Ladbon Khajeh

The introductory chapter 1 describes the clinical signs and symptoms of subarachnoid hemorrhage (SAH) and hypopituitarism. It provides a short background of current knowledge of the possible association of SAH with hypopituitarism and its possible consequences for outcome after SAH. This chapter explains the rationale of the present study. To better understand the long-term consequences of SAH, we have studied the occurrence of hypopituitarism in patients with SAH, and the effect of hypopituitarism and clinical predictors on fatigue and physical fitness up to 14 months after SAH.

Chapter 2 reviews the literature on the occurrence, possible pattern and severity of endocrine abnormalities. As fatigue, slowness, apathy and decrease in level of activity are common long-term complaints after a SAH and as they resemble the symptoms frequently found in patients with endocrine dysfunction, we attempted to identify risk factors for hypopituitarism after SAH. Pituitary dysfunction may be the direct result of SAH or of its complications such as hydrocephalus or vasospasm. We found the prevalence of endocrine dysfunction to vary from 0 to 55%, and the affected pituitary axes differed between studies. This great variation is due to differences in patient selection, study design, time elapsed between SAH and endocrine evaluation, different methodology of endocrine tests and definitions of hypopituitarism between the studies. After assessment of all the strengths and weaknesses of the studies we concluded that a good quality study was lacking.

In Chapter 3, the objective was to determine the diagnostic value of a ghrelin test in the diagnosis of growth hormone deficiency (GHD) shortly after SAH. Therefore, a ghrelin test was carried out after the acute phase within 3 months of SAH and a growth hormone releasing hormone (GHRH) arginine test 6 months post SAH. As ghrelin test is a novel test, we needed a confirmatory test, for which we used GHRH-arginine test. A cut-off limit of a GH peak of 15 μg/L corresponded with a sensitivity of 100 % and a false positive rate of 40% (ROC: 0.869 under the curve). No serious adverse events or idiosyncratic reactions were observed in subjects undergoing a ghrelin test. We concluded that Ghrelin test is a valid and safe test which is also easy to apply in the early phase of SAH.

Chapter 4 describes the incidence and course of pituitary dysfunction (PD) after SAH at baseline, 6 and 14 months and identify clinical determinants for PD in patients with recent SAH. Almost 40% of SAH survivors in our cohort of 84 patients had PD. In 7% GHD or gonadotropin deficiency persists until at least 14 months. Hydrocephalus is independently associated with PD 6 months after SAH (odds-ratio 3.3 CI 2.7-3.8). Whether SAH patients should be screened for PD is under debate, because clinical significance is not clear. However, there are several reasons to consider early neuro-endocrine evaluation of SAH patients. These concern the possibility of adrenal insufficiency which is life-threatening in the early stressful period after SAH and the possible association with long-term symptoms such as fatigue, low energy level which can influence and hamper the rehabilitation and outcome of these patients.

Chapter 5 describes the possible association between fatigue after SAH and long-term pituitary deficiency in SAH survivors. Fatigue is a common symptom after SAH and in PD, in particular in patients with GHD. Fatigue was measured with the Fatigue Severity Scale (FSS). Seventy six percent of SAH survivors have pathological fatigue directly after SAH and almost 60% of patients still have pathological levels of fatigue after 14 months. There was no effect of PD (p=0.8) or GHD (p=0.23) on fatigue. The Severity of World Federation of Neurosurgical Societies score is a clinical predictor (p=0.008) of fatigue in SAH survivors.

Chapter 6 describes physical fitness in the first year after SAH, its relation with physical activity, sedentary behavior and functional outcome and disease-related characteristics as potential predictors. Physical fitness was assessed by evaluating cardiorespiratory fitness and knee muscle strength. Physical behavior, comprising physical activity and sedentary behavior, were determined by accelerometry-based activity monitoring. The functional independence measure and functional assessment measure were used to evaluate functional outcome. Physical fitness remained very low in more than one-third of the patients over the first year after SAH, and is related to physical inactivity and impaired functional outcome.

The general discussion is chapter 7 of this thesis. In this chapter the main findings are discussed. At first the relation between hypopituitarism and SAH is discussed. After that the relations between fatigue, physical fitness with SAH and PD are discussed. We take notice of the fact that a large proportion of patients suffer from PD directly after SAH, but this number declines in the first year after SAH. Hypopituitarism does not seem to be the only cause of long-term symptoms of SAH survivors but it can be seen as one of the possible factors that may influence long-term symptoms. Furthermore, the strengths and limitations such as number of participants, observational type of study and incomplete endocrine testing in some cases as well as recommendations for future studies are discussed. We conclude that, based on our findings, screening of all patients early after SAH cannot be recommended. Testing of selected cases can be clinically relevant. Further studies should help define the clinical profile of SAH patients at risk of hypopituitarism.