[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.

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.

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 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.

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.

31Phosphorus magnetic resonance spectroscopy of the dorsolateral prefrontal region in schizophrenics--a study including 50 patients and 36 controls.

BACKGROUND: In a preliminary study we found decreased phosphodiester (PDE)% values and an increased phosphomonoester (PME)/phosphodiester ratio in the dorsolateral prefrontal region (DLPFR) of 13 chronic schizophrenics vs. 14 controls using 31phosphorus magnetic resonance spectroscopy (31P-MRS). Since these results are in contrast to the findings of other groups, we increased our study group to a total of 50 chronic schizophrenics on stable neuroleptic medication and 36 controls to minimize the possibility of a chance result due to small sample size. METHODS: An image-selected in vivo 31P-MRS method on a Philips Gyroscan ACS II scanner working at 1.5 T was used. RESULTS: We could confirm our earlier findings of decreased PDE% levels in schizophrenics. Additionally, we found phosphocreatine (PCr)% and PCr/adenosine triphosphate (ATP) to be increased in the schizophrenics. While no association between PME% and PDE% with neuroleptic medication was found, ATP% correlated positively and PCr/ATP negatively with the chlorpromazine equivalent dose. CONCLUSIONS: The decreased PDE% levels might be characteristic only for chronic, neuroleptic-treated patients. The finding of altered high-energy phosphate levels can be interpreted as an indication of decreased energy-demanding processes in the DLPFR of the investigated patients compared to controls.

Impaired sensory processing in male patients with schizophrenia: a magnetoencephalographic study of auditory mismatch detection.

The generation of mismatch negativity (MMN) as a component of auditory evoked event-related brain potentials has been reported previously to be severely disturbed in patients with schizophrenia. In the present study, we extended these findings to magnetoencephalography and investigated the neuromagnetic mismatch field (MMNm) in 15 male schizophrenic inpatients as compared to 16 healthy male volunteers. A standard tone of 1000 Hz and three different types of mismatch (1050-Hz tone, 5000-Hz tone, tone omission) were employed within the same paradigm, each mismatch occurring with a 10% pseudorandom probability. After correction for eye artifacts, the mean global field power of the mismatch reaction was calculated. Mismatch generation in patients with schizophrenia proved to be significantly impaired for all three conditions. This result confirms the theory of impaired auditory information processing in patients with schizophrenia at the level of the primary auditory cortex. Deficient generation of MMNm probably represents an impaired generation and/or faster decay of the sensory memory trace on the basis of disturbed sensory processing in male patients with schizophrenia.

High-energy phosphates in the frontal lobe correlate with Wisconsin Card Sort Test performance in controls, not in schizophrenics: a 31phosphorus magnetic resonance spectroscopic and neuropsychological investigation.

In recent years, a number of 31phosphorus magnetic resonance spectroscopy (P-MRS) studies on the frontal lobe of schizophrenics have been performed, reporting alterations of phospholipids and high-energy phosphates. Deicken et al. (1994b) recently found positive correlations between left frontal phosphomonoester% (PME%) levels and the performance of a specific frontal lobe task, the Wisconsin Card Sorting Test (WCST), in schizophrenics. In the present paper, the correlations between phospholipids and high-energy phosphates in the frontal lobe of 26 schizophrenics and 23 controls measured with a volume-selective P-MRS method were investigated. Overall, we could not find any correlations between WCST results and phospholipid levels, but in controls phosphocreatine% (PCr%) and PCr/adenenosine triphosphate (ATP) ratios were negatively correlated with test performance. Since PCr behaves as a buffer of ATP, in the sense that when ATP is consumed by neuronal activity PCr is catalysed rapidly to ATP, increased PCr% values and, moreover, increased PCr/ATP ratios point to a decreased ATP consumption. Thus, the correlations found between PCr% and PCr/ATP and test performance in controls point to an association between reduced performance in a specific frontal lobe task and decreased energy demanding processes at rest. This association was not found in schizophrenics, possibly due to the influence of neuroleptic medication or the disease process per se.

Effect of ketamine on the neuromagnetic mismatch field in healthy humans.

Mismatch negativity (MMN) is a component of the auditory evoked event-related potentials (ERP) that assesses automatic sound change detection and is disturbed in schizophrenic patients. Animal experimental evidence has linked the generation of MMN to the N-methyl-D-aspartate (NMDA) receptor. We investigated the neuromagnetic mismatch field (MMF) in healthy volunteers before and after intravenous application of a subanesthetic dose of the NMDA receptor antagonist ketamine (0.3 mg/kg). Ketamine had a significant influence on latency and dipole moment of the MMF, whereas the N100m latency of the standard tone was not prolonged and its dipole moment remained stable. Our results suggest that ketamine interferes with aspects of preattentive information processing and is in line with the view that disturbed NMDA receptor function may mediate the deficient auditory mismatch response in patients with schizophrenia.

Enlarged gamma band response of neuromagnetic auditory evoked fields in a visually impaired subject.

Under acoustic stimulation a phase-locked response in the gamma band (near 40 Hz) in the latency range between 20 and 130 ms is evoked. We report on a considerably visually impaired woman with Grönblad-Strandberg syndrome which involves degeneration at the level of retina, but has no overt central nervous component to the degeneration. The subject exhibited an extraordinarily high power in the phase-locked gamma band response (GBR) which was found to be more than three, and sometimes more than four, standard deviations above the average of a group of 25 subjects with normal vision. Furthermore, the dipoles of her mismatch reaction and M200 were found to be located posteriorly to the dipoles of the M100. Overall, both enlarged GBR and changed cortical representation could be results of cortical plasticity related to visual impairment.

Habituation of the auditory evoked field component N100m in male patients with schizophrenia.

The auditory evoked field (AEF) component N100m represents the most prominent and stable peak of the AEF, and its alterations in patients with schizophrenia are an extensive topic of neuropsychiatric research. In our current study, the degree of N100m habituation was investigated in 20 male schizophrenics and 19 healthy male controls. Participants were stimulated monaurally with 270 trials of 1000 Hz tones separated by an interstimulus interval between 800-1800 ms. The trial sample of the bilaterally recorded AEF was separated into three consecutive blocks of 90 trials and these blocks were compared with each other. The mean global field power (MGFP) of the N100m decreased on average 9.1% from the first to the third trial block, while the N100m latency was increasing. The analyses of the influence of habituation revealed a systematic change of dipole location in inferior-superior direction, mainly in the left hemisphere. This habituation effect was found to be the same for both groups. The groups also did not differ in the N100m latency increase and MGFP decrease, except for one parameter. The right-hemispheric MGFP decrease from the first to second block was found to be more pronounced in patients compared to controls. However, this difference was related to medication with clozapine. Overall, the habituation behaviour of the N100m seems to be undisturbed in schizophrenic patients.

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.

Hemispheric differences in frequency dependent dipole orientation of the human auditory evoked field component N100m.

Auditory evoked fields (AEF) of 19 healthy male subjects were recorded bilaterally with a Philips 31 -channel biomagnetometer, using two conditions of stimulation (1000 vs. 5000 Hz tones). The N100m latency was characterized by a single moving dipole for each condition and hemisphere using a boundary element model (BEM) as volume conductor. While the right hemispheric dipole orientations and locations did not change with respect to condition, the left hemispheric dipoles differed significantly between the 1000 and 5000 Hz tones, especially in dipole orientation. The left hemispheric dipoles were orientated on average 10.8 degrees more vertically for the 5000 Hz condition. This result points to interhemispheric differences on the level of sensory processing.

Spatio-temporal source imaging reveals subcomponents of the human auditory mismatch negativity in the cingulum and right inferior temporal gyrus.

We investigated the generators of the mismatch negativity by means of spatio-temporal source imaging on the basis of 64-channel electroencephalography data in order to study the time course and localization of proposed frontal sources. Results indicate that there are additional generators located both within the anterior cingulate gyrus and in the right inferior temporal gyrus, clearly separated from the supratemporal generators in space and time course. The cingulate generator is activated later than the temporal ones, which supports the hypothesis of a frontally located mechanism of involuntary switching of attention triggered by the temporal change detection system. Evidence for an additional right inferior temporal generator supports the hypothesis of right hemispheric dominance in early sound discrimination.

Cognitive deficits in the acute stage after subarachnoid hemorrhage.

OBJECTIVE: In spite of fundamentally improved medical management of subarachnoid hemorrhage (SAH), many patients remain mentally impaired. However, the causes of these disturbances are unclear. The present study was performed to elucidate the significance of the hemorrhage itself and related events in the neuropsychological performance of patients in the acute stage after SAH. METHODS: A series of 51 patients were examined, by means of a battery of cognitive tests, 1 to 13 days (mean, 5.9 d) after SAH. Thirty-three patients had experienced ruptured aneurysms, and 18 had sustained SAH of unknown origin. Furthermore, 25 patients who had undergone surgical treatment (a mean of 5.0 d earlier) of prolapsed lumbar discs served as a control group. RESULTS: The cognitive deficits of the patients after aneurysmal SAH proved to be comparable to those after spontaneous SAH of unknown origin, with the single exception of a significantly worse (P = 0.003) concentration capacity in the surgically treated group. The severity of SAH in computed tomographic scans correlated (up to r = 0.57, P < 0.001) with poor performance on tests of memory, concentration, divided attention, and perseveration. Frontal intracerebral hemorrhage led to significantly more errors in an aphasia screening test (P < 0.001) and a test of perseveration (P < 0.001). If acute hydrocephalus was present, the patients exhibited worse long-term memory (P < 0.001), showed slower reaction times (P = 0.01), and made more errors in the perseveration test (P = 0.004). Patients with intraventricular blood performed at significantly lower levels in the concentration (P = 0.001), divided attention (P = 0.01), long-term memory (P < 0.001), and perseveration (P = 0.003) tests. CONCLUSION: The results emphasize that the severity of SAH (Fisher score) is the most important factor related to cognitive dysfunction, but frontal hematoma, intraventricular hemorrhage, and acute hydrocephalus were also associated with cognitive deficits, compared with patients with SAH without these findings.