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1.
Brain Inj ; 28(11): 1425-9, 2014.
Article in English | MEDLINE | ID: mdl-24911541

ABSTRACT

PRIMARY OBJECTIVE: Hypopituitarism is a frequent complication in patients after traumatic brain injury (TBI). Both TBI and hypopituitarism can lead to complex cognitive and affective deficits. This study was intended to examine the quality-of-life in patients with post-traumatic hypopituitarism (PTH) and to discern the effect of this endocrinological disorder on general outcome of patients after TBI including earning capacity. Research type: Retrospective analysis of clinical data. METHODS AND PROCEDURES: Ninety-seven symptomatic patients were screened after TBI for PTH. Their results were examined in the SF-36 [a standardized questionnaire for quality of life (QoL)] comparing the groups with or without PTH. After 6 months of hormone substitution (if necessary), patients were asked to repeat the SF-36. MAIN OUTCOMES AND RESULTS: Forty-six patients were diagnosed with PTH (47.5%). All patients included had a significantly lower QoL compared to the standard population. QoL was significantly worse in patients with PTH. There was no significant difference with regard to earning capacity. After hormone substitution, patients achieved better SF-36-results, albeit the difference was lacking statistical significance. CONCLUSIONS: PTH is frequent after TBI. PTH turns out to further diminish QoL, without affecting earning capacity. Hormone substitution might improve QoL in patients with PTH, but future research is needed to confirm this hypothesis.


Subject(s)
Brain Injuries/psychology , Hormone Replacement Therapy/methods , Hypopituitarism/psychology , Quality of Life/psychology , Return to Work/psychology , Adolescent , Adult , Brain Injuries/complications , Brain Injuries/epidemiology , Brain Injuries/physiopathology , Child , Child, Preschool , Cognition Disorders/epidemiology , Cognition Disorders/etiology , Female , Germany/epidemiology , Humans , Hypopituitarism/epidemiology , Hypopituitarism/etiology , Hypopituitarism/physiopathology , Male , Middle Aged , Mood Disorders/epidemiology , Mood Disorders/etiology , Pituitary Hormones/therapeutic use , Prevalence , Prognosis , Retrospective Studies , Risk Factors , Surveys and Questionnaires , Work Capacity Evaluation
2.
Int J Rehabil Res ; 33(2): 151-7, 2010 Jun.
Article in English | MEDLINE | ID: mdl-19966571

ABSTRACT

For the rehabilitation process, the treatment of patients surviving brain injury in a vegetative state is still a serious challenge. The aim of this study was to investigate patients exhibiting severely disturbed consciousness using functional magnetic resonance imaging. Five cases of posttraumatic vegetative state and one with minimal consciousness close to the vegetative state were studied clinically, electrophysiologically, and by means of functional magnetic resonance imaging. Visual, sensory, and acoustic paradigms were used for stimulation. In three patients examined less than 2 months after trauma, a consistent decrease in blood oxygen level dependent (BOLD) signal ('negative activation') was observed for visual stimulation; one case even showed a decrease in BOLD activation for all three activation paradigms. In the remaining three cases examined more than 6 months after trauma, visual stimulation yielded positive BOLD contrast or no activation. In all cases, sensory stimulation was followed by a decrease in BOLD signal or no activation, whereas auditory stimulation failed to elicit any activation with the exception of one case. Functional magnetic resonance imaging in the vegetative state indicates retained yet abnormal brain function; this abnormality can be attributed to the impairment of cerebral vascular autoregulation or an increase in the energy consumption of activated neocortex in severe traumatic brain injury.


Subject(s)
Brain Injuries/physiopathology , Echo-Planar Imaging , Persistent Vegetative State/physiopathology , Acoustic Stimulation , Adolescent , Adult , Brain Injuries/rehabilitation , Brain Mapping , Case-Control Studies , Cerebrovascular Circulation , Echo-Planar Imaging/methods , Evoked Potentials , Female , Homeostasis , Humans , Male , Oxygen/blood , Persistent Vegetative State/rehabilitation , Photic Stimulation
3.
Brain Inj ; 21(5): 451-5, 2007 May.
Article in English | MEDLINE | ID: mdl-17522984

ABSTRACT

OBJECTIVE: The increasing number of patients surviving severe traumatic brain injury (sTBI) but with significant sensorimotor and neuropsychological deficits is a challenge to rehabilitation medicine. So far, most research initiatives have focused on mortality rates, physiological or economic parameters to estimate therapeutic effects of rehabilitation strategies. Investigations on health-related quality of life (HRQoL) after TBI with and without concomitant polytrauma are rare compared to other disorders. DESIGN/PATIENTS: A prospective study was conducted to investigate HRQoL using the SF-36 questionnaire in 49 patients with sTBI (Glasgow Coma Scale < 9 for more than 24 hours) with and without concomitant polytrauma 6 and 12 months after injury. RESULTS: The SF-36 score profiles 6 and 12 months after trauma were similar. Scores 12 months after trauma, however, were higher in 7/8 dimensions indicating an improvement over time. Similar observations were made for physical and mental sum scores. There was no difference in the SF-36 scoring pattern between the patients with isolated TBI and the patients with concomitant polytrauma, except for physical functioning after 12 months. CONCLUSION: While there is significant overall improvement of HRQoL over time, sTBI appears to bear major influence on post-traumatic HRQoL and outcome.


Subject(s)
Brain Injuries/complications , Health Status , Multiple Trauma/complications , Quality of Life , Adolescent , Adult , Aged , Brain Injuries/diagnosis , Brain Injuries/rehabilitation , Case-Control Studies , Cohort Studies , Female , Glasgow Coma Scale , Health Surveys , Humans , Injury Severity Score , Male , Middle Aged , Multiple Trauma/diagnosis , Multiple Trauma/rehabilitation , Prognosis , Time Factors
4.
Eur Radiol ; 16(10): 2229-33, 2006 Oct.
Article in English | MEDLINE | ID: mdl-16625350

ABSTRACT

The effect of stereotactic thalamotomy was assessed with pre- and postoperative functional magnetic resonance imaging (fMRI) under motor stimulation. A patient with unilateral essential tremor (ET) of the left arm underwent stereotactically guided thalamotomy of the right ventral intermediate thalamic nucleus (VIM). FMRI was done directly before and after surgery on a 1.5-Tesla scanner. The stimulation paradigm was maintainance of the affected arm in an extended position and hand clenching being performed in a block design manner. Statistical analysis was done with Brain Voyager 2000. After thalamotomy the tremor diminished completely. As a difference between the pre- and postoperative fMRI, a significant activation was found in the VIM contralateral to the activation site, adjacent to the inferior olivary nucleus contralateral to the activation site and in the dorsal cingulum. In conclusion, fMRI can detect the functional effect of thalamotomy for tremor treatment. Direct postoperative fMRI provides a sufficient method for estimating the effect of thalamotomy immediately after intervention. The importance of the intermediate thalamic nucleus and the olivary nucleus in tremor generation is supported by our findings.


Subject(s)
Essential Tremor/surgery , Magnetic Resonance Imaging , Stereotaxic Techniques , Humans , Linear Models , Male , Middle Aged
5.
J Neuropathol Exp Neurol ; 64(1): 66-73, 2005 Jan.
Article in English | MEDLINE | ID: mdl-15715086

ABSTRACT

The present study describes a new model of autoimmune neuritis in C57BL/6 mice induced by immunization with the novel neuritogenic epitope P0(106-125), derived from mouse peripheral myelin protein P0. Immunization with this peptide in combination with pertussis toxin induced high levels of peptide-specific CD4+ T cells in spleen and popliteal lymph nodes. Clinical symptoms of autoimmune neuritis started with a flaccid tail at day 10 postimmunization (p.i.), progressed to moderate paraparesis at day 15 p.i., declining thereafter with undetectable symptoms at day 40 p.i. Clinical disease activity paralleled decreased sciatic nerve motor conduction and histopathologic alterations of sciatic nerves. These included inflammatory infiltrates, mainly consisting of inducible nitric oxide synthase (iNOS)+ macrophages and CD4+ T cells. These data fit into the pathogenetic concept of murine autoimmune neuritis as a CD4+ TH1 cell-mediated disease. Our new mouse model provides an attractive tool to identify critical factors that regulate the severity of autoimmune responses in the peripheral nervous system.


Subject(s)
Epitopes, T-Lymphocyte/administration & dosage , Epitopes, T-Lymphocyte/immunology , Myelin P0 Protein/administration & dosage , Myelin P0 Protein/immunology , Neuritis, Autoimmune, Experimental/immunology , Peptide Fragments/administration & dosage , Peptide Fragments/immunology , Amino Acid Sequence , Animals , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/metabolism , Epitopes, T-Lymphocyte/genetics , Injections, Subcutaneous , Lymph Nodes/cytology , Lymph Nodes/immunology , Lymph Nodes/metabolism , Male , Mice , Mice, Inbred C57BL , Molecular Sequence Data , Myelin P0 Protein/genetics , Neuritis, Autoimmune, Experimental/genetics , Neuritis, Autoimmune, Experimental/pathology , Peptide Fragments/genetics , Spleen/cytology , Spleen/immunology , Spleen/metabolism
6.
Anesth Analg ; 99(5): 1402-1407, 2004 Nov.
Article in English | MEDLINE | ID: mdl-15502038

ABSTRACT

We performed this study to assess the recovery period after neuromuscular blockade by electromyographic F-wave analysis, a method that supplies more information about more proximal parts of the motor system than conventionally used methods, e.g., mechanomyography (MMG). In 20 neurosurgical ASA physical status I or II patients anesthesia was induced and maintained with IV fentanyl and midazolam. Patients were randomly assigned to receive either 0.25 mg/kg mivacurium (MV group, n = 10) or 0.1 mg/kg pancuronium (PC group, n = 10) intraoperatively. MMG monitoring of the adductor pollicis muscle was performed continuously. F waves were recorded at the abductor pollicis muscle of the contralateral hand at train-of-four (TOF) ratios of 0.1, 0.25, 0.5, 0.7, 0.75, 0.8, 0.85, 0.9, and 0.95. Recovery of F-wave amplitudes after neuromuscular blockade with pancuronium was significantly slower compared with mivacurium (P = 0.004) during the clinically important recovery period defined by MMG TOF ratios from 0.7 to 0.95. This electrophysiologic finding suggests a differential recovery of the motor system after administration of pancuronium and mivacurium not detected by MMG.


Subject(s)
Isoquinolines , Neuromuscular Blockade , Neuromuscular Nondepolarizing Agents , Pancuronium , Adult , Aged , Anesthesia Recovery Period , Double-Blind Method , Electric Stimulation , Electromyography , Female , Humans , Male , Middle Aged , Mivacurium , Monitoring, Intraoperative , Peripheral Nerves/physiology
7.
J Magn Reson Imaging ; 20(2): 321-6, 2004 Aug.
Article in English | MEDLINE | ID: mdl-15269960

ABSTRACT

PURPOSE: To compare the performance of single shot echo planar imaging (SSEPI) with three-dimensional-multishot echo-planar imaging (EPI) based on principles-of-echo-shifting-with-a-train-of-observations (PRESTO) in combination with a standard quadrature head coil and, as an alternative, a multiple receiver coil in intraoperative functional magnetic resonance imaging (fMRI). MATERIALS AND METHODS: Six healthy subjects underwent fMRI with visual stimulation using a SSEPI and a PRESTO-sequence with both coil systems. Statistical evaluation was done with a scanner-based post-processing software and SPM 99. The number of activated voxels in the visual cortex, the percent signal change between rest and activation, and finally the signal-to-noise ratio (SNR) during time course were measured and compared for both coil systems and both sequences, used in four different combinations. RESULTS: Blood oxygen level dependent (BOLD) signal changes were the lowest with PRESTO and standard head coil and the highest for SSEPI and phased array coil. For the latter combination, a significantly higher signal change and larger activation size was observed together with a better SNR. SSEPI yielded similar performance using both coils. CONCLUSION: SSEPI was superior due to its better SNR and a higher BOLD signal change in the defined settings, irrespective of the coil used. In a stereotactical setup the phased array coil can be used to generate fMRI data without loss of image quality.


Subject(s)
Brain/anatomy & histology , Magnetic Resonance Imaging/instrumentation , Oxygen/blood , Signal Processing, Computer-Assisted , Adult , Brain/physiology , Humans , Magnetic Resonance Imaging/methods , Male
8.
J Neurosurg ; 100(1 Suppl Spine): 52-5, 2004 Jan.
Article in English | MEDLINE | ID: mdl-14748574

ABSTRACT

OBJECT: Extensive epidural fibrosis after lumbar surgery may be the underlying cause in most cases of failed-back surgery syndrome. Various materials have been used to prevent epidural fibrosis, but only moderate success has been shown. Mitomycin C, an alkylosing antibiotic substance isolated from Streptomyces caespitosus, potentially supresses fibroblast proliferation after surgery. In this study, the authors investigated the effect of mitomycin C by local application on spinal epidural fibrosis in a rat laminectomy model. METHODS: Five Wistar rats underwent laminectomy at cervical, thoracic, and lumbar levels. Based on data obtained from ophthalmological studies, mitomycin C was applied to the laminectomy sites in various concentrations (0.01, 0.05, and 0.1 mg/ml). One laminectomy site in each rat was left untreated and thus served as a control. Evoked potentials were measured pre- and postoperatively, and all rats underwent clinical evaluation. Mobility status and evidence of neurological deficit were recorded. Twelve weeks later, the rats were killed, and the spinal column, including surrounding muscle tissue, was removed en bloc, decalcified, and fixed in formaldehyde. Epidural fibrosis was evaluated histologically. In all mitomycin C-treated laminectomy sites, epidural scarring was significantly reduced compared with control sites. Remarkably, dural adhesions were absent in laminectomy defects treated with mitomycin C concentrations of 0.05 and 0.1 mg/ml. Moderate to marked epidural fibrosis with adhesion to the dura mater was noted at sites receiving 0.01 mg/ml of mitomycin C. All control sites showed dense epidural fibrosis with marked dura adherence. CONCLUSIONS: In this experimental model, mitomycin C applied locally at a concentration of 0.1 mg/ml effectively reduced epidural fibrosis, completely avoided dural adherence, and induced no side effects.


Subject(s)
Alkylating Agents/pharmacology , Back Pain/prevention & control , Epidural Space/pathology , Laminectomy , Meningitis/prevention & control , Mitomycin/pharmacology , Postoperative Complications/prevention & control , Animals , Back Pain/pathology , Dose-Response Relationship, Drug , Dura Mater/pathology , Fibrosis/pathology , Fibrosis/prevention & control , Male , Meningitis/pathology , Postoperative Complications/pathology , Rats , Secondary Prevention , Tissue Adhesions/pathology , Tissue Adhesions/prevention & control
9.
Eur Radiol ; 14(4): 686-90, 2004 Apr.
Article in English | MEDLINE | ID: mdl-14513267

ABSTRACT

This article deals with technical aspects of intraoperative functional magnetic resonance imaging (fMRI) for monitoring the effect of deep brain stimulation (DBS) in a patient with Parkinson's disease. Under motor activation, therapeutic high-frequency stimulation of the subthalamic nucleus was accompanied by an activation decrease in the contralateral primary sensorimotor cortex and the ipsilateral cerebellum. Furthermore, an activation increase in the contralateral basal ganglia and insula region were detected. These findings demonstrate that fMRI constitutes a promising clinical application for investigating brain activity changes induced by DBS.


Subject(s)
Brain/physiopathology , Electric Stimulation Therapy/methods , Magnetic Resonance Imaging , Parkinson Disease/surgery , Aged , Brain/pathology , Electrodes, Implanted , Female , Humans , Intraoperative Care , Parkinson Disease/physiopathology , Stereotaxic Techniques , Subthalamic Nucleus/surgery
10.
Otolaryngol Head Neck Surg ; 129(1): 114-20, 2003 Jul.
Article in English | MEDLINE | ID: mdl-12869926

ABSTRACT

OBJECTIVE: To investigate the diagnostic yield of facial F wave recording in patients with acoustic neurinomas intraoperatively and extraoperatively. Study design and setting Prospective study, comparative evaluation of facial F waves, transcranial magnetic stimulation of the facial motor cortex, blink reflex, and intraoperative online electromyographic activity. The study was performed in the neurosurgical department of a university hospital. RESULTS: Extraoperatively, only F wave latencies were closely correlated to tumor diameter as an independent variable. Intraoperatively, loss of F waves was specific for the development of a severe to total facial paresis postoperatively. A transient loss of F waves heralds an imminent danger of severe facial dysfunction. CONCLUSION: Facial F wave recording provides valuable information on the functional status of the nerve intra- and extraoperatively. SIGNIFICANCE: Facial F wave recording should be used as a standard electrodiagnostic technique in addition to transcranial magnetic stimulation and blink reflex recording. It seems particularly useful for intraoperative facial nerve monitoring.


Subject(s)
Electromyography/methods , Facial Nerve Injuries/diagnosis , Facial Nerve/physiology , Monitoring, Intraoperative/methods , Neuroma, Acoustic/surgery , Otologic Surgical Procedures/methods , Electric Stimulation/methods , Facial Nerve Injuries/prevention & control , Humans , Middle Aged , Prospective Studies
11.
Anesth Analg ; 96(2): 449-55, table of contents, 2003 Feb.
Article in English | MEDLINE | ID: mdl-12538195

ABSTRACT

Propofol provides some degree of muscle relaxation. Previous studies have investigated the effects of propofol on either the central or peripheral parts of the motor system. In this study, we simultaneously assessed both central (spinal) and peripheral effects. In 15 patients, general anesthesia was induced and maintained with fentanyl and midazolam. Neuromuscular blocking drugs were not administered. To investigate the central portion of the motor system, we monitored spinal F waves, an electrophysiologic variable of alpha-motoneuron excitability. Direct electrophysiologic muscle responses (M waves) and mechanomyography were studied to detect the peripheral effects of propofol on neuromuscular transmission or muscle contraction strength. After baseline recordings, 3 IV boluses of propofol (2 times 1 mg/kg followed by 2 mg/kg) were administered at 5-min intervals. Mean F-wave amplitudes were significantly reduced compared with baseline measurements (mean +/- SD, 0.22 +/- 0.13 mV) after the first (0.13 +/- 0.08 mV; P < 0.05), second (0.08 +/- 0.09 mV; P < 0.05), and third (0.03 +/- 0.04 mV; P < 0.01) propofol injections. M-wave amplitudes and mechanomyography signals remained unchanged. Our data suggest that the central part, but not the peripheral part, of the motor system is impaired after bolus administration of propofol.


Subject(s)
Anesthetics, Intravenous/pharmacology , Central Nervous System/drug effects , Motor Neurons/drug effects , Peripheral Nervous System/drug effects , Propofol/pharmacology , Aged , Axons/drug effects , Brain Neoplasms/surgery , Craniotomy , Dose-Response Relationship, Drug , Electric Stimulation , Electromyography , Female , Humans , Male , Middle Aged , Muscle Contraction/drug effects , Muscle, Skeletal/drug effects , Muscle, Skeletal/innervation , Myography , Neural Conduction/drug effects , Spinal Cord/cytology , Spinal Cord/drug effects
12.
Brain Inj ; 17(1): 49-54, 2003 Jan.
Article in English | MEDLINE | ID: mdl-12519647

ABSTRACT

PRIMARY OBJECTIVE: To assess the outcome of severe traumatic brain injury 1 year after trauma. RESEARCH DESIGN: Prospective study conducted at the neurosurgical department of a university hospital. METHODS AND PROCEDURES: A total of 24 patients were included. Outcome was assessed by means of Glasgow outcome scale, Barthel index, Functional independence measure (FIM) and Disability rating scale (DRS). Need of care and job ability were also evaluated. EXPERIMENTAL INTERVENTIONS: Patients received multimodal early-onset stimulation and continuous inpatient and outpatient rehabilitation therapy. MAIN OUTCOMES AND RESULTS: Six patients died, three remained in a vegetative state, six were severely disabled, six were moderately disabled and three achieved a good recovery 1 year after injury. Mean Barthel index was 68.9, mean FIM was 88.3 and mean DRS 27.7. The majority of patients still were at least intermittently dependent on care. Most of the trauma survivors were unable to work. CONCLUSIONS: Despite intensive rehabilitation treatment, severe traumatic brain injury is still burdened with significant mortality and morbidity.


Subject(s)
Brain Injuries/mortality , Coma/mortality , Adolescent , Adult , Aged , Brain Injuries/rehabilitation , Coma/etiology , Coma/rehabilitation , Female , Follow-Up Studies , Glasgow Outcome Scale , Humans , Male , Middle Aged , Persistent Vegetative State/mortality , Prognosis , Prospective Studies , Recovery of Function , Survivors , Work Capacity Evaluation
13.
Muscle Nerve ; 26(2): 270-3, 2002 Aug.
Article in English | MEDLINE | ID: mdl-12210392

ABSTRACT

The yield of magnetic resonance imaging (MRI) and electrophysiological studies in detecting brainstem lesions was assessed in 35 patients suffering from traumatic brain injury (Glasgow Coma Scale, 3-10). As an inclusion criterion, all patients had brainstem trauma as revealed by early MRI or electrophysiological studies. Of the 35 cases, 7 (20%) had brainstem lesions detected by MRI only, whereas in 10 patients (29%), electrophysiological examination disclosed impairment of brainstem function with normal MRI. In 18 (51%) subjects, both diagnostic techniques revealed brainstem lesions. The midbrain was the most common location of lesions. Masseter reflex recording had the highest yield (93%) of abnormal findings. No mismatch with respect to site and side of abnormality occurred between MRI and electrophysiological studies. Outcome analysis indicated an unfavorable course for the vast majority (83%) of patients, regardless of the diagnostic means disclosing traumatic brainstem injury. Therefore, both techniques are effective in disclosing traumatic brainstem injury, with diagnostic overlap in about 50% of cases. In contrast to MRI, electrophysiological investigation is easily performed and repeated at low cost in the setting of an intensive care unit, where such patients are typically hospitalized after trauma. In addition to electrophysiological assessment of brainstem function, MRI is recommended in each case having normal electrophysiological findings when brainstem injury is suspected.


Subject(s)
Brain Injuries/pathology , Brain Injuries/physiopathology , Brain Stem/pathology , Brain Stem/physiopathology , Evoked Potentials, Auditory, Brain Stem , Magnetic Resonance Imaging , Adolescent , Adult , Aged , Blinking , Female , Humans , Male , Masseter Muscle/physiology , Middle Aged , Retrospective Studies
14.
Eur Radiol ; 12 Suppl 3: S1-3, 2002 Dec.
Article in English | MEDLINE | ID: mdl-12522590

ABSTRACT

We report on an isolated enlargement of the fourth ventricle in a patient with neurosarcoidosis which developed 3 years after the insertion of a ventriculo-atrial shunt. Repeated MRI images were obtained in a patient with known neurosarcoidosis between 1995 and 2000. Imaging findings were correlated to the medical course of the patient, who developed a hydrocephalus and a trapped fourth ventricle consecutively. The isolation was presumably due to granulomatous inflammation of the ependyma surrounding the fourth ventricular outlets. The isolated fourth ventricle was responsible for a deterioration of neurological status. Neurosarcoidosis is a severe complication in sarcoidosis patients. An isolated enlargement of the fourth ventricle is a rare complication in clinically deteriorated patients with neurosarcoidosis and ventricular drainage, which may require neurosurgical treatment.


Subject(s)
Central Nervous System Diseases/diagnosis , Cerebral Ventricles/pathology , Sarcoidosis/diagnosis , Adult , Central Nervous System Diseases/surgery , Cerebral Ventricles/surgery , Humans , Magnetic Resonance Imaging , Sarcoidosis/surgery , Ventriculoperitoneal Shunt
15.
Eur Radiol ; 12 Suppl 3: S18-24, 2002 Dec.
Article in English | MEDLINE | ID: mdl-12522595

ABSTRACT

Two cases of aneurysmal re-rupture during intracranial angiography are presented. This event is accompanied by disastrous consequences with regard to the clinical condition of the patient, as is evident from the cases presented as well as from the literature. Acute alterations of intraluminal pressure as well as a time interval of less than 6 h seems to increase the risk of re-bleeding during angiography. The introduction of and the growing experience with CT and MR angiography may in the near future provide sufficient diagnostic information for surgical planning and thus help to overcome the risk of aneurysmal re-rupture during intra-arterial angiography.


Subject(s)
Aneurysm, Ruptured/diagnostic imaging , Intracranial Aneurysm/diagnostic imaging , Adult , Aneurysm, Ruptured/etiology , Cerebral Angiography/adverse effects , Female , Humans , Intracranial Aneurysm/etiology , Middle Aged , Recurrence , Subarachnoid Hemorrhage/complications , Subarachnoid Hemorrhage/diagnostic imaging , Tomography, X-Ray Computed/adverse effects
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