Claire Feeney

Pituitary dysfunction after blast traumatic brain injury: The UK BIOSAP study.

Pituitary dysfunction is a recognized consequence of traumatic brain injury (TBI) that causes cognitive, psychological, and metabolic impairment. Hormone replacement offers a therapeutic opportunity. Blast TBI (bTBI) from improvised explosive devices is commonly seen in soldiers returning from recent conflicts. We investigated: (1) the prevalence and consequences of pituitary dysfunction following moderate to severe bTBI and (2) whether it is associated with particular patterns of brain injury.

Prevalence and correlates of vitamin D deficiency in adults after traumatic brain injury

Traumatic brain injury (TBI) is a major cause of long‐term disability with variable recovery. Preclinical studies suggest that vitamin D status influences the recovery after TBI. However, there is no published clinical data on links between vitamin D status and TBI outcomes. The aim was to determine the (i) prevalence of vitamin D deficiency/insufficiency, and associations of vitamin D status with (ii) demographic factors and TBI severity, and with (iii) cognitive function, symptoms and quality of life, in adults after TBI.

Minocycline reduces chronic microglial activation after brain trauma but increases neurodegeneration

Head injury survivors can develop neurodegeneration associated with persistent neuroinflammation, but whether the latter is harmful or beneficial is unclear. Scott et al. report that minocycline reduces neuroinflammation months and years after injury but increases a blood marker of neurodegeneration, suggesting that persistent neuroinflammation has reparative effects long after injury.

Serum insulin-like growth factor-I levels are associated with improved white matter recovery after traumatic brain injury

Traumatic brain injury (TBI) is a common disabling condition with limited treatment options. Diffusion tensor imaging measures recovery of axonal injury in white matter (WM) tracts after TBI. Growth hormone deficiency (GHD) after TBI may impair axonal and neuropsychological recovery, and serum insulin‐like growth factor‐I (IGF‐I) may mediate this effect. We conducted a longitudinal study to determine the effects of baseline serum IGF‐I concentrations on WM tract and neuropsychological recovery after TBI.

The screening and management of pituitary dysfunction following traumatic brain injury in adults: British Neurotrauma Group guidance

Pituitary dysfunction is a recognised, but potentially underdiagnosed complication of traumatic brain injury (TBI). Post-traumatic hypopituitarism (PTHP) can have major consequences for patients physically, psychologically, emotionally and socially, leading to reduced quality of life, depression and poor rehabilitation outcome. However, studies on the incidence of PTHP have yielded highly variable findings. The risk factors and pathophysiology of this condition are also not yet fully understood. There is currently no national consensus for the screening and detection of PTHP in patients with TBI, with practice likely varying significantly between centres. In view of this, a guidance development group consisting of expert clinicians involved in the care of patients with TBI, including neurosurgeons, neurologists, neurointensivists and endocrinologists, was convened to formulate national guidance with the aim of facilitating consistency and uniformity in the care of patients with TBI, and ensuring timely detection or exclusion of PTHP where appropriate. This article summarises the current literature on PTHP, and sets out guidance for the screening and management of pituitary dysfunction in adult patients with TBI. It is hoped that future research will lead to more definitive recommendations in the form of guidelines.

Serum IGF-I levels are associated with improved white matter recovery after TBI

Traumatic brain injury (TBI) is a common disabling condition with limited treatment options. Diffusion tensor imaging measures recovery of axonal injury in white matter (WM) tracts after TBI. Growth hormone deficiency (GHD) after TBI may impair axonal and neuropsychological recovery, and serum insulin‐like growth factor‐I (IGF‐I) may mediate this effect. We conducted a longitudinal study to determine the effects of baseline serum IGF‐I concentrations on WM tract and neuropsychological recovery after TBI.

Seeds of neuroendocrine doubt

The possibility of human-to-human transmission of Alzheimer’s disease has not been considered until recently. A landmark study, published in September 2015 in Nature, reports the probable seeding of amyloid-β (Aβ; a pathological hallmark of Alzheimer’s disease) from cadaveric human growth hormone (c-hGH) pituitary preparations in individuals who also developed iatrogenic Creutzfeldt–Jakob Disease (iCJD) from the same source1. Here, we argue that c-hGH was historically used to treat rare neuroendocrine disease and that these diseases or treatment with growth hormone could result in Aβ pathology per se. Without a control group of the same patient cohort who neither received c-hGH nor developed iCJD, we believe that the authors are premature to infer an iatrogenic source of Alzheimer’s disease. There is a Reply to this Brief Communication Arising by Collinge, J. et al. Nature 535, http://dx.doi.org/10.1038/ nature18603 (2016). Cadaveric-hGH was previously used to growth hormone deficiency (GHD) in children. In the UK, growth hormone was extracted from a cadaveric pool of approximately 400,000 pituitary glands and offered as an intramuscular treatment to selected patients. Given scarce resources and laborious extraction, its use was coordinated in the UK by a Medical Research Council working party in 1959 that was superseded by the Health Services Human Growth Hormone Committee in 19772. In the UK, 1,908 people were registered as having received c-hGH from 1959 to 1985 when it was withdrawn worldwide after an initial report documenting three deaths from CJD in the US and one in the UK. This number rose to 226 incidences worldwide in 20123. From 1985 onwards c-hGH became obsolete after being superseded by synthetic recombinant forms. The diverse clinical indications for c-hGH treatment until 1985 are clearly presented in a comprehensive epidemiological review which used data from the Health Services Human Growth Hormone Committee records in the UK4. Of the 1,908 patients registered as having received c-hGH in the UK, 1,004 (52.6%) had ‘idiopathic’ isolated GHD, 188 (10%) ‘idiopathic’ panhypopituitarism, 230 (12.1%) craniopharyngioma, 194 (10.2%) other intracranial tumour, 62 (3.3%) other neurological disease for example, hydrocephalus or postmeningitis, 62 (3.3%) genetic short stature and growth delay or both and 44 (2.3%) Turner’s syndrome. The remaining causes included Prader–Willi syndrome, low birth weight, haematological disease, histiocytosis and septo-optic dysplasia. These well-recorded historical data demonstrate the heterogeneity and severity of neuroendocrine disease necessitating c-hGH treatment in the UK before 1985. Supplementary material from the article in question reports the clinical details of all eight patients and the indication for c-hGH treatment, summarized in Table 1. All patients received c-hGH as children or adolescents and duration of treatment was 2–12 years. From an aetiological perspective, 3 of 8 subjects had panhypopituitarism (one also with mental retardation and microcephaly), 1 of 8 had craniopharyngioma and 4 of 8 are reported to have been treated for short stature alone. This is surprising as short stature alone was an uncommon indication for c-hGH before 1985, although trials were starting to emerge for this indication just before the withdrawal of c-hGH5. Short stature should not be confused with GHD as the former can be constitutional and the latter is a neuroendocrine disease which can lead to short stature. We therefore believe it likely that the ‘short stature’ group disguises a more complicated clinical picture. At the other end of the clinical spectrum, one of the four patients reported as having moderate to severe grey matter and vascular Aβ pathology had a craniopharyngioma. These unusual pituitary tumours can be large, often require neurosurgery and/or cranial radiation and are prone to recurrence and multiple pituitary hormone deficiencies. Notably, the one patient in the sporadic CJD control group (aged ~65 years) who also had similar levels of cerebral amyloid angiopathy to the iCJD group was labelled as an outlier and it was stated that the subject had a surgical intervention 40 years before death (Jaunmuktane et al.1 Extended Data Figs 2 and 3). Jaunmuktane and colleagues’ article was preceded by a case series from the same research group of the clinical, imaging, molecular and autopsy findings of the whole iCJD cohort (n = 22)6. One patient had a history of long-term cognitive problems and additional MRI findings included one patient with septo-optic dysplasia and partial agenesis of the corpus callosum. It is not clear whether these particular patients were the ones included in the current article, but together with the historical records and the supplementary clinical details provided, highlight our argument that these patients had complex, rare and potentially severe neuroendocrine disease. With this in mind, an alternative hypothesis contributing to the findings is that these pre-existing and underlying conditions could by themselves lead to Aβ pathology and abnormal brain structure. Growth hormone is known to have various cognitive effects on the brain and isolated GHD in children can lead to lower IQ, impaired cognition, reduction brain volumes and white matter abnormalities7,8. If GHD continued into adulthood (as it usually does) and was untreated then significant cognitive impairments are likely to have persisted9.