More: American Academy of Neurology 59th Annual Meeting

Selection from: AAN 2007: Degenerative Disorders
Advances in Neuromuscular Disease CME
Carmel Armon, MD, MHS
Disclosures


Introduction
Numerous advances in the understanding of amyotrophic lateral sclerosis (ALS) etiology, epidemiology, pathophysiology, and treatment approaches were the high point of this year's American Academy of Neurology (AAN) 59th Annual Meeting in Boston, Massachusetts.

Advances in ALS
Cycad Seed Exposure and Risk for ALS
Borenstein and colleagues[1] reported on cycad seed exposure and risk for dementia, mild cognitive impairment (MCI), and ALS/parkinsonism-dementia complex (PDC) in the Chamorro population of Guam. They conducted a prevalence study among all Chamorros aged 65 and over living on Guam who were alive on February 1, 2004. A total of 1984 individuals (71.6%) formed the baseline cohort. Unaffected individuals included 1654 cohort members who were not demented on clinical examination or who performed well on cognitive and motor testing. They defined 4 sets of cases for this analysis -- any dementia (non-PDC) (n = 208), Alzheimer's disease (n = 174), MCI (n = 87), and ALS/PDC (n = 30) -- and reported their associations with the use of cycad-containing products in traditional food (fadang) and medicine as well as the consumption of fruit bats gleaned from structured, in-person risk factor questionnaires. Odds ratios adjusted for age, sex, and education and their 95% confidence intervals for picking, processing, and eating fadang in young adulthood ranged from 1.42 (1.05-1.91) to 1.97 (1.21-3.18) and were consistently elevated and statistically significant across all outcomes. Men showed stronger and more consistent associations across exposure groups in young adulthood compared with women. No associations were found for exposure to fadang used as a medicine or the consumption of fruit bats for any of the outcomes. These findings confirm Marjorie Whiting's hypothesis[2] that consumption of food products made from Cycas circinalis was implicated in producing Guamanian ALS/PDC, and constitute the first confirmation of a definite environmental cause for a form of ALS.

Minocycline in ALS
Paul H. Gordon and colleagues[3] reported on the results of a National Institutes of Health (NIH)-funded, multicenter, phase 3, randomized, double-blind, placebo-controlled trial of minocycline in patients with ALS. Four hundred seventy patients were enrolled at 31 centers across the United States. After a 4-month lead-in phase to measure baseline rates of progression, 412 patients were randomized either to minocycline in doses of up to 400 mg/day or to identical-appearing placebo for 9 additional months. The primary outcome measure was change in the slope of the ALS Functional Rating Scale-Revised (ALSFRS-R). The ALSFRS-R is a composite measure of motor function that has been validated in patients with ALS. Secondary outcome measures included survival, forced vital capacity, strength testing, and frequency of adverse events. Unfortunately, patients on minocycline declined on the ALSFRS-R scale 24% faster (ie, worse) than those on placebo (P < .005). The decline in forced vital capacity and in strength also was greater in the treated group. Survival and quality of life were similar in the 2 groups. As a result of this study, we know that minocycline should not be given to patients with ALS if the intent is to slow disease progression. Minocycline joined a lengthening list of agents that had shown efficacy in slowing disease progression in the transgenic SOD1 mutant mouse model, but had shown no efficacy or negative impact on humans with sporadic ALS. As articulated by Michael Benatar,[4] these circumstances call into question the utility of such preclinical data for identifying potentially useful therapeutic agents for sporadic ALS. It is more realistic to use data in the transgenic SOD1 mutant mouse model to select treatments for patients with SOD1 mutant familial ALS. Dr. Benatar[4] suggested that an anti-inflammatory/antiapoptotic agent, such as minocycline, appears to be the most promising for prevention of onset, and an antioxidative agent, such as creatine or the manganese porphyrin AEOL-10150, appears to be the most promising for therapeutic trials after disease onset in patients with familial ALS. However, Dr. Benatar suggested that these conclusions should be tempered due to the limited methodological quality of most studies.

The results of the minocycline study reinforced 2 important points for patients with ALS and the physicians who care for them. First, the value of placebo controls was reaffirmed. Second, the inadvisability of "off-label" use of prescription medications to try to slow the progression of ALS was demonstrated. It was very difficult to enroll into the minocycline study due to the preference of many patients to take the medication off-label, rather than enroll in a placebo-controlled study to find out whether it worked. Physicians were under pressure to prescribe minocycline on a "compassionate" basis. The community of patients with ALS and those who care for them is indebted to the patients who volunteered for this and other placebo-controlled studies, and to the researchers who conducted a very challenging clinical trial.

A final matter is to determine why the patients on minocycline fared worse than those on placebo. In 3 previous instances (with human recombinant ciliary neurotrophic factor [CNTF], topiramate, and antiretroviral treatments), dose-related side effects caused treated patients to fare worse than those receiving placebo. In terms of understanding the mechanisms of progression of sporadic ALS, it would be greatly informative if the difference between the 2 groups in the minocycline study was shown to be greater than what can be explained by minocycline-related side effects. The publication of the full report of this study and the investigators' discussion of this question are awaited eagerly.

Epidemiologic Data of the European Consortium of ALS Registries
Logroscino and colleagues[5] presented epidemiologic data from the European consortium of ALS registries (EURALS), the collaborative project unifying 6 European population-based ALS registers. Data were available from a European population of 23,869,485. Over a 2-year period, 1032 incident cases were diagnosed: 477 women and 555 men. The crude incidence of ALS was 2.16 per 100,000 person-years. Men had a higher incidence of ALS than women (2.39 and 1.95 per 100,000 person-years; male-to-female ratio, 1.2:1), and the incidence increased steeply with age. It was 0.27 per 100,000 person-years below the age of 45 years, 4.10 among the 45- to 70-year-old age group, and 6.77 after age 70 years. A peak in the incidence was noted at ages 70-74 years; however, this peak was attributable entirely to the incidence patterns of spinal-onset ALS in men. Incidence in all other groups showed a plateau between ages 60 and 80 years.

This is the largest ALS population-based study to date, and the results showed that ALS incidence is homogeneous in Europe, increases with age, and is higher in men than in women. The crude incidence numbers are comparable to those found in a few well-studied populations in the United States, where case finding has been complete. The EURALS collaboration has set a standard for population-based registries for patients with ALS, and may provide the foundation for epidemiologic studies untarnished by referral bias looking for potential genetic and environmental risk factors for the disease. It may provide the foundation for population-based randomized controlled trials of new treatments, which would establish a new standard in clinical trials.

Testing for Nogo-A Expression
Pradat and colleagues[6] evaluated the utility of testing for Nogo-A expression in making a diagnosis of ALS in patients presenting exclusively with lower motor neuron (LMN) signs. Nogo-A is a potent neurite growth inhibitor in vitro and plays a role both in the restriction of axonal regeneration after injury and in structural plasticity in the central nervous system of higher vertebrates. The study authors showed that Nogo-A expression in muscle was detected in patients with typical ALS but not in normal controls or patients with peripheral neuropathies. To evaluate the utility of early detection of Nogo-A expression in predicting progression to ALS, they followed 33 patients who had a muscle biopsy when they presented with a spinal-onset LMN syndrome. Patients were diagnosed with ALS if they developed, during the follow-up period, upper motor neuron signs, bulbar symptoms, or respiratory insufficiency in the absence of evidence of other disease processes that might explain LMN signs. Fifteen of 17 patients positive for Nogo-A expression developed ALS, as did 1 of 16 patients who was negative for Nogo-A expression. Consequently, the detection of Nogo-A in muscle biopsy samples from patients presenting with LMN syndromes identified patients who subsequently progressed to ALS with a positive predictive value of 88% and a negative predictive value of 94%. In the 16 patients who later developed typical ALS, Nogo-A was detectable as early as 3 months after the onset of symptoms.

If the test can be made available widely, it may aid the early diagnosis of ALS. The predictive values will require independent confirmation in additional, well-characterized patient populations. It will be necessary also to determine what percentage of patients who present for ALS diagnosis might benefit from this test. Understanding why Nogo-A is overexpressed in the muscles of patients with ALS may provide insight into the pathophysiology of this disease.

Follow-up Research in Promising Areas
Several reports provided follow-up research in directions identified as promising in last year's annual meeting highlights.[7]

Miller and colleagues[8] provided additional data from their experiments in transgenic SOD1 G93A mutant rat models of ALS. They reported that antisense oligonucleotides, which downregulate the production of mutant SOD1, extend survival by 30 days when treatment is begun early (when the rats are 30 days old) compared with 10 days' extension if the treatment is begun late, at age 65 days -- closer to clinical disease onset. Yokota and colleagues[9] reported that the addition of silencing mRNA genes halted or delayed the emergence of ALS in transgenic mutant SOD1 mice.

Sargsyan and colleagues[10] studied the cellular properties of microglia isolated from transgenic mice expressing the human mutant SOD1 gene G93A. They showed that activated mutant SOD1 G93A microglia have a greater inflammatory potential and differ significantly from those of activated nontransgenic cells. These properties enable the transgenic microglia to propagate neurodegeneration by secreting neurotoxic cytokines, and possibly because they are unable to regulate their activated state as well as the nontransgenic cells. This observation may account for the efficacy on anti-inflammatory agents in transgenic models of ALS. However, lack of efficacy of the same agents in sporadic human ALS raises the question of whether the same glial processes affect the course of sporadic ALS in humans.

Cronin and colleagues[11] reported on studies of paraoxonases in the population of Irish patients with ALS. The paraoxonases PON1, PON2, and PON3 play a major protective role both against environmental toxins and as part of the antioxidant defense system. In 2 previous studies in Polish[12] and US[13] populations, different single nucleotide polymorphisms (SNPs) were associated with increased risk for sporadic ALS. The present study[9] comprised 221 Irish patients with sporadic ALS and 202 spousal/community control subjects of similar age, sex, and ethnicity. Specific paraoxonase SNPs were associated with sporadic ALS in the Irish population. The risk allele identified in the present study in PON1, although different from that of the Polish study,[12] is also associated with an amino acid variation known to lower PON1 enzyme kinetics. The PON3 intronic marker identified supports the previous association with this variant in a US ALS population.[13] These data suggested that genetic variation across the paraoxonase loci may be common susceptibility factors for sporadic ALS. It is hypothesized that reduced paraoxonase activity may place individuals at increased risk for sporadic ALS through reduced ability to detoxify environmental toxins. Specific toxins have not been linked to these polymorphisms. This direction of research supports the hypothesis that genetic predisposition may place some individuals at increased risk of developing sporadic ALS. It is not clear why different polymorphisms are implicated in different populations. It has been proposed that a polymorphism is likely to be detected only if the population in question is exposed to a toxin, the detoxification of which is impaired by that polymorphism; otherwise, the polymorphism would not be a risk factor in that population. Further identification of genetic risk factors for sporadic ALS is anticipated in the coming years, providing additional direction in the search for possible causes of sporadic ALS.

Finally, Niimi and colleagues[14] reported on the effectiveness of an antiandrogen LHRH analog in reversing, in part, clinical and electrophysiologic markers of disease progression in 3 of 4 cases of spinobulbar muscular atrophy (Kennedy's disease), followed for 3 years. Greatest effectiveness was achieved in patients treated early in the course of the disease. The magnitude of benefit was 28% for muscle strength measures and 23% for an electrophysiologic measure (median nerve compound muscle action potential amplitude). This observation will need to be reproduced independently in additional patients to define: who might benefit most; the magnitude of benefit, using clinical and electrophysiologic measures of function; duration of benefit; and side-effect profile.

Summary
Many additional, excellent studies were presented at this year's AAN meeting. With regret, most cannot be reflected in this selection of highlights.

This meeting may be considered a turning point in understanding ALS:

An environmental cause for Guamanian ALS/PDC -- consumption or preparation of cycad products -- was confirmed.[1]


Serious doubts were raised in regard to the relevance of transgenic models of mutant SOD1 ALS to the identification of treatments for sporadic ALS.[3,4] As a result, a major paradigm shift in the approach to the development of new treatments for sporadic ALS is expected.


A loud cautionary note was sounded against the off-label use of medications available for other indications to try to slow disease progression in ALS. Minocycline was shown to be harmful to patients with ALS.[3]


The power of a European consortium of population-based ALS patient registries was demonstrated[5] as a benchmark for international collaboration.


A prognostic marker was identified for evolution of ALS presenting as a LMN syndrome into definitive disease: Nogo-A expression in muscle.[6]


The effectiveness of silencing of mutant SOD1 mRNA production in slowing or preventing mutant SOD1 disease expression was confirmed in 2 animal models.[8,9]


Mechanisms by which microglia may affect disease progression in a mutant SOD1 model of the disease continued to be explored.[10]


Specific SNPs in paraoxonase loci were shown to confer an increased risk for sporadic ALS in an Irish population,[11] elaborating on data reported last year in Polish and US populations.[12,13]


Antiandrogen therapy was shown to be effective in reversing, in part, disease progression in 3 of 4 patients with spinobulbar muscular atrophy.[14]

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References
http://www.medscape.com/viewarticle/560935