Edward J. Kasarskis

Practice parameter: The care of the patient with amyotrophic lateral sclerosis (an evidence-based review) Report of the Quality Standards Subcommittee of the American Academy of Neurology

Mission statement. The Quality Standards Subcommittee (QSS) of the American Academy of Neurology (AAN) is charged with developing practice parameters for physicians. This evidence-based review addresses some of the major management issues in patients with ALS, and highlights the many areas in which more research is needed. ALS is a progressive, degenerative motor neuron disease of unknown cause. Muscle atrophy and spasticity in limb and bulbar muscles result in weakness and loss of ambulation, oropharyngeal dysfunction, weight loss, and ultimately respiratory failure. Although advances in understanding the pathophysiology of ALS have stimulated the development of new drug therapies,1 the mainstay of treatment for ALS patients remains symptomatic management. The practice parameters presented here comprise the first recommendations for the management of ALS based on a prescribed review and analysis of the peer-reviewed literature. These practice parameters were developed to improve the care and the quality of life of people with ALS by providing a rational basis for managing the disease. A multidisciplinary task force, all with extensive ALS experience, included 19 physicians, 3 patients with ALS, 1 gastroenterologist, 1 pulmonologist, 1 occupational therapist whose mother has ALS, and 1 nurse. In addition, consultants with expertise on ethics, practice parameter development, and medical library research participated in the process. The task force agreed to investigate five areas: 1) informing the patient and the family about the diagnosis and prognosis (also called “breaking the news”) of ALS; 2) symptomatic treatment; 3) nutrition, and decisions about percutaneous endoscopic gastroscopy (PEG); 4) respiratory insufficiency and mechanical ventilation; and 5) advance directives and palliative care. To help achieve this goal, they developed several guiding principles or attributes of care: Principles of ALS management

Practice Parameter update: The care of the patient with amyotrophic lateral sclerosis: Drug, nutritional, and respiratory therapies (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 slowing disease progression, nutrition, and respiratory management for patients with ALS. Results: The authors identified 8 Class I studies, 5 Class II studies, and 43 Class III studies in ALS. Important treatments are available for patients with ALS that are underutilized. Noninvasive ventilation (NIV), percutaneous endoscopic gastrostomy (PEG), and riluzole are particularly important and have the best evidence. More studies are needed to examine the best tests of respiratory function in ALS, as well as the optimal time for starting PEG, the impact of PEG on quality of life and survival, and the effect of vitamins and supplements on ALS. Recommendations: Riluzole should be offered to slow disease progression (Level A). PEG should be considered to stabilize weight and to prolong survival in patients with ALS (Level B). NIV should be considered to treat respiratory insufficiency in order to lengthen survival (Level B), and may be considered to slow the decline of forced vital capacity (Level C) and improve quality of life (Level C). Early initiation of NIV may increase compliance (Level C), and insufflation/exsufflation may be considered to help clear secretions (Level C).

Practice parameter: The care of the patient with amyotrophic lateral sclerosis (An evidence-based review)

Neurology E. A. Oppenheimer Borasio, W. G. Bradley, M. B. Bromberg, B. R. Brooks, E. J. Kasarskis, T. L. Munsat and R. G. Miller, J. A. Rosenberg, D. F. Gelinas, H. Mitsumoto, D. Newman, R. Sufit, G. D. American Academy of Neurology evidence-based review): Report of the Quality Standards Subcommittee of the Practice parameter: The care of the patient with amyotrophic lateral sclerosis (an This information is current as of August 7, 2006 http://www.neurology.org/cgi/content/full/52/7/1311 the World Wide Web at: The online version of this article, along with updated information and services, is located on ISSN: 0028-3878. Online ISSN: 1526-632X. Print published continuously since 1951. Copyright

Rapid-onset dystonia-parkinsonism.

We studied a large family with a previously undescribed, autosomal dominant dystonia-parkinsonism syndrome. We chose to call the disorder “rapid-onset dystonia-parkinsonism” (RDP) based on the unusually rapid evolution of signs and symptoms. Affected individuals developed dystonia and parkinsonism between 14 and 45 years of age. The onset was acute in six individuals with the abrupt onset of symptoms over the course of several hours, and subacute in four others who had evolution over several days or weeks. Thereafter, progression of symptoms was usually very slow. Two had intermittent focal dystonia without parkinsonism, and one obligate gene carrier was asymptomatic at 68 years. CSF levels of homovanillic acid were decreased in the two individuals tested, but dopaminergic therapy provided only slight benefit. The DYT1 gene responsible for early-onset, generalized idiopathic torsion dystonia in Jewish and some non-Jewish families has been mapped to chromosome 9q34. Linkage analysis with three markers near the DYT1 gene showed several obligate recombinations, excluding DYT1 as a candidate gene for RDP. We believe RDP is unique and should be classified separately from other forms of hereditary dystonia-parkinsonism.

Phase II trial of CoQ10 for ALS finds insufficient evidence to justify phase III

Amyotrophic lateral sclerosis (ALS) is a devastating, and currently incurable, neuromuscular disease in which oxidative stress and mitochondrial impairment are contributing to neuronal loss. Coenzyme Q10 (CoQ10), an antioxidant and mitochondrial cofactor, has shown promise in ALS transgenic mice, and in clinical trials for neurodegenerative diseases other than ALS. Our aims were to choose between two high doses of CoQ10 for ALS, and to determine if it merits testing in a Phase III clinical trial.

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.

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/Parkinsons 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.

Motor neurons are rich in non-phosphorylated neurofilaments: cross-species comparison and alterations in ALS

The localization and distribution of non-phosphorylated neurofilaments (NP-NF) in the upper and lower motor neurons was investigated in the rat, the common marmoset, the rhesus monkey and man using the SMI-32 antibody. Within the spinal cord of all species studied, the most intense NP-NF immunoreactivity was observed within the ventral horn alpha-motor neurons. Concurrent staining for the cholinergic marker choline acetyltransferase (ChAT) demonstrated that virtually all of the ChAT-positive alpha-motor neurons contain NP-NF immunoreactivity. Although NP-NF staining was also observed in other neurons within the ventral and intermediate horns, these neurons were loosely scattered and contained a considerably lower staining intensity. The only other prominent NP-NF staining in the spinal cord occurred within the neurons of the dorsal nucleus of Clark and the intermediolateral cell column. Phosphorylated neurofilament (P-NF) immunoreactivity was found primarily in neuronal processes. Occasionally, a solitary motor neuron contained weak P-NF immunoreactivity. Within the brainstem, neurons in all cranial nerve motor nuclei contained intense NP-NF immunoreactivity. The distribution and apparent density of NP-NF immunoreactive neurons in these nuclei was virtually identical to that observed for neurons immunoreactive for ChAT. NP-NF immunoreactive neurons of relatively lower intensity were found in many other regions of the brainstem. All of the giant Betz cells of layer (L) V in the motor cortex contained dark NP-NF immunoreactivity. Within the spinal cord of amyotrophic lateral sclerosis (ALS) patients, both Nissl and NP-NF staining demonstrated the dramatic loss of alpha-motor neurons characteristic of this disorder. Some of the remaining motor neurons contained intense P-NF immunoreactivity. These observations suggest that NP-NF immunoreactivity is a good marker for motor neurons in health and disease and may be a useful tool for studies of motor neuron degeneration (MND).

The prostate apoptosis response-4 protein participates in motor neuron degeneration in amyotrophic lateral sclerosis

Prostate apoptosis response‐4 (Par‐4), a protein containing a leucine zipper domain within a death domain, is up‐regulated in prostate cancer cells and hippocampal neurons induced to undergo apoptosis. Here, we report higher Par‐4 levels in lumbar spinal cord samples from patients with amyotrophic lateral sclerosis (ALS) than in lumbar spinal cord samples from neurologically normal patients. We also compared the levels of Par‐4 in lumbar spinal cord samples from wild‐type and transgenic mice expressing the human Cu/Zn‐superoxide dis‐mutase gene with a familial ALS mutation. Relative to control samples, higher Par‐4 levels were observed in lumbar spinal cord samples prepared from the transgenic mice at a time when they had hind‐limb paralysis. Immunohistochemical analyses of human and mouse lumbar spinal cord sections revealed that Par‐4 is localized to motor neurons in the ventral horn region. In culture studies, exposure of primary mouse spinal cord motor neurons or NSC‐19 motor neuron cells to oxidative insults resulted in a rapid and large increase in Par‐4 levels that preceded apoptosis. Pretreatment of the motor neuron cells with a Par‐4 antisense oligonucleotide prevented oxidative stress‐induced apoptosis and reversed oxi‐dative stress‐induced mitochondrial dysfunction that preceded apoptosis. Collectively, these data suggest a role for Par‐4 in models of motor neuron injury relevant to ALS.—Pedersen W. W., Luo H., Kruman, I., Kasarskis, E., Mattson, M. P. The prostate apopto‐sis response‐4 protein participates in motor neuron degeneration in amyotrophic lateral sclerosis. FASEB J. 14, 913–924 (2000)