Neuromuscular Disorders

Distinguish between clinical constructs.

Four clinical constructs are commonly attributed to nervous system Lyme disease, but only one of these actually represents nervous system infection with Borrelia burgdorferi, also known as neuroborreliosis. However, there are legitimate and important research questions for each construct.

Neuroborreliosis manifests as lymphocytic meningitis, multifocal inflammation of nerves and nerve roots, and – very rarely – multifocal inflammation of the CNS. This is probably the only one of these four constructs in which animal models, primarily nonhuman primates, can be informative.

Although antibiotics are curative for neuroborreliosis, it is virtually impossible (except in meningitis) to demonstrate spirochetes in involved tissue. Immune activation and amplification appear to play key roles in pathogenesis, but their mechanisms require clarification. Are there specific markers that predict which patients will develop neuroborreliosis and its particular form? Are there predictors of the rate or completeness of antimicrobial response? Do similarities between host and spirochete antigens cause antispirochete antibodies to attack the host?

Current diagnostic tools for neuroborreliosis are excellent. However, the sensitivity and specificity of cerebrospinal fluid (CSF) antibody measurement and polymerase chain reaction should be explored in well-defined populations with CNS infection. Measures of treatment response need improvement, be they nonspecific or specific. Although the currently recommended parenteral antibiotic regimens are highly effective, several European studies indicate that oral doxycycline is as effective as parenteral antibiotics for all but parenchymal CNS disease (Neurology 2007;69:91-102). This requires confirmation in U.S. patients.

A second clinical entity, referred to as Lyme encephalopathy, manifests as altered cognitive function in the setting of extraneurologic (but usually not nervous system) infection. Like patients with many other systemic inflammatory states, individuals with active Lyme disease often describe cognitive and memory difficulties, in the absence of CNS infection. An understanding of this disorder, which presumably is mediated by cytokines or other soluble molecules that are produced systemically and diffuse into the CNS, may well provide broad insights into the delirium seen in many other systemic infections. Studies should focus on the range of neuroimmunomodulators that are present in the serum and CSF of such patients, as well as microorganism characteristics. Then researchers can explore more specific therapeutic interventions.

Posttreatment Lyme disease syndrome (PLDS) manifests typically as fatigue, perceived cognitive and memory difficulty, widespread pain, sleep disorders, and other symptoms overlapping extensively with chronic fatigue syndrome, fibromyalgia, and similar states. These symptoms occur and persist for many months following usually curative treatment of patients with clear-cut Lyme disease. Identical symptoms have been observed following other infectious or inflammatory states.

Larger prospective studies are needed to establish whether PLDS occurs more frequently after Lyme disease than in control populations. If so, understanding its pathophysiology may be informative both for this state and for a broader range of similar, postinfectious states. Additional studies should focus on both who is affected and why. Work to date indicates that PLDS is not caused by ongoing infection, but rather appears to relate to pre-illness traits. Recovery seems to correlate best with patients' emotional resilience (Am. J. Med. 2009;122:843-50) and only inconsistently with psychiatric comorbidities.

Assays of markers of innate and acquired immunity both in serum and CSF could be performed to test whether or not there is ongoing immune stimulation in PLDS. A possible role of coinfections with other tick-borne infections such as flaviviruses can be assessed as well. The role of learned behavioral responses to stressors can be assessed by prospective studies using neuropsychological metrics and brain functional MRI or possibly PET scans. Treatment recommendations would follow from the demonstrated pathophysiology.

In other instances, individuals are diagnosed with and treated for “chronic Lyme disease” despite the absence of any evidence of their ever having had this infection. These symptoms are identical to PLDS and significantly impact quality of life in an estimated 2% of the general population (Med. Care 2005;43:1078-86), but often do not have an identifiable cause.

http://www.ncbi.nlm.nih.gov/e

Make use of new detection, diagnostic methods.

Although progress has been made in our understanding of neurologic Lyme disease, important questions and unmet needs remain, particularly with respect to diagnostic tests and the cause and treatment of chronic sequelae.

The following five steps will further advance our understanding:

▸ Conduct a large prospective study of neurologic Lyme disease, which may clarify the incidence of chronic symptoms after standard treatment and identify risk factors that influence relapse vs. recovery.

▸ Apply newly developed technologies to identify better diagnostics and biomarkers and to examine the pathophysiology of chronic symptoms.

▸ Create a national repository of clinical specimens from patients at different stages of disease and recovery in order to apply this emerging technology rapidly. These patients need to be extremely well characterized across multiple disciplines via validated measures in order to bring maximal yield.

▸ Conduct a noninferiority, double-blind, randomized, controlled trial to determine whether oral doxycycline is as good as IV ceftriaxone (as has been demonstrated in Europe) for acute neurologic Lyme disease.

▸ Test nonantimicrobial therapies to help patients who have chronic symptoms despite taking antibiotics.

This five-step approach will lead to better diagnostic tests, will help elucidate the prevalence and pathophysiology of chronic persistent symptoms, and will lead to more rational and effective treatment selection.

To determine whether unsuspected coinfections or uncommon strains of Borrelia burgdorferi are the culprits for persistent symptoms, many powerful techniques are now available to address such issues. Whole-genome sequencing has enabled the mapping of 13 additional U.S. strains of B. burgdorferi that should help to clarify whether distinct B. burgdorferi variants lead to different clinical manifestations and treatment responses. The combination of multiplex polymerase chain reaction with mass spectrometry (called MassTag PCR) can screen for multiple tick-borne pathogens using a single sample. This technology has revealed that 30% of ticks in New York state have a polymicrobial infection and that 2% carry the Powassan virus (Vector Borne Zoonotic Dis. 2010;10:217-21). Another technology, such as the Ibis T5000, uses broad-range PCR followed by electrospray ionization mass spectrometry to probe specimens for potential microbes in a nonbiased manner. It produces results within hours. Furthermore, “deep sequencing” technology can probe the entire microbial population in a single sample.

Advances in neuroimaging can help clarify the pathophysiology of chronic symptoms. Recent progress in the identification of radioligands that target the peripheral benzodiazepine receptor will allow PET scanning to determine whether patients with posttreatment Lyme disease syndrome (PLDS) have CNS microglial activation. Patients with PLDS often complain of multifocal pain, and many report diffuse hyperalgesia and/or allodynia. Could this result from central mechanisms that augment pain or attenuate activity in descending antinociceptive pathways, as has been demonstrated in fibromyalgia? The demonstration of abnormally activated central pain neural circuits in PLDS would suggest new directions in treatment. Such research could include peripheral tests of pain thresholds (pressure, heat, auditory), functional MRI studies of central sensory augmentation, and probing neurotransmitter activity via CSF and MR spectroscopy.

Recent animal and human studies also provide new directions. Could persistent symptoms among PLDS patients reflect the immune response to a small reservoir of persistent infection, as has been suggested by the finding of persistent B. burgdorferi in mouse and canine models after antibiotic treatment in U.S. and European studies? (These studies have led to a xenodiagnosis study in humans that is funded by the National Institute of Allergy and Infectious Diseases. It will test whether an uninfected tick feeding on a PLDS patient can attract B. burgdorferi even if B. burgdorferi was nondetectable in that human host by culture or PCR.) Do persistent symptoms reflect a persistently activated immune response with a persistent sickness syndrome, as has been suggested for many postinfectious illnesses? Recent studies demonstrate that approximately 50% of patients with PLDS have elevated antineuronal antibodies, with total antibody reactivity comparable to that seen among patients with systemic lupus erythematosus but far higher than among recovered controls (Brain Behav. Immun. 2010;24:1018-24). The pathophysiology underlying this immune abnormality and its relationship to clinical symptomatology deserve further study as it may suggest future immunologically based therapies.

Distinguish between clinical constructs.

Four clinical constructs are commonly attributed to nervous system Lyme disease, but only one of these actually represents nervous system infection with Borrelia burgdorferi, also known as neuroborreliosis. However, there are legitimate and important research questions for each construct.

Neuroborreliosis manifests as lymphocytic meningitis, multifocal inflammation of nerves and nerve roots, and – very rarely – multifocal inflammation of the CNS. This is probably the only one of these four constructs in which animal models, primarily nonhuman primates, can be informative.

Although antibiotics are curative for neuroborreliosis, it is virtually impossible (except in meningitis) to demonstrate spirochetes in involved tissue. Immune activation and amplification appear to play key roles in pathogenesis, but their mechanisms require clarification. Are there specific markers that predict which patients will develop neuroborreliosis and its particular form? Are there predictors of the rate or completeness of antimicrobial response? Do similarities between host and spirochete antigens cause antispirochete antibodies to attack the host?

Current diagnostic tools for neuroborreliosis are excellent. However, the sensitivity and specificity of cerebrospinal fluid (CSF) antibody measurement and polymerase chain reaction should be explored in well-defined populations with CNS infection. Measures of treatment response need improvement, be they nonspecific or specific. Although the currently recommended parenteral antibiotic regimens are highly effective, several European studies indicate that oral doxycycline is as effective as parenteral antibiotics for all but parenchymal CNS disease (Neurology 2007;69:91-102). This requires confirmation in U.S. patients.

A second clinical entity, referred to as Lyme encephalopathy, manifests as altered cognitive function in the setting of extraneurologic (but usually not nervous system) infection. Like patients with many other systemic inflammatory states, individuals with active Lyme disease often describe cognitive and memory difficulties, in the absence of CNS infection. An understanding of this disorder, which presumably is mediated by cytokines or other soluble molecules that are produced systemically and diffuse into the CNS, may well provide broad insights into the delirium seen in many other systemic infections. Studies should focus on the range of neuroimmunomodulators that are present in the serum and CSF of such patients, as well as microorganism characteristics. Then researchers can explore more specific therapeutic interventions.

Posttreatment Lyme disease syndrome (PLDS) manifests typically as fatigue, perceived cognitive and memory difficulty, widespread pain, sleep disorders, and other symptoms overlapping extensively with chronic fatigue syndrome, fibromyalgia, and similar states. These symptoms occur and persist for many months following usually curative treatment of patients with clear-cut Lyme disease. Identical symptoms have been observed following other infectious or inflammatory states.

Larger prospective studies are needed to establish whether PLDS occurs more frequently after Lyme disease than in control populations. If so, understanding its pathophysiology may be informative both for this state and for a broader range of similar, postinfectious states. Additional studies should focus on both who is affected and why. Work to date indicates that PLDS is not caused by ongoing infection, but rather appears to relate to pre-illness traits. Recovery seems to correlate best with patients' emotional resilience (Am. J. Med. 2009;122:843-50) and only inconsistently with psychiatric comorbidities.

Assays of markers of innate and acquired immunity both in serum and CSF could be performed to test whether or not there is ongoing immune stimulation in PLDS. A possible role of coinfections with other tick-borne infections such as flaviviruses can be assessed as well. The role of learned behavioral responses to stressors can be assessed by prospective studies using neuropsychological metrics and brain functional MRI or possibly PET scans. Treatment recommendations would follow from the demonstrated pathophysiology.

In other instances, individuals are diagnosed with and treated for “chronic Lyme disease” despite the absence of any evidence of their ever having had this infection. These symptoms are identical to PLDS and significantly impact quality of life in an estimated 2% of the general population (Med. Care 2005;43:1078-86), but often do not have an identifiable cause.

http://www.ncbi.nlm.nih.gov/e

Make use of new detection, diagnostic methods.

Although progress has been made in our understanding of neurologic Lyme disease, important questions and unmet needs remain, particularly with respect to diagnostic tests and the cause and treatment of chronic sequelae.

The following five steps will further advance our understanding:

▸ Conduct a large prospective study of neurologic Lyme disease, which may clarify the incidence of chronic symptoms after standard treatment and identify risk factors that influence relapse vs. recovery.

▸ Apply newly developed technologies to identify better diagnostics and biomarkers and to examine the pathophysiology of chronic symptoms.

▸ Create a national repository of clinical specimens from patients at different stages of disease and recovery in order to apply this emerging technology rapidly. These patients need to be extremely well characterized across multiple disciplines via validated measures in order to bring maximal yield.

▸ Conduct a noninferiority, double-blind, randomized, controlled trial to determine whether oral doxycycline is as good as IV ceftriaxone (as has been demonstrated in Europe) for acute neurologic Lyme disease.

▸ Test nonantimicrobial therapies to help patients who have chronic symptoms despite taking antibiotics.

This five-step approach will lead to better diagnostic tests, will help elucidate the prevalence and pathophysiology of chronic persistent symptoms, and will lead to more rational and effective treatment selection.

To determine whether unsuspected coinfections or uncommon strains of Borrelia burgdorferi are the culprits for persistent symptoms, many powerful techniques are now available to address such issues. Whole-genome sequencing has enabled the mapping of 13 additional U.S. strains of B. burgdorferi that should help to clarify whether distinct B. burgdorferi variants lead to different clinical manifestations and treatment responses. The combination of multiplex polymerase chain reaction with mass spectrometry (called MassTag PCR) can screen for multiple tick-borne pathogens using a single sample. This technology has revealed that 30% of ticks in New York state have a polymicrobial infection and that 2% carry the Powassan virus (Vector Borne Zoonotic Dis. 2010;10:217-21). Another technology, such as the Ibis T5000, uses broad-range PCR followed by electrospray ionization mass spectrometry to probe specimens for potential microbes in a nonbiased manner. It produces results within hours. Furthermore, “deep sequencing” technology can probe the entire microbial population in a single sample.

Advances in neuroimaging can help clarify the pathophysiology of chronic symptoms. Recent progress in the identification of radioligands that target the peripheral benzodiazepine receptor will allow PET scanning to determine whether patients with posttreatment Lyme disease syndrome (PLDS) have CNS microglial activation. Patients with PLDS often complain of multifocal pain, and many report diffuse hyperalgesia and/or allodynia. Could this result from central mechanisms that augment pain or attenuate activity in descending antinociceptive pathways, as has been demonstrated in fibromyalgia? The demonstration of abnormally activated central pain neural circuits in PLDS would suggest new directions in treatment. Such research could include peripheral tests of pain thresholds (pressure, heat, auditory), functional MRI studies of central sensory augmentation, and probing neurotransmitter activity via CSF and MR spectroscopy.

Recent animal and human studies also provide new directions. Could persistent symptoms among PLDS patients reflect the immune response to a small reservoir of persistent infection, as has been suggested by the finding of persistent B. burgdorferi in mouse and canine models after antibiotic treatment in U.S. and European studies? (These studies have led to a xenodiagnosis study in humans that is funded by the National Institute of Allergy and Infectious Diseases. It will test whether an uninfected tick feeding on a PLDS patient can attract B. burgdorferi even if B. burgdorferi was nondetectable in that human host by culture or PCR.) Do persistent symptoms reflect a persistently activated immune response with a persistent sickness syndrome, as has been suggested for many postinfectious illnesses? Recent studies demonstrate that approximately 50% of patients with PLDS have elevated antineuronal antibodies, with total antibody reactivity comparable to that seen among patients with systemic lupus erythematosus but far higher than among recovered controls (Brain Behav. Immun. 2010;24:1018-24). The pathophysiology underlying this immune abnormality and its relationship to clinical symptomatology deserve further study as it may suggest future immunologically based therapies.

Distinguish between clinical constructs.

Four clinical constructs are commonly attributed to nervous system Lyme disease, but only one of these actually represents nervous system infection with Borrelia burgdorferi, also known as neuroborreliosis. However, there are legitimate and important research questions for each construct.

Neuroborreliosis manifests as lymphocytic meningitis, multifocal inflammation of nerves and nerve roots, and – very rarely – multifocal inflammation of the CNS. This is probably the only one of these four constructs in which animal models, primarily nonhuman primates, can be informative.

Although antibiotics are curative for neuroborreliosis, it is virtually impossible (except in meningitis) to demonstrate spirochetes in involved tissue. Immune activation and amplification appear to play key roles in pathogenesis, but their mechanisms require clarification. Are there specific markers that predict which patients will develop neuroborreliosis and its particular form? Are there predictors of the rate or completeness of antimicrobial response? Do similarities between host and spirochete antigens cause antispirochete antibodies to attack the host?

Current diagnostic tools for neuroborreliosis are excellent. However, the sensitivity and specificity of cerebrospinal fluid (CSF) antibody measurement and polymerase chain reaction should be explored in well-defined populations with CNS infection. Measures of treatment response need improvement, be they nonspecific or specific. Although the currently recommended parenteral antibiotic regimens are highly effective, several European studies indicate that oral doxycycline is as effective as parenteral antibiotics for all but parenchymal CNS disease (Neurology 2007;69:91-102). This requires confirmation in U.S. patients.

A second clinical entity, referred to as Lyme encephalopathy, manifests as altered cognitive function in the setting of extraneurologic (but usually not nervous system) infection. Like patients with many other systemic inflammatory states, individuals with active Lyme disease often describe cognitive and memory difficulties, in the absence of CNS infection. An understanding of this disorder, which presumably is mediated by cytokines or other soluble molecules that are produced systemically and diffuse into the CNS, may well provide broad insights into the delirium seen in many other systemic infections. Studies should focus on the range of neuroimmunomodulators that are present in the serum and CSF of such patients, as well as microorganism characteristics. Then researchers can explore more specific therapeutic interventions.

Posttreatment Lyme disease syndrome (PLDS) manifests typically as fatigue, perceived cognitive and memory difficulty, widespread pain, sleep disorders, and other symptoms overlapping extensively with chronic fatigue syndrome, fibromyalgia, and similar states. These symptoms occur and persist for many months following usually curative treatment of patients with clear-cut Lyme disease. Identical symptoms have been observed following other infectious or inflammatory states.

Larger prospective studies are needed to establish whether PLDS occurs more frequently after Lyme disease than in control populations. If so, understanding its pathophysiology may be informative both for this state and for a broader range of similar, postinfectious states. Additional studies should focus on both who is affected and why. Work to date indicates that PLDS is not caused by ongoing infection, but rather appears to relate to pre-illness traits. Recovery seems to correlate best with patients' emotional resilience (Am. J. Med. 2009;122:843-50) and only inconsistently with psychiatric comorbidities.

Assays of markers of innate and acquired immunity both in serum and CSF could be performed to test whether or not there is ongoing immune stimulation in PLDS. A possible role of coinfections with other tick-borne infections such as flaviviruses can be assessed as well. The role of learned behavioral responses to stressors can be assessed by prospective studies using neuropsychological metrics and brain functional MRI or possibly PET scans. Treatment recommendations would follow from the demonstrated pathophysiology.

In other instances, individuals are diagnosed with and treated for “chronic Lyme disease” despite the absence of any evidence of their ever having had this infection. These symptoms are identical to PLDS and significantly impact quality of life in an estimated 2% of the general population (Med. Care 2005;43:1078-86), but often do not have an identifiable cause.

http://www.ncbi.nlm.nih.gov/e

Make use of new detection, diagnostic methods.

Although progress has been made in our understanding of neurologic Lyme disease, important questions and unmet needs remain, particularly with respect to diagnostic tests and the cause and treatment of chronic sequelae.

The following five steps will further advance our understanding:

▸ Conduct a large prospective study of neurologic Lyme disease, which may clarify the incidence of chronic symptoms after standard treatment and identify risk factors that influence relapse vs. recovery.

▸ Apply newly developed technologies to identify better diagnostics and biomarkers and to examine the pathophysiology of chronic symptoms.

▸ Create a national repository of clinical specimens from patients at different stages of disease and recovery in order to apply this emerging technology rapidly. These patients need to be extremely well characterized across multiple disciplines via validated measures in order to bring maximal yield.

▸ Conduct a noninferiority, double-blind, randomized, controlled trial to determine whether oral doxycycline is as good as IV ceftriaxone (as has been demonstrated in Europe) for acute neurologic Lyme disease.

▸ Test nonantimicrobial therapies to help patients who have chronic symptoms despite taking antibiotics.

This five-step approach will lead to better diagnostic tests, will help elucidate the prevalence and pathophysiology of chronic persistent symptoms, and will lead to more rational and effective treatment selection.

To determine whether unsuspected coinfections or uncommon strains of Borrelia burgdorferi are the culprits for persistent symptoms, many powerful techniques are now available to address such issues. Whole-genome sequencing has enabled the mapping of 13 additional U.S. strains of B. burgdorferi that should help to clarify whether distinct B. burgdorferi variants lead to different clinical manifestations and treatment responses. The combination of multiplex polymerase chain reaction with mass spectrometry (called MassTag PCR) can screen for multiple tick-borne pathogens using a single sample. This technology has revealed that 30% of ticks in New York state have a polymicrobial infection and that 2% carry the Powassan virus (Vector Borne Zoonotic Dis. 2010;10:217-21). Another technology, such as the Ibis T5000, uses broad-range PCR followed by electrospray ionization mass spectrometry to probe specimens for potential microbes in a nonbiased manner. It produces results within hours. Furthermore, “deep sequencing” technology can probe the entire microbial population in a single sample.

Advances in neuroimaging can help clarify the pathophysiology of chronic symptoms. Recent progress in the identification of radioligands that target the peripheral benzodiazepine receptor will allow PET scanning to determine whether patients with posttreatment Lyme disease syndrome (PLDS) have CNS microglial activation. Patients with PLDS often complain of multifocal pain, and many report diffuse hyperalgesia and/or allodynia. Could this result from central mechanisms that augment pain or attenuate activity in descending antinociceptive pathways, as has been demonstrated in fibromyalgia? The demonstration of abnormally activated central pain neural circuits in PLDS would suggest new directions in treatment. Such research could include peripheral tests of pain thresholds (pressure, heat, auditory), functional MRI studies of central sensory augmentation, and probing neurotransmitter activity via CSF and MR spectroscopy.

Recent animal and human studies also provide new directions. Could persistent symptoms among PLDS patients reflect the immune response to a small reservoir of persistent infection, as has been suggested by the finding of persistent B. burgdorferi in mouse and canine models after antibiotic treatment in U.S. and European studies? (These studies have led to a xenodiagnosis study in humans that is funded by the National Institute of Allergy and Infectious Diseases. It will test whether an uninfected tick feeding on a PLDS patient can attract B. burgdorferi even if B. burgdorferi was nondetectable in that human host by culture or PCR.) Do persistent symptoms reflect a persistently activated immune response with a persistent sickness syndrome, as has been suggested for many postinfectious illnesses? Recent studies demonstrate that approximately 50% of patients with PLDS have elevated antineuronal antibodies, with total antibody reactivity comparable to that seen among patients with systemic lupus erythematosus but far higher than among recovered controls (Brain Behav. Immun. 2010;24:1018-24). The pathophysiology underlying this immune abnormality and its relationship to clinical symptomatology deserve further study as it may suggest future immunologically based therapies.

New insights into the genetic basis of facioscapulohumeral muscular dystrophy, one of the more common forms of muscular dystrophy, suggest that the disorder may arise only in people with specific chromosomal variants that permit the unusual stability of a pathogenic gene transcript.

Prior to the current discovery by Richard J.L.F. Lemmers, Ph.D., of Leiden (Netherlands) University Medical Center and his colleagues (Science 2010;329:1650-3), the complexity of the genetic setting in which facioscapulohumeral muscular dystrophy (FSHD) skvelops has long hampered efforts to unravel the pathogenic mechanism of the disease.

Most people have a long repeated sequence of nucleotide bases called a macrosatellite repeat array on chromosome 4q35. In healthy people, this 3.3-kilobase sequence on 4q35, called D4Z4 repeats 11-100 times. Patients with autosomal dominant FSHD have a shortened array, with only 1-10 D4Z4 units. At least one D4Z4 unit is necessary to cause FSHD. A nearly identical repeat array also occurs on chromosome 10q, but a decrease in the number of repeated units on that chromosome has not been known to cause FSHD.

Other studies have shown that translocated copies of the repeated units from either chromosome 4 or 10 are often found on the end of either chromosome. But FSHD is known to occur with only certain variants of the repeat array that is found on the end of chromosome 4q.

The major transcript from each D4Z4 unit is the DUX4 gene, which codes for a double homeobox protein. But none of these transcripts has appeared to be stable except for a transcript of DUX4 from the distal D4Z4 unit. After observing that only one D4Z4 unit is necessary to cause FSHD, Dr. Lemmers and his associates chose to examine what makes the transcriptional profile of the distal unit pathogenic.

They found that a nucleotide sequence termed pLAM that lies next to the distal D4Z4 unit gives stability to the unit's DUX4 transcript. This sequence was not found in other D4Z4 repeat-array configurations of other variants of chromosome 4q or chromosome 10q.

This finding suggested to the researchers that “FSHD may arise through a toxic gain of function attributable to the stabilized distal DUX4 transcript.”

Dr. Lemmers and his colleagues then studied four families with one or more affected individuals who carried unusual hybrid D4Z4 repeat-array structures composed of units from chromosome 4q and 10q. This repeat array in one affected individual even resided on chromosome 10 rather than chromosome 4, which indicated that genes nearby the repeat array on chromosome 4q do not play a key role in the pathogenesis of FSHD. This means that when the last D4Z4 unit and its nearby pLAM sequence are found together, they cause the disease regardless of their chromosomal location.

The study “not only explains the striking chromosome specificity of the disorder, but also provides a genetic mechanism that may unify the genetic observations in patients with FSHD,” the researchers concluded.

The study was supported by grants from 11 organizations, health and science agencies, and foundations.

Report by Jeff Evans, Managing Editor.

Adviser's Viewpoint

'Toxic Gain of Function' Not Unique

Richard J.L.F. Lemmers, Ph.D., and colleagues, part of an international consortium of scientists probing the causes of facioscapulohumeral muscular dystrophy (FSHD), have come upon a coherent genetic model of this disease that ties up many of the confusing loose ends of the FSHD puzzle, a subject which has long baffled researchers in the field and clinicians who care for FSHD patients and their families. In their report, Dr. Lemmer and coworkers found that all FSHD patients the group studied had an identical DNA sequence in the last D4Z4 unit and the immediate flanking pLAM sequence of genetic material. Quite remarkably, the specific gene sequence variants appear to convey pathogenicity to the repeat whether they occur on chromosome 4 (the traditional site of the FSHD gene) or chromosome 10. Furthermore, they propose that this faulty terminal D4Z4 unit and adjacent pLAM sequence mediate what has been termed a “toxic gain of function.”

Other neurologic disorders are known to be caused by a toxic gain of function, most notably familial amyotrophic lateral sclerosis, where a superoxide dismutase 1 (SOD1) mutation is responsible for the condition, and Huntington's disease, where CAG repeats are thought to mediate the disease. Toxic gain of function has been proposed as a mechanism in other diseases as well, including idiopathic Parkinson's disease, where alpha synuclein aggregates lead to degeneration of mesencephalic neurons, and Alzheimer's disease, where tau phosphorylation in the hippocampus is thought to lead to neuronal deterioration.

The report from Dr. Lemmer's group provides convincing genetic data for a plausible model of FSHD. The hypothesis that this muscle disease occurs on the basis of a toxic gain of function brought about by stabilized DUX4 transcript may turn out to be sound. Investigation of further FSHD kindreds by Dr. Lemmer's group and others will determine whether this pathogenic model will stand the test of time.

What do these findings mean for FSHD patients and the neurology community? Establishing an incontrovertible molecular mechanism for this common inherited muscle disease is the first step to devising therapies aimed at correcting or replacing the faulty genetic machinery that underlies FSHD.

Vitals

BENN E. SMITH, M.D., is an associate professor of neurology and the director of the sensory laboratory at the Mayo Clinic Arizona, Scottsdale.

New insights into the genetic basis of facioscapulohumeral muscular dystrophy, one of the more common forms of muscular dystrophy, suggest that the disorder may arise only in people with specific chromosomal variants that permit the unusual stability of a pathogenic gene transcript.

Prior to the current discovery by Richard J.L.F. Lemmers, Ph.D., of Leiden (Netherlands) University Medical Center and his colleagues (Science 2010;329:1650-3), the complexity of the genetic setting in which facioscapulohumeral muscular dystrophy (FSHD) skvelops has long hampered efforts to unravel the pathogenic mechanism of the disease.

Most people have a long repeated sequence of nucleotide bases called a macrosatellite repeat array on chromosome 4q35. In healthy people, this 3.3-kilobase sequence on 4q35, called D4Z4 repeats 11-100 times. Patients with autosomal dominant FSHD have a shortened array, with only 1-10 D4Z4 units. At least one D4Z4 unit is necessary to cause FSHD. A nearly identical repeat array also occurs on chromosome 10q, but a decrease in the number of repeated units on that chromosome has not been known to cause FSHD.

Other studies have shown that translocated copies of the repeated units from either chromosome 4 or 10 are often found on the end of either chromosome. But FSHD is known to occur with only certain variants of the repeat array that is found on the end of chromosome 4q.

The major transcript from each D4Z4 unit is the DUX4 gene, which codes for a double homeobox protein. But none of these transcripts has appeared to be stable except for a transcript of DUX4 from the distal D4Z4 unit. After observing that only one D4Z4 unit is necessary to cause FSHD, Dr. Lemmers and his associates chose to examine what makes the transcriptional profile of the distal unit pathogenic.

They found that a nucleotide sequence termed pLAM that lies next to the distal D4Z4 unit gives stability to the unit's DUX4 transcript. This sequence was not found in other D4Z4 repeat-array configurations of other variants of chromosome 4q or chromosome 10q.

This finding suggested to the researchers that “FSHD may arise through a toxic gain of function attributable to the stabilized distal DUX4 transcript.”

Dr. Lemmers and his colleagues then studied four families with one or more affected individuals who carried unusual hybrid D4Z4 repeat-array structures composed of units from chromosome 4q and 10q. This repeat array in one affected individual even resided on chromosome 10 rather than chromosome 4, which indicated that genes nearby the repeat array on chromosome 4q do not play a key role in the pathogenesis of FSHD. This means that when the last D4Z4 unit and its nearby pLAM sequence are found together, they cause the disease regardless of their chromosomal location.

The study “not only explains the striking chromosome specificity of the disorder, but also provides a genetic mechanism that may unify the genetic observations in patients with FSHD,” the researchers concluded.

The study was supported by grants from 11 organizations, health and science agencies, and foundations.

Report by Jeff Evans, Managing Editor.

Adviser's Viewpoint

'Toxic Gain of Function' Not Unique

Richard J.L.F. Lemmers, Ph.D., and colleagues, part of an international consortium of scientists probing the causes of facioscapulohumeral muscular dystrophy (FSHD), have come upon a coherent genetic model of this disease that ties up many of the confusing loose ends of the FSHD puzzle, a subject which has long baffled researchers in the field and clinicians who care for FSHD patients and their families. In their report, Dr. Lemmer and coworkers found that all FSHD patients the group studied had an identical DNA sequence in the last D4Z4 unit and the immediate flanking pLAM sequence of genetic material. Quite remarkably, the specific gene sequence variants appear to convey pathogenicity to the repeat whether they occur on chromosome 4 (the traditional site of the FSHD gene) or chromosome 10. Furthermore, they propose that this faulty terminal D4Z4 unit and adjacent pLAM sequence mediate what has been termed a “toxic gain of function.”

Other neurologic disorders are known to be caused by a toxic gain of function, most notably familial amyotrophic lateral sclerosis, where a superoxide dismutase 1 (SOD1) mutation is responsible for the condition, and Huntington's disease, where CAG repeats are thought to mediate the disease. Toxic gain of function has been proposed as a mechanism in other diseases as well, including idiopathic Parkinson's disease, where alpha synuclein aggregates lead to degeneration of mesencephalic neurons, and Alzheimer's disease, where tau phosphorylation in the hippocampus is thought to lead to neuronal deterioration.

The report from Dr. Lemmer's group provides convincing genetic data for a plausible model of FSHD. The hypothesis that this muscle disease occurs on the basis of a toxic gain of function brought about by stabilized DUX4 transcript may turn out to be sound. Investigation of further FSHD kindreds by Dr. Lemmer's group and others will determine whether this pathogenic model will stand the test of time.

What do these findings mean for FSHD patients and the neurology community? Establishing an incontrovertible molecular mechanism for this common inherited muscle disease is the first step to devising therapies aimed at correcting or replacing the faulty genetic machinery that underlies FSHD.

Vitals

BENN E. SMITH, M.D., is an associate professor of neurology and the director of the sensory laboratory at the Mayo Clinic Arizona, Scottsdale.

New insights into the genetic basis of facioscapulohumeral muscular dystrophy, one of the more common forms of muscular dystrophy, suggest that the disorder may arise only in people with specific chromosomal variants that permit the unusual stability of a pathogenic gene transcript.

Prior to the current discovery by Richard J.L.F. Lemmers, Ph.D., of Leiden (Netherlands) University Medical Center and his colleagues (Science 2010;329:1650-3), the complexity of the genetic setting in which facioscapulohumeral muscular dystrophy (FSHD) skvelops has long hampered efforts to unravel the pathogenic mechanism of the disease.

Most people have a long repeated sequence of nucleotide bases called a macrosatellite repeat array on chromosome 4q35. In healthy people, this 3.3-kilobase sequence on 4q35, called D4Z4 repeats 11-100 times. Patients with autosomal dominant FSHD have a shortened array, with only 1-10 D4Z4 units. At least one D4Z4 unit is necessary to cause FSHD. A nearly identical repeat array also occurs on chromosome 10q, but a decrease in the number of repeated units on that chromosome has not been known to cause FSHD.

Other studies have shown that translocated copies of the repeated units from either chromosome 4 or 10 are often found on the end of either chromosome. But FSHD is known to occur with only certain variants of the repeat array that is found on the end of chromosome 4q.

The major transcript from each D4Z4 unit is the DUX4 gene, which codes for a double homeobox protein. But none of these transcripts has appeared to be stable except for a transcript of DUX4 from the distal D4Z4 unit. After observing that only one D4Z4 unit is necessary to cause FSHD, Dr. Lemmers and his associates chose to examine what makes the transcriptional profile of the distal unit pathogenic.

They found that a nucleotide sequence termed pLAM that lies next to the distal D4Z4 unit gives stability to the unit's DUX4 transcript. This sequence was not found in other D4Z4 repeat-array configurations of other variants of chromosome 4q or chromosome 10q.

This finding suggested to the researchers that “FSHD may arise through a toxic gain of function attributable to the stabilized distal DUX4 transcript.”

Dr. Lemmers and his colleagues then studied four families with one or more affected individuals who carried unusual hybrid D4Z4 repeat-array structures composed of units from chromosome 4q and 10q. This repeat array in one affected individual even resided on chromosome 10 rather than chromosome 4, which indicated that genes nearby the repeat array on chromosome 4q do not play a key role in the pathogenesis of FSHD. This means that when the last D4Z4 unit and its nearby pLAM sequence are found together, they cause the disease regardless of their chromosomal location.

The study “not only explains the striking chromosome specificity of the disorder, but also provides a genetic mechanism that may unify the genetic observations in patients with FSHD,” the researchers concluded.

The study was supported by grants from 11 organizations, health and science agencies, and foundations.

Report by Jeff Evans, Managing Editor.

Adviser's Viewpoint

'Toxic Gain of Function' Not Unique

Richard J.L.F. Lemmers, Ph.D., and colleagues, part of an international consortium of scientists probing the causes of facioscapulohumeral muscular dystrophy (FSHD), have come upon a coherent genetic model of this disease that ties up many of the confusing loose ends of the FSHD puzzle, a subject which has long baffled researchers in the field and clinicians who care for FSHD patients and their families. In their report, Dr. Lemmer and coworkers found that all FSHD patients the group studied had an identical DNA sequence in the last D4Z4 unit and the immediate flanking pLAM sequence of genetic material. Quite remarkably, the specific gene sequence variants appear to convey pathogenicity to the repeat whether they occur on chromosome 4 (the traditional site of the FSHD gene) or chromosome 10. Furthermore, they propose that this faulty terminal D4Z4 unit and adjacent pLAM sequence mediate what has been termed a “toxic gain of function.”

Other neurologic disorders are known to be caused by a toxic gain of function, most notably familial amyotrophic lateral sclerosis, where a superoxide dismutase 1 (SOD1) mutation is responsible for the condition, and Huntington's disease, where CAG repeats are thought to mediate the disease. Toxic gain of function has been proposed as a mechanism in other diseases as well, including idiopathic Parkinson's disease, where alpha synuclein aggregates lead to degeneration of mesencephalic neurons, and Alzheimer's disease, where tau phosphorylation in the hippocampus is thought to lead to neuronal deterioration.

The report from Dr. Lemmer's group provides convincing genetic data for a plausible model of FSHD. The hypothesis that this muscle disease occurs on the basis of a toxic gain of function brought about by stabilized DUX4 transcript may turn out to be sound. Investigation of further FSHD kindreds by Dr. Lemmer's group and others will determine whether this pathogenic model will stand the test of time.

What do these findings mean for FSHD patients and the neurology community? Establishing an incontrovertible molecular mechanism for this common inherited muscle disease is the first step to devising therapies aimed at correcting or replacing the faulty genetic machinery that underlies FSHD.

Vitals

BENN E. SMITH, M.D., is an associate professor of neurology and the director of the sensory laboratory at the Mayo Clinic Arizona, Scottsdale.

Major Finding: Among patients with MD, the median age at death was significantly higher for white males than it was for black males (33 years vs. 23 years).

Data Source: The 1986-2005 National Center for Health Statistics' Multiple Cause Mortality Files.

Disclosures: Lead investigator Dr. Kenneson reported research grants from the CDC; a coinvestigator reported receiving advisory fees and research support from several pharmaceutical companies and MD-related support from foundations.

The median age at the time of death for white patients with muscular dystrophy is 10-12 years older than it is for black patients with the disease, according an analysis of data from all death certificates in the United States.

Moreover, in the 5 most recent years of the study's 20-year time period, 24.5% of black males with muscular dystrophy (MD) had cardiomyopathy, compared with 12.8% of white males with the disease.

The findings “might have been related to different prevalences of the various types of MD, different natural histories, or differences in environmental, genetic, or behavioral risk factors,” wrote Aileen Kenneson, Ph.D., and her colleagues.

With her associates, Dr. Kenneson, who is currently affiliated with consulting firm McKing Consulting Corporation in Atlanta, looked at records from the National Center for Health Statistics' Multiple Cause Mortality Files, which contain data from all death certificates in the United States, including immediate and underlying causes of death coded with the International Classification of Diseases.

The group confined their search to the period between 1986 and 2005; they excluded congenital MD from their analysis, since “the distribution of age at death [among these patients] indicated that they were clinically distinct” from other MD patient types.

Overall, there were 18,315 MD-associated deaths from 1986 through 2005; roughly three-quarters were male. The overwhelming majority (90.6%) were white, while 7.7% of deaths occurred among black patients. The remaining 1.7% were among patients identified as being from other races (Neurology 2010;75:982-9).

The authors found a significantly lower median age at death among black females with MD compared with white females (51 years vs. 63 years, respectively).

They also noted that among white women, the proportion who were 45 years or older at death increased, from 78.7% in the first decade of the study period to 83.8% in the second decade.

“In comparison, only about 63% of black females were 45 years or older at death, and this proportion did not change over time,” the investigators wrote.

Among males, the median age at death was significantly lower among blacks than whites (23 years vs. 33 years, respectively).

The median age at death during the 20-year time span of the study increased significantly by 1.3 years annually for white males without cardiomyopathy and 0.2 years annually for those with cardiomyopathy. In contrast, the median age at death increased just 0.33 years annually for black patients without cardiomyopathy. Black patients with cardiomyopathy showed no significant gain in life expectancy at all.

The authors pointed out that although cardiomyopathy was more often reported among blacks than whites, this finding was true “even early in the study period before the widespread use of corticosteroids and [noninvasive ventilation] were likely to have had an effect.”

That could mean that the increased incidence of cardiomyopathy among nonwhite patients is due to simple racial differences the course of MD, or to the higher frequency of cardiomyopathy among blacks in general, rather than a disparity in treatment.

Dr. Kenneson and her coauthors noted that “while the database contains some possible social effect modifiers, such as education and marital status, it does not include information to assess sufficiently other sociocultural variables, such as health insurance and family structure.”

Major Finding: Among patients with MD, the median age at death was significantly higher for white males than it was for black males (33 years vs. 23 years).

Data Source: The 1986-2005 National Center for Health Statistics' Multiple Cause Mortality Files.

Disclosures: Lead investigator Dr. Kenneson reported research grants from the CDC; a coinvestigator reported receiving advisory fees and research support from several pharmaceutical companies and MD-related support from foundations.

The median age at the time of death for white patients with muscular dystrophy is 10-12 years older than it is for black patients with the disease, according an analysis of data from all death certificates in the United States.

Moreover, in the 5 most recent years of the study's 20-year time period, 24.5% of black males with muscular dystrophy (MD) had cardiomyopathy, compared with 12.8% of white males with the disease.

The findings “might have been related to different prevalences of the various types of MD, different natural histories, or differences in environmental, genetic, or behavioral risk factors,” wrote Aileen Kenneson, Ph.D., and her colleagues.

With her associates, Dr. Kenneson, who is currently affiliated with consulting firm McKing Consulting Corporation in Atlanta, looked at records from the National Center for Health Statistics' Multiple Cause Mortality Files, which contain data from all death certificates in the United States, including immediate and underlying causes of death coded with the International Classification of Diseases.

The group confined their search to the period between 1986 and 2005; they excluded congenital MD from their analysis, since “the distribution of age at death [among these patients] indicated that they were clinically distinct” from other MD patient types.

Overall, there were 18,315 MD-associated deaths from 1986 through 2005; roughly three-quarters were male. The overwhelming majority (90.6%) were white, while 7.7% of deaths occurred among black patients. The remaining 1.7% were among patients identified as being from other races (Neurology 2010;75:982-9).

The authors found a significantly lower median age at death among black females with MD compared with white females (51 years vs. 63 years, respectively).

They also noted that among white women, the proportion who were 45 years or older at death increased, from 78.7% in the first decade of the study period to 83.8% in the second decade.

“In comparison, only about 63% of black females were 45 years or older at death, and this proportion did not change over time,” the investigators wrote.

Among males, the median age at death was significantly lower among blacks than whites (23 years vs. 33 years, respectively).

The median age at death during the 20-year time span of the study increased significantly by 1.3 years annually for white males without cardiomyopathy and 0.2 years annually for those with cardiomyopathy. In contrast, the median age at death increased just 0.33 years annually for black patients without cardiomyopathy. Black patients with cardiomyopathy showed no significant gain in life expectancy at all.

The authors pointed out that although cardiomyopathy was more often reported among blacks than whites, this finding was true “even early in the study period before the widespread use of corticosteroids and [noninvasive ventilation] were likely to have had an effect.”

That could mean that the increased incidence of cardiomyopathy among nonwhite patients is due to simple racial differences the course of MD, or to the higher frequency of cardiomyopathy among blacks in general, rather than a disparity in treatment.

Dr. Kenneson and her coauthors noted that “while the database contains some possible social effect modifiers, such as education and marital status, it does not include information to assess sufficiently other sociocultural variables, such as health insurance and family structure.”

Major Finding: Among patients with MD, the median age at death was significantly higher for white males than it was for black males (33 years vs. 23 years).

Data Source: The 1986-2005 National Center for Health Statistics' Multiple Cause Mortality Files.

Disclosures: Lead investigator Dr. Kenneson reported research grants from the CDC; a coinvestigator reported receiving advisory fees and research support from several pharmaceutical companies and MD-related support from foundations.

The median age at the time of death for white patients with muscular dystrophy is 10-12 years older than it is for black patients with the disease, according an analysis of data from all death certificates in the United States.

Moreover, in the 5 most recent years of the study's 20-year time period, 24.5% of black males with muscular dystrophy (MD) had cardiomyopathy, compared with 12.8% of white males with the disease.

The findings “might have been related to different prevalences of the various types of MD, different natural histories, or differences in environmental, genetic, or behavioral risk factors,” wrote Aileen Kenneson, Ph.D., and her colleagues.

With her associates, Dr. Kenneson, who is currently affiliated with consulting firm McKing Consulting Corporation in Atlanta, looked at records from the National Center for Health Statistics' Multiple Cause Mortality Files, which contain data from all death certificates in the United States, including immediate and underlying causes of death coded with the International Classification of Diseases.

The group confined their search to the period between 1986 and 2005; they excluded congenital MD from their analysis, since “the distribution of age at death [among these patients] indicated that they were clinically distinct” from other MD patient types.

Overall, there were 18,315 MD-associated deaths from 1986 through 2005; roughly three-quarters were male. The overwhelming majority (90.6%) were white, while 7.7% of deaths occurred among black patients. The remaining 1.7% were among patients identified as being from other races (Neurology 2010;75:982-9).

The authors found a significantly lower median age at death among black females with MD compared with white females (51 years vs. 63 years, respectively).

They also noted that among white women, the proportion who were 45 years or older at death increased, from 78.7% in the first decade of the study period to 83.8% in the second decade.

“In comparison, only about 63% of black females were 45 years or older at death, and this proportion did not change over time,” the investigators wrote.

Among males, the median age at death was significantly lower among blacks than whites (23 years vs. 33 years, respectively).

The median age at death during the 20-year time span of the study increased significantly by 1.3 years annually for white males without cardiomyopathy and 0.2 years annually for those with cardiomyopathy. In contrast, the median age at death increased just 0.33 years annually for black patients without cardiomyopathy. Black patients with cardiomyopathy showed no significant gain in life expectancy at all.

The authors pointed out that although cardiomyopathy was more often reported among blacks than whites, this finding was true “even early in the study period before the widespread use of corticosteroids and [noninvasive ventilation] were likely to have had an effect.”

That could mean that the increased incidence of cardiomyopathy among nonwhite patients is due to simple racial differences the course of MD, or to the higher frequency of cardiomyopathy among blacks in general, rather than a disparity in treatment.

Dr. Kenneson and her coauthors noted that “while the database contains some possible social effect modifiers, such as education and marital status, it does not include information to assess sufficiently other sociocultural variables, such as health insurance and family structure.”

Major Finding: No serious cardiovascular adverse events or clinically meaningful changes in QT interval were recorded.

Data Source: The STAR trial, a 12-week randomized, placebo-controlled trial of 326 patients with pseudobulbar affect, followed by a 12-week open-label extension phase.

Disclosures: The study was supported by Avanir Pharmaceuticals. Dr. Pioro has received personal compensation for serving as a consultant and scientific advisory board member for Avanir. Dr. Kaye is the chief medical officer of Avanir.

TORONTO — The combination of dextromethorphan and quinidine to treat pseudobulbar affect does not appear to cause serious cardiovascular adverse events or clinically meaningful changes in QT interval, according to a 12-week, randomized, placebo-controlled trial.

The analysis was undertaken to address safety concerns expressed in October 2006 by the Food and Drug Administration in an approvable letter that the agency sent to Avanir Pharmaceuticals Inc., the company seeking to bring the combination medication (Zenvia) to market.

At a press conference at the annual meeting of the American Academy of Neurology, Dr. Erik P. Pioro, director of the section of ALS and Related Disorders at the Cleveland Clinic, explained that one of the FDA's concerns was the potential for quinidine to have a proarrhythmic effect, even though the dose used for pseudobulbar affect (PBA) is lower than that recommended to treat dysrhythmias. This might be particularly problematic for patients taking higher quinidine doses or those having pre-existing conditions such as torsades de pointes.

“We found no red flags at all that were clinically significant [and] no indication of cardiovascular problems,” Dr. Pioro said.

PBA refers to a syndrome of disinhibition of emotional expression. Patients with neurologic conditions such as multiple sclerosis, amyotrophic lateral sclerosis, and Parkinson's disease sometimes display uncontrollable episodes of laughing, crying, or other emotions that have no apparent cause. Patients who have PBA can have more than 30 or more episodes per week.

No drugs are currently approved for the treatment of PBA in the United States. Dr. Pioro said antidepressants are commonly used off-label, with variable efficacy and a high side-effect profile.

Previous work has shown that dextromethorphan, an N-methyl-D-aspartate-receptor antagonist and sigma-1-receptor agonist, in combination with quinidine, can reduce the frequency and severity of PBA episodes (Neurology 2004;63:1364–70; Ann. Neurol. 2006;59:780–7). Quinidine is used to increase the bioavailability of dextromethorphan.

In the STAR trial, the investigators randomized 326 patients to receive 30 mg of dextromethorphan plus 10 mg of quinidine (DMq-30), 20 mg of dextromethorphan plus 10 mg of quinidine (DMq-20), or placebo for 12 weeks. During the first week of the study, patients ingested a single capsule of study drug in the morning, but this increased to twice-daily dosing during weeks 2 through 12. Twelve-lead electrocardiograms were performed at baseline and on days 15, 29, 57, and 84.

Almost 87% of patients completed the trial. Approximately 60% of the patients had ALS, and 40% had multiple sclerosis. Effectiveness was assessed using the Center for Neurologic Study Lability Scale; a minimum score of 13 was needed to enroll in the trial.

Changes in QT interval were considered small and not clinically meaningful, with a mean change of 6.6 msec and 8.3 msec for the DMq-20 and DMq-30 groups, respectively.

Corrected mean changes in QT interval showed changes of less than 5 msec from baseline. No subjects had QT or corrected QT intervals of more than 500 msec at day 84, according to Dr. Randall Kaye, who presented the results at the meeting.

There were few cardiac or vascular adverse events, and none were considered serious. “QT prolonged” was reported in 2 subjects, including one in the placebo group. Neither event was assessed as serious or clinically meaningful.

Eight reports of cardiac adverse events were noted in the treated groups, including sinus bradycardia (two), palpitations (one), AV block first degree (two), tachycardia (one), sinus tachycardia (one), and atrial fibrillation (one).

Dr. Pioro also reported safety and tolerability results of a 12-week open-label extension of the STAR trial that enrolled 253 of the 283 patients who completed the double-blind trial; all of these patients received the DMq-30 combination.

During this open-label extension, no treatment-related or cardiovascular serious adverse events were reported. A total of 74% of patients reported one or more adverse events, with similar rates reported no matter which group they had been in during the controlled trial.

Major Finding: No serious cardiovascular adverse events or clinically meaningful changes in QT interval were recorded.

Data Source: The STAR trial, a 12-week randomized, placebo-controlled trial of 326 patients with pseudobulbar affect, followed by a 12-week open-label extension phase.

Disclosures: The study was supported by Avanir Pharmaceuticals. Dr. Pioro has received personal compensation for serving as a consultant and scientific advisory board member for Avanir. Dr. Kaye is the chief medical officer of Avanir.

TORONTO — The combination of dextromethorphan and quinidine to treat pseudobulbar affect does not appear to cause serious cardiovascular adverse events or clinically meaningful changes in QT interval, according to a 12-week, randomized, placebo-controlled trial.

The analysis was undertaken to address safety concerns expressed in October 2006 by the Food and Drug Administration in an approvable letter that the agency sent to Avanir Pharmaceuticals Inc., the company seeking to bring the combination medication (Zenvia) to market.

At a press conference at the annual meeting of the American Academy of Neurology, Dr. Erik P. Pioro, director of the section of ALS and Related Disorders at the Cleveland Clinic, explained that one of the FDA's concerns was the potential for quinidine to have a proarrhythmic effect, even though the dose used for pseudobulbar affect (PBA) is lower than that recommended to treat dysrhythmias. This might be particularly problematic for patients taking higher quinidine doses or those having pre-existing conditions such as torsades de pointes.

“We found no red flags at all that were clinically significant [and] no indication of cardiovascular problems,” Dr. Pioro said.

PBA refers to a syndrome of disinhibition of emotional expression. Patients with neurologic conditions such as multiple sclerosis, amyotrophic lateral sclerosis, and Parkinson's disease sometimes display uncontrollable episodes of laughing, crying, or other emotions that have no apparent cause. Patients who have PBA can have more than 30 or more episodes per week.

No drugs are currently approved for the treatment of PBA in the United States. Dr. Pioro said antidepressants are commonly used off-label, with variable efficacy and a high side-effect profile.

Previous work has shown that dextromethorphan, an N-methyl-D-aspartate-receptor antagonist and sigma-1-receptor agonist, in combination with quinidine, can reduce the frequency and severity of PBA episodes (Neurology 2004;63:1364–70; Ann. Neurol. 2006;59:780–7). Quinidine is used to increase the bioavailability of dextromethorphan.

In the STAR trial, the investigators randomized 326 patients to receive 30 mg of dextromethorphan plus 10 mg of quinidine (DMq-30), 20 mg of dextromethorphan plus 10 mg of quinidine (DMq-20), or placebo for 12 weeks. During the first week of the study, patients ingested a single capsule of study drug in the morning, but this increased to twice-daily dosing during weeks 2 through 12. Twelve-lead electrocardiograms were performed at baseline and on days 15, 29, 57, and 84.

Almost 87% of patients completed the trial. Approximately 60% of the patients had ALS, and 40% had multiple sclerosis. Effectiveness was assessed using the Center for Neurologic Study Lability Scale; a minimum score of 13 was needed to enroll in the trial.

Changes in QT interval were considered small and not clinically meaningful, with a mean change of 6.6 msec and 8.3 msec for the DMq-20 and DMq-30 groups, respectively.

Corrected mean changes in QT interval showed changes of less than 5 msec from baseline. No subjects had QT or corrected QT intervals of more than 500 msec at day 84, according to Dr. Randall Kaye, who presented the results at the meeting.

There were few cardiac or vascular adverse events, and none were considered serious. “QT prolonged” was reported in 2 subjects, including one in the placebo group. Neither event was assessed as serious or clinically meaningful.

Eight reports of cardiac adverse events were noted in the treated groups, including sinus bradycardia (two), palpitations (one), AV block first degree (two), tachycardia (one), sinus tachycardia (one), and atrial fibrillation (one).

Dr. Pioro also reported safety and tolerability results of a 12-week open-label extension of the STAR trial that enrolled 253 of the 283 patients who completed the double-blind trial; all of these patients received the DMq-30 combination.

During this open-label extension, no treatment-related or cardiovascular serious adverse events were reported. A total of 74% of patients reported one or more adverse events, with similar rates reported no matter which group they had been in during the controlled trial.

Major Finding: No serious cardiovascular adverse events or clinically meaningful changes in QT interval were recorded.

Data Source: The STAR trial, a 12-week randomized, placebo-controlled trial of 326 patients with pseudobulbar affect, followed by a 12-week open-label extension phase.

Disclosures: The study was supported by Avanir Pharmaceuticals. Dr. Pioro has received personal compensation for serving as a consultant and scientific advisory board member for Avanir. Dr. Kaye is the chief medical officer of Avanir.

TORONTO — The combination of dextromethorphan and quinidine to treat pseudobulbar affect does not appear to cause serious cardiovascular adverse events or clinically meaningful changes in QT interval, according to a 12-week, randomized, placebo-controlled trial.

The analysis was undertaken to address safety concerns expressed in October 2006 by the Food and Drug Administration in an approvable letter that the agency sent to Avanir Pharmaceuticals Inc., the company seeking to bring the combination medication (Zenvia) to market.

At a press conference at the annual meeting of the American Academy of Neurology, Dr. Erik P. Pioro, director of the section of ALS and Related Disorders at the Cleveland Clinic, explained that one of the FDA's concerns was the potential for quinidine to have a proarrhythmic effect, even though the dose used for pseudobulbar affect (PBA) is lower than that recommended to treat dysrhythmias. This might be particularly problematic for patients taking higher quinidine doses or those having pre-existing conditions such as torsades de pointes.

“We found no red flags at all that were clinically significant [and] no indication of cardiovascular problems,” Dr. Pioro said.

PBA refers to a syndrome of disinhibition of emotional expression. Patients with neurologic conditions such as multiple sclerosis, amyotrophic lateral sclerosis, and Parkinson's disease sometimes display uncontrollable episodes of laughing, crying, or other emotions that have no apparent cause. Patients who have PBA can have more than 30 or more episodes per week.

No drugs are currently approved for the treatment of PBA in the United States. Dr. Pioro said antidepressants are commonly used off-label, with variable efficacy and a high side-effect profile.

Previous work has shown that dextromethorphan, an N-methyl-D-aspartate-receptor antagonist and sigma-1-receptor agonist, in combination with quinidine, can reduce the frequency and severity of PBA episodes (Neurology 2004;63:1364–70; Ann. Neurol. 2006;59:780–7). Quinidine is used to increase the bioavailability of dextromethorphan.

In the STAR trial, the investigators randomized 326 patients to receive 30 mg of dextromethorphan plus 10 mg of quinidine (DMq-30), 20 mg of dextromethorphan plus 10 mg of quinidine (DMq-20), or placebo for 12 weeks. During the first week of the study, patients ingested a single capsule of study drug in the morning, but this increased to twice-daily dosing during weeks 2 through 12. Twelve-lead electrocardiograms were performed at baseline and on days 15, 29, 57, and 84.

Almost 87% of patients completed the trial. Approximately 60% of the patients had ALS, and 40% had multiple sclerosis. Effectiveness was assessed using the Center for Neurologic Study Lability Scale; a minimum score of 13 was needed to enroll in the trial.

Changes in QT interval were considered small and not clinically meaningful, with a mean change of 6.6 msec and 8.3 msec for the DMq-20 and DMq-30 groups, respectively.

Corrected mean changes in QT interval showed changes of less than 5 msec from baseline. No subjects had QT or corrected QT intervals of more than 500 msec at day 84, according to Dr. Randall Kaye, who presented the results at the meeting.

There were few cardiac or vascular adverse events, and none were considered serious. “QT prolonged” was reported in 2 subjects, including one in the placebo group. Neither event was assessed as serious or clinically meaningful.

Eight reports of cardiac adverse events were noted in the treated groups, including sinus bradycardia (two), palpitations (one), AV block first degree (two), tachycardia (one), sinus tachycardia (one), and atrial fibrillation (one).

Dr. Pioro also reported safety and tolerability results of a 12-week open-label extension of the STAR trial that enrolled 253 of the 283 patients who completed the double-blind trial; all of these patients received the DMq-30 combination.

During this open-label extension, no treatment-related or cardiovascular serious adverse events were reported. A total of 74% of patients reported one or more adverse events, with similar rates reported no matter which group they had been in during the controlled trial.

Major Finding: ALS patients experienced similar numbers of events (a decline of six or more points on the ALSFRS-R or death) during treatment with lithium plus riluzole or placebo plus riluzole (22 of 40 patients vs. 20 of 44 patients, respectively).

Data Source: Double-blind, randomized, placebo-controlled trial of 84 patients.

Disclosures: The trial was funded by the National Institute for Neurological Disorders and Stroke and the ALS Society of Canada. Mr. Swash and the investigators reported no relevant conflicts of interest.

The addition of lithium to riluzole for the treatment of amyotrophic lateral sclerosis does not substantially slow disease progression compared with riluzole alone, according to data from a double-blind, randomized, phase II study.

The findings contradict those of a small pilot study that was published in 2008 suggesting that the addition of lithium to standard riluzole therapy led to a slower decline in disease-related disability compared with riluzole therapy alone, according to the lead investigator Dr. Swati P. Aggarwal of Massachusetts General Hospital, Boston, and her colleagues.

The investigators stopped the trial on the recommendation of the data and safety monitoring board and the National Institute of Neurological Disorders and Stroke after the first planned interim analysis showed that lithium in combination with riluzole provided no added benefit over placebo plus riluzole (Lancet Neurol. 2010 April 6 [doi:10.1016/S1474-4422(10)70068-5

Although the findings of the phase II study provide “no convincing evidence for the use of lithium as a treatment for patients with ALS,” Dr. Aggarwal and her associates wrote that future studies should assess the possibility of smaller beneficial effects of lithium in ALS and the therapeutic potential of compounds that target the induction of autophagy.

The phase II trial of 84 patients with ALS from the United States and Canada used a time-to-event design to try to validate the promising results of the earlier study (Proc. Natl. Acad. Sci. U.S.A. 2008;105:2052–7).

This design allowed the investigators to compare the distributions of how long it took patients to show a decrease of at least six points on the ALS functional rating scale–revised (ALSFRS-R) or to die. The study was designed to have greater than 80% power to detect a 40% decrease in the rate of ALSFRS-R decline if all of the originally planned 250 patients had completed the study, they noted.

In an accompanying editorial, Michael Swash from Barts and the London School of Medicine and Dentistry, London, praised the novelty of the study's time-to-event design, which was powered specifically to detect a major effect of lithium, because of the potential for a rapid result and the possibility of crossover from placebo to treatment (Lancet Neurol. 2010 April 6 [doi:10.1016/S1474-4422(10)70085-5

“Use of this study design in trials of ALS represents an important advance,” he wrote.

“Now all that is required is a drug that has plausible pharmacology and pharmacokinetics, and has a favorable side effect profile, which has been studied in rigorous experiments using SOD1 mice.” This tall order, he noted, is “worth striving for.”

Of the 40 patients in the lithium group, 1 patient died and 21 had a decrease of at least six points on the ALSFRS-R. In the placebo group, 3 of 44 patients died and 17 had a decrease of six points or more on the ALSFRS-R. In addition to the reported deaths, 18 patients experienced 29 serious events after randomization, with no difference in the rate of occurrence between the two groups, Dr. Aggarwal and her coauthors reported.

The lithium doses in the study ranged from 150 mg to 1,050 mg per day to achieve a serum concentration of 0.4–0.8 mEq/L, which matches the range used in the pilot study, the authors wrote.

Although the investigators could not rule out the possibility of a small positive effect associated with lithium or that other serum concentration ranges could be beneficial, “the lower limit of the 95% CI around the difference in rates of decline of the ALSFRS-R total score was −0.43, suggesting that although a modest benefit of lithium was not ruled out by this study, an effect of 43% or more could be eliminated,” they wrote.

Major Finding: ALS patients experienced similar numbers of events (a decline of six or more points on the ALSFRS-R or death) during treatment with lithium plus riluzole or placebo plus riluzole (22 of 40 patients vs. 20 of 44 patients, respectively).

Data Source: Double-blind, randomized, placebo-controlled trial of 84 patients.

Disclosures: The trial was funded by the National Institute for Neurological Disorders and Stroke and the ALS Society of Canada. Mr. Swash and the investigators reported no relevant conflicts of interest.

The addition of lithium to riluzole for the treatment of amyotrophic lateral sclerosis does not substantially slow disease progression compared with riluzole alone, according to data from a double-blind, randomized, phase II study.

The findings contradict those of a small pilot study that was published in 2008 suggesting that the addition of lithium to standard riluzole therapy led to a slower decline in disease-related disability compared with riluzole therapy alone, according to the lead investigator Dr. Swati P. Aggarwal of Massachusetts General Hospital, Boston, and her colleagues.

The investigators stopped the trial on the recommendation of the data and safety monitoring board and the National Institute of Neurological Disorders and Stroke after the first planned interim analysis showed that lithium in combination with riluzole provided no added benefit over placebo plus riluzole (Lancet Neurol. 2010 April 6 [doi:10.1016/S1474-4422(10)70068-5

Although the findings of the phase II study provide “no convincing evidence for the use of lithium as a treatment for patients with ALS,” Dr. Aggarwal and her associates wrote that future studies should assess the possibility of smaller beneficial effects of lithium in ALS and the therapeutic potential of compounds that target the induction of autophagy.

The phase II trial of 84 patients with ALS from the United States and Canada used a time-to-event design to try to validate the promising results of the earlier study (Proc. Natl. Acad. Sci. U.S.A. 2008;105:2052–7).

This design allowed the investigators to compare the distributions of how long it took patients to show a decrease of at least six points on the ALS functional rating scale–revised (ALSFRS-R) or to die. The study was designed to have greater than 80% power to detect a 40% decrease in the rate of ALSFRS-R decline if all of the originally planned 250 patients had completed the study, they noted.

In an accompanying editorial, Michael Swash from Barts and the London School of Medicine and Dentistry, London, praised the novelty of the study's time-to-event design, which was powered specifically to detect a major effect of lithium, because of the potential for a rapid result and the possibility of crossover from placebo to treatment (Lancet Neurol. 2010 April 6 [doi:10.1016/S1474-4422(10)70085-5

“Use of this study design in trials of ALS represents an important advance,” he wrote.

“Now all that is required is a drug that has plausible pharmacology and pharmacokinetics, and has a favorable side effect profile, which has been studied in rigorous experiments using SOD1 mice.” This tall order, he noted, is “worth striving for.”

Of the 40 patients in the lithium group, 1 patient died and 21 had a decrease of at least six points on the ALSFRS-R. In the placebo group, 3 of 44 patients died and 17 had a decrease of six points or more on the ALSFRS-R. In addition to the reported deaths, 18 patients experienced 29 serious events after randomization, with no difference in the rate of occurrence between the two groups, Dr. Aggarwal and her coauthors reported.

The lithium doses in the study ranged from 150 mg to 1,050 mg per day to achieve a serum concentration of 0.4–0.8 mEq/L, which matches the range used in the pilot study, the authors wrote.

Although the investigators could not rule out the possibility of a small positive effect associated with lithium or that other serum concentration ranges could be beneficial, “the lower limit of the 95% CI around the difference in rates of decline of the ALSFRS-R total score was −0.43, suggesting that although a modest benefit of lithium was not ruled out by this study, an effect of 43% or more could be eliminated,” they wrote.

Major Finding: ALS patients experienced similar numbers of events (a decline of six or more points on the ALSFRS-R or death) during treatment with lithium plus riluzole or placebo plus riluzole (22 of 40 patients vs. 20 of 44 patients, respectively).

Data Source: Double-blind, randomized, placebo-controlled trial of 84 patients.

Disclosures: The trial was funded by the National Institute for Neurological Disorders and Stroke and the ALS Society of Canada. Mr. Swash and the investigators reported no relevant conflicts of interest.

The addition of lithium to riluzole for the treatment of amyotrophic lateral sclerosis does not substantially slow disease progression compared with riluzole alone, according to data from a double-blind, randomized, phase II study.

The findings contradict those of a small pilot study that was published in 2008 suggesting that the addition of lithium to standard riluzole therapy led to a slower decline in disease-related disability compared with riluzole therapy alone, according to the lead investigator Dr. Swati P. Aggarwal of Massachusetts General Hospital, Boston, and her colleagues.

The investigators stopped the trial on the recommendation of the data and safety monitoring board and the National Institute of Neurological Disorders and Stroke after the first planned interim analysis showed that lithium in combination with riluzole provided no added benefit over placebo plus riluzole (Lancet Neurol. 2010 April 6 [doi:10.1016/S1474-4422(10)70068-5

Although the findings of the phase II study provide “no convincing evidence for the use of lithium as a treatment for patients with ALS,” Dr. Aggarwal and her associates wrote that future studies should assess the possibility of smaller beneficial effects of lithium in ALS and the therapeutic potential of compounds that target the induction of autophagy.

The phase II trial of 84 patients with ALS from the United States and Canada used a time-to-event design to try to validate the promising results of the earlier study (Proc. Natl. Acad. Sci. U.S.A. 2008;105:2052–7).

This design allowed the investigators to compare the distributions of how long it took patients to show a decrease of at least six points on the ALS functional rating scale–revised (ALSFRS-R) or to die. The study was designed to have greater than 80% power to detect a 40% decrease in the rate of ALSFRS-R decline if all of the originally planned 250 patients had completed the study, they noted.

In an accompanying editorial, Michael Swash from Barts and the London School of Medicine and Dentistry, London, praised the novelty of the study's time-to-event design, which was powered specifically to detect a major effect of lithium, because of the potential for a rapid result and the possibility of crossover from placebo to treatment (Lancet Neurol. 2010 April 6 [doi:10.1016/S1474-4422(10)70085-5

“Use of this study design in trials of ALS represents an important advance,” he wrote.

“Now all that is required is a drug that has plausible pharmacology and pharmacokinetics, and has a favorable side effect profile, which has been studied in rigorous experiments using SOD1 mice.” This tall order, he noted, is “worth striving for.”

Of the 40 patients in the lithium group, 1 patient died and 21 had a decrease of at least six points on the ALSFRS-R. In the placebo group, 3 of 44 patients died and 17 had a decrease of six points or more on the ALSFRS-R. In addition to the reported deaths, 18 patients experienced 29 serious events after randomization, with no difference in the rate of occurrence between the two groups, Dr. Aggarwal and her coauthors reported.

The lithium doses in the study ranged from 150 mg to 1,050 mg per day to achieve a serum concentration of 0.4–0.8 mEq/L, which matches the range used in the pilot study, the authors wrote.

Although the investigators could not rule out the possibility of a small positive effect associated with lithium or that other serum concentration ranges could be beneficial, “the lower limit of the 95% CI around the difference in rates of decline of the ALSFRS-R total score was −0.43, suggesting that although a modest benefit of lithium was not ruled out by this study, an effect of 43% or more could be eliminated,” they wrote.

Identifying myositis-specific and myositis-associated antibodies is important for determining subclasses of idiopathic inflammatory myopathies so that appropriate and timely therapy can be initiated, judging from findings from a retrospective study of 169 patients.

Researchers examined the sera from 130 patients who had been initially classified as having primary myositis, and from another 39 patients who had been classified as having overlap myositis (systemic sclerosis [13], rheumatoid arthritis [12], systemic lupus erythematosus [5] and Sj gren's syndrome [9]).

The initial classifications were made using original Bohan and Peter criteria, which are commonly used for classifying idiopathic inflammatory myopathy patients, but which don't take into consideration the presence of myositis-specific and myositis-associated antibodies.

Reevaluation of these patients based on the presence of myositis-specific and -associated antibodies led to 11 (8.5%) of the patients in the primary myositis group being reclassified as having overlap myositis. That classification means that the patients also fulfilled revised American College of Rheumatology criteria for systemic lupus erythematosus, rheumatic arthritis, systemic sclerosis, or Sj gren's syndrome, said Dr. Andrea V ncsa of the University of Debrecen Medical and Health Science Center (Hungary) and colleagues.

In addition to determining the prevalence of various myositis-specific and myositis-associated antibodies, the investigators also identified the clinical characteristics, disease course, and response to therapy associated with the antibodies. Myositis-specific antibodies included anti–Jo-1, –PL-7, –PL-12, –Mi-2, and –SRP. Myositis-associated antibodies included anti–SS-A, –SS-B, –U1snRNP, –Pm/Scl, and –Ku. The investigators characterized the patients into different clinicoserologic groups based on whether myositis-specific and myositis-associated antibodies were present, and further classified the patients as having polymyositis or dermatomyositis (Joint Bone Spine 2010 Feb. 24 [doi:10.1016/j.jbspin.2009.0.008]).

The researchers found that polymyositis was the most common myositis in overlap disease, occurring in 87% of patients in that group. Scleroderma was the most common overlapping disease, occurring in a third of patients in that group.

Antinuclear antibodies (ANA) were present in about 62% of overlap patients, compared with 25% of the primary myositis patients. ANA positivity was associated with an increased risk of associated connective tissue disease (odds ratio, 6.47), the investigators found.

Overall, nearly 40% of the myositis patients had autoantibodies, with anti–Jo-1 occurring most often and in similar frequency in both primary and overlap patients (in 18% and 19%, respectively). The presence of anti–Jo-1 was predominantly associated with polymyositis (in 84% of patients), vs. dermatomyositis, they noted.

Improving the classification of myositis patients using information about myositis-specific and -associated antibodies is important. Clinicians have to consider a variety of these overlap syndromes when treating myositis because the initial treatment provides the best chance of effectively controlling the disease and preventing long-term organ damage.

For example, the researchers found that interstitial lung disease, fever, arthritis, and mechanic's hand were all significantly positively associated with anti–Jo-1 autoantibody positivity in the patients in this study, and that anti–Jo-1 positivity was associated with a need for second-line treatment in primary myositis (OR, 1.95), but not in overlap disease (OR, 0.8).

Identifying myositis-specific and myositis-associated antibodies is important for determining subclasses of idiopathic inflammatory myopathies so that appropriate and timely therapy can be initiated, judging from findings from a retrospective study of 169 patients.

Researchers examined the sera from 130 patients who had been initially classified as having primary myositis, and from another 39 patients who had been classified as having overlap myositis (systemic sclerosis [13], rheumatoid arthritis [12], systemic lupus erythematosus [5] and Sj gren's syndrome [9]).

The initial classifications were made using original Bohan and Peter criteria, which are commonly used for classifying idiopathic inflammatory myopathy patients, but which don't take into consideration the presence of myositis-specific and myositis-associated antibodies.

Reevaluation of these patients based on the presence of myositis-specific and -associated antibodies led to 11 (8.5%) of the patients in the primary myositis group being reclassified as having overlap myositis. That classification means that the patients also fulfilled revised American College of Rheumatology criteria for systemic lupus erythematosus, rheumatic arthritis, systemic sclerosis, or Sj gren's syndrome, said Dr. Andrea V ncsa of the University of Debrecen Medical and Health Science Center (Hungary) and colleagues.

In addition to determining the prevalence of various myositis-specific and myositis-associated antibodies, the investigators also identified the clinical characteristics, disease course, and response to therapy associated with the antibodies. Myositis-specific antibodies included anti–Jo-1, –PL-7, –PL-12, –Mi-2, and –SRP. Myositis-associated antibodies included anti–SS-A, –SS-B, –U1snRNP, –Pm/Scl, and –Ku. The investigators characterized the patients into different clinicoserologic groups based on whether myositis-specific and myositis-associated antibodies were present, and further classified the patients as having polymyositis or dermatomyositis (Joint Bone Spine 2010 Feb. 24 [doi:10.1016/j.jbspin.2009.0.008]).

The researchers found that polymyositis was the most common myositis in overlap disease, occurring in 87% of patients in that group. Scleroderma was the most common overlapping disease, occurring in a third of patients in that group.

Antinuclear antibodies (ANA) were present in about 62% of overlap patients, compared with 25% of the primary myositis patients. ANA positivity was associated with an increased risk of associated connective tissue disease (odds ratio, 6.47), the investigators found.

Overall, nearly 40% of the myositis patients had autoantibodies, with anti–Jo-1 occurring most often and in similar frequency in both primary and overlap patients (in 18% and 19%, respectively). The presence of anti–Jo-1 was predominantly associated with polymyositis (in 84% of patients), vs. dermatomyositis, they noted.

Improving the classification of myositis patients using information about myositis-specific and -associated antibodies is important. Clinicians have to consider a variety of these overlap syndromes when treating myositis because the initial treatment provides the best chance of effectively controlling the disease and preventing long-term organ damage.

For example, the researchers found that interstitial lung disease, fever, arthritis, and mechanic's hand were all significantly positively associated with anti–Jo-1 autoantibody positivity in the patients in this study, and that anti–Jo-1 positivity was associated with a need for second-line treatment in primary myositis (OR, 1.95), but not in overlap disease (OR, 0.8).

Identifying myositis-specific and myositis-associated antibodies is important for determining subclasses of idiopathic inflammatory myopathies so that appropriate and timely therapy can be initiated, judging from findings from a retrospective study of 169 patients.

Researchers examined the sera from 130 patients who had been initially classified as having primary myositis, and from another 39 patients who had been classified as having overlap myositis (systemic sclerosis [13], rheumatoid arthritis [12], systemic lupus erythematosus [5] and Sj gren's syndrome [9]).

The initial classifications were made using original Bohan and Peter criteria, which are commonly used for classifying idiopathic inflammatory myopathy patients, but which don't take into consideration the presence of myositis-specific and myositis-associated antibodies.

Reevaluation of these patients based on the presence of myositis-specific and -associated antibodies led to 11 (8.5%) of the patients in the primary myositis group being reclassified as having overlap myositis. That classification means that the patients also fulfilled revised American College of Rheumatology criteria for systemic lupus erythematosus, rheumatic arthritis, systemic sclerosis, or Sj gren's syndrome, said Dr. Andrea V ncsa of the University of Debrecen Medical and Health Science Center (Hungary) and colleagues.

In addition to determining the prevalence of various myositis-specific and myositis-associated antibodies, the investigators also identified the clinical characteristics, disease course, and response to therapy associated with the antibodies. Myositis-specific antibodies included anti–Jo-1, –PL-7, –PL-12, –Mi-2, and –SRP. Myositis-associated antibodies included anti–SS-A, –SS-B, –U1snRNP, –Pm/Scl, and –Ku. The investigators characterized the patients into different clinicoserologic groups based on whether myositis-specific and myositis-associated antibodies were present, and further classified the patients as having polymyositis or dermatomyositis (Joint Bone Spine 2010 Feb. 24 [doi:10.1016/j.jbspin.2009.0.008]).

The researchers found that polymyositis was the most common myositis in overlap disease, occurring in 87% of patients in that group. Scleroderma was the most common overlapping disease, occurring in a third of patients in that group.

Antinuclear antibodies (ANA) were present in about 62% of overlap patients, compared with 25% of the primary myositis patients. ANA positivity was associated with an increased risk of associated connective tissue disease (odds ratio, 6.47), the investigators found.

Overall, nearly 40% of the myositis patients had autoantibodies, with anti–Jo-1 occurring most often and in similar frequency in both primary and overlap patients (in 18% and 19%, respectively). The presence of anti–Jo-1 was predominantly associated with polymyositis (in 84% of patients), vs. dermatomyositis, they noted.

Improving the classification of myositis patients using information about myositis-specific and -associated antibodies is important. Clinicians have to consider a variety of these overlap syndromes when treating myositis because the initial treatment provides the best chance of effectively controlling the disease and preventing long-term organ damage.

For example, the researchers found that interstitial lung disease, fever, arthritis, and mechanic's hand were all significantly positively associated with anti–Jo-1 autoantibody positivity in the patients in this study, and that anti–Jo-1 positivity was associated with a need for second-line treatment in primary myositis (OR, 1.95), but not in overlap disease (OR, 0.8).

Spinal muscular atrophy, a disease for which there is currently no effective treatment, might one day yield to gene replacement therapy. Two recent studies offer some intriguing insights into possible future directions of work in this field.

Early postnatal delivery of the gene for survival motor neuron 1 protein substantially increased survival rates and motor function in mice that were bred to display the spinal muscular atrophy.

Previous attempts to improve the long-term survival of mice that lack functional copies of the survival motor neuron 1 (SMN) gene have been unsuccessful, increasing survival only a few days to several weeks beyond the 15-day median life span of the mouse model of spinal muscular atrophy (SMA). But in two new studies, researchers increased the life span of the mice to beyond 250 days.

Both research groups used self-complementary adeno-associated virus vectors constructed with SMN (scAAV-SMN) to transduce lumbar spinal motor neurons and increase SMN protein levels in the brain and spinal cord, and—in the setting of intravenous administration—the muscles and vascular endothelium.

SMA in humans is caused by autosomal recessive inheritance of mutated SMN. “Although SMA children are often asymptomatic at birth, newborn screening that can detect SMA has been developed, supporting the feasibility of delivering SMN-scAAV9 to affected children,” Kevin D. Foust, Ph.D., of the Research Institute at Nationwide Children's Hospital, Columbus, Ohio, and his colleagues wrote in their report (Nat. Biotechnol. 2010 Feb. 28 [doi:10.1038/nbt.1610]).

They found that a single intravenous injection of scAAV9-SMN into 1-day-old SMA mice significantly improved their motor function and locomotive abilities. It also significantly improved their weight, but only to half that of control mice, likely because of incomplete transduction of all cells, wrote the researchers. Their work was funded with support from the Miracles for Madison Fund and the National Institute for Neurological Disorders and Stroke.

Aside from the mice that were euthanized for further analyses or died from an incidental cause, all lived beyond 250 days. By days 90-99, mice treated with scAAV9-SMN had fully restored neuromuscular transmission at neuromuscular junctions and a marked reduction in the accumulation of neurofilament at the junctions. If treatment was withheld until postnatal day 2, there was no difference in therapeutic effect, but if treatment was administered on postnatal day 5, survival was limited to 30 days. SMA mice that received treatment on postnatal day 10 were indistinguishable from those that did not receive scAAV9-SMN.

In a second study, Marco A. Passini, Ph.D., and his colleagues at the Genzyme Corp., Framingham, Mass., injected a similar SMN-integrated scAAV vector, scAAV8-SMN, into the cerebral lateral ventricles and the upper lumbar spinal cord of newborn SMA mice. They survived to a median of 157 days, gained weight, and were ambulatory throughout life (J. Clin. Invest. 2010 [doi:10.1172/JCI41615]).

At the age of 16 days, SMA mice treated with scAAV8-SMN expressed SMN at levels about 60%-90% of those seen in wild-type mice. At ages 58-66 and 120-220 days, the mice had SMN levels in the lumbar and thoracic segments that met or exceeded the levels in wild-type mice. At all time points, SMN levels were relatively low in the cervical spinal cord.

Improvements in the number of collapsed neuromuscular junctions were seen at 16 days of age in the quadriceps and intercostal muscles of SMA mice treated with scAAV8-SMN, but the number of these nonfunctional junctions later increased in mice that lived to 216-269 days.

Previous studies attempting treatment of SMA in mice have reported necrosis of the extremities and internal tissues. Dr. Passini and his colleagues observed a “very mild” necrosis of the distal hind legs after treatment that did not require euthanasia. Most (60%) mice in that study were sacrificed because of a sudden appearance of respiratory distress.

Dr. Foust and his coauthors reported only vascular necrosis of the pinna after treatment with scAAV9-SMN.

Dr. Smith's comment: Gene replacement therapy is the holy grail of a number of life-threatening inherited neurological diseases. Inroads on new treatments have been made for Duchenne's muscular dystrophy and Pompe's disease, but not for hereditary anterior horn cell diseases such as the autosomal recessive SMAs.

Attempts to improve muscle function and increase the expression of survival motor neuron 1 (SMN1) using inhibitors of histone deacetylase have yielded only modest results in human subjects with SMA types III or IV. However, in the current studies, researchers were able to increase motor function and survival rates substantially.

The promising results obtained by Dr. Foust's and Dr. Passini's research teams are an early step in the long road of seeking to establish gene replacement therapy as a viable treatment in patients with SMA. Even so, they are a ray of hope on what has been a very dark horizon for families and their loved ones diagnosed with one of these serious disorders. The field anxiously awaits (with appropriately cautious optimism) publication of additional efforts to take gene replacement therapy of SMA (and perhaps in time other inherited motor neuronopathies) closer to the goal of efficacious treatment.

Research report by Jeff Evans, Managing Editor

A monkey's motor neurons (middle, red) were successfully transduced (left, green; right, merged) 25 days after an intravenous injection of scAAV9 vector on the day of birth.

Source Courtesy Kevin D. Foust, Ph.D.

Spinal muscular atrophy, a disease for which there is currently no effective treatment, might one day yield to gene replacement therapy. Two recent studies offer some intriguing insights into possible future directions of work in this field.

Early postnatal delivery of the gene for survival motor neuron 1 protein substantially increased survival rates and motor function in mice that were bred to display the spinal muscular atrophy.

Previous attempts to improve the long-term survival of mice that lack functional copies of the survival motor neuron 1 (SMN) gene have been unsuccessful, increasing survival only a few days to several weeks beyond the 15-day median life span of the mouse model of spinal muscular atrophy (SMA). But in two new studies, researchers increased the life span of the mice to beyond 250 days.

Both research groups used self-complementary adeno-associated virus vectors constructed with SMN (scAAV-SMN) to transduce lumbar spinal motor neurons and increase SMN protein levels in the brain and spinal cord, and—in the setting of intravenous administration—the muscles and vascular endothelium.

SMA in humans is caused by autosomal recessive inheritance of mutated SMN. “Although SMA children are often asymptomatic at birth, newborn screening that can detect SMA has been developed, supporting the feasibility of delivering SMN-scAAV9 to affected children,” Kevin D. Foust, Ph.D., of the Research Institute at Nationwide Children's Hospital, Columbus, Ohio, and his colleagues wrote in their report (Nat. Biotechnol. 2010 Feb. 28 [doi:10.1038/nbt.1610]).

They found that a single intravenous injection of scAAV9-SMN into 1-day-old SMA mice significantly improved their motor function and locomotive abilities. It also significantly improved their weight, but only to half that of control mice, likely because of incomplete transduction of all cells, wrote the researchers. Their work was funded with support from the Miracles for Madison Fund and the National Institute for Neurological Disorders and Stroke.

Aside from the mice that were euthanized for further analyses or died from an incidental cause, all lived beyond 250 days. By days 90-99, mice treated with scAAV9-SMN had fully restored neuromuscular transmission at neuromuscular junctions and a marked reduction in the accumulation of neurofilament at the junctions. If treatment was withheld until postnatal day 2, there was no difference in therapeutic effect, but if treatment was administered on postnatal day 5, survival was limited to 30 days. SMA mice that received treatment on postnatal day 10 were indistinguishable from those that did not receive scAAV9-SMN.

In a second study, Marco A. Passini, Ph.D., and his colleagues at the Genzyme Corp., Framingham, Mass., injected a similar SMN-integrated scAAV vector, scAAV8-SMN, into the cerebral lateral ventricles and the upper lumbar spinal cord of newborn SMA mice. They survived to a median of 157 days, gained weight, and were ambulatory throughout life (J. Clin. Invest. 2010 [doi:10.1172/JCI41615]).

At the age of 16 days, SMA mice treated with scAAV8-SMN expressed SMN at levels about 60%-90% of those seen in wild-type mice. At ages 58-66 and 120-220 days, the mice had SMN levels in the lumbar and thoracic segments that met or exceeded the levels in wild-type mice. At all time points, SMN levels were relatively low in the cervical spinal cord.

Improvements in the number of collapsed neuromuscular junctions were seen at 16 days of age in the quadriceps and intercostal muscles of SMA mice treated with scAAV8-SMN, but the number of these nonfunctional junctions later increased in mice that lived to 216-269 days.

Previous studies attempting treatment of SMA in mice have reported necrosis of the extremities and internal tissues. Dr. Passini and his colleagues observed a “very mild” necrosis of the distal hind legs after treatment that did not require euthanasia. Most (60%) mice in that study were sacrificed because of a sudden appearance of respiratory distress.

Dr. Foust and his coauthors reported only vascular necrosis of the pinna after treatment with scAAV9-SMN.

Dr. Smith's comment: Gene replacement therapy is the holy grail of a number of life-threatening inherited neurological diseases. Inroads on new treatments have been made for Duchenne's muscular dystrophy and Pompe's disease, but not for hereditary anterior horn cell diseases such as the autosomal recessive SMAs.

Attempts to improve muscle function and increase the expression of survival motor neuron 1 (SMN1) using inhibitors of histone deacetylase have yielded only modest results in human subjects with SMA types III or IV. However, in the current studies, researchers were able to increase motor function and survival rates substantially.

The promising results obtained by Dr. Foust's and Dr. Passini's research teams are an early step in the long road of seeking to establish gene replacement therapy as a viable treatment in patients with SMA. Even so, they are a ray of hope on what has been a very dark horizon for families and their loved ones diagnosed with one of these serious disorders. The field anxiously awaits (with appropriately cautious optimism) publication of additional efforts to take gene replacement therapy of SMA (and perhaps in time other inherited motor neuronopathies) closer to the goal of efficacious treatment.

Research report by Jeff Evans, Managing Editor

A monkey's motor neurons (middle, red) were successfully transduced (left, green; right, merged) 25 days after an intravenous injection of scAAV9 vector on the day of birth.

Source Courtesy Kevin D. Foust, Ph.D.

Spinal muscular atrophy, a disease for which there is currently no effective treatment, might one day yield to gene replacement therapy. Two recent studies offer some intriguing insights into possible future directions of work in this field.

Early postnatal delivery of the gene for survival motor neuron 1 protein substantially increased survival rates and motor function in mice that were bred to display the spinal muscular atrophy.

Previous attempts to improve the long-term survival of mice that lack functional copies of the survival motor neuron 1 (SMN) gene have been unsuccessful, increasing survival only a few days to several weeks beyond the 15-day median life span of the mouse model of spinal muscular atrophy (SMA). But in two new studies, researchers increased the life span of the mice to beyond 250 days.

Both research groups used self-complementary adeno-associated virus vectors constructed with SMN (scAAV-SMN) to transduce lumbar spinal motor neurons and increase SMN protein levels in the brain and spinal cord, and—in the setting of intravenous administration—the muscles and vascular endothelium.

SMA in humans is caused by autosomal recessive inheritance of mutated SMN. “Although SMA children are often asymptomatic at birth, newborn screening that can detect SMA has been developed, supporting the feasibility of delivering SMN-scAAV9 to affected children,” Kevin D. Foust, Ph.D., of the Research Institute at Nationwide Children's Hospital, Columbus, Ohio, and his colleagues wrote in their report (Nat. Biotechnol. 2010 Feb. 28 [doi:10.1038/nbt.1610]).

They found that a single intravenous injection of scAAV9-SMN into 1-day-old SMA mice significantly improved their motor function and locomotive abilities. It also significantly improved their weight, but only to half that of control mice, likely because of incomplete transduction of all cells, wrote the researchers. Their work was funded with support from the Miracles for Madison Fund and the National Institute for Neurological Disorders and Stroke.

Aside from the mice that were euthanized for further analyses or died from an incidental cause, all lived beyond 250 days. By days 90-99, mice treated with scAAV9-SMN had fully restored neuromuscular transmission at neuromuscular junctions and a marked reduction in the accumulation of neurofilament at the junctions. If treatment was withheld until postnatal day 2, there was no difference in therapeutic effect, but if treatment was administered on postnatal day 5, survival was limited to 30 days. SMA mice that received treatment on postnatal day 10 were indistinguishable from those that did not receive scAAV9-SMN.

In a second study, Marco A. Passini, Ph.D., and his colleagues at the Genzyme Corp., Framingham, Mass., injected a similar SMN-integrated scAAV vector, scAAV8-SMN, into the cerebral lateral ventricles and the upper lumbar spinal cord of newborn SMA mice. They survived to a median of 157 days, gained weight, and were ambulatory throughout life (J. Clin. Invest. 2010 [doi:10.1172/JCI41615]).

At the age of 16 days, SMA mice treated with scAAV8-SMN expressed SMN at levels about 60%-90% of those seen in wild-type mice. At ages 58-66 and 120-220 days, the mice had SMN levels in the lumbar and thoracic segments that met or exceeded the levels in wild-type mice. At all time points, SMN levels were relatively low in the cervical spinal cord.

Improvements in the number of collapsed neuromuscular junctions were seen at 16 days of age in the quadriceps and intercostal muscles of SMA mice treated with scAAV8-SMN, but the number of these nonfunctional junctions later increased in mice that lived to 216-269 days.

Previous studies attempting treatment of SMA in mice have reported necrosis of the extremities and internal tissues. Dr. Passini and his colleagues observed a “very mild” necrosis of the distal hind legs after treatment that did not require euthanasia. Most (60%) mice in that study were sacrificed because of a sudden appearance of respiratory distress.

Dr. Foust and his coauthors reported only vascular necrosis of the pinna after treatment with scAAV9-SMN.

Dr. Smith's comment: Gene replacement therapy is the holy grail of a number of life-threatening inherited neurological diseases. Inroads on new treatments have been made for Duchenne's muscular dystrophy and Pompe's disease, but not for hereditary anterior horn cell diseases such as the autosomal recessive SMAs.

Attempts to improve muscle function and increase the expression of survival motor neuron 1 (SMN1) using inhibitors of histone deacetylase have yielded only modest results in human subjects with SMA types III or IV. However, in the current studies, researchers were able to increase motor function and survival rates substantially.

The promising results obtained by Dr. Foust's and Dr. Passini's research teams are an early step in the long road of seeking to establish gene replacement therapy as a viable treatment in patients with SMA. Even so, they are a ray of hope on what has been a very dark horizon for families and their loved ones diagnosed with one of these serious disorders. The field anxiously awaits (with appropriately cautious optimism) publication of additional efforts to take gene replacement therapy of SMA (and perhaps in time other inherited motor neuronopathies) closer to the goal of efficacious treatment.

Research report by Jeff Evans, Managing Editor

A monkey's motor neurons (middle, red) were successfully transduced (left, green; right, merged) 25 days after an intravenous injection of scAAV9 vector on the day of birth.

Source Courtesy Kevin D. Foust, Ph.D.

Major Finding: Men with spinal and bulbar muscular atrophy who were treated with dutasteride for 2 years had significantly better physical quality of life, but significantly worse mental quality of life, than did placebo-treated patients. No differences in muscle strength were found.

Data Source: A phase II, randomized, double-blind, placebo-controlled trial of 50 men

Disclosures: The trial was funded by the National Institute of Neurological Diseases and Stroke. None of the investigators had relevant disclosures.

BALTIMORE — Long-term dutasteride therapy in men with spinal and bulbar muscular atrophy does not appear to improve muscle strength or fatigue and might actually lower mental quality of life, according to the results of a phase II, randomized, double-blind, placebo-controlled trial.

Patients derived some benefit from treatment with the 5-alpha reductase inhibitor, which converts testosterone into more potent dihydrotestosterone, as a result of a significant reduction in their number of falls and improvement in their physical quality of life.

Spinal and bulbar muscular atrophy (SBMA) is characterized by a toxic buildup of mutant androgen receptors with an excessively long string of glutamine residues in motor neurons. This buildup weakens bulbar and extremity muscles, causing difficulty with gait and dysphagia, and also might lead to gynecomastia, infertility, and other manifestations of androgen insensitivity. Dutasteride has been thought to be a potential therapy for SBMA because experiments in mice that were bred to express the mutant androgen receptor showed that reducing androgen levels could mitigate the toxicity of the mutant phenotype.

To evaluate the efficacy and safety of dutasteride (Avodart), Dr. Kenneth H. Fischbeck, chief of the Neurogenetics Branch of the National Institute of Neurological Diseases and Stroke and his colleagues randomized 50 men with SBMA to either 0.5 mg/day of dutasteride or placebo. That dose of dutasteride is the same as that approved for treating symptomatic benign prostatic hyperplasia.

The men in each group were an average age of about 53 years, and had an average CAG repeat length of 4 codons (compared with wild-type human repeat length of 36 codons or less), a mean duration of weakness of about 12 years, and an average body mass index of about 28 kg/m

After 2 years, patients treated with dutasteride had virtually no appreciable increase in weight-scaled quantitative muscle assessment scores from baseline—the primary efficacy measure—whereas the scores in patients taking placebo declined by 5% from baseline. This difference was not significant, according to the investigators, who reported their results in a poster session at the annual meeting of the American Neurological Association.

On the Short Form–36 quality of life questionnaire (version 2), the physical component summary improved by about 14% from baseline for dutasteride-treated patients, which was significantly different from the 10% drop recorded in placebo-treated patients.

Significantly fewer falls occurred among patients who were treated with dutasteride than among those who received placebo (9 patients reporting 40 falls vs. 16 subjects reporting 63 falls).

However, patients who took dutasteride fared more poorly than those who took placebo on the mental component summary of the questionnaire, in which patients on placebo had a 10% improvement and patients on dutasteride worsened by about 7%.

Modified barium swallow scores, a measurement for dysphagia severity, worsened by a similar amount in subsets of patients from both arms.

Major Finding: Men with spinal and bulbar muscular atrophy who were treated with dutasteride for 2 years had significantly better physical quality of life, but significantly worse mental quality of life, than did placebo-treated patients. No differences in muscle strength were found.

Data Source: A phase II, randomized, double-blind, placebo-controlled trial of 50 men

Disclosures: The trial was funded by the National Institute of Neurological Diseases and Stroke. None of the investigators had relevant disclosures.

BALTIMORE — Long-term dutasteride therapy in men with spinal and bulbar muscular atrophy does not appear to improve muscle strength or fatigue and might actually lower mental quality of life, according to the results of a phase II, randomized, double-blind, placebo-controlled trial.

Patients derived some benefit from treatment with the 5-alpha reductase inhibitor, which converts testosterone into more potent dihydrotestosterone, as a result of a significant reduction in their number of falls and improvement in their physical quality of life.

Spinal and bulbar muscular atrophy (SBMA) is characterized by a toxic buildup of mutant androgen receptors with an excessively long string of glutamine residues in motor neurons. This buildup weakens bulbar and extremity muscles, causing difficulty with gait and dysphagia, and also might lead to gynecomastia, infertility, and other manifestations of androgen insensitivity. Dutasteride has been thought to be a potential therapy for SBMA because experiments in mice that were bred to express the mutant androgen receptor showed that reducing androgen levels could mitigate the toxicity of the mutant phenotype.

To evaluate the efficacy and safety of dutasteride (Avodart), Dr. Kenneth H. Fischbeck, chief of the Neurogenetics Branch of the National Institute of Neurological Diseases and Stroke and his colleagues randomized 50 men with SBMA to either 0.5 mg/day of dutasteride or placebo. That dose of dutasteride is the same as that approved for treating symptomatic benign prostatic hyperplasia.

The men in each group were an average age of about 53 years, and had an average CAG repeat length of 4 codons (compared with wild-type human repeat length of 36 codons or less), a mean duration of weakness of about 12 years, and an average body mass index of about 28 kg/m

After 2 years, patients treated with dutasteride had virtually no appreciable increase in weight-scaled quantitative muscle assessment scores from baseline—the primary efficacy measure—whereas the scores in patients taking placebo declined by 5% from baseline. This difference was not significant, according to the investigators, who reported their results in a poster session at the annual meeting of the American Neurological Association.

On the Short Form–36 quality of life questionnaire (version 2), the physical component summary improved by about 14% from baseline for dutasteride-treated patients, which was significantly different from the 10% drop recorded in placebo-treated patients.

Significantly fewer falls occurred among patients who were treated with dutasteride than among those who received placebo (9 patients reporting 40 falls vs. 16 subjects reporting 63 falls).

However, patients who took dutasteride fared more poorly than those who took placebo on the mental component summary of the questionnaire, in which patients on placebo had a 10% improvement and patients on dutasteride worsened by about 7%.

Modified barium swallow scores, a measurement for dysphagia severity, worsened by a similar amount in subsets of patients from both arms.

Major Finding: Men with spinal and bulbar muscular atrophy who were treated with dutasteride for 2 years had significantly better physical quality of life, but significantly worse mental quality of life, than did placebo-treated patients. No differences in muscle strength were found.

Data Source: A phase II, randomized, double-blind, placebo-controlled trial of 50 men

Disclosures: The trial was funded by the National Institute of Neurological Diseases and Stroke. None of the investigators had relevant disclosures.

BALTIMORE — Long-term dutasteride therapy in men with spinal and bulbar muscular atrophy does not appear to improve muscle strength or fatigue and might actually lower mental quality of life, according to the results of a phase II, randomized, double-blind, placebo-controlled trial.

Patients derived some benefit from treatment with the 5-alpha reductase inhibitor, which converts testosterone into more potent dihydrotestosterone, as a result of a significant reduction in their number of falls and improvement in their physical quality of life.

Spinal and bulbar muscular atrophy (SBMA) is characterized by a toxic buildup of mutant androgen receptors with an excessively long string of glutamine residues in motor neurons. This buildup weakens bulbar and extremity muscles, causing difficulty with gait and dysphagia, and also might lead to gynecomastia, infertility, and other manifestations of androgen insensitivity. Dutasteride has been thought to be a potential therapy for SBMA because experiments in mice that were bred to express the mutant androgen receptor showed that reducing androgen levels could mitigate the toxicity of the mutant phenotype.

To evaluate the efficacy and safety of dutasteride (Avodart), Dr. Kenneth H. Fischbeck, chief of the Neurogenetics Branch of the National Institute of Neurological Diseases and Stroke and his colleagues randomized 50 men with SBMA to either 0.5 mg/day of dutasteride or placebo. That dose of dutasteride is the same as that approved for treating symptomatic benign prostatic hyperplasia.

The men in each group were an average age of about 53 years, and had an average CAG repeat length of 4 codons (compared with wild-type human repeat length of 36 codons or less), a mean duration of weakness of about 12 years, and an average body mass index of about 28 kg/m

After 2 years, patients treated with dutasteride had virtually no appreciable increase in weight-scaled quantitative muscle assessment scores from baseline—the primary efficacy measure—whereas the scores in patients taking placebo declined by 5% from baseline. This difference was not significant, according to the investigators, who reported their results in a poster session at the annual meeting of the American Neurological Association.

On the Short Form–36 quality of life questionnaire (version 2), the physical component summary improved by about 14% from baseline for dutasteride-treated patients, which was significantly different from the 10% drop recorded in placebo-treated patients.

Significantly fewer falls occurred among patients who were treated with dutasteride than among those who received placebo (9 patients reporting 40 falls vs. 16 subjects reporting 63 falls).

However, patients who took dutasteride fared more poorly than those who took placebo on the mental component summary of the questionnaire, in which patients on placebo had a 10% improvement and patients on dutasteride worsened by about 7%.

Modified barium swallow scores, a measurement for dysphagia severity, worsened by a similar amount in subsets of patients from both arms.

SANTA CLARA, CA—In recent years, researchers have begun to view a group of episodic neurologic disorders—seemingly disparate on the surface—as clinically related as well as genetically linked. Many patients with these disorders appear to be completely healthy between attacks. Marked by such features as migraine, seizure, cardiac arrhythmia, or an episodic movement disorder, these intermittent attacks are often triggered by environmental stressors or dietary factors such as alcohol or caffeine, and many of the drugs used to treat one of these diseases are applied in the management of others. Findings from recent and ongoing genetic and molecular studies have important diagnostic implications for the practice of clinical neurology and could help lead to novel targets for the treatment of epilepsy, migraine, and other more common episodic disorders.

Louis J. Ptácˇek, MD, PhD, John C. Coleman Distinguished Professor in Neurodegenerative Diseases and Professor of Neurology at the University of California, San Francisco (UCSF), has been studying episodic neurologic disorders for almost 20 years. His views have been substantially altered by his own research, as well as that of other investigators. In time, recognizable patterns emerged among many of his patients with episodic disorders.

“They can be completely normal in between attacks, and yet, under certain environmental stressors, they’re pushed over some threshold into an attack of head pain, seizure, hyperexcitability transitioning to weakness, cardiac arrhythmia, or episodic movement disorder,” Dr. Ptácˇek said at the 37th National Meeting of the Child Neurology Society. “As I saw these patients more and more through the years, I became very impressed with the amount of overlap. Despite being fundamentally different disorders on the surface, there were a lot of similarities that I found really striking.”

One area of overlap involves the cause of onset. “The precipitating factors for one disorder among this diverse group are often the same precipitating factors for other disorders—stress being the most prominent, but also dietary factors,” Dr. Ptácˇek said, citing the role of alcohol and caffeine in one phenotype, paroxysmal nonkinesigenic dyskinesia (PNKD).

In addition, the history can be similar among many patients, as the disease often has a childhood onset that worsens through adolescence and young adult life and then decreases in severity and sometimes completely resolves in middle and later adult life. Hormonal factors can also play an important role, Dr. Ptácˇek emphasized. “Catamenial forms of epilepsy and migraine, periodic paralyses, and other episodic disorders can get better or worse in different patients during a woman’s menses,” he said.

Pharmacotherapy of Episodic Disorders
The drugs used to treat these disorders also overlap. Carbonic anhydrase inhibitors have been found to be effective for many of the diseases, as have anticonvulsants and medications given for cardiac arrhythmias.

Recent advances in understanding episodic disorders have the potential to pay big dividends in the area of pharmacotherapy. Dr. Ptácˇek cited research by John Newsom-Davis, Angela Vincent, and others demonstrating that antibodies against ion channels can cause neurologic phenotypes such as stiff person syndrome—representing, in essence, an acquired channelopathy. Another example is PNKD, which Dr. Ptácˇek referred to as an enzyme and a stress-response pathway.

“It raises the possibility of a completely novel place where mutations in a protein that change the gain on stress-response pathways might contribute to membrane excitability,” he said. “[That] is a very exciting possibility—because all of the anticonvulsants and many of the migraine drugs that we use are targeted for voltage- and ligand-gated channels of various sorts, and many were ‘dirty drugs.’” In other words, they are not specific for one target (channel) but rather affect multiple channels. “To have novel targets to look for new candidate molecules for treating patients with epilepsy, migraine, and other episodic disorders would be a whole new area that might help these patients who don’t respond well or who don’t always respond to some of the drugs that we use in our armamentarium.”

A Highly Variable Disorder
Dr. Ptácˇek highlighted three broad categories of episodic neurologic disease: (1) disorders of the human circadian system such as an autosomal-dominant, highly penetrant phenotype that encompasses familial advanced sleep phase syndrome, asthma, and migraine with aura; (2) sodium, calcium, and potassium channelopathies, with a focus on PNKD and the use of caffeine and ethanol to induce attacks in mouse models; and (3) periodic paralyses such as Andersen-Tawil syndrome.

For the tissues or phenotypes in which researchers can measure electric phenomena in such disorders as periodic paralysis, highly organized but very abnormal regenerative action potentials known as myotonia exist. Although these different tissues are associated with different physiologies, they all share what Dr. Ptácˇek called the “remarkable” similarity of highly synchronous and organized, but abnormal, electric activity.

“Beginning in the early 1990s, I, and then later my group, began systematically cloning genes for many of these disorders,” he said. “The first and second [genes]—and the subsequent ones as well—all turned out to be ion-channel genes encoding sodium channels, calcium chloride, or potassium channels. Multiple phenotypes that are clinically distinct can be caused by different mutations in the same gene. The same disease—phenotypically indistinguishable—can arise from mutations in different genes as well. And so this knowledge of the genetic and molecular basis of these disorders led us to refine the classification that had been defined so beautifully by clinical leaders in these groups of diseases over the years.”

Among periodic paralyses, the familial forms constitute less than 10% of all patients. Through extensive and careful phenotype/genotype studies conducted in hundreds of patients with these disorders, Dr. Ptácˇek and his colleagues have shown that a large proportion of the cases can be explained by mutations in one of several identified genes.

“There are still some individuals in small families that we can’t explain, but [they are] decidedly a minority,” he said. “The rest is predominantly made up of a sporadic form of disease called thyrotoxic hypokalemic periodic paralysis, and very recently we cloned a gene that has mutated in that disorder in a quarter to a third of the patients…. That is also what we believe is a genetic disease, but it looks sporadic in families, because … the phenotype can only be uncovered in those individuals who happen to be thyrotoxic.”

Although many of the periodic paralyses are isolated muscle diseases, one disorder that stands out among them, in Dr. Ptácˇek’s view, is Andersen-Tawil syndrome, in which patients have cardiac arrhythmia as well as periodic paralysis. “All the other genes causing periodic paralysis are restricted in their expression pattern of skeletal muscle,” he pointed out. “But as one would predict, this gene [for Andersen-Tawil syndrome] is expressed in both skeletal muscle and heart.”

Patients with Andersen-Tawil syndrome have such dysmorphic features as micrognathia, clinodactyly, and hypertelorism, in addition to heart and muscle phenotypes. Most patients have, for example, some degree of syndactyly. Dr. Ptácˇek and his laboratory team at UCSF have brought patients with Andersen-Tawil syndrome to their clinical research center and characterized them in “exquisite detail.” It is an extremely variable disorder with regard to expressivity, he noted.

“It’s highly penetrant with very variable expressivity, with some people being more dramatically affected [than others],” Dr. Ptácˇek said. “We described a new dental phenotype: These patients can have oligodontia or persistent primary dentition, and the highest expression of this gene turns up in the frontal lobe. Through extensive neurocognitive studies with Bruce Miller and Joel Kramer at UCSF, we showed that these patients have similar IQs to their mutation-negative siblings but that they have a very distinctive neurocognitive phenotype with deficits in the abilities of executive function and abstract reasoning. So this disorder is one in which the gene is widely expressed and where two electric phenotypes—cardiac arrhythmia and periodic paralysis—are present in both….

“The gene encodes a protein that is an inwardly rectifying potassium channel, with mutations scattered throughout this protein in hundreds of patients we’ve collected from around the world. All can lead to dominant negative effects and the manifestation of this disease, Andersen-Tawil syndrome.”

SANTA CLARA, CA—In recent years, researchers have begun to view a group of episodic neurologic disorders—seemingly disparate on the surface—as clinically related as well as genetically linked. Many patients with these disorders appear to be completely healthy between attacks. Marked by such features as migraine, seizure, cardiac arrhythmia, or an episodic movement disorder, these intermittent attacks are often triggered by environmental stressors or dietary factors such as alcohol or caffeine, and many of the drugs used to treat one of these diseases are applied in the management of others. Findings from recent and ongoing genetic and molecular studies have important diagnostic implications for the practice of clinical neurology and could help lead to novel targets for the treatment of epilepsy, migraine, and other more common episodic disorders.

Louis J. Ptácˇek, MD, PhD, John C. Coleman Distinguished Professor in Neurodegenerative Diseases and Professor of Neurology at the University of California, San Francisco (UCSF), has been studying episodic neurologic disorders for almost 20 years. His views have been substantially altered by his own research, as well as that of other investigators. In time, recognizable patterns emerged among many of his patients with episodic disorders.

“They can be completely normal in between attacks, and yet, under certain environmental stressors, they’re pushed over some threshold into an attack of head pain, seizure, hyperexcitability transitioning to weakness, cardiac arrhythmia, or episodic movement disorder,” Dr. Ptácˇek said at the 37th National Meeting of the Child Neurology Society. “As I saw these patients more and more through the years, I became very impressed with the amount of overlap. Despite being fundamentally different disorders on the surface, there were a lot of similarities that I found really striking.”

One area of overlap involves the cause of onset. “The precipitating factors for one disorder among this diverse group are often the same precipitating factors for other disorders—stress being the most prominent, but also dietary factors,” Dr. Ptácˇek said, citing the role of alcohol and caffeine in one phenotype, paroxysmal nonkinesigenic dyskinesia (PNKD).

In addition, the history can be similar among many patients, as the disease often has a childhood onset that worsens through adolescence and young adult life and then decreases in severity and sometimes completely resolves in middle and later adult life. Hormonal factors can also play an important role, Dr. Ptácˇek emphasized. “Catamenial forms of epilepsy and migraine, periodic paralyses, and other episodic disorders can get better or worse in different patients during a woman’s menses,” he said.

Pharmacotherapy of Episodic Disorders
The drugs used to treat these disorders also overlap. Carbonic anhydrase inhibitors have been found to be effective for many of the diseases, as have anticonvulsants and medications given for cardiac arrhythmias.

Recent advances in understanding episodic disorders have the potential to pay big dividends in the area of pharmacotherapy. Dr. Ptácˇek cited research by John Newsom-Davis, Angela Vincent, and others demonstrating that antibodies against ion channels can cause neurologic phenotypes such as stiff person syndrome—representing, in essence, an acquired channelopathy. Another example is PNKD, which Dr. Ptácˇek referred to as an enzyme and a stress-response pathway.

“It raises the possibility of a completely novel place where mutations in a protein that change the gain on stress-response pathways might contribute to membrane excitability,” he said. “[That] is a very exciting possibility—because all of the anticonvulsants and many of the migraine drugs that we use are targeted for voltage- and ligand-gated channels of various sorts, and many were ‘dirty drugs.’” In other words, they are not specific for one target (channel) but rather affect multiple channels. “To have novel targets to look for new candidate molecules for treating patients with epilepsy, migraine, and other episodic disorders would be a whole new area that might help these patients who don’t respond well or who don’t always respond to some of the drugs that we use in our armamentarium.”

A Highly Variable Disorder
Dr. Ptácˇek highlighted three broad categories of episodic neurologic disease: (1) disorders of the human circadian system such as an autosomal-dominant, highly penetrant phenotype that encompasses familial advanced sleep phase syndrome, asthma, and migraine with aura; (2) sodium, calcium, and potassium channelopathies, with a focus on PNKD and the use of caffeine and ethanol to induce attacks in mouse models; and (3) periodic paralyses such as Andersen-Tawil syndrome.

For the tissues or phenotypes in which researchers can measure electric phenomena in such disorders as periodic paralysis, highly organized but very abnormal regenerative action potentials known as myotonia exist. Although these different tissues are associated with different physiologies, they all share what Dr. Ptácˇek called the “remarkable” similarity of highly synchronous and organized, but abnormal, electric activity.

“Beginning in the early 1990s, I, and then later my group, began systematically cloning genes for many of these disorders,” he said. “The first and second [genes]—and the subsequent ones as well—all turned out to be ion-channel genes encoding sodium channels, calcium chloride, or potassium channels. Multiple phenotypes that are clinically distinct can be caused by different mutations in the same gene. The same disease—phenotypically indistinguishable—can arise from mutations in different genes as well. And so this knowledge of the genetic and molecular basis of these disorders led us to refine the classification that had been defined so beautifully by clinical leaders in these groups of diseases over the years.”

Among periodic paralyses, the familial forms constitute less than 10% of all patients. Through extensive and careful phenotype/genotype studies conducted in hundreds of patients with these disorders, Dr. Ptácˇek and his colleagues have shown that a large proportion of the cases can be explained by mutations in one of several identified genes.

“There are still some individuals in small families that we can’t explain, but [they are] decidedly a minority,” he said. “The rest is predominantly made up of a sporadic form of disease called thyrotoxic hypokalemic periodic paralysis, and very recently we cloned a gene that has mutated in that disorder in a quarter to a third of the patients…. That is also what we believe is a genetic disease, but it looks sporadic in families, because … the phenotype can only be uncovered in those individuals who happen to be thyrotoxic.”

Although many of the periodic paralyses are isolated muscle diseases, one disorder that stands out among them, in Dr. Ptácˇek’s view, is Andersen-Tawil syndrome, in which patients have cardiac arrhythmia as well as periodic paralysis. “All the other genes causing periodic paralysis are restricted in their expression pattern of skeletal muscle,” he pointed out. “But as one would predict, this gene [for Andersen-Tawil syndrome] is expressed in both skeletal muscle and heart.”

Patients with Andersen-Tawil syndrome have such dysmorphic features as micrognathia, clinodactyly, and hypertelorism, in addition to heart and muscle phenotypes. Most patients have, for example, some degree of syndactyly. Dr. Ptácˇek and his laboratory team at UCSF have brought patients with Andersen-Tawil syndrome to their clinical research center and characterized them in “exquisite detail.” It is an extremely variable disorder with regard to expressivity, he noted.

“It’s highly penetrant with very variable expressivity, with some people being more dramatically affected [than others],” Dr. Ptácˇek said. “We described a new dental phenotype: These patients can have oligodontia or persistent primary dentition, and the highest expression of this gene turns up in the frontal lobe. Through extensive neurocognitive studies with Bruce Miller and Joel Kramer at UCSF, we showed that these patients have similar IQs to their mutation-negative siblings but that they have a very distinctive neurocognitive phenotype with deficits in the abilities of executive function and abstract reasoning. So this disorder is one in which the gene is widely expressed and where two electric phenotypes—cardiac arrhythmia and periodic paralysis—are present in both….

“The gene encodes a protein that is an inwardly rectifying potassium channel, with mutations scattered throughout this protein in hundreds of patients we’ve collected from around the world. All can lead to dominant negative effects and the manifestation of this disease, Andersen-Tawil syndrome.”

SANTA CLARA, CA—In recent years, researchers have begun to view a group of episodic neurologic disorders—seemingly disparate on the surface—as clinically related as well as genetically linked. Many patients with these disorders appear to be completely healthy between attacks. Marked by such features as migraine, seizure, cardiac arrhythmia, or an episodic movement disorder, these intermittent attacks are often triggered by environmental stressors or dietary factors such as alcohol or caffeine, and many of the drugs used to treat one of these diseases are applied in the management of others. Findings from recent and ongoing genetic and molecular studies have important diagnostic implications for the practice of clinical neurology and could help lead to novel targets for the treatment of epilepsy, migraine, and other more common episodic disorders.

Louis J. Ptácˇek, MD, PhD, John C. Coleman Distinguished Professor in Neurodegenerative Diseases and Professor of Neurology at the University of California, San Francisco (UCSF), has been studying episodic neurologic disorders for almost 20 years. His views have been substantially altered by his own research, as well as that of other investigators. In time, recognizable patterns emerged among many of his patients with episodic disorders.

“They can be completely normal in between attacks, and yet, under certain environmental stressors, they’re pushed over some threshold into an attack of head pain, seizure, hyperexcitability transitioning to weakness, cardiac arrhythmia, or episodic movement disorder,” Dr. Ptácˇek said at the 37th National Meeting of the Child Neurology Society. “As I saw these patients more and more through the years, I became very impressed with the amount of overlap. Despite being fundamentally different disorders on the surface, there were a lot of similarities that I found really striking.”

One area of overlap involves the cause of onset. “The precipitating factors for one disorder among this diverse group are often the same precipitating factors for other disorders—stress being the most prominent, but also dietary factors,” Dr. Ptácˇek said, citing the role of alcohol and caffeine in one phenotype, paroxysmal nonkinesigenic dyskinesia (PNKD).

In addition, the history can be similar among many patients, as the disease often has a childhood onset that worsens through adolescence and young adult life and then decreases in severity and sometimes completely resolves in middle and later adult life. Hormonal factors can also play an important role, Dr. Ptácˇek emphasized. “Catamenial forms of epilepsy and migraine, periodic paralyses, and other episodic disorders can get better or worse in different patients during a woman’s menses,” he said.

Pharmacotherapy of Episodic Disorders
The drugs used to treat these disorders also overlap. Carbonic anhydrase inhibitors have been found to be effective for many of the diseases, as have anticonvulsants and medications given for cardiac arrhythmias.

Recent advances in understanding episodic disorders have the potential to pay big dividends in the area of pharmacotherapy. Dr. Ptácˇek cited research by John Newsom-Davis, Angela Vincent, and others demonstrating that antibodies against ion channels can cause neurologic phenotypes such as stiff person syndrome—representing, in essence, an acquired channelopathy. Another example is PNKD, which Dr. Ptácˇek referred to as an enzyme and a stress-response pathway.

“It raises the possibility of a completely novel place where mutations in a protein that change the gain on stress-response pathways might contribute to membrane excitability,” he said. “[That] is a very exciting possibility—because all of the anticonvulsants and many of the migraine drugs that we use are targeted for voltage- and ligand-gated channels of various sorts, and many were ‘dirty drugs.’” In other words, they are not specific for one target (channel) but rather affect multiple channels. “To have novel targets to look for new candidate molecules for treating patients with epilepsy, migraine, and other episodic disorders would be a whole new area that might help these patients who don’t respond well or who don’t always respond to some of the drugs that we use in our armamentarium.”

A Highly Variable Disorder
Dr. Ptácˇek highlighted three broad categories of episodic neurologic disease: (1) disorders of the human circadian system such as an autosomal-dominant, highly penetrant phenotype that encompasses familial advanced sleep phase syndrome, asthma, and migraine with aura; (2) sodium, calcium, and potassium channelopathies, with a focus on PNKD and the use of caffeine and ethanol to induce attacks in mouse models; and (3) periodic paralyses such as Andersen-Tawil syndrome.

For the tissues or phenotypes in which researchers can measure electric phenomena in such disorders as periodic paralysis, highly organized but very abnormal regenerative action potentials known as myotonia exist. Although these different tissues are associated with different physiologies, they all share what Dr. Ptácˇek called the “remarkable” similarity of highly synchronous and organized, but abnormal, electric activity.

“Beginning in the early 1990s, I, and then later my group, began systematically cloning genes for many of these disorders,” he said. “The first and second [genes]—and the subsequent ones as well—all turned out to be ion-channel genes encoding sodium channels, calcium chloride, or potassium channels. Multiple phenotypes that are clinically distinct can be caused by different mutations in the same gene. The same disease—phenotypically indistinguishable—can arise from mutations in different genes as well. And so this knowledge of the genetic and molecular basis of these disorders led us to refine the classification that had been defined so beautifully by clinical leaders in these groups of diseases over the years.”

Among periodic paralyses, the familial forms constitute less than 10% of all patients. Through extensive and careful phenotype/genotype studies conducted in hundreds of patients with these disorders, Dr. Ptácˇek and his colleagues have shown that a large proportion of the cases can be explained by mutations in one of several identified genes.

“There are still some individuals in small families that we can’t explain, but [they are] decidedly a minority,” he said. “The rest is predominantly made up of a sporadic form of disease called thyrotoxic hypokalemic periodic paralysis, and very recently we cloned a gene that has mutated in that disorder in a quarter to a third of the patients…. That is also what we believe is a genetic disease, but it looks sporadic in families, because … the phenotype can only be uncovered in those individuals who happen to be thyrotoxic.”

Although many of the periodic paralyses are isolated muscle diseases, one disorder that stands out among them, in Dr. Ptácˇek’s view, is Andersen-Tawil syndrome, in which patients have cardiac arrhythmia as well as periodic paralysis. “All the other genes causing periodic paralysis are restricted in their expression pattern of skeletal muscle,” he pointed out. “But as one would predict, this gene [for Andersen-Tawil syndrome] is expressed in both skeletal muscle and heart.”

Patients with Andersen-Tawil syndrome have such dysmorphic features as micrognathia, clinodactyly, and hypertelorism, in addition to heart and muscle phenotypes. Most patients have, for example, some degree of syndactyly. Dr. Ptácˇek and his laboratory team at UCSF have brought patients with Andersen-Tawil syndrome to their clinical research center and characterized them in “exquisite detail.” It is an extremely variable disorder with regard to expressivity, he noted.

“It’s highly penetrant with very variable expressivity, with some people being more dramatically affected [than others],” Dr. Ptácˇek said. “We described a new dental phenotype: These patients can have oligodontia or persistent primary dentition, and the highest expression of this gene turns up in the frontal lobe. Through extensive neurocognitive studies with Bruce Miller and Joel Kramer at UCSF, we showed that these patients have similar IQs to their mutation-negative siblings but that they have a very distinctive neurocognitive phenotype with deficits in the abilities of executive function and abstract reasoning. So this disorder is one in which the gene is widely expressed and where two electric phenotypes—cardiac arrhythmia and periodic paralysis—are present in both….

“The gene encodes a protein that is an inwardly rectifying potassium channel, with mutations scattered throughout this protein in hundreds of patients we’ve collected from around the world. All can lead to dominant negative effects and the manifestation of this disease, Andersen-Tawil syndrome.”