Biomedical subjects
Publications and source records attributed to B Ljunggren.
The authors present two patients with continuous focal epileptic seizures intractable to conventional antiepileptic therapy. Both cases were successfully treated with intravenous nimodipine.
Using the mouse, photoallergy to the antiarrhythmic agent quinidine could be induced following systemic administration. After pretreatment with cyclophosphamide 150 mg/kg, groups of 5-10 mice were injected i.p. with quinidine chloride 100 mg/kg on 2 consecutive days, followed by exposure of shaved abdominal skin to UVB 0.1 J/cm2 and UVA 5.0 J/cm2. Five days later challenge was performed on the left ear and on the tail, using the same dose of quinidine and UVA 5.0 J/cm2. The reaction was elevated 24 h later by measuring the increase in ear thickness as well as the wet weight increase of ear and tail. Significant 24 h reactions could be measured using all three evaluation systems. Control animals treated according to the protocol, but not UV-exposed during induction, were negative, thus excluding a phototoxic reaction. The histology of the left ear at challenge showed a round cell infiltrate preferentially of the exposed outer face of the ear consistent with an immunologic reaction. The time course of the reaction showed a maximum at 24 h. Photosensitization to quinidine could be achieved with UVA alone during the induction phase. Quinidine photoallergy can be induced in the mouse after systemic administration, and the reaction measured both at ear and tail. These findings support the assumption that clinical photoreactions to quinidine may have an immunological basis.
Clinical photoreactions have been reported for quinine and quinidine after systemic and topical administration. We have investigated the phototoxic properties of these two quinoline methanol isomers in vitro using the Candida albicans inhibition test and photohemolysis, and in vivo with the mouse tail phototoxicity test. Both isomers were phototoxic in the hemolysis model, quinine being the more potent compound. In the Candida test only quinidine was phototoxically active. In the mouse tail model, measuring edema, the phototoxic activity of quinidine was comparatively low, causing a 7.3% wet weight increase of tail tissue at a dose of 150 mg/kg intraperitoneally of drug and 54 J/cm2 of UVA. In spite of its structural similarity to quinidine, quinine was not phototoxic in the mouse. These studies support the assumption, based on clinical data, that quinine photoreactions probably have a non-phototoxic mechanism. For quinidine, however, light-induced reactions based on phototoxicity can not be ruled out, since low-grade phototoxic properties were demonstrated in vivo.
Photoallergic dermatitis was induced in the mouse following the systemic administration of quinidine in combination with UVB and UVA. The reaction was recorded as ear wet weight, ear thickness and tail wet weight. Statistical calculations showed ear wet weight to be the most sensitive evaluation technique. By varying the quinidine dose administered in induction (2.5-100 mg/kg) and challenge (10-100 mg/kg), dose-response conditions were established. It was shown that the induction dose necessary to obtain a statistically significant reaction was considerably lower than the minimal challenge dose (25 mg/kg). This method is well suited for studies of the dynamics of the induction and elicitation phases of systemically induced photoallergy.
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The acute vascular effects of tetraethylammonium chloride (TEA) were examined on annular segments of rabbit basilar arteries. Contractions induced by the potassium channel blocker were compared with those obtained for potassium chloride, 5-hydroxytryptamine (5-HT) and norepinephrine (NE). The greater magnitude of the contractions was of the following order: [K+] greater than 5-HT greater than TEA greater than NE. High concentrations of TEA alone (10(-2) M) generated spontaneous oscillatory contractions in cerebral vessels that were normally quiescent. Low concentrations of TEA (10(-8)-10(-6) M), which had no vasomotor properties per se, enhanced the contractile response of submaximal concentrations of 5-HT (10(-7) M) and NE (3 X 10(-6) M) and attenuated the contraction produced by 60 mM [K+]. An increased vascular response to the amines was still evident up to 3 h after the addition of TEA despite frequent rinsing with fresh buffer solutions. On arteries precontracted with TEA (10(-2) M), but not high [K+], the subsequent addition of 5-HT (10(-7) M) still induced a powerful constriction. Repeated concentration-response curves for [K+] were reproducible and, in the presence of TEA (10(-8) or 10(-6) M), the curve was displaced to the right in a competitive manner. A higher concentration of TEA (10(-4) M) was devoid of any blocking properties on the [K+]-induced response whereas, at 10(-3) M TEA, the response was potentiated, as evidenced by a shift of the curve to the left. Interactions between TEA and the cumulative response to 5-HT were difficult to interpret. Repeated exposures of the artery to 5-HT resulted in an increased maximal response with each determination (EAm = 127 +/- 9% and 149 +/- 14% of control values following the second and third applications, respectively). With TEA (10(-6) M), the increase in the maximal contractile effect noted previously was not observed. Contractions induced by single concentrations of TEA (10(-2) M) or [K+] (60 mM) were calcium dependent, were abolished completely in a calcium-free medium, and were depressed by the calcium antagonist nimodipine. 5-Hydroxytryptamine-induced contractions (10(-5) M) were less sensitive to withdrawal of calcium from the extracellular medium (31 +/- 6% relative to the maximal response at 4 mM calcium). Hence, an acute reduction in potassium conductance in cerebrovascular smooth muscle produced by TEA has complex, concentration-dependent effects and reproduces only part of the spectrum of effects of cisternal injection of blood on cerebrovascular reactivity.
Mean hemispheric cerebral blood flow (CBF) was studied after the intravenous administration of xenon-133 in 20 anesthetized patients with aneurysmal subarachnoid hemorrhage. Before early aneurysm operation, repeated CBF measurements were made to evaluate the cerebral vascular reactivity to controlled hyperventilation. Thirteen individuals received intravenous treatment with the calcium channel blocker nimodipine, whereas the other seven patients did not receive such specific antiischemic treatment. Five of the latter patients had an impaired CO2 response, and three showed delayed ischemic deterioration (DID), whereas none of the seven nimodipine-treated patients with impaired CO2 response showed DID. One nimodipine-treated patient with a preserved CO2 response, in whom operation was complicated, developed DID. The observed findings indicate that DID after uncomplicated early aneurysm operation may be associated with an early disturbance of cerebral vasoreactivity. Treatment with nimodipine may counteract the development of DID in patients with an impaired CBF CO2 response.
Four women, aged 39 to 46 years, were urgently admitted to our neurosurgical unit after strokes. On admission, all appeared moribund, presenting with deep coma, pupils bilaterally dilated and fixed, decerebrate posture, and markedly abnormal respiratory patterns. Computed tomography revealed subarachnoid hemorrhage with an associated large intracerebral hematoma and pronounced shift of midline structures in all four cases. Because of the clinical appearance, the patients were given urea and were operated without preceding angiography. The origin of the hemorrhage was identified as a middle cerebral artery (MCA) bifurcation berry aneurysm in one patient and giant MCA aneurysms in the other three. The hematomas were evacuated, and the aneurysms were occluded. All four patients received intravenous nimodipine, none showed any sign of delayed ischemic deterioration, and all regained full consciousness within a few days. One patient died 3 weeks later from a pulmonary embolus. Three patients are presently at home with moderate focal neurological deficits and moderate to marked cognitive impairment. The psychosocial readjustment was very good in a patient with a left giant aneurysm, satisfactory in a patient with a right giant aneurysm, and unsatisfactory in a patient with a right berry aneurysm. The indications, ethical considerations, and technical aspects of operating on seemingly moribund patients who probably harbor a ruptured MCA aneurysm are discussed.
Does early aneurysm operation, while lowering the overall management mortality, result in an unacceptable morbidity in terms of increased cognitive disturbances and psychosocial maladjustment? The present study evaluates quality of life, degree of cognitive dysfunction, and adjustment of 93 patients with satisfactory neurological recoveries after operations for ruptured supratentorial aneurysms. All patients had been in neurological Grades I to III (Hunt and Hess) after subarachnoid hemorrhage (SAH). Fifty-five patients were operated upon during the acute state, i.e., within 72 hours after bleeding (early surgery = ES), and 38 patients had been subjected to late surgery (LS), i.e., were operated on 9 days or more after SAH. Each patient was subjected to a clinical interview and a comprehensive neuropsychological investigation. The time interval between SAH and assessment varied between 12 and 103 months (mean, 56 months). The results confirm that there are indication of cognitive malfunctioning and psychosocial disturbances of varying severity and distribution in patients who have undergone LS. The pattern and distribution of sequelae after LS did not differ substantially from that in patients subjected to ES. The results offer strong support to the concept that remaining disturbances in cognition are mainly related to the impact of the initial hemorrhage per se. In patients with anterior communicating artery aneurysms, a larger decrease in tempo and perceptual vigilance was noted, suggesting that the subfrontal midline structures are particularly involved in processes demanding flexibility, attention, and capacity to adapt to novel demands in a perceptual situation.
The discouraging history associated with management of aneurysmal subarachnoid haemorrhage (SAH) is reviewed along with improvements in outlook attributable to progress made within the past decade. Among the new developments is the introduction of microsurgical techniques that allow elective surgery in the acute stage thereby preventing repeat haemorrhages. Early operation also offers the possibility of a more aggressive pharmacological anti-ischaemic treatment. Notwithstanding the improved results of acute elective surgery and the fact that delayed ischaemic deterioration (symptomatic cerebral vasospasm) now may be almost eliminated, the overall outcome remains gloomy. Despite recent advances not more than one out of three individuals, who are struck by the rupture of an intracranial aneurysm, may be expected to make a good neurological and functional recovery. Hope for further improvements may depend on the development of techniques that can identify intracranial aneurysms before they rupture and increased knowledge of the aetiology of such arterial wall lesions.
Olof af Acrel, the father of Swedish Surgery, operated in 1768 upon a young nobleman who had experienced an increasing swelling on the skull, due to a tumour which also turned out to be growing deep into the brain parenchyma. The patient survived the operation for 3 days. Edvard Bull in 1877, after diagnosing a ruptured internal carotid artery aneurysm in a young female who temporarily recovered after her first hemorrhage, emphasised that the risk of a second, fatal haemorrhage--which in fact occurred--was immediate. He predicted that carotid ligation might be a way to reduce the risk of repeated haemorrhage from such aneurysms. Virtually unknown to modern neurosurgeons are many remarkable Nordic pioneers who, in the 1800's and early 1900's, rendered major contributions to the birth of modern neurological surgery. Thus early neurosurgical operations were performed by Carl Daniel von Haartman in Finland and by Christopher Withusen and Gundelach Møller in Denmark. von Haartman and Withusen had both visited Sir Astley Cooper in London in 1816. Vilhelm Magnus of Oslo was a neurosurgical giant, who had been trained by Victor Horsley during visits to London in 1903 and 1904. Magnus performed his first two-stage operation for a tumour located deep in the left cerebral hemisphere in 1903. By 1921, he had operated upon 112 cases of intracranial tumour with an 8.1% surgical mortality. His results were certainly fully comparable with those of his contemporary American pioneer--Harvey Cushing. Vilhelm Magnus, who worked alone under primitive conditions in small private hospitals, published altogether 70 scientific papers. In 1925 his series comprised 189 patients operated upon for brain tumours with 7.7% surgical mortality in supratentorial, and 17.8% mortality in infratentorial tumours. Magnus was congratulated on his brilliant achievements by a Swedish colleague 20 years his junior, Herbert Olivecrona, the man who was to carry on his pioneering work in Sweden.
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A double blind cross-over phototoxicity study using demethylchlortetracycline (DMCT) 0.3 g x 2, doxycycline 0.1 g x 2, lymecycline 0.6 g x 2 and placebo was performed on 8 healthy human volunteers. Drugs were given for 3 consecutive days, and on the third day the volunteers were tested with different modalities of artificial long-wave ultraviolet radiation (UVA) and assessed 24 h later for objective as well as subjective abnormal photoreactions. All 4 substances were tested in each individual at weekly intervals and serum concentrations of tetracycline were determined. It was found most convenient to irradiate relatively large skin areas using fluorescent tubes emitting mainly UVA but also a small proportion of UVB. Using this type of irradiation, weak erythemal reactions were obtained with all 3 derivatives. Taking only stronger reactions and stinging sensations into account, 0/8 reacted to lymecycline, 0/8 to DMCT and 4/8 to doxycycline. There was no significant difference in serum concentration among the 3 derivatives. It is concluded that doxycycline is the most potent photosensitizer at the dosage tested.
Patients with a ruptured supratentorial aneurysm undergoing early surgery after the subarachnoid haemorrhage were treated postoperatively with nimodipine to prevent delayed ischaemic dysfunction. It was given first as a continuous intravenous infusion 2 mg/h (mean dose 0.5 micrograms/kg/min) for at least 7 days, and then orally (45 mg X 6) for at least a further 7 days. During the i.v. infusion, the mean plasma concentration was 26.6 +/- 1.8 ng/ml. The plasma clearance ranged from 0.57 to 1.771/kg/h and was negatively correlated with the age of the patient. Immediately prior to successive oral doses, the mean plasma concentration was 13.2 ng/ml (range less than 3-38.8 ng/ml). The peak level was usually found after 1 h; it ranged from 7.0-96.0 ng/ml. Mean bioavailability was 15.9%. The nitropyridine metabolite was found in measurable concentrations only after oral treatment with nimodipine. In some cases, the concentration of metabolite exceeded that of the parent compound. The three patients investigated who developed delayed ischaemic dysfunction had plasma concentrations well within the range in patients who did not, so it seems unlikely that the therapeutic failure could be attributed to individual deviations in the pharmacokinetics of the drug.
Regrowth of bone after craniectomy for craniosynostosis is still a problem, despite the advent of newer and extensive surgical techniques. A clinical study on 25 consecutive patients was undertaken to determine whether a modification of previous routines could retain the advantages of a tissue fixative, Zenker's solution, while eliminating the drawback of convulsive activity. After brief coagulation, Zenker's solution was sparingly applied to the dural surface for maximally one minute followed by copious irrigation of the surgical field. The results were satisfactory and postoperative complications unrelated to the fixative. The present procedure seems safe, effective, and easy to use.