μU/mL 1.28 (0.76–1.98) 0.31 (0.18–0.40) 1.24 (0.81–1.78) 3.12 (2.16–4.18)

Age, y 70 (62–78) 75 (61–80) 70 (64–79) 68 (56–76)

Female 71 (43) 10 (53) 50 (41) 11 (48)

Coronary artery disease 23 (14) 4 (21) 17 (14) 2 (9)

Diabetes mellitus 23 (14) 1 (5) 17 (14) 5 (22)

Arterial hypertension 119 (72) 14 (74) 87 (71) 18 (78)

Heart rate, bpm 76 (68–84) 80 (69–88) 76 (68–84) 73 (64–83)

BMI, kg/m2 25.9 (4.0) 24.3 (2.9) 26.0 (3.8) 27.0 (5.3)

Atrial fibrillation* 42 (25) 7 (37) 28 (23) 7 (30)

NIHSS 2 (1–4) 2 (2–8) 2 (1–4) 2 (1–4)

TOAST

Large-artery atherosclerosis 21 (13) 1 (5) 17 (14) 3 (13)

Cardioembolic 47 (28) 7 (37) 34 (28) 6 (26)

Small-artery occlusion 21 (13) 1 (5) 17 (14) 3 (13)

Competing causes 10 (6) 1 (5) 8 (6) 1 (4)

Other 6 (4) 2 (11) 4 (3) 0

Undefined 60 (36) 7 (37) 43 (35) 10 (43)

Laboratory findings

LDL cholesterol (mg/dL) 129 (107–151) 98 (82–134) 130 (108–153) 136 (123–149)

HDL cholesterol (mg/dL) 49 (41–63) 53 (40–66) 49 (41–64) 47 (42–56)

Free T4 (ng/dL)† … 1.3 (1.2–1.4) … 1.2 (1.1–1.4)

Free T3 (pg/mL)† … 2.6 (2.3–3.0) … 2.6 (2.4–2.9)

Data are given as medians (interquartile range), means (SD), and frequencies (percentages). BMI indicates body mass index; HDL, High-Density Lipoprotein; LDL, Low-Density Lipoprotein; NIHSS, National Institute of Health Stroke Scale; TOAST, the Trial of Org 10172 in Acute Stroke Treatment classification; and TSH, thyroid-stimulating hormone.

*History of or newly diagnosed intermittent, persistent, or permanent atrial fibrillation.†fT4 and fT3 were analyzed if TSH was out of the reference limit of 0.44<TSH<2.5 μU/mL.

Figure. Functional outcome assessed by modified Rankin scale 3 months after acute ischemic stroke stratified by thyroid function.

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1448 Stroke May 2013

DiscussionThis study demonstrates that subclinical hyperthyroidism is an independent risk factor for poor functional outcome 3 months after ischemic stroke. Our findings must be interpreted in the context of recent studies that have shown multiple effects of subclinical thyroid disease on the cardiovascular system.1 Subclinical hyperthyroidism increases the risk of AF3 and cardioembolic stroke, which has a less favorable short-term outcome than other stroke subtypes.10 In the current study, AF was more common in patients with subclinical hyperthyroid-ism than in patients with euthyroid state. However, the associ-ation with poor outcome remained significant after adjustment for AF, and AF was likewise more common in patients with subclinical hypothyroidism, which showed a favorable effect on outcome in this and in earlier studies.5,6

Long-lasting subclinical hyperthyroidism has been associ-ated with heart failure.2 None of our patients showed signs of heart failure, but cardiac function was not quantitatively assessed and therefore cannot be excluded as a contributing factor. Other mechanisms to be considered are changes in coagulation parameters11 and an increased sympathetic nervous system tone.12 Elevated concentrations of thyroid hormones are associated with an increase in energy and oxygen demand,12 which would be expected to impair ischemic tolerance in the brain. However, more detailed studies are required to deter-mine the impact of thyroid function on cerebral ischemia.

Serum thyroid-stimulating hormone reference limits remain a matter of debate. This in part relates to the impact of age, sex, ethnicity, diurnal variations, and acute illnesses.1 In the current study, we accounted for these factors by standard-ized blood sampling by excluding patients with symptom onset >72 hours and by including age, sex, and time of blood sampling in our statistical models. Limitations of this study include the relatively small number of patients with subclini-cal thyroid disease, a potential bias toward recruitment of less severely affected patients, and that the outcome had to be assessed by telephone interviews in some patients. Also, we did not perform systematic imaging on the thyroid gland.

Our findings contribute to the growing evidence for adverse effects resulting from subclinical hyperthyroidism.1 Although significant for both end points, our findings require confirma-tion in additional cohorts.

AcknowledgmentsThe authors thank M. Deschner, A. Dörr, T. Hasselwander, A. Zollver, and M. Vogeser for their support.

Sources of FundingThis work was supported by Vascular Dementia Research Foundation.

DisclosuresNone.

References 1. Cooper DS, Biondi B. Subclinical thyroid disease. Lancet.

2012;379:1142–1154. 2. Biondi B. Mechanisms in endocrinology: heart failure and thyroid dys-

function. Eur J Endocrinol. 2012;167:609–618. 3. Auer J, Scheibner P, Mische T, Langsteger W, Eber O, Eber B.

Subclinical hyperthyroidism as a risk factor for atrial fibrillation. Am Heart J. 2001;142:838–842.

4. Dörr M, Empen K, Robinson DM, Wallaschofski H, Felix SB, Völzke H. The association of thyroid function with carotid artery plaque burden and strokes in a population-based sample from a previously iodine-deficient area. Eur J Endocrinol. 2008;159:145–152.

5. Akhoundi FH, Ghorbani A, Soltani A, Meysamie A. Favorable func-tional outcomes in acute ischemic stroke patients with subclinical hypo-thyroidism. Neurology. 2011;77:349–354.

6. Baek JH, Chung PW, Kim YB, Moon HS, Suh BC, Jin DK, et al. Favorable influence of subclinical hypothyroidism on the functional out-comes in stroke patients. Endocr J. 2010;57:23–29.

7. Vogeser M, Weigand M, Fraunberger P, Fischer H, Cremer P. Evaluation of the ADVIA Centaur TSH-3 assay. Clin Chem Lab Med. 2000;38:331–334.

8. Cappola AR, Fried LP, Arnold AM, Danese MD, Kuller LH, Burke GL, et al. Thyroid status, cardiovascular risk, and mortality in older adults. J Am Med Assoc. 2006;295:1033–1041.

9. Lees KR, Bath PM, Schellinger PD, Kerr DM, Fulton R, Hacke W, et al; European Stroke Organization Outcomes Working Group. Contemporary outcome measures in acute stroke research: choice of primary outcome measure. Stroke. 2012;43:1163–1170.

10. Lavados PM, Sacks C, Prina L, Escobar A, Tossi C, Araya F, et al. Incidence, case-fatality rate, and prognosis of ischaemic stroke subtypes in a predominantly Hispanic-Mestizo population in Iquique, Chile (PISCIS project): a community-based incidence study. Lancet Neurol. 2007;6:140–148.

11. Erem C. Blood coagulation, fibrinolytic activity and lipid profile in sub-clinical thyroid disease: subclinical hyperthyroidism increases plasma factor X activity. Clin Endocrinol (Oxf). 2006;64:323–329.

12. López M, Varela L, Vázquez MJ, Rodríguez-Cuenca S, González CR, Velagapudi VR, et al. Hypothalamic AMPK and fatty acid metabolism mediate thyroid regulation of energy balance. Nat Med. 2010;16:1001–1008.

Table 2. TSH-Level and Functional Outcome 3 Months After Ischemic Stroke

Model 1 Model 2

OR (95% CI); P Value OR (95% CI); P Value

Modified Rankin Scale

Hyperthyroidism vs euthyroid state 2.63 (1.02–6.82); P=0.046 3.95 (1.25–12.47); P=0.019

Hypothyroidism vs euthyroid state 0.78 (0.27–2.22); P=0.64 0.75 (0.22–2.55); P=0.64

Barthel Index

Hyperthyroidism vs euthyroid state 3.63 (1.27–10.35); P=0.016 9.12 (2.08–39.89); P=0.003

Hypothyroidism vs euthyroid state 0.90 (0.25–3.18); P=0.87 0.52 (0.09–2.80); P=0.44

Associations were determined using ordinal logistic regression; functional outcome was categorized into 3 groups (modified Rankin Scale: 0–1 [n=109], 2–3 [n=41], and 4–6 [n=15]; Barthel Index: >95 [n=125], 86–95 [n=19], and ≤85 [n=21]). Model 1: adjusted for age, sex, smoking status, and time between symptom onset and blood sampling. Model 2: additionally adjusted for National Institute of Health Stroke Scale, transient ischemic attack, C-reactive protein, atrial fibrillation, body mass index, and total cholesterol. CI indicates confidence interval; OR, odds ratio; and TSH, thyroid-stimulating hormone.

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Martin DichgansFrank Arne Wollenweber, Vera Zietemann, Andreas Gschwendtner, Christian Opherk and

Ischemic StrokeSubclinical Hyperthyroidism Is a Risk Factor for Poor Functional Outcome After

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1

SUPPLEMENTAL MATERIAL

Subclinical hyperthyroidism is a risk factor for poor functional outcome after ischemic

stroke

Supplementary methods

Study design and study population. Patients were recruited through an on-going

observational cohort study conducted at the Interdisciplinary Stroke Centre Munich, a tertiary

level hospital. Enrollment occurred between February 2011 and March 2012.

Patients of both sexes aged 18 years or older with ischemic stroke were recruited through the

local stroke unit. Inclusion criterion was an acute ischemic stroke defined by an acute focal

neurological deficit documented by either a diffusion weighted imaging (DWI)-positive lesion

on MR imaging or a new lesion on a delayed CT scan. Exclusion criteria were known thyroid

disease, a biochemically detected overt thyroid disease, medication with thyroid affecting

drugs, time since symptom onset of greater than 72 hours, brain tumor or brain metastasis.

As displayed in figure e-1 1008 patients were seen at the recruiting stroke unit during the

enrollment phase. 843 were not included in the analysis. 540 of them did not meet the

inclusion criterion. Another 67 patients were excluded because of a stroke going back more

than 72-hours at time of admittance and 71 patients could not be contacted during their

hospital stay. The remaining 330 patients were asked to participate in the study. 142 patients

were not willing or able to participate for various reasons (e.g. severe impairment with

inability to participate into the interview, lack of German language skills). 188 patients agreed

to participate in the study. 18 patients were excluded from analysis because of thyroid-

affecting medication use before stroke (n=14) or overt thyroid dysfunction (n=4). Of the 170

patients that were available for baseline-assessment 70% had been admitted within 12 hours

after symptom onset, 82% within 24 hours, and 96% within 48 hours.

2

Outcome measures were obtained at 3 months after stroke (median time: 90 days, interquartile

range [IQR] 81-99 days), conducted by a structured interview via telephone or face to face

depending on the patient’s feasibility to return to the study center. The interview was

performed with the patient or, if not possible, with a close relative. 160 patients completed the

3 months follow-up. Five patients died within 3 months and 5 were lost to follow-up (figure e-

1). Statistical analyses were performed on the 165 patients with known functional outcome

after 3 months. The representativeness of the 165 analyzed and 303 not analyzed patients with

acute ischemic stroke is shown in table e-1.

Standard protocol approvals, registrations, and patient consent. The study was conducted

according to the Declaration of Helsinki and approved by the local ethics committee. Written

informed consent was obtained by patient or legal guardian prior to study participation.

Data collection. Information on demographic variables, living situation, functional pre-stroke

outcome, lifestyle habits, health history as well as medication before stroke was provided by

the patient or the closest relative at baseline examination. Stroke severity was assessed using

the National Institutes of Health Stroke Survey (NIHSS) by a certified study clinician. Stroke

etiology was determined according to the criteria of the TOAST and ASCO classification.1

Patients received a continuous 72h-ECG recording at baseline and a 12-channel ECG at the

follow-up. Furthermore all patients received complete two-dimensional (2D) and Doppler

echocardiography, however left atrial diameter, ejection fraction and premature atrial

contractions were not quantitatively assessed. All examinations were performed and

interpreted by an independent observer who was unaware of the clinical data.

Exposure measurement. Blood samples were drawn in the morning between 6 and 9 am to

minimize variations caused by circadian rhythm. They were taken within 3 days after

symptom onset and adjusted for time differences in multivariable analyses. Serum thyroid-

stimulating hormone (TSH), free thyroxin (fT4) and free tri-iodothyronine (fT3)

concentrations were quantified using a chemiluminescence-based immunoassay implemented

3

on a fully automated immunoanalyzer system (ADVIA Centaur TSH, Siemens Healthcare

Diagnostics, Tarrytown NY, USA).2

In the recent literature different reference-limits have been proposed for hypothyroidism:

Akhoundi et al.3 defined subclinical hypothyroidism as serum TSH level in the range of 2.5-

10mIU/L, Baek et al.4 defined subclinical hypothyroidism as TSH >5μU/mL. In the current

study we adopted the lower cut point of 2.5 to be comparable with the more recent work of

Akhoundi et al.3 For hyperthyroidism we adopted the cut point used by Cappola et al.

5, who

determined the relationship between baseline thyroid status and incident atrial fibrillation.

Thus, euthyroid state was defined by a serum TSH-level between 0.44 and 2.5 μU/ml,

subclinical hyperthyroidism was defined by a serum TSH-level between 0.11 and 0.44

μU/ml plus normal fT4 and fT3 and subclinical hypothyroidism was defined by a serum TSH-

level between ≥2.5 and <20 μU/ml plus normal fT4 and fT3.3, 5

Reference values for fT4 were

0.9-1.8 ng/dl and for fT3 2.3-4.2 pg/ml. All measurements were performed by laboratory staff

unaware of the patients’ clinical characteristics.

Outcome measurement. The modified Rankin Scale (mRS) was used as the primary

functional outcome measure after 3 months follow-up as recommended in the literature.6 The

Barthel Index (BI) was used as a supporting scale to assess consistency in direction of effect.6

Both outcome measurements were determined by trained raters who were unaware of the

laboratory results.

Statistical analysis. Data are given as means (SD) for normally distributed interval variables,

as medians (IQR) for skewed data or scores, and as frequencies (percentage) for categorical

variables.

Associations between TSH and functional outcomes 3 months after stroke were determined

using ordinal logistic regression with euthyroid state as reference because an ordinal analysis

is statistically more powerful and avoids the difficulty of choosing one cut point.6,7

We

performed score tests to test the proportionality hypothesis. To avoid inappropriately small

4

patient numbers within individual cells outcome measures were categorized into 3 groups:

mRS: 0-1, 2-3 and 4-6; BI: ≤85, 86-95 and >95 (table e-2).

Adjusted associations were calculated to investigate confounding and direct effects. Model 1

was adjusted for the possible confounder age, sex, and smoking status as smoking is known to

influence the TSH-level 8 and was found to be associated with TSH-levels in our data set.

Model 2 furthermore included known risk factors for functional outcome after stroke (NIHSS,

TIA and serum CRP) as well as variables previously reported to be affected by thyroid

function (intermediate variables) such as AF, total cholesterol and body mass index (BMI).

LDL cholesterol, medication before stroke for dyslipidemia and mRS at baseline was not

included in the multivariable models to avoid multicollinearity. All models were adjusted for

the time between symptom onset and blood sampling. Continuous variables were categorized

into quartiles to account for nonlinear relations with the outcome. Odds ratios (OR) were

reported with 95% confidence intervals (CI). All analyses were two-sided, conducted at a 0.05

level of significance and carried out using SAS version 9.3 (SAS Institute Inc., Cary, NC).

5

Figure e-1. Study profile (enrollment between February 2011 and March 2012)

1008 patients admitted to the hospital

No final diagnosis of acute ischemic stroke: n=540 (54%)

- Time since symptom onset >72h or time unknown: n=67 (14%)

- Patient could not be contacted: n=71 (15%)

- Patient refused: n=62 (19%)

- Patient rapidly transferred / not reached for interview: n=6 (2%)

- Patient could not be informed & no informant available: n=17 (5%)

- Patient in bad condition & no informant available: n=9 (3%)

- Patient does not speak German good enough: n=11 (3%)

- Patient is living too far away: n=16 (5%)

- Others: n=21 (6%)

188 patients recruited

330 patients contacted

468 patients with acute ischemic

stroke*

Patient excluded because of:

- thyroid affecting medication use before stroke: n=14 (7%)

(amiodarone: n=1; carbimazole: n=1; levothyroxine: n=12)

- overt thyroid dysfunction: n=4 (2%)

(TSH-level >20 μU/ml: n=1; TSH-level <0.1 μU/ml: n=3)

170 patients with baseline-data

Patient lost to follow-up after 3 months because:

- patient could only be interviewed >9 months after baseline: n=2 (1%)

- relative discontinued interview because of poor health status of the

patient: n=1 (1%)

- patient alive but could not be contacted (information from the

registry office): n=2 (1%)

165 patients included in analysis

* defined by a new focal neurological deficit with a corresponding lesion on a MR or CT scan

6

Table e-1. Representativeness of the cohort with acute ischemic stroke

Patients analyzed

(N=165)

Patients with ischemic

stroke not entering the

analysis

(N=303)

Age: median [IQR] 70 [62-78] 73 [62-81]

Female: % 43 46

Coronary artery disease

Diabetes mellitus

Peripheral artery disease

Arterial hypertension

Dyslipidaemia

14

14

9

72

37

18

22

9

75

37

Table e-2. Functional outcome 3 months after acute ischemic stroke

Total Subclinical

hyperthyroidism

Euthyroid state Subclinical

hypothyroidism

Modified Rankin Scale: n

(%)

≤1

2-3

>3

109

(66)

41 (25)

15 (9)

9 (47)

5 (26)

5 (26)

83 (68)

31 (25)

9 (7)

17 (74)

5 (22)

1 (4)

Barthel Index: n (%)

>95

86-95

≤85

125

(76)

19 (11)

21 (13)

10 (53)

3 (16)

6 (31)

96 (78)

13 (11)

14 (11)

19 (83)

3 (13)

1 (4)

7

References

1. Amarenco P, Bogousslavsky J, Caplan LR, Donnan GA, Hennerici MG. New

approach to stroke subtyping: The a-s-c-o (phenotypic) classification of stroke.

Cerebrovasc Dis. 2009;27:502-508

2. Vogeser M, Weigand M, Fraunberger P, Fischer H, Cremer P. Evaluation of the advia

centaur tsh-3 assay. Clin Chem Lab Med. 2000;38:331-334

3. Akhoundi FH, Ghorbani A, Soltani A, Meysamie A. Favorable functional outcomes in

acute ischemic stroke patients with subclinical hypothyroidism. Neurology.

2011;77:349-354

4. Baek JH, Chung PW, Kim YB, Moon HS, Suh BC, Jin DK, et al. Favorable influence

of subclinical hypothyroidism on the functional outcomes in stroke patients. Endocr J.

2010;57:23-29

5. Cappola AR, Fried LP, Arnold AM, Danese MD, Kuller LH, Burke GL, et al. Thyroid

status, cardiovascular risk, and mortality in older adults. JAMA. 2006;295:1033-1041

6. Lees KR, Bath PM, Schellinger PD, Kerr DM, Fulton R, Hacke W, et al.

Contemporary outcome measures in acute stroke research: Choice of primary outcome

measure. Stroke. 2012;43:1163-1170

7. Bath PM, Lees KR, Schellinger PD, Altman H, Bland M, Hogg C, et al. Statistical

analysis of the primary outcome in acute stroke trials. Stroke. 2012;43:1171-1178

8. Cooper DS, Biondi B. Subclinical thyroid disease. Lancet. 2012;379:1142-1154