Practice parameter update: the care of the patient with amyotrophic lateral sclerosis: multidisciplinary care, symptom management, and cognitive/behavioral impairment (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology.

OBJECTIVE: To systematically review evidence bearing on the management of patients with amyotrophic lateral sclerosis (ALS). METHODS: The authors analyzed studies from 1998 to 2007 to update the 1999 practice parameter. Topics covered in this section include breaking the news, multidisciplinary clinics, symptom management, cognitive and behavioral impairment, communication, and palliative care for patients with ALS. RESULTS: The authors identified 2 Class I studies, 8 Class II studies, and 30 Class III studies in ALS, but many important areas have been little studied. More high-quality, controlled studies of symptomatic therapies and palliative care are needed to guide management and assess outcomes in patients with ALS. RECOMMENDATIONS: Multidisciplinary clinic referral should be considered for managing patients with ALS to optimize health care delivery and prolong survival (Level B) and may be considered to enhance quality of life (Level C). For the treatment of refractory sialorrhea, botulinum toxin B should be considered (Level B) and low-dose radiation therapy to the salivary glands may be considered (Level C). For treatment of pseudobulbar affect, dextromethorphan and quinidine should be considered if approved by the US Food and Drug Administration (Level B). For patients who develop fatigue while taking riluzole, withholding the drug may be considered (Level C). Because many patients with ALS demonstrate cognitive impairment, which in some cases meets criteria for dementia, screening for cognitive and behavioral impairment should be considered in patients with ALS (Level B). Other management strategies all lack strong evidence.

Mutations in the FUS/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a fatal degenerative motor neuron disorder. Ten percent of cases are inherited; most involve unidentified genes. We report here 13 mutations in the fused in sarcoma/translated in liposarcoma (FUS/TLS) gene on chromosome 16 that were specific for familial ALS. The FUS/TLS protein binds to RNA, functions in diverse processes, and is normally located predominantly in the nucleus. In contrast, the mutant forms of FUS/TLS accumulated in the cytoplasm of neurons, a pathology that is similar to that of the gene TAR DNA-binding protein 43 (TDP43), whose mutations also cause ALS. Neuronal cytoplasmic protein aggregation and defective RNA metabolism thus appear to be common pathogenic mechanisms involved in ALS and possibly in other neurodegenerative disorders.

A retrospective study of percutaneous endoscopic gastrostomy in ALS patients during the BDNF and CNTF trials.

Percutaneous endoscopic gastrostomy (PEG) provides a reliable route for nutrition and hydration in ALS patients with dysphagia. We performed a retrospective analysis of the CNTF and BDNF databases to determine the clinical status of ALS patients within 30 days preceding PEG insertion. This analysis revealed an approximately 50% reduction of function across multiple measures of ALS disease status. A trend to earlier intervention with PEG was apparent upon review of published studies and the CNTF and BDNF studies. By comparing the rate of decline pre- and post-PEG, nutritional supplementation via PEG stabilized the weight loss experienced by patients. Death within 30 days post-PEG was associated with a marked reduction in forced vital capacity (FVC) and identified a group of ALS patients in whom PEG should be cautiously performed. These data emphasize the importance of sequential measurement of FVC in managing ALS patients to guide the timing of nutritional intervention with PEG.

An intronic NF-kappaB element is essential for induction of the human manganese superoxide dismutase gene by tumor necrosis factor-alpha and interleukin-1beta.

Tumor necrosis factor-alpha (TNF) and interleukin-1beta (IL-1) are cytokines that induce expression of various genes through activation of the redox-sensitive transcription factor nuclear factor-kappaB (NF-kappaB). We have previously cloned the entire human MnSOD (SOD2) gene and found several NF-kappaB-binding sites in the 5' and 3' flanking and intronic regions. To test whether these putative NF-kappaB-binding sites are able to respond to TNF and IL-1, we performed induction analysis using various deletion constructs ligated to a luciferase reporter gene. We found that the 5' and 3' flanking regions containing several NF-kappaB-binding sites do not mediate MnSOD induction by TNF or IL-1. When a 342-bp intron 2 fragment containing NF-kappaB, C/EBP, and NF-1 binding sites was linked to the basal promoter of the SOD2 gene, transcriptional activities were significantly increased in response to TNF and IL-1 in an orientation- and position-independent manner. To accurately identify the element that is most critical for the enhancer activity, deletions and specific mutations of each individual site were studied. The results indicated that the NF-kappaB binding site is essential but not sufficient for TNF- or IL-1-mediated induction. Furthermore, NF-kappaB elements in the 5' and 3' flanking regions could be made to function in TNF or IL-1 induction when they were transposed to the intronic fragment. Taken together, these results suggest that an NF-kappaB element and its location in the SOD2 gene is critical for TNF/IL-1-mediated induction. However, a complex interaction between NF-kappaB and other transcription elements is needed for a high-level induction.

Mutations in the promoter reveal a cause for the reduced expression of the human manganese superoxide dismutase gene in cancer cells.

Manganese superoxide dismutase (MnSOD) has been shown to play an important role in preventing the development of cancer. MnSOD activity is reduced in many transformed cells and tumor tissues. We previously showed that the reduced level of MnSOD activity in cancer cells was not due to a defect in the primary structure of MnSOD protein, but rather was due to defects in gene expression. To elucidate the cause for the reduced expression of human MnSOD in cancer, we investigated the nucleotide sequence in the regulatory region of the MnSOD gene in a normal human cell line and various human tumor cell lines. A DNA fragment spanning 3.4 kb 5' flanking region of the MnSOD gene isolated from a normal human genomic DNA library was used to determine the DNA sequence of MnSOD promoter. PCR primers were used for amplification of the 3.4 kb 5' flanking region of the human MnSOD gene in cancer cells. Sequence analysis identified three heterozygous mutations in the proximal region of the promoter in five human tumor cell lines. These mutations, clustered around the GC-rich region of the human MnSOD promoter, change the binding pattern of AP-2 and lead to a reduction in transcription activity using a luciferase reporter assay system. These results suggest that the reduced level of MnSOD expression in some tumor cells is, at least in part, due to a defect in the DNA sequence of the promoter region.

Aluminum, calcium, and iron in the spinal cord of patients with sporadic amyotrophic lateral sclerosis using laser microprobe mass spectroscopy: a preliminary study.

We measured aluminum (Al), calcium (Ca), and iron (Fe) levels in neuronal cytoplasm and nucleus, capillaries, and neuropil in samples of ventral cervical spinal cord from 5 patients with sporadic amyotrophic lateral sclerosis (ALS) and 5 age-matched controls using laser microprobe mass spectrometry (LMMS). The concentration of Al was not altered in any area in the ALS samples. In contrast, Fe and Ca were increased 1.5-2-fold in the nucleus and cytoplasm of ALS neurons but not in capillaries and neuropil. These findings do not support the hypothesis that Al is enriched in spinal cord of sporadic ALS as has been reported for Guamanian ALS/Parkinson's dementia. The elevations of Fe in spinal neurons are consistent with reports of increased Fe in bulk samples of ALS spinal cord. The presence of increased Fe within spinal neurons may be significant in the pathogenesis of motor neuron degeneration by catalyzing the generation of reactive oxygen species within specific cells.

Embolic stroke from cardiac papillary fibroelastomas.

We describe two patients with cerebral emboli originating from a cardiac papillary fibroelastoma and compared them with six patients reported in the literature. Surgical excision was curative in both of our patients. The surface topography of the tumor, as visualized by scanning electron microscopy, is described.

Cerebellar hemangioblastoma symptomatic during pregnancy.

An 18-year-old woman presented during the 2nd month of her pregnancy with noncommunicating hydrocephalus due to a cerebellar hemangioblastoma. The tumor rapidly enlarged over a 12-day period after ventriculoperitoneal shunting, probably because of expansion of the vascular compartment. Serial computed tomography and magnetic resonance imaging observations support previous speculations in the literature that vascular engorgement of hemangioblastomas probably accounts for the rapid deterioration of some patients during pregnancy.

Amygdalar kindling is associated with elevated zinc concentration in the cortex and hippocampus of rats.

The reported convulsant properties of zinc and its association with hippocampal function prompted investigation of zinc levels during the induction and maintenance of kindling. Rats were fed zinc adequate diets during kindling, incited by daily amygdalar stimulation. The concentration of zinc in hippocampus was unperturbed during 3 stages of kindling induction when compared to either naive, sham surgery, or electroshock controls. In contrast, cortical zinc increased during kindling induction but returned to control levels in fully kindled animals. Two weeks after full kindling was established, the concentration of zinc in the hippocampus and overlying cortex increased significantly, in the absence of further electrical stimulation. The effect was restricted to the central nervous system inasmuch as zinc levels were unaffected in liver and other extracerebral tissues. Moreover, the zinc concentration was relatively unchanged during the 24 h period following a single electroconvulsive seizure, implying that the observed changes were not simply a postictal phenomenon. The results of this study suggest that long-lasting elevations in zinc are present after kindling is established. Whether this finding is related to the perpetuation of abnormal neuronal excitability or represents a compensatory response remains to be elucidated.

A method for enriching the cadmium content of cigarette smoke and effect of exposure to this smoke on coronary vascular reactivity in the rat.

To study the effect of smoke-borne cadmium on the cardiovascular system, a method was developed to vary the cadmium content in the smoke of Kentucky 2R1 reference cigarettes. 2R1 filler tobacco was sprayed with aqueous solutions of CdSO4; cigarettes were prepared from this tobacco and smoked through Cambridge filters. These treatments increased the cadmium content of the cigarette smoke from 0.23 +/- 0.01 micrograms Cd/2R1 cigarette to 0.317 +/- 0.029, 2.38 +/- 0.092, and 4.9 +/- 0.1 micrograms Cd/cigarette for 500 microM, and 50 mM CdSO4, respectively. Male Sprague-Dawley rats were exposed for 5 or 23 weeks to smoke from 2R1 reference cigarettes and cigarettes prepared from 2R1 tobacco that was treated with 500 microM CdSO4. Following 5 weeks of smoke exposure, neither kidney cadmium amount nor coronary vascular reactivity to angiotensin was altered in either smoke-exposed group compared to cage controls or sham-smoked animals. After 23 weeks of exposure, cadmium amounts in kidneys from animals exposed to cadmium-enriched smoke were significantly greater than quantities observed in any other group. Exposure to either type of cigarette smoke increased coronary vascular reactivity above either control group. Exposure to cadmium-enriched cigarette smoke increased coronary vascular reactivity to angiotensin above the amount observed following exposure to 2R1 cigarette smoke. This finding indicates that smoke-borne cadmium may mediate the observed increases in coronary vascular reactivity following exposure to cigarette smoke.

Functional consequences of zinc deficiency.

Zinc is an essential trace element necessary for over 200 zinc metalloenzymes and required for normal nucleic acid, protein, and membrane metabolism. During the past two decades there has been a rapid expansion of knowledge concerning zinc metabolism in both normal and disease situations, including mechanisms for zinc absorption, excretion and internal redistribution of zinc after stress or trauma. Acrodermatitis enteropathica has been recognized to be a disease of impaired zinc absorption in man. A host of disease processes now are recognized to be complicated by zinc deficiency including alcoholic liver disease, sickle cell anemia, protein calorie malnutrition, and a variety of intestinal diseases including Crohn's disease, sprue, short bowel syndrome and after jejunal ileal bypass. Zinc has proved to be an extremely interesting mineral to nutritionists and physicians because of its importance in normal physiology and biochemistry and because of the diverse presenting features of zinc deficiency. This paper reviews ten functional consequences of zinc deficiency and emphasizes certain consequences in which there have been new discoveries concerning their mechanism (e.g., anorexia) or their clinical importance (e.g., immune dysfunction).