Medical ethics, logic traps, and game theory: an illustrative tale of brain death.

Decision making and choices are frequent themes in medical ethics. Game theory is based upon modelled decision making. Game theory, and associated logic traps, may have relevance to the clinical practice of medicine and medical ethics. The "prisoner's dilemma" is one logic trap from game theory in which "rational" decision making on the part of participating individuals can lead to "suboptimal" situations. An example of such a situation involving brain death is presented and discussed from the perspective of the prisoner's dilemma.

Clinicopathological features of genetically confirmed Danon disease.

BACKGROUND: Danon disease is due to primary deficiency of lysosome-associated membrane protein-2. OBJECTIVE: To define the clinicopathologic features of Danon disease. METHODS: The features of 20 affected men and 18 affected women in 13 families with genetically confirmed Danon disease were reviewed. RESULTS: All patients had cardiomyopathy, 18 of 20 male patients (90%) and 6 of 18 female patients (33%) had skeletal myopathy, and 14 of 20 male patients (70%) and one of 18 female patients (6%) had mental retardation. Men were affected before age 20 years whereas most affected women developed cardiomyopathy in adulthood. Muscle histology revealed basophilic vacuoles that contain acid phosphatase-positive material within membranes that lack lysosome-associated membrane protein-2. Heart transplantation is the most effective treatment for the otherwise lethal cardiomyopathy. CONCLUSIONS: Danon disease is an X-linked dominant multisystem disorder affecting predominantly cardiac and skeletal muscles.

Delayed diffuse neurodegeneration after cerebral concussion.

A 27-month-old girl developed severe diffuse neurological disability that was progressive between 2 weeks and 2 years after a closed head injury. After stabilization of her disability for 1 year, mild improvement in neurological function began in the third year after the concussion. Multiple imaging studies of the neural axis remained normal during a 5-year period after the initial injury. Delayed and diffuse trauma-induced neuronal apoptosis is a pathogenic mechanism that could explain this unusual neurodegenerative syndrome.

The latency between traumatic axonal injury and the onset of amyotrophic lateral sclerosis in young adult men.

Traumatic axonal injury-induced apoptotic motor neuron cell death in neonatal rats is an established animal model used to study potential therapeutic agents in amyotrophic lateral sclerosis (ALS). In an analogous manner, trauma causing motor neuron axonal injury (which included focal neuropathy, plexopathy, and radiculopathy) preceded the onset of ALS in nine young adult men (age range, 28-43 years). The latency between the traumatic axonal injury and the onset of ALS symptoms in these patients ranged from 5 to 42 months (mean, 14.6 months).

Creutzfeldt-Jakob disease and blood transfusions: a meta-analysis of case-control studies.

A meta-analysis of five published case-control studies that examined the association between previous blood transfusions and Creutzfeld-Jakob disease was performed. The results demonstrated that controls were more likely (p < 0.001, odds ratio = 1.56, 95% confidence interval, 1.22-1.98) to have received previous blood transfusions (18.7%) than Creutzfeld-Jakob disease patients (12.9%), suggesting that selection bias of the control populations had occurred.

Ethanol-mediated CYP1A1/2 induction in rat skeletal muscle tissue.

The causes of non-trauma-mediated rhabdomyolysis are not well understood. It has been speculated that ethanol-associated rhabdomyolysis may be attributed to ethanol induction of skeletal muscle cytochrome P450(s), causing drugs such as acetaminophen or cocaine to be metabolized to myotoxic compounds. To examine this possibility, the hypothesis that feeding ethanol induces cytochrome P450 in skeletal muscle was tested. To this end, rats were fed an ethanol-containing diet and skeletal muscle tissue was assessed for induction of CYP2E1 and CYP1A1/2 by immunohistochemical procedures; liver was examined as a positive control tissue. Enzymatic assays and Western blot analyses were also performed on these tissues. In one feeding system, ethanol-containing diets induced CYP1A1/2 in soleus, plantaris, and diaphragm muscles, with immunohistochemical staining predominantly localized to capillaries surrounding myofibers. Antibodies to CYP2E1 did not react with skeletal muscle tissue from animals receiving a control or ethanol-containing diet. However, neither skeletal muscle CYP1A1/2 nor CYP2E1 was induced when ethanol diets were administered by a different feeding system. Ethanol consumption can induce some cytochrome P450 isoforms in skeletal muscle tissue; however, the mechanism of CYP induction is apparently complex and appears to involve factors in addition to ethanol, per se.

Fulminant peripheral neuropathy with severe quadriparesis associated with vincristine therapy.

OBJECTIVE: To report a case of fulminant neuropathy with severe quadriparesis associated with vincristine chemotherapy. CASE SUMMARY: A 48-year-old white man with acute lymphoblastic leukemia was started on an induction chemotherapeutic regimen that included intravenous vincristine. He received a total of 6 mg of vincristine over two weeks during induction chemotherapy. Over the next two weeks, he developed a fulminant peripheral neuropathy with severe quadriparesis. DISCUSSION: Although commonly associated with peripheral neuropathy, vincristine neurotoxicity only rarely involves instances of fulminant peripheral neuropathy with severe quadriparesis. Guillain-Barré syndrome is also associated with leukemia and may present as a fulminant peripheral neuropathy with severe quadriparesis. CONCLUSIONS: Fulminant neuropathy with severe quadriparesis occurring in patients with leukemia being treated with vincristine (and who do not have coexistent Charcot-Marie-Tooth disease) is more likely due to Guillain-Barré syndrome than to vincristine neurotoxicity.

The biphasic pattern of age-specific malignant brain tumor mortality rates.

Many aging-associated neurologic disorders, including primary malignant brain tumors (MBT), share a common biphasic age-specific mortality rate pattern: initially increasing exponentially with age, and then declining. A modeling study using MBT mortality was conducted to determine if the observed biphasic pattern of MBT age-specific mortality rates emerges if one assumes that there exists a population subset that is inherently susceptible to MBT, and that the risk of mortality from MBT in that susceptible population subset continues to increase exponentially with age. A hypothetical population was subjected to 1988 general mortality risks. A population subset susceptible to MBT was subjected to both exponentially increasing 1988 general and MBT mortality risks. Expected MBT age-specific mortality rates in the total population (both general and MBT susceptible subsets) were determined. Expected MBT age-specific mortality rates in the total population initially increase exponentially with age, and then decline. Moreover, when the size of the MBT-susceptible population subset was set at 1/125 of the size of the general population size, the modeled pattern of age-specific MBT mortality rates closely mimicked the observed pattern of age-specific MBT mortality rates. The observed biphasic pattern of age-specific MBT mortality rates can be explained by the existence of an MBT-susceptible population subset in whom the risk of MBT mortality increases exponentially with age and population subset depletion occurs.

Primary LAMP-2 deficiency causes X-linked vacuolar cardiomyopathy and myopathy (Danon disease).

"Lysosomal glycogen storage disease with normal acid maltase" which was originally described by Danon et al., is characterized clinically by cardiomyopathy, myopathy and variable mental retardation. The pathological hallmark of the disease is intracytoplasmic vacuoles containing autophagic material and glycogen in skeletal and cardiac muscle cells. Sarcolemmal proteins and basal lamina are associated with the vacuolar membranes. Here we report ten unrelated patients, including one of the patients from the original case report, who have primary deficiencies of LAMP-2, a principal lysosomal membrane protein. From these results and the finding that LAMP-2-deficient mice manifest a similar vacuolar cardioskeletal myopathy, we conclude that primary LAMP-2 deficiency is the cause of Danon disease. To our knowledge this is the first example of human cardiopathy-myopathy that is caused by mutations in a lysosomal structural protein rather than an enzymatic protein.

Antibodies to glutamic acid decarboxylase and peripheral nerve function in type 1 diabetes.

Autoimmune mechanisms have been implicated in the pathophysiology of diabetic neuropathy. We studied the association between glutamic acid decarboxylase (GAD65) and islet cell (IA-2) autoantibodies as well as autoantibodies to the autonomic nervous system and peripheral nerve function in recent onset type 1 diabetes. Thirty-seven patients (27 females and 10 males) enrolled 2-22 months after diagnosis. Humoral factors, glycemic control, and peripheral nerve function were measured annually for 3 yr. Patients with high GAD65Ab had worse glycemic control and higher insulin requirements. Patients with high GAD65Ab had slower motor nerve conduction velocities in the median, ulnar, and peroneal nerves (P < 0.025 for each nerve). The mean motor nerve conduction velocity Z scores at the time of the third evaluation was 0.341 +/- 0.25 for the low GAD65Ab patients and -0.600 +/- 0.25 for the high GAD65Ab patients (P < 0.01). Similar differences between the low and high GAD65Ab groups were observed for F wave latencies, thermal threshold detection, and cardiovascular autonomic function. The composite peripheral nerve function Z scores in the low GAD65Ab patients were 0.62 +/- 11, 0.71 +/- 0.19, and 0.21 +/- 0.14 at the first, second, and third evaluations, significantly different from those in the high GAD65Ab patients in whom they were -0.35 +/- 0.15, -0.46 +/- 0.18, and -0.42 +/- 0.16 (P < 0.001). In summary, GAD65Ab in patients with recent onset type 1 diabetes are associated with worse glycemic control and slightly worse peripheral nerve function. Although the latter remained within normal limits and none of the patients had clinical neuropathy, the GAD65Ab-related differences in composite peripheral nerve function were highly significant (P < 0.001) and could not be attributed to GAD65Ab-related differences in glycemic control.

Central pontine myelinolysis: association with parenteral magnesium administration.

A 29-year-old woman with diabetes mellitus and nephrotic syndrome was given 30 g of magnesium sulfate over 14 hours after a cesarian section. Her serum magnesium level increased to 7.4 mg/dl. Five days later, she became quadriplegic with inability to speak or swallow. Cranial magnetic resonance imaging demonstrated central pontine myelinolysis (CPM). Initial serum sodium was not measured. Although CPM is usually associated with a rapid increase in serum osmolality, most patients who experience a rapid increase in serum osmolality do not develop the clinical syndrome of CPM. Consequently, additional factors may also be important in the pathogenesis of CPM. Parenteral magnesium administration may be a potential contributing factor in the pathogenesis of some cases of CPM.

Self-limited recurrent multifocal neurological symptoms, headache, and cerebrospinal fluid lymphocytic pleocytosis: a benign syndrome with a predilection for young adult men.

Two young men, aged 34 and 30 years, developed transient recurrent multifocal neurological symptoms with associated severe headache over a 2-week period. Both had a lymphocytic pleocytosis in their cerebrospinal fluid. Cranial imaging studies were normal. All symptoms resolved without recurrence. Although the cause and pathogenesis are undefined, this self-limited benign neurological syndrome may be more common than previously recognized and has a predilection for young adult men.

Fulminant CNS perivascular lymphocytic proliferation: association with sargramostim, a hematopoietic growth factor.

Sargramostim (GM-CSF) therapy was instituted in a 49-year-old woman with hepatitis C on chronic interferon alpha-2b therapy. Within two weeks, she developed progressive confusion, lethargy, and gait disturbance. At autopsy 4 months later, diffuse perivascular nonmonoclonal lymphoid infiltrates were demonstrated throughout the central nervous system (CNS). As the use of hematopoietic growth factors in clinical practice increases, potential adverse effects, such as the fulminant CNS lymphocytic proliferation in this patient, are more likely to be encountered.

Exertional myalgia syndrome associated with diminished serum ammonia elevation in ischemic exercise testing.

A 36-year-old man with chronic severe exertional myalgias had a normal serum lactate elevation and diminished serum ammonia elevation on an ischemic forearm exercise test (IFET). The IFET is commonly performed in the evaluation of patients with complaints of exertional myalgias, cramps, and rhabdomyolysis. The finding of a normal serum lactate elevation and a diminished serum ammonia elevation after ischemic exercise is usually considered indicative of myoadenylate deaminase deficiency. However, myoadenylate deaminase activity was normal in this man's muscle biopsy specimen. This case suggests that a diminished serum ammonia elevation in the IFET is not always indicative of myoadenylate deaminase deficiency, a disorder of ammonia production. A diminished serum ammonia elevation in the IFET could also reflect an impairment of net ammonia efflux from muscle into blood.

Delayed diffuse upper motor neuron syndrome after compressive thoracic myelopathy.

A 54-year-old man developed progressive spastic paraparesis beginning 2 weeks after a back injury caused by a subacute compressive thoracic myelopathy attributable to a post-traumatic arachnoid cyst. Three to 18 months after surgical decompression of the thoracic arachnoid cyst, the patient developed a diffuse predominantly upper motor neuron syndrome characterized by spastic quadriparesis, pseudobulbar paresis, and pseudobulbar affect. Retrograde corticospinal tract degeneration and upper motor neuron death after spinal cord injury is recognized. This case suggests that focal upper motor neuron injury can occasionally precipitate diffuse upper motor neuron dysfunction.

Myotonia associated with sarcoidosis: marked exacerbation with pravastatin.

A 37-year-old man with sarcoidosis developed severe electrical and clinical myotonia while taking pravastatin for hypercholesterolemia. Myotonia associated with sarcoidosis is rare. Pravastatin is associated with myotonia in animals. This case suggests that sarcoidosis and pravastatin, two entities not frequently associated with myotonia, may interact in a synergistic manner to produce severe clinical myotonia in humans.

Persistent occipital electrographic status epilepticus.

A 13-year-old girl of normal intellect had clinically silent occipital electrographic status epilepticus that persisted for more than 3 years. Neurologic examination and cranial magnetic resonance imaging were entirely normal. [18F]Fluorodeoxyglucose positron emission tomography demonstrated a hypermetabolic focus in the right occipital lobe. Electrographic status lasting years can be seen in epilepsia partialis continua. However, the absence of focal clinical seizures, nonprogressive course, and normal magnetic resonance imaging study seen in this patient are not features characteristic of epilepsia partialis continua.