From Antiquity to the N-Methyl-D-Aspartate Receptor: A History of Delirium Tremens.

Delirium associated with excessive alcohol consumption has been known since antiquity. This condition became more common as the supply of distilled fermented liquors increased. Delirium, including delirium associated with excessive alcohol consumption, was for many centuries regarded as a form of brain inflammation - "phrenitis" - and was treated with depletion. At the end of the eighteenth century treatment by depletion of alcohol-related delirium began to be replaced by sedation and led to significantly better outcomes. Thomas Sutton established that alcohol-related delirium was a disease sui generis, distinct from phrenitis, and he named it delirium tremens. Because historical accounts of this disease are rare, brief, and not easily accessible, we offer this account of events that culminated in the discovery of the molecular basis of delirium tremens.

Ischemic stroke associated with activated protein C resistance and aortic valvular papillary fibroelastoma.

We report an unusual case of a pontine ischemic stroke associated with activated protein C resistance as well as an embolic source in the form of a cardiac valvular lesion. A 31-year-old man had a sudden onset of right hemiparesis and a severe dysarthria. Cranial magnetic resonance imaging (MRI) showed a nonhemorrhagic pontine lesion with essentially negative craniocervical MR angiography. His transesophageal echocardiogram showed a papillary fibroelastoma on the aortic valve. His laboratory studies showed significant activated protein C resistance at 1.7 (normal, >2.1). Other laboratory parameters, including sedimentation rate, were unremarkable. This case suggests that activated protein C resistance may serve as a cofactor in some cases of ischemic stroke, particularly stroke associated with emboligenic cardiac lesions.

Differentiation of acute cortical and subcortical ischemic stroke by risk factors and clinical examination findings.

BACKGROUND: Differentiation between acute cortical and subcortical ischemic stroke may be problematic when cortical stroke presents without obvious cortical deficits such as aphasia, neglect or hemianopia. This study explores stroke risk factors and clinical variables that may assist in this differentiation. METHODS: Records of consecutive patients with acute ischemic stroke, examined within 72 h of symptom onset, were reviewed. Stroke type was verified by clinical course and follow-up imaging. Stroke risk factors and acute examination findings were compared by odds ratios and positive predictive values for cortical and subcortical stroke. RESULTS: For 355 patients studied, 237 had cortical stroke and 118 had subcortical stroke. Odds ratios for cortical stroke were highest for atrial fibrillation by EKG (OR = 4.77, CI = 2.08-10.94), recent hospitalization (OR = 4.51, CI = 2.39-8.53) and nonalert mental status (OR = 4.50, CI = 2.29-8.87). Possible cardioembolic condition, ischemic heart disease and peripheral vascular disease were also significant, but hypertension, age and diabetes mellitus were not significantly different for the stroke subtypes. Cortical deficits were absent in 19.4% of cortical stroke patients on initial examination. Predictive models were generated based on the presence or absence of cortical deficits and the interaction of significant risk factors with degree of motor deficit. CONCLUSIONS: There are clinical features that, in addition to initial examination, may help differentiate cortical from subcortical ischemic stroke. These features may be relevant to both diagnostic and therapeutic approaches to acute stroke.

Cerebral venous thrombosis and activated protein C resistance.

BACKGROUND: Activated protein C resistance (APC-R) due to factor V Leiden has recently been established as an important risk factor for cerebral venous thrombosis (CVT). The clinical significance of abnormal or borderline functional APC-R in the absence of factor V Leiden is uncertain. Our observations suggest that APC-R due to mechanisms other than factor V Leiden may also contribute to the development of CVT. CASE DESCRIPTIONS: We describe three women who had superior sagittal and lateral sinus thrombosis while taking oral contraceptives and had a number of additional risk factors for CVT. Each had APC-R for different reasons. CONCLUSIONS: Inherited thrombophilia, including APC-R, should be looked for in all patients with CVT. Functional APC-R is a highly prevalent coagulopathy, but the reasons for this abnormality are diverse; abnormal and borderline functional APC-R results should be supplemented by DNA analysis for the presence of factor V Leiden.

Botulinum toxin--a possible new treatment for axillary hyperhidrosis.

The inhibitory action of botulinum toxin is not limited to the neuromuscular junction. The toxin also blocks the autonomic cholinergic fibres, including the sympathetic fibres to sweat glands. We have previously demonstrated that the toxin produces localized anhidrosis. To determine the dosage, pattern and duration of the anhidrotic effect of botulinum toxin and to test the efficacy of axillary injections, we further studied seven healthy volunteers. Two individuals had subcutaneous injections of botulinum toxin (20 mouse units, Dysport-Porton Products) in the dorsum of the hand. Five healthy volunteers had 15-50U of botulinum toxin A (Botox) injected in one axilla. A circular area of complete anhidrosis on the dorsum of the hand was evident on day 2 and persisted for 11 months. By day 3, two of the axillae (injected with 50 U each) were totally dry and in one (injected with 30 U) the sweating was substantially reduced. The effect persisted for 6-8 months before wearing off. No effect was appreciated in two axillae (injected with 15 and 20 U). No significant side-effects were encountered. Subcutaneous injections of botulinum toxin causes chemodenervation of the sweat glands. In normal individuals axillary sweating can be abolished by 50 U of botulinum toxin A (Botox). The results offer a possible novel treatment for severe cases of axillary hyperhidrosis.

Sarcoidosis of the spinal cord with extensive vertebral involvement: a case report.

We report on a patient with systemic sarcoidosis who was presented with myelopathy and backache. Plain spinal films were normal, CT scan showed sclerotic lesions within the vertebrae. MRI showed more extensive involvement of the spine with multiple vertebral lesions which were hypointense on both T1W1 and T2W1 and did not enhance with gadolinium. MRI also showed high signal lesions within the cervical and lumbar spinal cord on T2-weighted images (T2W1) which were isointense on T1-weighted images (T1W1) and did not enhance. Vertebral biopsy results were consistent with the diagnosis of sarcoidosis. MRI is very sensitive in detecting sarcoidosis of bone but non-specific and other types of sclerotic or lytic bone lesions (notably metastases) need to be excluded.

Acute myopathy with selective degeneration of myosin filaments following status asthmaticus treated with methylprednisolone and vecuronium.

We report two cases of severe, acute myopathy with selective degeneration of myosin filaments in asthmatics who developed respiratory failure with hypercapnia and acidosis requiring endotracheal intubation, administration of vecuronium and prolonged ventilatory support. Hypoxia was documented in one case and probably present in the other. Both patients received prolonged treatment with high doses of intravenous methylprednisolone. Flaccid quadriparesis was noted after discontinuation of vecuronium. Muscle biopsy showed nonspecific myopathic changes on light microscopy. Electron microscopy revealed selective loss of myosin filaments in many fibers. Recovery occurred within 2 months with supportive treatment. This entity is probably related to a combination of high doses of corticosteroids, vecuronium administration and metabolic abnormalities associated with respiratory failure.

Cerebral venous thrombosis with plasminogen deficiency.

We describe a patient with inherited plasminogen deficiency who developed extensive cerebral venous thrombosis. Several other conditions that might have contributed to a hypercoagulable state, including mild thrombocytosis, thyrotoxicosis, and a chronic inflammatory lung disorder, were present. We also discuss the evidence linking plasminogen deficiency with a thrombophilic state. The diagnosis of cerebral venous thrombosis in this case was readily established by nuclear magnetic resonance imaging, a technique that is ideally suited for the evaluation and follow-up of patients with this condition.

Cerebral venous thrombosis due to heparin-induced thrombocytopenia.

A patient with polycythemia vera who was treated with heparin for superficial septic thrombophlebitis developed heparin-induced thrombocytopenia and cerebral venous thrombosis with superior sagittal sinus occlusion 11 days after the institution of heparin therapy. We suggest that the severe thrombotic response to the heparin-induced platelet disorder in this patient occurred because the polycythemia vera and the purulent infection enhanced the thrombophilia caused by heparin-induced thrombocytopenia. This condition can be avoided in most instances if heparin is used for no longer than 5 days.

Elevated calmodulin levels and reduced calmodulin-stimulated calcium-ATPase in Duchenne progressive muscular dystrophy.

We determined the calmodulin concentration and Ca2+-ATPase activity in subcellular fractions recovered from samples of vastus lateralis muscle obtained from 18 patients with Duchenne muscular dystrophy, 10 patients with other primary myopathies, 5 with spinal muscular atrophy, and 16 age-matched controls. Calmodulin levels were increased in the cytosol, plasmalemma, and heavy sarcoplasmic reticulum fractions from Duchenne dystrophy patients; the greatest increases occurred at early stages of disease or in mildly progressive cases. The total Ca2+-ATPase activities were decreased in the Duchenne dystrophy muscles; calmodulin caused a minimal stimulation of the activity in calmodulin-depleted membranes from Duchenne dystrophy compared with control membranes. The changes in calmodulin concentration and Ca2+-ATPase activity complement previous observations of reduced calsequestrin and dystrophin concentrations in Duchenne dystrophy muscles and suggest that these muscles lose calcium regulatory functions at early stages of the disease process.

Periodic hyperammonemic encephalopathy associated with a ureterosigmoidostomy.

Ureterosigmoidostomy, a urinary diversion procedure performed for treatment congenital urologic defects or bladder cancer, may be associated with hyperammonemia. A delayed periodic encephalopathy, characterized by dysarthria, ataxia, and coma, developed in a 44-year-old woman who had undergone this procedure. Hyperammonemia-associated neurotoxicity resolved after surgical revision of the ureterosigmoidostomy to a uretero-ileostomy. Therefore, a treatable episodic encephalopathy may occur in association with hyperammonemia in patients who have undergone ureterosigmoidostomy.

"Eight-drugs-in-one-day" chemotherapy administered before and after radiotherapy to adult patients with malignant gliomas.

Thirty-one adult patients with malignant glioma (23 with glioblastoma multiforme, six with anaplastic astrocytoma, and two with brainstem glioma) were treated with up to ten cycles of "eight-drugs-in-one-day" chemotherapy (methylprednisolone 300 mg/m2, vincristine 1.5 mg/m2 [maximum of 2 mg/cycle], CCNU 75 mg/m2, procarbazine 75 mg/m2, hydroxyurea 3000 mg/m2, cisplatin 90 mg/m2, cytosine arabinoside 300 mg/m2, and imidazole carboxamide 150 mg/m2). Chemotherapy was planned as two cycles before and eight cycles after 60 Gy of involved brain irradiation. A total of 117 cycles of chemotherapy was administered. There was one treatment-related death. Myelosuppression was the most frequent toxic effect (leucopenia was less than 1000/mm3 in 9% of cycles and 1000-2500/mm3 in 25%; thrombocytopenia was less than 100,000/mm3 in 33% of cycles). Sixteen patients developed infections requiring treatment, two of which were life-threatening. Five patients suffered ototoxicity. Nausea and vomiting were observed in 35% of patients. A reversible rise in creatinine was observed in five patients. One patient developed a severe motor neuropathy, and three patients developed mild peripheral neuropathies. Three patients had episodes of atrial fibrillation. One new bundle branch block with supraventricular tachycardia was observed in a patient with pulmonary embolus. Five patients developed thrombophlebitis, three of whom had pulmonary emboli. Two patients suffered strokes in areas anatomically separate from their tumor. Eleven patients declined to continue therapy after receiving an average of three cycles. Two had complete, and five had partial responses. The median survival time was 47 weeks. The responses and survival times observed are comparable to less toxic treatment protocols for adults with malignant gliomas.

Proteins of muscle subcellular fractions in Duchenne progressive muscular dystrophy stained with "stains-all" cationic carbocyanine dye and with Coomassie Blue.

The protein compositions of subcellular fractions of muscle obtained from 17 Duchenne dystrophy patients, 15 disease controls (10 different primary myopathies, 5 spinal muscular atrophy patients), and 10 normals were examined by polyacrylamide gel electrophoresis. The gels were stained with Coomassie Brilliant Blue and with "Stains-all," which stains calcium-binding proteins, sialic acid-rich glycoproteins, and phosphoproteins. In muscle membrane fractions of Duchenne dystrophy patients there was a marked reduction in the concentrations of calsequestrin and a 39 kDa protein that stained blue with "Stains-all." There were changes in the proteins of all subcellular fractions of Duchenne's patients; some of these changes appear to be specific for Duchenne dystrophy (DD). There was no apparent correlation between the protein changes observed on acrylamide gels and the age of the patients, the duration of the disease, the degree of disability, or activity of creatine kinase. A decreased level of calsequestrin in DD sarcoplasmic reticulum may contribute to an increased level of free calcium seen in muscle from these patients.

Eight-drugs-in-one-day chemotherapy in postirradiated adult patients with malignant gliomas.

Fifteen patients, 12 with glioblastoma multiforme and 3 with anaplastic astrocytoma, were treated with "eight-drugs-in-one-day" chemotherapy [methylprednisolone 300 mg/m2, vincristine 1.5 mg/m2 (maximum of 2 mg/cycle), CCNU 75 mg/m2, procarbazine 75 mg/m2, hydroxyurea 3,000 mg/m2, cisplatin 90 mg/m2, cytosine arabinoside 300 mg/m2, and imidazole carboxamide 150 mg/m2]. All patients had prior brain irradiation but none had previous chemotherapy. The population included 10 patients with progressive disease after irradiation and 5 who presented within 2 months of completing radiation. Patients received an average of 5 monthly cycles of chemotherapy. Three patients achieved a complete and 2 a partial response (CR + PRrate was 33%). The median survival time was 46 weeks. Myelosuppression was the dose-limiting toxicity. Leucocyte counts between 2.0-4.5 x 10(3)/mm3 were observed in 40% of patients, between 1.0- less than 2.0 x 10(3)/mm3 in 33%, and less than 1.0 x 10(3)/mm3 in 7%. Platelet counts between 50-130 x 10(3)/mm3 were observed in 27% of patients, and less than 50 x 10(3)/mm3 in 33%. Six patients suffered infections, 4 had reversible renal toxicity, 2 developed paresthesias, and one a debilitating myopathy related to treatment with dexamethasone. Ototoxicity was seen in 3 patients. Two patients developed pulmonary emboli. Nine patients had nausea and vomiting, in one case associated with Candida esophagitis. One long-term survivor developed necrosis of the corpus callosum and dementia. Four patients discontinued treatment after an average of 3.5 cycles because of toxicity. Although extremely toxic, this regimen has modest activity in previously irradiated adult patients with malignant glioma.

Anti-neurofilament antibodies in the sera of patients with small cell carcinoma of the lung and with visual paraneoplastic syndrome.

The sera of patients with small cell carcinoma of the lung (SCCL) and an associated visual paraneoplastic syndrome (VPNS) have high titer immunoglobulins that react with retinal ganglion cells and with cloned lines of the SCCL. The immunoglobulins in the sera of two patients with SCCL and VPNS reacted with at least one common antigen shared by neural cells and cloned lines of the SCCL. The molecular weights of the predominant neural and tumor antigens were 205,000, 145,000, 65,000, and 20,000-24,000 as determined by Western blots. Three of the antigens from neural tissue copurify and comigrate electrophoretically with neurofilament proteins. Polyclonal antibodies prepared against authentic neurofilament proteins react with antigens having molecular weights identical to those of proteins that react with immunoglobulins from the SCCL-VPNS patients. Polyclonal antibodies that were prepared against isolated retinal ganglion cells and that were shown previously to cause the immunoablation of the ganglion cells in vivo reacted most intensely with the Mr 205,000 antigen and weakly with the Mr 145,000 and Mr 70,000 antigens. Treatment of the Western blots with alkaline phosphatase from Escherichia coli did not affect the immunoreactivity between the immunoglobulins and the purified neurofilament proteins. It is proposed that the immunoglobulins in the sera of patients with SCCL-VPNS may be involved etiologically in the development of the VPNS.