Decision-making in patients with advanced cancer compared with amyotrophic lateral sclerosis.

AIM: Patients with advanced cancer need information about end-of-life treatment options in order to make informed decisions. Clinicians vary in the frequency with which they initiate these discussions. PATIENTS AND METHODS: As part of a long-term longitudinal study, patients with an expected 2-year survival of less than 50% who had advanced gastrointestinal or lung cancer or amyotrophic lateral sclerosis (ALS) were interviewed. Each patient's medical record was reviewed at enrollment and at 3 months for evidence of the discussion of patient wishes concerning ventilator support, artificial nutrition and hydration (ANH), resuscitation (DNR) and hospice care. A Kaplan-Meier analysis was also performed and 2-year survival calculated. RESULTS: 60 cancer and 32 ALS patients were enrolled. ALS patients were more likely than cancer patients to have evidence of discussion about their wishes for ventilator support (31% vs 0%, p<0.001), ANH (38% vs 0%, p<0.001), DNR (25% vs 0%, p<0.001) and hospice care (22% vs 5%, p = 0.03). At 6 months, 91% of ALS patients were alive compared with 62% of cancer patients; at 2 years, 63% of ALS patients were alive compared with 23% of cancer patients (p<0.001). CONCLUSIONS: Cancer patients were less likely than ALS patients to have had documented advanced care planning discussions despite worse survival. This may reflect perceptions that ALS has a more predictable course, that advanced cancer has a greater number of treatment options, or differing views about hope. Nevertheless, cancer patients may be less adequately prepared for end-of-life decision-making.

Hospitalization in amyotrophic lateral sclerosis: causes, costs, and outcomes.

OBJECTIVE: As ALS progresses, extensive supportive care is required, including multidisciplinary outpatient care and hospitalization. The authors studied the causes, health care utilization, and outcomes for hospitalized patients with ALS. METHODS: With use of the 1996 Nationwide Inpatient Sample, an administrative database representing 20% of U.S. hospitals, 1,600 hospitalizations in patients with ALS were identified and compared with 5,364,728 non-ALS hospitalizations. RESULTS: The most common concurrent diagnoses in patients with ALS were dehydration and malnutrition (574 patients, 36%), pneumonia (507 patients, 32%), and respiratory failure (398 patients, 25%). Only 38% of patients with ALS were discharged to home without home health care compared with 73% of patients with non-ALS. Fifteen percent of patients with ALS died in the hospital compared with 3% of non-ALS patients. The average length of hospital stay and charges were greater for patients with ALS than for non-ALS patients (8.4 days and $19,810 for ALS patients and 5.4 days and $11,924 for non-ALS patients). Mortality was significantly associated with emergency room admission (versus nonemergency admission; OR = 1.60), increasing age (per year; OR = 1.03), respiratory failure (OR = 3.37), and pneumonia (OR = 2.02) (p < 0.01 for all comparisons). CONCLUSIONS: Patients with ALS have lengthy and costly hospital admissions, a high in-hospital mortality rate, and few routine discharges. Recognition of the issues that precipitate hospitalization may allow development of preventive strategies.

The ALS Patient Care Database: insights into end-of-life care in ALS.

OBJECTIVE: To study clinical practices and patient outcomes near the end of life in amyotrophic lateral sclerosis (ALS). BACKGROUND: Patients, families, and healthcare providers face several dilemmas in selecting and delivering care near the end of life in ALS. Published data on clinical practices and their benefits during end-of-life care for ALS patients consist of anecdotal reports based on small case series or individual case reports. METHODS: Data were obtained from 1014 American and Canadian patients with ALS who died while participating in a large observational registry (the ALS Patient Care Database) during the past four years. Following death, a caregiver or family member provided data for each patient using a standard questionnaire. Data were principally generated through American and Canadian ALS multidisciplinary centers of excellence. RESULTS: Most patients died peacefully (90.7%) and 62.4% died in a hospice-supported environment. Advance directives were in place for 88.9% of patients and were followed in 96.8%. Among the 67 patients who exhibited distress in the dying process, symptoms included breathing difficulties (82.1%), fear/anxiety (55.2%), pain (23.9%), insomnia (14.9%), and choking (14.93%). Oxygen was given to 52.6% of patients, and pain medications were given to 74%. CONCLUSION: These data suggest that palliative care at the end of life was relatively well managed for most patients with ALS who participated in this study; nevertheless, several opportunities for improvement were identified.

Aberrant RNA processing in a neurodegenerative disease: the cause for absent EAAT2, a glutamate transporter, in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that is characterized by selective upper and lower motor neuron degeneration, the pathogenesis of which is unknown. About 60%-70% of sporadic ALS patients have a 30%-95% loss of the astroglial glutamate transporter EAAT2 (excitatory amino acid transporter 2) protein in motor cortex and spinal cord. Loss of EAAT2 leads to increased extracellular glutamate and excitotoxic neuronal degeneration. Multiple abnormal EAAT2 mRNAs, including intron-retention and exon-skipping, have now been identified from the affected areas of ALS patients. The aberrant mRNAs were highly abundant and were found only in neuropathologically affected areas of ALS patients but not in other brain regions. They were found in 65% of sporadic ALS patients but were not found in nonneurologic disease or other disease controls. They were also detectable in the cerebrospinal fluid (CSF) of living ALS patients, early in the disease. In vitro expression studies suggest that proteins translated from these aberrant mRNAs may undergo rapid degradation and/ or produce a dominant negative effect on normal EAAT2 resulting in loss of protein and activity. These findings suggest that the loss of EAAT2 in ALS is due to aberrant mRNA and that these aberrant mRNAs could result from RNA processing errors. Aberrant RNA processing could be important in the pathophysiology of neurodegenerative disease and in excitotoxicity. The presence of these mRNA species in ALS CSF may have diagnostic utility.

Pediatricians' pet peeves about mental health referrals.

This chapter has described a number of problems encountered by pediatricians when referring their patients for mental health services; these are related to access to care, quality of providers and service, attitudes of patients and providers, and lack of adequate communication. We have discussed some of the reasons for these difficulties, provided information that may assist pediatricians in making referrals to appropriate mental health providers, and offered suggestions to facilitate the referral process. We have highlighted the utility of developing and maintaining a relationship with mental health referral sources, and noted a number of advantages of including mental health providers in pediatric practices.

Entrapment of motor nerves in motor neuron disease: does double crush occur?

OBJECTIVE: To investigate whether "diseased nerves" are more prone to entrapment neuropathy than normal nerves. Nerve conduction studies of human neuropathies have shown that electrophysiological abnormalities are often most prominent at potential sites of nerve entrapment, and entrapments are more common in patients with radiculopathies--a concept designated as "double crush". As entrapment neuropathies commonly occur in otherwise healthy subjects, it is unclear whether this relation is coincidental or whether peripheral nerves affected by disease are rendered more susceptible to effects of repeated minor trauma, traction, or mechanical compression. METHODS: Sequential ulnar nerve conduction studies were prospectively performed at baseline and at four, eight, and 12 month intervals in 16 patients with amyotrophic lateral sclerosis. Ulnar nerve entrapment was defined as a focal reduction (> 10 m/s) in conduction velocity in the across-elbow segment. RESULTS: Ulnar sensory and motor nerve fibres showed similar findings of ulnar nerve entrapment at baseline and at follow up over the period of the study. Nerves with ulnar nerve entrapment showed a significantly greater reduction in distal motor amplitudes than nerves without entrapment, even though distal ulnar sensory amplitudes remained unchanged. CONCLUSIONS: Motor nerves in motor neuron disease do not seem to be more susceptible to entrapment at the elbow than do healthy sensory nerves, thus casting doubt on the double crush hypothesis. Nerves with double pathology (amyotrophic lateral sclerosis and ulnar nerve entrapment), however, seem to undergo more rapid axonal loss than do nerves with single pathology (amyotrophic lateral sclerosis or ulnar nerve entrapment alone).

Data-gathering tools for "real world" clinical settings: a multisite feasibility study.

OBJECTIVE: To determine the mental health needs and optimal treatments for children and families in "real world" settings, data-gathering strategies are needed that can be easily implemented across a variety of clinical settings. To address this need, the authors developed and piloted a "clinician-friendly" questionnaire that includes demographic, psychosocial, medical, and family history variables, such as those routinely gathered in standard clinical evaluations. METHOD: Optical scanning technology was used to encode data from more than 1,900 children, including 1,458 consecutive referrals in four military child psychiatry clinics, 285 consecutive admissions to a civilian psychiatric state hospital, 71 pediatric patients, and a community sample of 113 children. RESULTS: Despite geographic and logistic obstacles, clinical data were reliably obtained across multiple settings. Data analyses revealed meaningful differences across samples in subjects' presenting complaints, and a range of psychosocial, demographic, and background variables. Data were characterized by an apparently high degree of accuracy and completeness. CONCLUSIONS: Findings illustrate the importance and feasibility of standardized data-gathering approaches in routine clinical settings and clarify the hazards as well as the opportunities afforded by these research approaches. Such data-gathering tools appear to have significant merit and deserve further implementation and testing across a range of clinical and research settings.

Substance abuse and sexual activity in an overseas population of adolescent military dependents.

To determine the incidence of high-risk behaviors, such as substance abuse and sexual activity, in an overseas population of adolescents, and how these rates compared to the general population in the United States, a survey of high school-aged military dependents residing overseas was undertaken. A questionnaire was designed and distributed to all 8th through 12th graders at the Department of Defense Dependent's School in Seoul, Korea. Use of tobacco products and a history of illicit drug use was similar to that of referant groups in the United States. Present use of illicit drugs was decreased. Use of alcohol was increased over that of similar age groups in America. The authors discuss these findings in light of the environmental differences in the overseas military community.

Trial of immunosuppression in amyotrophic lateral sclerosis using total lymphoid irradiation.

Although the cause of amyotrophic lateral sclerosis (ALS) remains unknown, recent studies have suggested an autoimmune mechanism of pathogenesis. Previous trials of immunosuppressive treatment have yielded inconclusive results. Our study was designed to determine whether more powerful and prolonged immunosuppression, produced by total lymphoid irradiation (TLI), would alter the course of ALS. In a double-blind, randomized, placebo-controlled study, 30 patients with classic ALS were treated with TLI, and 31 were given sham radiation. Quantitative measurements of muscle strength, functional motor activity, and humoral and cellular immune status were followed for 2 years, or until death or respirator dependence. Motor function in the TLI-treated and control groups showed no significant differences throughout the study. Overall survival was not significantly different in the TLI-treated and control groups. TLI effectively suppressed cellular and humoral immune function throughout the 2-year study period. Analysis of the relationship between immunosuppression and motor functions showed no consistent effect of treatment. We conclude that powerful and prolonged immunosuppression produced by TLI did not benefit patients with ALS. This fails to support the concept of an autoimmune mechanism of pathogenesis of ALS.

Nerve conduction studies in amyotrophic lateral sclerosis.

Nerve conduction studies (NCS) are an integral part of the evaluation of amyotrophic lateral sclerosis (ALS) patients and are useful in distinguishing ALS from disorders that mimic it. The question often arises whether in the presence of severe atrophy and reduction of the compound muscle action potential amplitude, abnormal conduction velocity (CV), distal latency (DL), or F-wave latency (F) exceeds what can be expected from ALS alone. To determine the limits of abnormality in classic ALS, we prospectively evaluated NCS data from 61 patients who met a strict clinical definition of ALS. We related CV, DL, and F to distal evoked amplitude (AMP) in peroneal (n = 63 observations), median (n = 50), and ulnar (n = 52) nerves. In nerves with reduced AMP, CV rarely fell to less than 80% of the lower limit of normal, and DL and F rarely exceeded 1.25 times the upper limit of normal. Utilizing the entire data set and regression analyses, 95% confidence limits for expected values for CV, F, and DL as a function of AMP were calculated. These limits thus derived suggest criteria for NCS abnormalities in ALS and may be useful in differentiating ALS from other illnesses.

Abnormal excitatory amino acid metabolism in amyotrophic lateral sclerosis.

Recently, the excitatory amino acid neurotransmitter glutamate was implicated in the pathogenesis of a variety of chronic degenerative neurological diseases in humans and animals. This report describes abnormalities in excitatory amino acids in the central nervous system of 18 patients with amyotrophic lateral sclerosis (ALS). The concentration of the excitatory amino acids glutamate and aspartate in the cerebrospinal fluid were increased significantly (p less than 0.01) by 100 to 200% in patients with ALS. Similarly, the concentrations of the excitatory neuropeptide N-acetyl-aspartyl glutamate and its metabolite, N-acetyl-aspartate, were elevated twofold to threefold in the cerebrospinal fluid from the patients. There was no relationship between amino acid concentrations and duration of disease, clinical impairment, or patient age. In the ventral horns of the cervical region of the spinal cord, the level of N-acetyl-aspartyl glutamate and N-acetyl-aspartate was decreased by 60% (p less than 0.05) and 40% (p less than 0.05), respectively, in 8 patients with ALS. Choline acetyltransferase activity was also diminished by 35% in the ventral horn consistent with motor neuron loss. We conclude that excitatory amino acid metabolism is altered in patients with ALS. Based on neurodegenerative disease models, these changes may play a role in motor neuron loss in ALS.

Structure of complex of synthetic HIV-1 protease with a substrate-based inhibitor at 2.3 A resolution.

The structure of a complex between a peptide inhibitor with the sequence N-acetyl-Thr-Ile-Nle-psi[CH2-NH]-Nle-Gln-Arg.amide (Nle, norleucine) with chemically synthesized HIV-1 (human immunodeficiency virus 1) protease was determined at 2.3 A resolution (R factor of 0.176). Despite the symmetric nature of the unliganded enzyme, the asymmetric inhibitor lies in a single orientation and makes extensive interactions at the interface between the two subunits of the homodimeric protein. Compared with the unliganded enzyme, the protein molecule underwent substantial changes, particularly in an extended region corresponding to the "flaps" (residues 35 to 57 in each chain), where backbone movements as large as 7 A are observed.

Conserved folding in retroviral proteases: crystal structure of a synthetic HIV-1 protease.

The rational design of drugs that can inhibit the action of viral proteases depends on obtaining accurate structures of these enzymes. The crystal structure of chemically synthesized HIV-1 protease has been determined at 2.8 angstrom resolution (R factor of 0.184) with the use of a model based on the Rous sarcoma virus protease structure. In this enzymatically active protein, the cysteines were replaced by alpha-amino-n-butyric acid, a nongenetically coded amino acid. This structure, in which all 99 amino acids were located, differs in several important details from that reported previously by others. The interface between the identical subunits forming the active protease dimer is composed of four well-ordered beta strands from both the amino and carboxyl termini and residues 86 to 94 have a helical conformation. The observed arrangement of the dimer interface suggests possible designs for dimerization inhibitors.

Differential effects of prednisone and cyclophosphamide on autoantibodies in human neuromuscular disorders.

We compared the effects of treatment of patients with prednisone or cyclophosphamide on a series of different types of autoantibodies. Levels of antiacetylcholine receptor (anti-AChR) antibodies and of antibodies to GM1 and GD1a gangliosides were measured in patients with a variety of neuromuscular disorders before and after treatment. Most patients had several autoantibodies present. We showed that prednisone treatment resulted in a reduction in titers of anti-AChR but not antiganglioside antibodies. Cyclophosphamide treatment produced a reduction of antiganglioside antibody titers. An intravenous and oral regimen was more effective than a single intravenous course of cyclophosphamide. We conclude that an immunosuppressive medication such as prednisone may reduce levels of some autoantibodies while producing no change in others, even in an individual patient. In addition, cyclophosphamide can suppress autoantibodies that prednisone does not. These differences in immunopharmacologic responses suggest that there are several distinct mechanisms of autoantibody production in humans. The utility of immunosuppressive medications in specific disease processes may be related in part to the mechanism of production of pathogenic antibodies.

Patterns of serum IgM antibodies to GM1 and GD1a gangliosides in amyotrophic lateral sclerosis.

We studied the incidence and clinical correlates of serum antibodies to GM1 and GD1a gangliosides in patients with classical amyotrophic lateral sclerosis (ALS) and other "motor nerve" syndromes. Serum antibodies to GM1 and GD1a gangliosides were measured using enzyme-linked immunosorbent assays. Our results showed that polyclonal immunoglobulin M (IgM) antibodies to the GM1 or GD1a ganglioside or both were present at serum dilutions of 1:25 to 1:4,000 in 78% (57/73) of patients with ALS. Only 8% of normal controls had similar antibodies. The pattern of serum antibody reactivity correlated with the pattern of clinical involvement in our patients. Selective reactivity to GD1a ganglioside was common when upper motor neuron signs were prominent. IgM reactivity to GM1 ganglioside was common in ALS patients with prominent lower motor neuron signs. Most patients with motor neuropathies had serum reactivity to both GM1 and GD1a gangliosides. These results provide further evidence of ongoing autoimmune processes in ALS patients. There is a strong relationship between serum antiganglioside antibodies and patterns of clinical involvement in ALS.

Serum antibodies to GM1 ganglioside in amyotrophic lateral sclerosis.

We report the presence of serum antibodies directed against GM1 ganglioside, a defined neural antigen, in many patients with amyotrophic lateral sclerosis (ALS). We examined serum from a series of patients with well-documented clinical diagnoses. Serum antibodies to GM1 ganglioside were measured using ELISA assays. Our results showed that polyclonal IgM anti-GM1 antibodies were present at dilutions of 1:25 to 1:2,000 in 42 of 74 (57%) patients with ALS. The anti-GM1 antibodies were especially frequent in patients with prominent lower motor neuron signs (41/59; 69%). Few normal controls (2/23) and motor-sensory neuropathy patients (3/27) had similar antibodies. Anti-GM1 antibodies did occur in patients with nonneural autoimmune disorders. However, the anti-GM1 antibodies in these patients tended to differ from those in ALS based on an analysis of their light chain types. Further examination of the role and spectrum of serum antiganglioside antibody activity in motor neuron syndromes is warranted.

Failure of naloxone to reverse clonidine toxic effect.

Acute ingestions of imidazoline compounds, including clonidine hydrochloride, are a recognized clinical entity. The signs and symptoms of this overdose superficially resemble those of opiate intoxication, leading to attempts to reverse this poisoning with naloxone hydrochloride. Despite previous descriptions of success using naloxone in acute clonidine poisoning, five cases of acute pediatric ingestions of clonidine ranging from mild to severe occurred in which naloxone hydrochloride in doses up to 0.1 mg/kg was unsuccessful in reversing the signs and symptoms of this intoxicant. Although naloxone can be safely administered to children who ingest clonidine to distinguish them from those who are intoxicated by opiates, it is not therapeutically useful to use naloxone to reverse poisoning with this class of agents.