Monocyte-derived dendritic cells display a highly activated phenotype and altered function in patients with familial Mediterranean fever.

Dendritic cells (DCs) are sentinels of the immune system that bridge innate and adaptive immunity. By capturing antigens in peripheral tissue, processing and presenting them with concurrent expression of co-stimulatory molecules and cytokine secretion they control and modulate immune reactions. Through pattern recognition receptors, DCs sense molecules that are associated with infection or tissue damage, frequently resulting in the formation of inflammasomes upon intracellular stimulation. The inherited autoinflammatory familial Mediterranean fever (FMF) is associated with deregulated activity of the pyrin inflammasome leading to acute inflammatory episodes. However, differentiation and function of DCs in this disease are as yet unclear. Therefore, we first determined DC subpopulation frequency in peripheral blood of a cohort of FMF patients. Joint evaluation without classification according to specific patient characteristics, such as mutational status, did not disclose significant differences compared to healthy controls. For the further examination of phenotype and function, we used immature and mature monocyte-derived DCs (imMo-DCs, mMo-DCs) that were generated in vitro from FMF patients. Immunophenotypical analysis of imMo-DCs revealed a significantly elevated expression of CD83, CD86 and human leukocyte antigen D-related (HLA-DR) as well as a significant down-regulation of CD206, CD209 and glycoprotein NMB (GPNMB) in our FMF patient group. Furthermore, FMF imMo-DCs presented a significantly higher capacity to migrate and to stimulate the proliferation of unmatched allogeneic T cells. Finally, the transition towards a more mature, and therefore activated, phenotype was additionally reinforced by the fact that peripheral blood DC populations in FMF patients exhibited significantly increased expression of the co-stimulatory molecule CD86.

Long-term suppression of extrapyramidal motor symptoms with deep brain stimulation (DBS).

Deep Brain Stimulation (DBS) was investigated for the treatment of extrapyramidal motor symptoms. Both tremor and rigidity as well as akinesia are known to be permanently suppressed by applying a high-frequency current to different basal ganglia nuclei. Chronic DBS was performed in 113 patients using stereotactically implanted quadripolar electrodes in the ventrolateral thalamus (n = 43), the globus pallidus internus (n = 15), or the subthalamic nucleus (n = 55). Subcutaneous implantation of the generator occurred during a second procedure following correct positioning of the electrodes and confirmation of effectiveness by external stimulation. Patients were followed up using standardized rating scales before and after surgery. Deep Brain Stimulation significantly suppresses extrapyramidal symptoms such as tremor (p < 0.001), rigidity (p < 0.001), dyskinesia (p < 0.01), akinesia, and dystonia (p < 0.05). Permanent side effects were avoided by changing the stimulation parameters. Severe complications occurred in only two patients (n = 2, 1.8 %). DBS is a safe and effective long-term treatment for tremor, rigidity, dyskinesia, akinesia and dystonia.

[Chronic high frequency deep brain stimulation of the globus pallidus internus for torsion dystonia]. / Chronische Tiefenhirnstimulation des Globus pallidus internus bei Torsionsdystonie.

Deep Brain Stimulation (DBS, chronic high frequency stimulation) is well established for Parkinson's disease and tremordominant movement disorders. Generalized dystonia is known as a type of movement disorder in which therapeutic options are very limited. A case of generalized dystonia is reported which was successfully treated by DBS in the Globus pallidus internus (GPI). A 26 years old male suffered from severe torsion dystonia of the lower limbs. The onset of symptoms was at age 7. It started with dystonia of the left foot. He very fast developed severe dystonia of the lower limbs. These complaints were initially treated by diazepam, later by baclofen (Lioresal ((R))) p.o em leader There was no L-DOPA response. Because of the rapid progression of the disease a cervical spinal cord stimulator was implanted with a transient success. Due to further progression of the disease the patient became wheelchair bounded and resistant for oral medication. Limited improvement of symptoms was achieved using continuous intrathecal administration of baclofen. Finally the patient was treated with 980 microgram intrathecal Baclofen (Lioresal ((R))) daily and up to 100 mg diazepam. Under these conditions the patient remained wheelchair bounded with severe lower limb dystonia. As an ultima ratio it was decided to treat the patient with stereotactic implantation of two electrodes (Medtronic 3387) and two neurostimulators (Medtronic ITREL ((R))II). The GPI was the bilateral target point. Intraoperative computerized tomography and ventriculography were used for target setting. Furthermore microrecordings were helpful to ensure the exact electrode positioning. Surgery was performed under sedation. Two weeks after surgery first improvement of symptoms was observed. Patient was able to stand with assistance. At the three months follow-up he could walk without assistance. Slight dystonic movement of the left ankle was the only remaining symptom under stimulation. The oral medication has been continuously reduced. After 6 months it was stopped. The intrathecal administered baclofen was diminished to 250 microgram daily. At the 24 months follow-up the effect of stimulation remained unchanged. However high stimulation parameters are required to maintain an optimal effect (3,5 V, 400 microseconds 145 Hz for both sides). Deep Brain Stimulation of the Globus Pallidus internus is an alternative approach for severe cases of generalized dystonia.

Can continuous intraoperative facial electromyography predict facial nerve function following cerebellopontine angle surgery?

Intraoperative cranial nerve monitoring has significantly improved the preservation of facial nerve function following surgery in the cerebellopontine angle (CPA). Facial electromyography (EMG) was performed in 60 patients during CPA surgery. Pairs of needle electrodes were placed subdermally in the orbicularis oris and orbicularis oculi muscles. The duration of facial EMG activity was noted. Facial EMG potentials occurring in response to mechanical or metabolic irritation of the corresponding nerve were made audible by a loudspeaker. Immediate (4-7 days after tumor excision) and late (6 months after surgery) facial nerve function was assessed on a modified House-Brackmann scale. Late facial nerve function was good (House-Brackmann 1-2) in 29 of 60 patients, fair (House-Brackmann 3-4) in 14, and poor (House-Brackmann 5-6) in 17. Postmanipulation facial EMG activity exceeding 5 minutes in 15 patients was associated with poor late function in five, fair function in six, and good function in four cases. Postmanipulation facial EMG activity of 2-5 minutes in 30 patients was associated with good late facial nerve function in 20, fair in eight, and poor in two. The loss of facial EMG activity observed in 10 patients was always followed by poor function. Facial nerve function was preserved postoperatively in all five patients in whom facial EMG activity lasted less than 2 minutes. Facial EMG is a sensitive method for identifying the facial nerve during surgery in the CPA. EMG bursts are a very reliable indicator of intraoperative facial nerve manipulation, but the duration of these bursts do not necessarily correlate with short- or long-term facial nerve function despite the fact that burst duration reflects the severity of mechanical aggression to the facial nerve.

Intra-operative mapping of the motor cortex during surgery in and around the motor cortex.

The intra-operative use of neurophysiological techniques allows reliable identification of the sensorimotor region, and constitutes a prerequisite for its anatomical and functional preservation. The present prospective study combines monopolar cortical stimulation (MCS) with the recording of phase reversal of somatosensory evoked potentials (SEP-PR) in a protocol for the intra-operative mapping of the motor cortex. Functional mapping of the motor cortex by SEP-PR and MCS was performed in 70 patients during surgery in and around the motor cortex. The central sulcus was identified by SEP-PR. Cortical motor mapping was then performed by monopolar anodal (400 Hz) stimulation. Motor responses were recorded by needle electrodes placed in the muscles of the contralateral extremities. Surgery was performed under general anaesthesia without muscle relaxants. Intra-operative localization of the central sulcus by SEP-PR was possible in 68 patients (97.14%). Motor evoked potentials (MEP) were elicited following MCS in 67 cases (95.7%). In 3 cases no MEP was recorded, not even after maximal stimulation intensity, the central sulcus being localized by SEP-PR only. On the other hand, MCS allowed localizing the motor cortex in the 2 cases with no recordable SEP-PR. Thus, combining SEP-PR and MCS allowed intra-operative localization of the sensorimotor cortex in 100% of the cases.

Spatiotemporal characteristics of human intrathalamic high-frequency (>400Hz) SEP components.

Somatosensory evoked potentials (SEP) were recorded in 11 awake patients from intrathalamic electrodes implanted for tremor treatment. A brief (7ms) polyphasic SEP burst (mean frequency > 1000 Hz, with occasional drops to 600 Hz) was found to be superimposed onto the primary thalamic low-frequency response at 16 ms (tP16) and preceeded a scalp-derived 600 Hz burst by 4 ms. Thalamic burst and tP16 generators had a close intrathalamic co-localization. The thalamic burst strength varied more than and independently from tP16. High-frequency thalamic SEP bursts probably reflect a superposition of slightly asynchronously triggered population spikes, generated e.g. by bursting thalamocortical relay cells. The thalamic burst amplitude fluctuations independent from low-frequency responses suggest a peculiar role for thalamic burst coding in awake subjects.

Comparison between monopolar and bipolar electrical stimulation of the motor cortex.

Intra-operative neurophysiological techniques allow reliable identification of the sensorimotor region and make their anatomical and functional preservation feasible. Monopolar cortical stimulation has recently been described as a new mapping technique. In the present study this method was compared to the "traditional" technique of bipolar stimulation. Functional mapping of the motor cortex was performed in 35 patients during surgery in the central region. The central sulcus (CS) was identified by somatosensory evoked potential (SEP) phase reversal. Cortical motor mapping was first performed by monopolar anodal stimulation with a train of 500 Hz (7-10 pulses) followed by bipolar stimulation (pulses at 60 Hz with max. 4 sec train duration). Surgery was performed under general anaesthesia without muscle relaxants. Of 280 motor responses elicited by bipolar cortical stimulation, 54.23% [152] were located in the primary motor cortex (PMC), 37.85% 106[ outside the motor strip in the secondary motor cortex (SMC), and 8% 22[ posterior to the CS. Of 175 motor responses elicited by monopolar cortical stimulation. 68.57% 120[ were located in the SMC, 23.42% 41[ in the SMC and 8% 14[ posterior to the CS. Contrary to the general clinical view, there is considerable overlapping of primary motor units over a cortical area much broader than the "classical" narrow motor strip along the CS. Bipolar cortical stimulation is more sensitive than monopolar for mapping motor function in the premotor frontal cortex. Both methods are equally sensitive for mapping the primary motor cortex.

Neoplasm of endolymphatic sac origin: clinical, radiological and pathological features.

This paper reports on a 55-year-old female who had undergone middle ear surgery 12 years previously and was admitted with a 6-months history of unilateral hearing loss and facial weakness. MRI and CT demonstrated a space-occupying lesion arising from the temporal bone and extending into the posterior fossa. Treatment consisted in complete tumour removal. Temporal and mastoid bone destruction associated with typical histological features led to the diagnosis of neoplasm of endolymphatic sac origin. Clinical, histological, radiological and intra-operative features of these rare tumours are described and discussed. The pertinent literature is reviewed.

Beta-carbolines in chronic alcoholics following trauma.

In our society every second polytraumatized patient is a chronic alcoholic. A patient's alcohol-related history is often unavailable and laboratory markers are not sensitive or specific enough to detect alcohol-dependent patients who are at risk of developing alcohol withdrawal syndrome (AWS) during their post-traumatic intensive care unit (ICU) stay. Previously, it has been found that plasma levels of norharman are elevated in chronic alcoholics. We investigated whether beta-carbolines, i.e. harman and norharman levels, could identify chronic alcoholics following trauma and whether possible changes during ICU stay could serve as a predictor of deterioration of clinical status. Sixty polytraumatized patients were transferred to the ICU following admission to the emergency room and subsequent surgery. Chronic alcoholics were included only if they met the DSM-III-R and ICD-10 criteria for alcohol dependence or chronic alcohol abuse/harmful use and their daily ethanol intake was > or =60 g. Harman and norharman levels were assayed on admission and on days 2, 4, 7 and 14 in the ICU. Harman and norharman levels were determined by high pressure liquid chromatography. Elevated norharman levels were found in chronic alcoholics (n = 35) on admission to the hospital and remained significantly elevated during their ICU stay. The area under the curves (AUC) showed that norharman was comparable to carbohydrate-deficient transferrin (CDT) and superior to conventional laboratory markers in detecting chronic alcoholics. Seventeen chronic alcoholics developed AWS; 16 of these patients experienced hallucinations or delirium. Norharman levels were significantly increased on days 2 and 4 in the ICU in patients who developed AWS compared with those who did not. An increase in norharman levels preceded hallucinations or delirium with a median period of approximately 3 days. The findings that elevated norharman levels are found in chronic alcoholics, that the AUC was in the range of CDT on admission and that norharman levels remained elevated during the ICU stay, support the view that norharman is a specific marker for alcoholism in traumatized patients. Since norharman levels increased prior to the onset of hallucinations and delirium it seems reasonable to investigate further the potential role of norharman as a possible substance which triggers AWS.