Effective pharmacotherapy of alcoholic amnestic disorder with fluvoxamine. Preliminary findings.

Ten patients with alcoholic chronic organic brain disease were categorized as having alcohol amnestic disorder, or Korsakoff's psychosis (n = 6), dementia associated with alcoholism (n = 3), or compensated alcoholic liver disease (n = 1). All patients had severe deficits in memory for recently acquired information (episodic memory). Patients with alcohol dementia also showed global intellectual decline, including decreased performance on measures of semantic (knowledge) memory and reduction in levels of cerebrospinal fluid somatostatin. In a 4-week double-blind crossover design, the serotonin-uptake blocker fluvoxamine maleate (100 to 200 mg/d) was found to improve episodic memory in only the patients with alcohol amnestic disorder. These improvements in memory were significantly correlated with reductions in levels of cerebrospinal fluid 5-hydroxyindoleacetic acid, suggesting that facilitation of serotonergic neurotransmission may ameliorate the episodic memory failure in patients with alcohol amnestic disorder.

Hypothalamic-pituitary-adrenal axis functioning and cerebrospinal fluid corticotropin releasing hormone and corticotropin levels in alcoholics after recent and long-term abstinence.

We assessed the plasma corticotropin (adrenocorticotropic hormone) and cortisol responses to ovine corticotropin releasing hormone (oCRH) and the cerebrospinal fluid levels of CRH and corticotropin in alcoholics at various durations of abstinence and compared these variables with age-equivalent controls. Alcoholics who were tested at 1 week of abstinence (n = 11) demonstrated a significantly attenuated corticotropin response to oCRH compared with their response at 3 weeks of abstinence. Nine of these alcoholic patients demonstrated a significantly blunted corticotropin response at both 1 and 3 weeks of abstinence compared with controls (n = 15). A markedly exaggerated corticotropin response to oCRH, associated with tachycardia, was exhibited by 2 alcoholics at both 1 and 3 weeks of abstinence. Alcoholics who were abstinent greater than 3 weeks did not differ in their response to oCRH compared with controls. Controls demonstrated a significant inverse correlation between baseline cortisol levels and the cortisol response to oCRH. This correlation was not evident in any of the alcoholic groups, including those patients who were abstinent greater than 6 months. There was a positive correlation between cerebrospinal fluid concentrations of CRH and corticotropin in all patient groups. These findings indicated that alcoholics have significantly altered hypothalamic-pituitary-adrenal axis functioning up to 3 weeks following the cessation of drinking, with a more subtle impairment present for greater than 6 months following abstinence.

Two-year results of once-weekly administration of alendronate 70 mg for the treatment of postmenopausal osteoporosis.

The aim of this study was to provide confirmation that once-weekly dosing with 70 mg of alendronate (seven times the daily oral dose) and twice-weekly dosing with 35 mg is equivalent to the 10-mg once-daily regimen and to gain more extensive safety experience with this new dosing regimen. Twelve hundred fifty-eight postmenopausal women (aged 42-95 years) with osteoporosis (bone mineral density [BMD] of either lumbar spine or femoral neck at least 2.5 SDs below peak young adult mean or prior vertebral or hip fracture) were assigned to receive oral once-weekly alendronate, 70 mg (n = 519); twice-weekly alendronate, 35 mg (n = 369); or daily alendronate 10 mg (n = 370) for a total of 2 years of double-blind experience. Mean BMD increases from baseline (95% CI) at 24 months in the once-weekly, twice-weekly, and daily treatment groups, respectively, were 6.8% (6.4, 7.3), 7.0% (6.6,7.5), and 7.4% (6.9,7.8) at the lumbar spine and 4.1% (3.8,4.5), 4.3% (3.9,4.7), and 4.3% (3.9,4.7) at the total hip. These increases in BMD as well as the BMD increases at the femoral neck, trochanter, and total body and the reductions of biochemical markers of bone resorption (urinary cross-linked N-telopeptides of type I collagen [NTx]) and bone formation (serum bone-specific alkaline phosphatase [BSAP]) were similar for the three dosing regimens. All treatment regimens were well tolerated with a similar incidence of upper gastrointestinal (GI) adverse experiences. The incidence rates of clinical fractures, captured as adverse experiences, were similar among the groups. The 2-year results confirm the conclusion reached after 1 year that once-weekly alendronate is therapeutically equivalent to daily dosing, providing patients with a more convenient dosing option that may potentially enhance adherence to therapy.

Disturbances of hypothalamic-pituitary-adrenal axis functioning during ethanol withdrawal in six men.

OBJECTIVE: Excessive exposure to glucocorticoids can have neurotoxic effects. The behavioral, cognitive, and neurochemical changes observed following the cessation of heavy drinking, therefore, may be associated with disturbances of the hypothalamic-pituitary-adrenal (HPA) axis. To investigate HPA axis disturbances during the ethanol withdrawal syndrome, the authors examined diurnal changes in plasma cortisol in six alcohol-dependent men following the abrupt discontinuation of alcohol intake. METHOD: Plasma cortisol concentrations were quantified every 30 minutes for 24 hours in the early stage (1 day after cessation) and the middle to late stage (3 days after cessation) of the ethanol withdrawal syndrome as well as after the resolution of acute symptoms (8 days or more after cessation). RESULTS: Plasma cortisol concentrations were almost twice as high during acute withdrawal as they were following recovery. The duration of the cortisol diurnal cycle on the first day of withdrawal was negatively correlated with the severity of withdrawal. CONCLUSIONS: There is a marked activation of the HPA axis associated with the ethanol withdrawal syndrome. The authors hypothesize that this activation may account for some of the signs and symptoms of acute and subacute withdrawal. They discuss the potential long-term physiological effects of the episodic increases in cortisol associated with repeated episodes of ethanol withdrawal. The alterations in cortisol rhythmicity during early withdrawal may also have clinical implications.

A comparison of calcium antagonists and diazepam in reducing ethanol withdrawal tremors.

The calcium antagonists nimodipine and dantrolene were compared with diazepam in an animal model of tolerance and physical dependence upon ethanol. Nimodipine and dantrolene were both effective in suppressing withdrawal tremors but diazepam was clearly superior to both agents. These results suggest that the ethanol withdrawal syndrome is only partially mediated by increased calcium flux.

Comparison of radiometric and gas capture system for blood cultures.

A single bottle blood culture system that detects the gas produced by micro-organisms from substrates in a specially formulated medium was compared with the Bactec radiometric system. A total of 725 blood samples collected from patients with suspected bacteraemia yielded 75 clinically important isolates. Fifty five (73%) of these cultures were detected by both methods, 16 (21%) by only the Bactec system, and four (5%) by only the Oxoid system. No significant differences were found between the two systems after allowance was made for the different volume of sample inoculated into each system.

Toe blood pressure by photoplethysmography: an index of healing in forefoot amputation.

The relative merits of toe systolic blood pressure and ankle systolic pressure in predicting the result of forefoot amputation were evaluated in 30 limbs of 27 patients who underwent digit or transmetatarsal amputation. Twenty-four (89%) patients were diabetic. An infrared photoplethysmograph placed distal to a pneumatic digit occluding cuff allowed rapid, simple preoperative assessment of toe systolic pressures. Ankle pressures was measured by Doppler ultrasound. Twenty (67%) amputations healed primarily, whereas 10 ultimately required reamputation at the below-knee level. The mean ankle pressure of limbs with healing of forefoot amputation, 136 +/- 39 mm Hg (+/- SD), did not differ significantly from those that failed to heal, 121 +/- 72 mm Hg (P greater than 0.4). Failure of an amputation to heal occurred in association with ankle pressures ranging from 60 to over 300 mm Hg. The mean value of toe pressures associated with healing of forefoot amputation, 86 +/- 39 mm Hg, was significantly higher than those not healing, 25 +/- 18 mm Hg (P less than 0.001). Failure of a forefoot amputation to heal occurred in all eight limbs with toe pressures less than 45 mm Hg, and in two of eight (25%) limbs with toe pressure between 45 and 55 mm Hg. Primary healing occurred in all 14 limbs with toe pressures greater than 55 mm Hg. These data suggest that toe pressure measurement may be a useful hemodynamic correlate of the healing potential of a forefoot amputation.

Limitations of the Doppler cerebrovascular examination in hemispheric cerebral ischemia.

The results of a directional Doppler ultrasound cerebrovascular examination were compared with arteriographic findings in 56 patients with resolved hemispheric strokes or transient ischemic attacks. Aortic arch arteriography revealed appropriate internal carotid artery lesions which were amenable to endarterectomy in 36 patients (64 percent). Of this group, abnormal Doppler findings were present in only 11 patients (31 percent). The definitive clinical applications of the Doppler cerebrovascular examination are limited to those settings in which demonstration of altered hemodynamics is decisive. In view of the apparent preponderance of embolic rather than hemodynamic mechanisms in the pathogenesis of focal cerebral ischemia, the Doppler examinations has only an adjunctive role in the evaluation of most patients with hemispheric symptoms of cerebrovascular occlusive disease. In such patients, preselection of candidates for diagnostic arteriography is an inappropriate application of the Doppler cerebrovascular examination.

Civilian popliteal artery trauma: an eleven year experience with 83 injuries.

Limb loss is the outcome in one third of previously reported popliteal artery injuries. This report summarizes 83 injuries with an amputation rate of 9.6%. Penetrating traumas accounted for 61 (73%) injuries and blunt traumas for 22 (27%). The incidence of amputation varied with injury type from none in seven stab wounds to three of 19 (15.8%) shotgun wounds. Distal ischemia or a pulse deficit highlights the presence of arterial trauma, and the external wound defines its site in most patients. Urgent operation is indicated by these findings. Equivocal findings suggest less compromised flow, and such patients are managed best by arteriographic confirmation before operation. Early systemic anticoagulation is indicated to decrease distal small-vessel thrombosis. The successful management of these injuries requires early and complete restoration of arterial and venous flow. This is accomplished most effectively by priority definitive reconstruction. Compulsive attention to complete restoration of arterial flow during the initial procedure is mandatory. Resection or bypass of all damaged arterial wall, liberal use of autogenous vein grafts, and repair of concomitant venous injuries enhance continued arterial patency. Routine distal catheter thrombectomy and frequent intraoperative arteriography promote and confirm complete reconstruction. Early performance of four quadrant fasciotomy is indicated if compartmental hypertension is suspected. Thorough debridement of injured and questionably viable soft tissue and adequate fracture stabilization are integral parts of successful revascularization.

Noninvasive ultrasonic carotid angiography: prospective validation by contrast arteriography.

Pulsed ultrasonic images of the carotid bifurcation in 82 vessels of 43 patients were compared independently with contrast arteriograms for stenosis (by percentage quartiles) or occlusion of the internal carotid artery. All 14 occluded vessels were identified correctly by ultrasound but were visualized on repeat examination. Estimation of percentage stenosis on ultrasonic images agreed with the quartile determination by contrast arteriography in 35 of 68 (51 percent) vessels and was within one quartile of correct interpretation in 48 of 68 (71 percent). The interpretative error of grading stenosis of ultrasonic images was due to vascular wall calcification which inhibited ultrasound transmission. This limitation was overcome by sound spectral (sonographic) analysis of distal internal carotid flow velocity which allowed estimation of stenosis within one quartile of that determined by contrast arteriography in 46 of 47 (98 percent) vessels.

Fluvoxamine treatment of alcoholic amnestic disorder.

The serotonin uptake inhibitor fluvoxamine was assessed in treatment of alcohol-induced Korsakoff's syndrome (KS) using fixed (4 weeks, 200 mg/day) or individualized (6 weeks, plasma concentration > or = 400 ng/ml) dosing in randomized placebo-controlled double-blind crossover studies. Cognitive functions and concentrations of the major cerebrospinal fluid (CSF) metabolites of serotonin (5-HIAA), norepinephrine (MHPG), and dopamine (HVA) were determined in abstinent, nondepressed KS patients (aged 45-75), at baseline and placebo (3-4 weeks), and after 3-4 (n = 10) or 6 (n = 4) weeks of fluvoxamine administration. Fluvoxamine decreased CSF 5-HIAA compared to placebo (P < 0.003) without consistent changes in HVA or MHPG. Reductions in 5-HIAA correlated with improvements on the Wechsler Memory Scale Memory Quotient (P < 0.05), independent of effects on attention/vigilance or Beck Depression Inventory scores. Reductions in 5-HIAA correlated with plasma fluvoxamine (P < 0.03) only for fluvoxamine concentrations below 450 ng/ml. These findings suggest improvement of memory consolidation and/or retrieval in patients with Korsakoff's syndrome by fluvoxamine via serotonergic mechanisms.

Treatment of gambiense sleeping sickness in the Sudan with oral DFMO (DL-alpha-difluoromethylornithine), an inhibitor of ornithine decarboxylase; first field trial.

Difluoromethylornithine (DFMO), a specific, irreversible inhibitor of polyamine biosynthesis shown to be curative in animal models inoculated with various Trypanosoma spp., was evaluated in the Southern Sudan in a preliminary open clinical field trial in patients infected with Trypanosoma brucei gambiense. 20 patients were studied including 18 with late-stage disease involving the central nervous system, 16 of whom were refractory to arsenical treatment. In late-stage disease monotherapy with oral DFMO doses of about 400 mg/kg/day for five to six weeks was associated with disappearance of parasites from cerebrospinal fluid (CSF), decreased CSF WBC counts and protein concentrations and reversal of clinical signs. Side effects associated with this dose regimen included diarrhoea, abdominal discomfort and anaemia, but were seldom sufficiently severe to prompt discontinuing therapy. In early-stage patients about 200 mg/kg/day for six weeks appears adequate to eliminate parasites and reverse clinical symptoms and is well tolerated. Three cases of late-stage sleeping sickness and two of early-stage disease followed up for approximately one and a half to two years after treatment indicated that DFMO monotherapy can be curative. Additional studies are needed to define optimal posology. Inhibition of polyamine biosynthesis is a promising new approach to therapy of trypanosomiasis.

alpha-Difluoromethylornithine induces protective immunity in mice inoculated with Plasmodium berghei sporozoites.

Mice inoculated weekly with Plasmodium berghei sporozoites while under treatment with alpha-difluoromethylornithine (DFMO), an inhibitor of ornithine decarboxylase, developed protective immunity against subsequent challenge with this parasite. The percentage of mice protected was similar whether DFMO alone (55%) or DFMO + chloroquine (65%) was used. With chloroquine alone, only 12% of mice were protected. This protection was long-lasting (at least six months). The immunity protected against sporozoites but not against erythrocytic form inoculation. It is suggested that this protection is induced by antigens released from exoerythrocytic schizonts whose further development is inhibited by DFMO.

Endoscopic surgery versus medical treatment for spontaneous intracerebral hematoma: a randomized study.

A controlled randomized study of endoscopic evacuation versus medical treatment was performed in 100 patients with spontaneous supratentorial intracerebral (subcortical, putaminal, and thalamic) hematomas. Patients with aneurysms, arteriovenous malformations, brain tumors, or head injuries were excluded. Criteria for inclusion were as follows: patients' age between 30 and 80 years; a hematoma volume of more than 10 cu cm; the presence of neurological or consciousness impairment; the appropriateness of surgery from a medical and anesthesiological point of view; and the initiation of treatment within 48 hours after hemorrhage. The criteria of randomization were the location, size, and side of the hematoma as well as the patient's age, state of consciousness, and history of hypertension. Evaluation of outcome was performed 6 months after hemorrhage. Surgical patients with subcortical hematomas showed a significantly lower mortality rate (30%) than their medically treated counterparts (70%, p less than 0.05). Moreover, 40% of these patients had a good outcome with no or only a minimal deficit versus 25% in the medically treated group; the difference was statistically significant for operated patients with no postoperative deficit (p less than 0.01). Surgical patients with hematomas smaller than 50 cu cm made a significantly better functional recovery than did patients of the medically treated group, but had a comparable mortality rate. By contrast, patients with larger hematomas showed significantly lower mortality rates after operation but had no better functional recovery than the medically treated group. This effect from surgery was limited to patients in a preoperatively alert or somnolent state; stuporous or comatose patients had no better outcome after surgery. The outcome of surgical patients with putaminal or thalamic hemorrhage was no better than for those with medical treatment; however, there was a trend toward better quality of survival and chance of survival in the operated group.

Value of segmental limb blood pressures in predicting results of aortofemoral bypass.

The efficacy of segmental limb blood pressure measurements, assessed noninvasively by Doppler ultrasound, in predicting the result of aortofemoral reconstruction was evaluated in fifty-two extremities with varying extent of aortoiliac and more distal arterial occlusive disease. Three prognostic correlates were analyzed: (1) preoperative proximal thigh/arm pressure index (TPI); (2) preoperative pressure gradient between adjacent leg segments (proximal thigh, above-knee, below-knee, and ankle), normally less than 30 mm Hg; and (3) early postoperative increase in the ankle/arm pressure index (API). After aortofemoral bypass, forty-one limbs (79 per cent) were asymptomatic or improved and eleven were unimproved. The mean TPI in extremities benefiting from aortofemoral bypass, 0.82 +/- 0.17 (+/-1SD) was significantly less than that of unimproved limbs, 1.01 +/- 0.09 (p less than 0.01). Aortofemoral bypass was beneficial in all twenty limbs with normal leg pressure gradients. Conversely, six of twenty-five legs with one abnormal gradient and five of seven with two abnormal gradients failed to improve. The postoperative increase in API was 0.1 or more in all forty-one improved extremities and was less than 0.1 in all eleven failures. Although eleven of thirty-two limbs (34 per cent) with arteriographic evidence of combined aortoiliac and subinguinal occlusive disease were not improved after proximal bypass, the result of operation could not be predicted from the angiographic pattern or severity of distal disease. Segmental limb blood pressures provide useful predictive indices of the efficacy of aortofemoral bypass and the potential need for more distal reconstruction in multisegmental disease.

Vancomycin resistance of clinical isolates of lactobacilli.

Strains of lactobacilli were cultured from two patients with clinical evidence of infection. Each isolate was found to be highly resistant to vancomycin but inactivation of the antibiotic could not be demonstrated. Lactobacillus isolates should be regarded as potential pathogens. Reliable vancomycin susceptibility testing is required since susceptibility among Gram-positive bacteria in general should not be assumed.

Evaluation of gross and fine motor functions in children with hemidecortication: predictors of outcomes and timing of surgery.

The purpose of this study is three-fold: First, to determine the levels of gross and fine motor functions in children before and after hemidecortication, using standardized measurement tools; second, to investigate if predictors of these outcomes can be characterized; and third, to explore if both clinical measures and functional magnetic resonance imaging (MRI) potentially can identify optimal timing of surgery. The Gross Motor Function Measure and the Quality of Upper Extremity Skills Test are shown to be comprehensive, standardized outcome measures of movement performance in affected children. Age at surgery and interval between age at seizure onset and age at surgery could be the most reliable predictors of clinical outcomes. Functional MRI studies are valuable in exploring the potential of the cortical reorganization that sustains residual sensorimotor function. The combination of clinical measures with functional MRI is a promising method of inquiry into developmental and plasticity processes.

[Intracranial arteritis with circulating immune complexes]. / Intrakranielle Arteriitis bei zirkulierenden Immunkomplexen (ZIK).

Thirty-eight patients below the age of 50 years were investigated and in twelve, circulating immune complexes were found. Eight of these had angiographic evidence of an arteritis of the intracranial vessels. The causative factors, the role of the circulating immune complexes and the angiographic appearances in intracranial arteritis are discussed.

[Reduction of the rate of cerebral angiography complications by a standardized study method]. / Senkung der Komplikationsrate zerebraler Angiographien durch eine standardisierte Untersuchungsmethode.

The complications from cerebral angiography encountered in 1034 patients between 1977 and 1982 are described. A standardised technique of cerebral transfemoral catheter angiography is outlined, which helps to reduce the number of complications. The role of the disease for which the examination is done, and the effect of the new contrast media on the risk of the examination, are discussed. Patients with a compromised blood-brain barrier and manifest reduction in cerebral blood flow run a greater risk than patients with other abnormalities. Low osmolar contrast media are better tolerated subjectively. Theoretically, their use would be expected to lead to a reduction in complications but, so far, it has not been possible to confirm this.

Stereotactic radiosurgery for hypothalamic hamartomas.

Hypothalamic hamartomas are nonneoplastic lesions often characterized by central precocious puberty and gelastic epilepsy. Due to the delicate location surgery is often unsuccessful and associated with considerable risks. In the presented series, Gamma Knife radiosurgery was applied. Four cases (aged between 5-13 years) who presented with medically intractable gelastic epilepsy and increasing secondary generalization, abnormal behaviour and precocious puberty (3 cases) are reported. Hypothalamic hamartomas sized 11-17 mm had been diagnosed by MR imaging. Radiosurgical treatment was performed in general anaesthesia with margin doses of 12-14 Gy to the 50-90% isodoses covering volumes of 600-2300 mm3. After follow-up periods of 12 to 68 months, a continuing decrease both in seizure frequency and intensity was noted (outcome according to Engel: II a (3 cases) and III a (1 case)). All patients are socially reintegrated. MR imaging did not reveal significant changes concerning the size of the lesions. Gamma Knife radiosurgery can be an effective and safe alternative treatment modality for HH capable of achieving good seizure control and improving behavioural disorders in selected cases.