Carney complex- why thorough medical history taking is so important - report of three cases and review of the literature.

PURPOSE: To present a new case series and to review the literature on Carney complex (CNC) with an emphasis on highlighting key clinical features of the disease and pointing out possibilities of shortening the diagnostic process. METHOD: Searches of PubMed, identifying relevant reports up to April 2022. RESULTS: CNC is a rare, autosomally dominant inherited neoplasia -endocrinopathy syndrome with high clinical variability, even among members of the same family. Data on length of diagnostic process are scarce with numerous case series reporting a diagnostic delay of decades. Suggestions to shorten the diagnostic process includes awareness of the multi-faceted clinical presentations of CNC, thorough history taking of index patients and family members and awareness of diagnostic pitfalls. Importantly, unusual symptom combinations should alert the clinician to suspect a rare endocrinopathy syndrome such as CNC. Already present and coming on the horizon are databases and novel phenotyping technologies that will aid endocrinologists in their quest for timely diagnosis. CONCLUSION: In this review, we examine the current state of knowledge in CNC and suggest avenues for shortening the diagnostic journey for the afflicted patients.

[Diagnostics and treatment of acromegaly : Necessity for targeted monitoring of comorbidities]. / Diagnostik und Therapie der Akromegalie : Notwendigkeit der gezielten Überwachung von Komorbiditäten.

Acromegaly is a rare and severe condition, presenting with typical signs and symptoms. The diagnosis is often initially made years after the first manifestations of the disease. In more than 99% of patients the disease is caused by a benign pituitary tumor that secretes growth hormone (GH). The diagnosis is based on the presence of increased insulin-like growth factor 1 (IGF-1) levels and a lack of GH suppression in the oral glucose tolerance test. The standard imaging procedure for tumor detection is magnetic resonance imaging in the region of the sella turcica. Treatment includes surgical, drug and radiation therapy. Important factors are an intensive aftercare of the patient, controls for detection of tumor recurrence and pituitary insufficiency as well as assessment of various organ functions and risk constellations. Patient care should involve close cooperation between endocrinologists, neurosurgeons and general practitioners as well as other specialist disciplines.

Expression pattern of neuronal intermediate filament α-internexin in anterior pituitary gland and related tumors.

PURPOSE: α-Internexin (INA) is a class IV neuronal intermediate filament protein that maintains the morphogenesis of neurons. It is expressed in developing neuroblasts and represents the major component of the cytoskeleton in cerebellar granule cells of adult central nervous system tissue. Data concerning INA expression in the human frontal pituitary lobe and related adenomas (PA) is missing. METHODS: Using immunohistochemistry we examined the distribution pattern of INA in a large cohort of 152 PA, 11 atypical PA, 4 pituitary carcinomas and 20 normal pituitaries (overall n = 187). Quantity of INA protein expression was semi-quantitatively evaluated and grouped into five categories (0 = 0%; 1 = >0-5%; 2 = >5-35%; 3 = >35-80%; 4 = >80% of cells). RESULTS: Cellular staining intensity of INA appeared significantly higher in gonadotropinomas (Go, n = 62), null cell adenomas (NC, n = 7) and thyrotropinomas (TSHomas, n = 7) compared to the other tumor subtypes (p ≤ 0.001). Furthermore, Go and NC showed a peculiar pseudorosette-like staining pattern surrounding blood vessels in 85.5% (59/69) of cases. Interestingly, areas exhibiting homogenous INA staining were often associated with oncocytic cell changes and decreased immunohistochemically detectable hormone expression. Only 8.5% (8/94) of other PA showed a comparable INA distribution (p ≤ 0.001). CONCLUSION: Go, NC as well as TSHomas exhibit high levels of intracellular INA protein indicating neuronal transdifferentiation. A possible impact on pathogenesis and endocrine activity needs further investigation.

Headache and pituitary disease: a systematic review.

Headache is very common in pituitary disease and is reported to be present in more than a third of all patients with pituitary adenomas. Tumour size, cavernous sinus invasion, traction or displacement of intracranial pain-sensitive structures such as blood vessels, cranial nerves and dura mater, and hormonal hypersecretion are implicated causes. The present review attempts to systematically review the literature for any combination of headache and pituitary or hormone overproduction or deficiency. Most data available are retrospective and/or not based on the International Headache Society (IHS) classification. Whereas in pituitary apoplexy a mechanical component explains the almost universal association of the condition with headaches, this correlation is less clear in other forms of pituitary disease and a positive impact of surgery on headaches is not guaranteed. Similarly, invasion into the cavernous sinus or local inflammatory changes have been linked to headaches without convincing evidence. Some studies suggest that oversecretion of GH and prolactin may be important for the development of headaches, and treatment, particularly with somatostatin analogues, has been shown to improve symptoms in these patients. Otherwise, treatment rests on general treatment options for headaches based on an accurate clinical history and a precise classification which includes assessment of the patient's psychosocial risk factors.

Blunted serum and enhanced salivary free cortisol concentrations in the chronic phase after aneurysmal subarachnoid haemorrhage--is stress the culprit?

Spontaneous aneurysmal subarachnoid haemorrhage (SAH) is a cause of stroke, which constitutes a severe trauma to the brain and may lead to serious long-term medical, psychosocial and endocrinological sequelae. Adrenocorticotrophic hormone deficiency, which is considered to occur in up to 20% of all survivors, is a possible consequence of bleeding. Moreover, preliminary data suggest that a poor psychosocial outcome in SAH survivors is linked to alterations in cortisol secretion. Despite these findings, investigation of diurnal cortisol profiles and the cortisol awakening response (CAR) in chronic SAH patients has not been done so far. In this study, basal serum cortisol and salivary cortisol concentration profiles were investigated in 31 SAH patients more than 1 year after the acute event and in 25 healthy controls. Additionally, low-dose dexamethasone (DEX) suppression tests were conducted, and sensitivity to stress was measured with a psychometric questionnaire (Neuropattern(TM)). Although significantly higher salivary cortisol concentrations were observed on waking in SAH patients (p = 0.013, ANOVA), without a CAR change, total serum cortisol concentrations were blunted, but only in patients with high levels of perceived stress (SAH high stress: 337 nmol/l, SAH low stress: 442 nmol/l, controls: 467 nmol/l; Controls vs. SAH high stress p = 0.018). DEX suppression of cortisol secretion was not significantly different between patients and controls. The results indicate that total (serum) and free (salivary) cortisol concentrations give different information about cortisol availability in patients after aneurysmal SAH. Enhanced free cortisol concentrations may reflect a meaningful biological coping mechanism in SAH patients.

Variation of the baseline characteristics and treatment parameters over time: an analysis of 15 years of growth hormone replacement in adults in the German KIMS database.

The purpose of this study is to examine potential implications of changes in the approach to adult growth hormone (GH) replacement (GHR) over the last 15 years. Therefore, we analysed the German KIMS database as one of the largest single country pharmacoepidemiological databases on adult GH deficiency (GHD). Based on the date of their first GH application patients were assigned to three intervals (1995-1999, 2000-2004, 2005-2009). A multivariate analysis of variance with interval and sex as independent variables was conducted. Differences were analysed with respect to IGF-I standard deviation score (SDS), quality of life, latency between GHD diagnosis and first GH dose, body mass index, waist-hip ratio, lipid profile, and GH dose. All analyses were conducted at baseline, 1 year, and 3 years of GHR. We detected significant associations between time interval and patient characteristics at baseline and with treatment effects. Recently, patients with less severe GHD (mean IGF-I SDS: -2.1, -1.6, -1.0 in the 1st, 2nd and 3rd interval; p = 0.000) are treated with lower GH starting doses (mean 0.30, 0.19, 0.21 mg/day in the 1st, 2nd and 3rd interval; p = 0.000). In the first time interval, IGF-I SDS was not normalized in females after 3 years of GHR. The results of our analysis demonstrate prominent changes in patient characteristics and handling of GHR. They highlight that approach to therapy and patient inclusion criteria change over time and may represent an important confounder for any analysis in epidemiological surveillance surveys.

[Neuroendocrine disturbances after acquired brain damage]. / Hormonstörungen nach erworbener Hirnschädigung.

Hypopituitarism is not a rare disease and its clinical signs and symptoms deserve the attention of the clinically practising neurologist. Next to the classical cause of hypopituitarism mediated by tumours of the hypothalamo-pituitary region, a number of recent articles have highlighted the high frequency of central endocrine disturbances in patients with brain damage, i. e. not only after traumatic brain injury and subarachnoid haemorrhage but also as a consequence of the treatment of childhood brain tumours. This article provides an overview of the clinical symptomatology and pathophysiology of hypopituitarism as well as the current knowledge about neuroendocrine disturbances in the adult patient suffering from the above-mentioned disorders.

The German database on hypopituitarism after traumatic brain injury and aneurysmal subarachnoid hemorrhage - description, objectives and design.

Within the last years, a number of clinical studies have addressed the topic of hypothalamo-pituitary dysfunction following traumatic brain injury (TBI) and aneurysmal subarachnoid hemorrhage (SAH). Clinical studies oftentimes reflect the investigation of highly selective patient groups, very standardized test procedures and may be influenced by a publication bias. Epidemiological data on the prevalence and incidence of hypopituitarism after TBI and SAH in the general population still do not exist. Moreover, very little is known about risk factors and clinical characteristics of pituitary impairment after brain damage. Epidemiologic surveys which aggregate information of many different treatment centers become an increasingly important means of bridging the gap between standardized study situations and clinical practice. Therefore, a multi-center, structured data assessment to create a national registry of TBI and SAH patients has been established in 2005. The Structured Data Assessment of Hypopituitarism after TBI and SAH is coordinated by the Department of Endocrinology, Max-Planck-Institute in Munich with participation of at present 13 neurosurgical, rehabilitation and endocrinological centers in Germany and one Austrian center. Within this database, a large scope of very detailed, clinical, endocrine and outcome information is collected. It also offers the possibility of long-term follow up of the recorded patients. This is the first report of the registry describing goals, organization, methodology, funding and the descriptive data of the first 1,242 patients entered until November 20th, 2008.

Etiology, baseline characteristics, and biochemical diagnosis of GH deficiency in the adult: are there regional variations?

Previous work has examined potential links between the etiology of GH deficiency (GHD) and the baseline characteristics of the patients including biochemical and psychometric parameters. Using an update of the KIMS pharmaco-epidemiological database (Pfizer International Metabolic Database), we addressed the question how well such results can be generalized and whether regional differences may play a role. From 30 different countries, 13 167 GH-deficient patients were included in KIMS at the data close in December 2008. In order to explore country-specific differences of baseline characteristics documented in KIMS, separate analyses of baseline characteristics of adult-onset GHD patients (n=7708) were performed for the six largest contributing European countries and the United States. This analysis revealed striking regional variations in the pathogenesis of the disease, clinical characteristics such as body mass index, and in the classical features of the metabolic syndrome such as blood pressure or lipid status between countries. Moreover, the approach to endocrine function testing was widely different between countries, as well as the distribution of etiologies of GHD. These data suggest that a complex relation between biochemical and clinical signs of GHD exists, and that the spectrum of adult GHD syndrome is influenced by regional diagnostic and clinical particularities.

The awakened intraspinal glass shard.

Penetrating spinal injuries from foreign bodies are an exceedingly rare pathological entity. In this report we present an unusual clinical report of an in-driven shard of glass in the cervical spine that remained without symptoms for many years and became symptomatic possibly because of narrowing of the diameter of the vertebral canal.

Growth hormone deficient patients after traumatic brain injury--baseline characteristics and benefits after growth hormone replacement--an analysis of the German KIMS database.

OBJECTIVE: In recent years, traumatic brain injury (TBI) has been identified as a significant cause of growth hormone deficiency (GHD). The aim of the present study was to characterize adult TBI patients with GHD to elucidate the effect of human growth hormone (hGH) replacement in TBI patients as documented in the German Pfizer International Metabolic (KIMS) database. DESIGN: As of October 2006, 84 TBI patients had been included in the German KIMS database (n=28 childhood-onset and 54 adult-onset GHD). All 84 TBI patients were matched with 84 patients with GHD due to non-functioning pituitary adenoma (NFPA) also included in this database. Analysis of clinical and outcome variables was performed, with comparisons of childhood vs. adult TBI, and TBI vs. NFPA patients, at baseline and one-year follow-up. RESULTS: TBI patients with GHD were significantly younger at the onset of pituitary disease and exhibited a significantly longer time span between GHD diagnosis and KIMS entry than NFPA patients. Those KIMS patients who had sustained their TBI in childhood were of significantly shorter stature than adult-onset TBI patients. At 1-year follow-up, insulin-like growth factor I (IGF-I) standard deviation score levels had returned to the normal range and quality of life (QoL), as measured by QoL- Assessment of Growth Hormone Deficiency in Adults (AGHDA) questionnaire, improved significantly in TBI as in NFPA patients. CONCLUSION: This analysis provides preliminary data that TBI patients with GHD benefit from hGH replacement in terms of improved QoL in a similar fashion as do NFPA patients. Moreover, it suggests that belated diagnosis and treatment in childhood-onset GHD due to TBI might be related to a shorter final height in these children.

Diagnosing neuroendocrine dysfunction in patients after aneurysmal subarachnoid hemorrhage in clinical practice - does basal hormone screening make sense?

Recent studies indicate that neuroendocrine dysfunction is a more frequent sequel of aneurysmal subarachnoid hemorrhage (SAH), than has so far been recognized. However, from the available data it remains unclear whether certain subgroups of SAH patients carry a higher risk to sustain endocrine sequelae due to the hemorrhage than others and should be specifically followed up in terms of hormone assessment. To investigate whether a basal hormone screening is a practical method in clinical routine to single out patients in whom endocrine function testing is warranted, we established a screening protocol, based on the findings from a cohort of 40 SAH patients (study group) who had all been investigated by basal hormone para meters as well as standardized endocrinological function testing, within the framework of a previously published clinical study. We then applied this protocol to 45 newly investigated SAH-patients (screening group). According to the thus established protocol, 20 of the 45 screened patients (44.4 %) were recommended further investigations, 12 of whom agreed to undergo dynamic endocrine function testing. Altogether, the percentage of test-confirmed neuroendocrine dysfunction was only 13.3 % (6/ 45) in the screening group as compared to 55 % in the study group. Low IGF-I (2 SD below normal) did not serve to predict growth hormone deficiency, whereas low 9 am serum cortisol was of limited value to single out ACTH-deficiency in SAH-patients. In summary we conclude that basal hormone screening is not sufficient to identify SAH patients with impaired hypothalamo-pituitary function, at least not in the context of clinical routine practice.

[Posttraumatic pituitary insufficiency]. / Gestörte Rehabilitation nach Schädel-Hirn-Trauma: Schuld war auch der Hormonmangel.

Even after a mild cranio-cerebral trauma, disturbances in the pituitary function can occur that fundamentally influence the posttraumatic progress.

A rare but life-threatening complication of ventriculo-atrial shunt.

Insertion of ventriculoperitoneal and ventriculoatrial shunts is routinely performed. Infarction pneumonia and atrial thrombus formation are described as very rare complications of ventriculoatrial shunts. We present the case of a female patient with ventriculoatrial shunt insertion as long term treatment for aequeductal stenosis who presented with recurrent episodes of dyspnoea, chest pain, and unilateral pleural effusion. Diagnostic evaluation revealed a positive D-dimer test, bilateral basal infiltrates and pleural effusion. Transesophageal echocardiography established the diagnosis of a thrombus in the right atrium. Laboratory testing for thrombophilia revealed a homozygous factor V Leiden mutation. In the following, a shunt revision was performed.

Motor evoked potentials following highly frequent transcranial magnetoelectrical motor cortex stimulation: normal data and potential modulation by stimulation-dependent inhibitory and activating mechanisms.

OBJECTIVE: To determine the normal values (latency, amplitude) of motor evoked potentials (MEP) of the abductor pollicis brevis (APB) and tibialis anterior (TA) muscle after high-frequency repetitive transcranial magnetic stimulation of the motor cortex (rTCMS), and to evaluate stimulation-dependent MEP modulations. PATIENTS AND METHODS: 29 healthy volunteers underwent rTCMS with 2 and 4 stimuli. The interstimulus interval (ISI) was 2, 3, and 4 ms respectively, which corresponded to frequencies between 250 and 500 stimuli/s. The evoked potentials of the relaxed and voluntarily contracted APB and TA were registered. RESULTS: Depending on the frequency and number of stimuli, the mean corticomuscular latency to the relaxed APB varied between 22.2 and 22.9 ms, and to the relaxed TA between 30.4 and 32.0 ms. The intra- and interindividual variability of the amplitudes was substantial. Voluntary contraction of the target muscle always led to a decrease in latency and increase in amplitude (p < 0.05). CONCLUSION: The high variability of the amplitudes does not allow the computation of meaningful normal values. The latencies after rTCMS are close to those of normal data after single TCMS, which indicates that in awake humans identical cortical and spinal structures are similarly activated. The discrete variations of latency and amplitude after changing the frequency and stimulus number suggest that inhibitory and excitatory mechanisms on the cortical and/or spinal level modulate the muscle response.

Head injury after a fall on stairs: poorer prognosis in inebriated patients?

AIM: The aim of the present study was to determine whether inebriated patients falling on stairs sustain more severe head injuries than sober patients because of a delayed reaction time and a pathological coagulation and clotting system. PATIENTS AND METHODS: The files of 140 head-injured patients who came to admission after falling on stairs were retrospectively reviewed with respect to demographic data, initial Glasgow coma scale (GCS) score, type of hematoma, coagulation parameters and outcome (death versus survival, Glasgow Outcome Scale [GOS] score GOS 3-5 vs. GOS 1 and 2). RESULTS: There were 69 patients who had an alcohol level of > or = 0.8 parts per thousand at the time of the fall (49.0 %). The mortality in the group of inebriated patients was 12.9 %, in the group of sober patients 33.3 % (p = 0.001). The characteristics of the two groups were comparable, except for age (50.4 vs. 69.1 years, p = 0.001). The analysis of mortality in relation to age confirmed the finding of a lower mortality rate in inebriated patients. CONCLUSION: The hypothesis that inebriated patients sustain more severe head injuries with higher mortality rates could not be validated. Routine laboratory tests did not detect coagulation and clotting disorders in inebriated patients. Instead, our study again showed that age is one of the major prognostic factors in head injury.

The dipole location shift within the auditory evoked neuromagnetic field components N100m and mismatch negativity (MMNm).

OBJECTIVE: To investigate whether within the latency range of the neuromagnetic mismatch negativity (MMNm) a similar dipole shift can be observed as found in previous studies for the auditory evoked field component N100m. METHODS: For this purpose selected neuromagnetic data of 29 subjects were analysed in a time window of 15 ms before and 15 ms beyond the peak maximum of both components. In our oddball paradigm, we applied frequency, duration and intensity deviants within one block. The time course of dipole location was analysed by means of a repeated measure analysis of variance (ANOVA). RESULTS: As expected, N100m dipoles shifted significantly from superior to inferior and from posterior to anterior within their latency range. In analogy, the MMNm dipoles of duration and intensity deviants also exhibited a significant shift from posterior to anterior within their latency range. However, the MMNm dipoles of all 3 deviants did not shift significantly from superior to inferior. Concerning this direction, the ANOVA revealed a significant TIME*COMPONENT interaction between the N100m and the MMNm of duration and intensity deviants. CONCLUSIONS: The finding of a different time course of N100m and MMNm dipoles does not support the assumption that the MMN represents an amplitude- and latency-modulated auditory N100 response.

[Mismatch negativity in schizophrenia research. An indicator of early processing disorders of acoustic information]. / Die Mismatch-Negativität (MMN) in der Schizophrenieforschung. Ein Indikator früher Störungen der akustischen Informationsverarbeitung.

Mismatch negativity (MMN) represents an event-related component of the auditory evoked potentials at about 100-250 ms, evoked by discernible changes in an ongoing uniform acoustic stimulation. The current paper reviews all recently published MMN studies in the field of schizophrenia research. A reduced MMN in schizophrenic patients is found in the majority of the studies. This deficit is likely to be related to the disorder, since antipsychotic medication seems to have little influence on these results. Interestingly, a reduced MMN is also found in first-degree relatives of patients. Clear evidence for a hemispheric lateralization of the MMN reduction in schizophrenic patients is lacking. A hypofunction of the N-methyl-D-aspartate (NMDA) receptor is discussed as a possible explanation of this deficit.

Measurement of motor evoked potentials following repetitive magnetic motor cortex stimulation during isoflurane or propofol anaesthesia.

BACKGROUND: Isoflurane and propofol reduce the recordability of compound muscle action potentials (CMAP) following single transcranial magnetic stimulation of the motor cortex (sTCMS). Repetition of the magnetic stimulus (repetitive transcranial magnetic stimulation, rTCMS) might allow the inhibition caused by anaesthesia with isoflurane or propofol to be overcome. METHODS: We applied rTCMS (four stimuli; inter-stimulus intervals of 3, 4, 5 ms (333, 250, 200 Hz), output 2.5 Tesla) in 27 patients and recorded CMAP from the hypothenar and anterior tibial muscle. Anaesthesia was maintained with fentanyl 0.5-1 microg kg(-1) x h(-1) and either isoflurane 1.2% (10 patients) or propofol 5 mg kg(-1) x h(-1) with nitrous oxide 60% in oxygen (17 patients). RESULTS: No CMAP were detected during isoflurane anaesthesia. During propofol anaesthesia 333 Hz, four-pulse magnetic stimulation evoked CMAP in the hypothenar muscle in 75%, and in the anterior tibial muscle in 65% of the patients. Less response was obtained with 250 and 200 Hz stimulation. CONCLUSIONS: In most patients, rTCMS can overcome suppression of CMAP during propofol/nitrous oxide anaesthesia, but not during isoflurane anaesthesia. A train of four magnetic stimuli at a frequency of 333 Hz is most effective in evoking potentials from the upper and lower limb muscles. The authors conclude that rTCMS can be used for evaluation of the descending motor pathways during anaesthesia.

Pituitary deficiency following aneurysmal subarachnoid haemorrhage.

OBJECTIVE: To investigate the incidence and severity of pituitary insufficiency after aneurysmal subarachnoid haemorrhage. METHODS: Pituitary function was tested in a series of patients more than 12 months but less than 60 months after aneurysmal subarachnoid haemorrhage using a combined TRH-LHRH-arginine test and the insulin tolerance test, to elucidate possible deficits in the gonadotrophic, somatotrophic, thyreotrophic, and corticotrophic hormonal axes. RESULTS: Of 21 patients screened, nine (43%) showed deficiencies of at least one pituitary hormone axis. Four patients had corticotrophin deficiency, one had partial growth hormone deficiency, two had severe growth hormone deficiency, and two had severe growth hormone deficiency plus corticotrophin deficiency. CONCLUSIONS: Persistent pituitary dysfunction may be more common after aneurysmal subarachnoid haemorrhage than has so far been recognised and warrants further investigation, given the possibility that some health and neurobehavioural problems in these patients could result from hormone deficiency.