- Email: [email protected]
96. Placebo-controlled study of alglucosidase alfa in adults with pompe disease
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Society Proceedings / Clinical Neurophysiology 120 (2009) e89–e126
75% representative samples and the MRI gave 85% (statistically not significant, Fisher Exact Test). Conclusions: The data indicate that even when using detailed anatomical (MRI) or functional (EMG) information, a proportion of biopsy samples remains nondiagnostic. Both the strategies employed by the authors yielded a comparable proportion of diagnostic samples. F.A. Barroso is a recipient of the 2008 IFCN North American Chapter Fellowship Award. doi:10.1016/j.clinph.2008.10.111
94. Pompe registry: Tracking pompe disease symptoms in a broad patient population—P. Kishnani 1, B. Byrne 2, L. Case 1, L. Merlini 3, W. Müeller-Felber 4, A. van der Ploeg 5, T. Miller 6 (1 Durham, NC, USA, 2 Gainesville, FL, USA, 3 Ferrara, Italy, 4 Munich, Germany, 5 Rotterdam, The Netherlands, 6 Cambridge, MA, USA) Introduction: Pompe disease (acid maltase deficiency) is a rare, progressive, and often fatal metabolic myopathy, which manifests as a clinical spectrum that varies with respect to age at onset, rate of disease progression, and extent of organ involvement. The underlying pathology is a deficiency of acid alpha-glucosidase (GAA). To gain a better understanding of the natural course of Pompe disease, a global, voluntary, and observational registry was developed to collect anonymous, longitudinal data. Results: As of September 2007, 400 patients from 23 countries had enrolled in the study; the majority (71%) are Caucasian. Europe and North America enrolled 85% of patients. For infants (n = 78, 20%), the median age at symptom onset was 2 months and median age at diagnosis was 4 months. For adults (n = 238, 60%), the median age at symptom onset was 26.3 years and median age at diagnosis was 34.5 years. Patients currently 18 years old (n = 259) most frequently report the following symptoms: muscle weakness [lower extremities (81%), upper extremities (71%), and trunk (57%)]; shortness of breath after exercise (61%) and at rest (33%); dependence on respiratory support (39%); sleep disturbance/apnea (37%); orthopnea (34%); and scapular winging (31%). Of the patients genotyped, 54% (76/ 140) expressed the IVS1-13T G mutation. Conclusion: The results indicate a significant delay from the time of symptom onset to diagnosis in adult patients and highlight the need for greater disease awareness. As the Pompe Registry matures, data on prevalence and age at onset of symptoms in various patient subgroups may allow physicians to identify patients at earlier stages of disease progression. Study supported by Genzyme. Dr. Kishnani is a speaker for Genzyme and also serves on a scientific advisory board for Genzyme. Dr. Case has served on Genzyme’s Pompe Registry Board of Advisers and has received research support from Genzyme. Dr. Müeller-Felber is a speaker for Genzyme. Dr. van der Ploeg has received research support from Genzyme. Dr. Miller is employed as a medical director for Genzyme. doi:10.1016/j.clinph.2008.10.112
95. A patient with malignant hyperthermia and phosphofructokinase deficiency—M. Alsharabati, A.M. Young, S.J. Oh (Birmingham, AL, USA) Introduction: Phosphofructokinase deficiency (Tarui disease) is a rare autosomal recessive type IV glycogen storage disease that af-
fects the muscle, predominantly in males. It is characterized by exercise intolerance and easy fatigability, myoglobinuria, and hemolysis. Malignant hyperthermia is an autosomal dominant disorder that occurs after general anesthesia. It may be associated with multicore and central core myopathy. Case report: The authors report a case of a 42-year-old male with phosphofructokinase deficiency and malignant hyperthermia. The patient is a professional biker and after long rides, experienced episodic severe muscle contractures for 25 years. Episodes of myoglobinuria, rhabdomyolysis, and heat stroke have occurred after heavy exercise. His creatine kinase (CK) was elevated (11,000) during one of the episodes. During hospitalization for surgery at age 18, he suffered malignant hyperthermia (CK 26,000). Two sisters also tested positive for malignant hyperthermia. A previous muscle biopsy was normal. He was presented for evaluation. The neurological examination was normal with the exception of minimal swelling in the left vastus lateralis muscle as compared to the right. CK was 543. Electromyography showed scattered short amplitude short duration motor unit action potentials with early recruitment (inactive myopathy). Ischemic exercise testing was normal. A muscle biopsy revealed an increase in internal nuclei and small type I fibers. Biochemical studies showed phosphofructokinase deficiency, diagnosing Tarui disease. The patient improved after treatment with dantrolene and a low carbohydrate diet. Genetic testing is pending. Conclusion: Phosphofructokinase deficiency can be associated with malignant hyperthermia. This is the first case reported in the literature. doi:10.1016/j.clinph.2008.10.113
96. Placebo-controlled study of alglucosidase alfa in adults with pompe disease—P.R. Clemens 1, A. van der Ploeg 2, D. Corzo 3, J. Florence 4, P. Laforet 5, S. Lake 3, A. Pestronk 4, B. Rosenbloom 6, A. Skrinar 3, M. Wasserstein 7, R. Leshner 8, D.M. Escolar 8, J. Mayhew 8, R. Leshner 8 (1 Pittsburgh, PA, USA, 2 Rotterdam, The Netherlands, 3 Cambridge, MA, USA, 4 St. Louis, MO, USA, 5 Paris, France, 6 Beverly Hills, CA, USA, 7 New York, NY, USA, 8 Washington, DC, USA) Background: Pompe disease (also known as acid maltase deficiency) is a rare, metabolic myopathy caused by a deficiency of acid a-glucosidase (GAA). In juveniles and adults, the disease is relentlessly progressive and leads to wheelchair dependency and respiratory failure. Methods: Patients were ambulatory, free of invasive ventilation, and had quantifiable respiratory and lower extremity muscle weakness. Patients from the United States and Europe were randomized in the ratio of 2:1 and received biweekly alglucosidase alfa 20 mg/ kg IV or placebo for 78 weeks. The co-primary endpoints included the distance walked in the 6 min walk test (6MWT) and percent predicted forced vital capacity (FVC). Results: Ninety patients (45 male, 45 female; 93% Caucasian; aged 10–70 years) were randomized in the study. Baseline mean 6MWT distance was 327.4 ± 128.0 meters (50.1% predicted) and mean FVC was 54.6 ± 14.8% predicted, indicating considerable disease burden at baseline. By last evaluation, the estimated mean absolute differences of 28.1 ± 13.1 meters in 6MWT distance (p = .03) and 3.4 ± 1.2% in percent predicted FVC (p = .003) were observed in favor of alglucosidase alfa versus placebo. The frequency of adverse events and infusion-associated reactions were comparable between groups. Three patients in the alglucosidase alfa group experienced hypersensitivity reactions, then discontinued treatment. One patient in the alglucosidase alfa group died from causes unrelated to
Society Proceedings / Clinical Neurophysiology 120 (2009) e89–e126
treatment. All evaluable patients in the alglucosidase alfa group (n = 59) developed IgG antibodies to rhGAA. A trend toward decreasing IgG titers was observed. Conclusions: In this first placebo-controlled study of rhGAA in juveniles and adults with Pompe disease, alglucosidase alfa was shown to improve walking and pulmonary outcomes as compared to placebo. This clinical trial was supported by Genzyme. Dr. Clemens received research funds from Genzyme for this study. Dr. Van Der Ploeg received research funds from Genzyme for this study. Deya Corzo, Stephen Lake, and Alison Skrinar are employees of Genzyme and hold stock in the company. Dr. Laforet is a member of the Genzyme advisory board. Dr. Pestronk is a speaker and receives license fee payments from Athena. He also received research support from Genzyme for this study. Dr. Rosenbloom was an investigator in this clinical trial sponsored by Genzyme Corporation. Dr. Escolar is an advisory board member for Orico, a medical advisor for Faust Pharmaceuticals, and an advisory board member for Acceleron. She also received research funds from Genzyme for this study. Ms. Mayhew is a consultant to Genzyme. Dr. Leshner is a speaker for Genzyme. He also received research support from Genzyme for this study. doi:10.1016/j.clinph.2008.10.114
97. Muscle strength and fatigue in patients with generalized myasthenia gravis—C.J. Symonette, B.V. Watson, W.J. Koopman, M.W. Nicolle, T.J. Doherty (London, Ont., Canada) Introduction: Patients with generalized myasthenia gravis (MG) characteristically present with fatigable muscle weakness resulting from impaired neuromuscular transmission (NMT). NMT failure is demonstrated by decrement of the compound muscle action potential with repetitive nerve stimulation (RNS). However, some patients with MG fail to show decrement despite symptoms of weakness and fatigue. Quantitative measurement of muscle strength and fatigue may provide evidence of NMT failure in the latter group despite normal RNS, or might show a pattern differentiating NMT from nonNMT causes for weakness. Objectives: To evaluate the strength and fatigue of patients with MG who present with and without decrement and to further determine whether the pattern of weakness in MG patients with normal RNS differs from those with decrement and control subjects. Methods: Subjects were divided into three groups (control subjects, nondecrementing MG, and decrementing MG) according to RNS of the spinal accessory and axillary nerves. Maximum voluntary isometric contraction (MVIC) strength and fatigue of shoulder abduction were measured. Questionnaires were used to further define the patient population in terms of additional fatigue and disease severity. Results: The decrementing MG group exhibited lower initial MVIC strength and no difference in fatigue than the nondecrementing MG and control groups. Patients with MG demonstrated greaterexperienced fatigue than the control group. Conclusion: The results indicate findings of reduced MVIC and no difference in fatigue in decrementing versus nondecrementing groups of patients with generalized MG. Greater experienced fatigue in MG may correspond to confounding variables such as physical
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inactivity. In addition, decrement upon RNS appears to relate best to disease severity and muscle weakness, but not to fatigue in this population. Study supported by Canada Research Chairs Program. doi:10.1016/j.clinph.2008.10.115
98. Clinical and electrophysiological characters of Lambert–Eaton syndrome—Y. Guan, L. Cui (Beijing, China) Introduction: The authors examined the symptoms and signs of Lambert-Easton myasthenic syndrome (LEMS) in 45 patients using retrospective analysis. Characteristics of electrophysiological examinations were investigated. Objectives: To analyze clinical and electrophysiological characteristic in LEMS. Methods: Forty-five LEMS patients’ records were reviewed and information gathered regarding clinical complaints, neurological symptoms, and other concomitant diseases. The records showed that repetitive nerve stimulation (RNS) and nerve conduction studies (NCSs) were performed on all of the patients. A needle electromyography (EMG) examination was performed on 30 of the 45 patients. Results: The authors identified the following three findings: (1) the two most common symptoms were weakness of lower extremities (n = 35) and a decreased or nonexistent deep tendon reflex (n = 40). (2) The types of diseases that occurred with LEMS included: small lung cell cancer (n = 9), lymphadenoma (n = 3), thymic hyperplasia (n = 2,), and other immune diseases (n = 3). Lymph node accretion in mediastina or lung without malignant tumor was found by pathology examination in 15 patients. Thirteen patients were found to have no neoplasm or autoimmune diseases. (3) RNS increased at 20 Hz when studying the abductor digiti minimi. Low frequency RNS abnormalities were found in 29 patients. Sensory NCS abnormalities or sensory and motor NCS abnormalities were found in 19 patients. Of the 30 patients who underwent a needle EMG examination, 20 had myogenic damage. Conclusions: Many abnormal electrophysiology results were found in LEMS patients, including NCS abnormalities and myopathy. These findings indicated that immune and pathological changes exceeded the neuromuscular junction and perhaps included the peripheral nerve and muscle. doi:10.1016/j.clinph.2008.10.116
99. Autoimmunity – myasthenia gravis, Graves’ disease and vitiligo: A case report—V. Serban (San Diego, CA, USA) Introduction: Myasthenia gravis (MG) is an autoimmune neuromuscular disease that is rarely associated with other autoimmune conditions. Epidemiologic studies report 5–10% occurrence of autoimmune thyroid disease (autoimmune thyroiditis and Graves’ disease) in patients with MG, whereas MG occurs in only 0.2% of patients with autoimmune thyroid disease. The clinical presentation of MG associated with autoimmune thyroid disease is frequently restricted to the eye muscles. There are few cases with the rare association of ocular MG, Graves’ disease and vitiligo. The reason for this is unknown, but hypothesized that it involves an immunological cross-reactivity of the epitopes. Case report: A 20-year-old right-handed man presented with diplopia, variable ptosis, and severely restricted eye movements.
Society Proceedings / Clinical Neurophysiology 120 (2009) e89–e126
75% representative samples and the MRI gave 85% (statistically not significant, Fisher Exact Test). Conclusions: The data indicate that even when using detailed anatomical (MRI) or functional (EMG) information, a proportion of biopsy samples remains nondiagnostic. Both the strategies employed by the authors yielded a comparable proportion of diagnostic samples. F.A. Barroso is a recipient of the 2008 IFCN North American Chapter Fellowship Award. doi:10.1016/j.clinph.2008.10.111
94. Pompe registry: Tracking pompe disease symptoms in a broad patient population—P. Kishnani 1, B. Byrne 2, L. Case 1, L. Merlini 3, W. Müeller-Felber 4, A. van der Ploeg 5, T. Miller 6 (1 Durham, NC, USA, 2 Gainesville, FL, USA, 3 Ferrara, Italy, 4 Munich, Germany, 5 Rotterdam, The Netherlands, 6 Cambridge, MA, USA) Introduction: Pompe disease (acid maltase deficiency) is a rare, progressive, and often fatal metabolic myopathy, which manifests as a clinical spectrum that varies with respect to age at onset, rate of disease progression, and extent of organ involvement. The underlying pathology is a deficiency of acid alpha-glucosidase (GAA). To gain a better understanding of the natural course of Pompe disease, a global, voluntary, and observational registry was developed to collect anonymous, longitudinal data. Results: As of September 2007, 400 patients from 23 countries had enrolled in the study; the majority (71%) are Caucasian. Europe and North America enrolled 85% of patients. For infants (n = 78, 20%), the median age at symptom onset was 2 months and median age at diagnosis was 4 months. For adults (n = 238, 60%), the median age at symptom onset was 26.3 years and median age at diagnosis was 34.5 years. Patients currently 18 years old (n = 259) most frequently report the following symptoms: muscle weakness [lower extremities (81%), upper extremities (71%), and trunk (57%)]; shortness of breath after exercise (61%) and at rest (33%); dependence on respiratory support (39%); sleep disturbance/apnea (37%); orthopnea (34%); and scapular winging (31%). Of the patients genotyped, 54% (76/ 140) expressed the IVS1-13T G mutation. Conclusion: The results indicate a significant delay from the time of symptom onset to diagnosis in adult patients and highlight the need for greater disease awareness. As the Pompe Registry matures, data on prevalence and age at onset of symptoms in various patient subgroups may allow physicians to identify patients at earlier stages of disease progression. Study supported by Genzyme. Dr. Kishnani is a speaker for Genzyme and also serves on a scientific advisory board for Genzyme. Dr. Case has served on Genzyme’s Pompe Registry Board of Advisers and has received research support from Genzyme. Dr. Müeller-Felber is a speaker for Genzyme. Dr. van der Ploeg has received research support from Genzyme. Dr. Miller is employed as a medical director for Genzyme. doi:10.1016/j.clinph.2008.10.112
95. A patient with malignant hyperthermia and phosphofructokinase deficiency—M. Alsharabati, A.M. Young, S.J. Oh (Birmingham, AL, USA) Introduction: Phosphofructokinase deficiency (Tarui disease) is a rare autosomal recessive type IV glycogen storage disease that af-
fects the muscle, predominantly in males. It is characterized by exercise intolerance and easy fatigability, myoglobinuria, and hemolysis. Malignant hyperthermia is an autosomal dominant disorder that occurs after general anesthesia. It may be associated with multicore and central core myopathy. Case report: The authors report a case of a 42-year-old male with phosphofructokinase deficiency and malignant hyperthermia. The patient is a professional biker and after long rides, experienced episodic severe muscle contractures for 25 years. Episodes of myoglobinuria, rhabdomyolysis, and heat stroke have occurred after heavy exercise. His creatine kinase (CK) was elevated (11,000) during one of the episodes. During hospitalization for surgery at age 18, he suffered malignant hyperthermia (CK 26,000). Two sisters also tested positive for malignant hyperthermia. A previous muscle biopsy was normal. He was presented for evaluation. The neurological examination was normal with the exception of minimal swelling in the left vastus lateralis muscle as compared to the right. CK was 543. Electromyography showed scattered short amplitude short duration motor unit action potentials with early recruitment (inactive myopathy). Ischemic exercise testing was normal. A muscle biopsy revealed an increase in internal nuclei and small type I fibers. Biochemical studies showed phosphofructokinase deficiency, diagnosing Tarui disease. The patient improved after treatment with dantrolene and a low carbohydrate diet. Genetic testing is pending. Conclusion: Phosphofructokinase deficiency can be associated with malignant hyperthermia. This is the first case reported in the literature. doi:10.1016/j.clinph.2008.10.113
96. Placebo-controlled study of alglucosidase alfa in adults with pompe disease—P.R. Clemens 1, A. van der Ploeg 2, D. Corzo 3, J. Florence 4, P. Laforet 5, S. Lake 3, A. Pestronk 4, B. Rosenbloom 6, A. Skrinar 3, M. Wasserstein 7, R. Leshner 8, D.M. Escolar 8, J. Mayhew 8, R. Leshner 8 (1 Pittsburgh, PA, USA, 2 Rotterdam, The Netherlands, 3 Cambridge, MA, USA, 4 St. Louis, MO, USA, 5 Paris, France, 6 Beverly Hills, CA, USA, 7 New York, NY, USA, 8 Washington, DC, USA) Background: Pompe disease (also known as acid maltase deficiency) is a rare, metabolic myopathy caused by a deficiency of acid a-glucosidase (GAA). In juveniles and adults, the disease is relentlessly progressive and leads to wheelchair dependency and respiratory failure. Methods: Patients were ambulatory, free of invasive ventilation, and had quantifiable respiratory and lower extremity muscle weakness. Patients from the United States and Europe were randomized in the ratio of 2:1 and received biweekly alglucosidase alfa 20 mg/ kg IV or placebo for 78 weeks. The co-primary endpoints included the distance walked in the 6 min walk test (6MWT) and percent predicted forced vital capacity (FVC). Results: Ninety patients (45 male, 45 female; 93% Caucasian; aged 10–70 years) were randomized in the study. Baseline mean 6MWT distance was 327.4 ± 128.0 meters (50.1% predicted) and mean FVC was 54.6 ± 14.8% predicted, indicating considerable disease burden at baseline. By last evaluation, the estimated mean absolute differences of 28.1 ± 13.1 meters in 6MWT distance (p = .03) and 3.4 ± 1.2% in percent predicted FVC (p = .003) were observed in favor of alglucosidase alfa versus placebo. The frequency of adverse events and infusion-associated reactions were comparable between groups. Three patients in the alglucosidase alfa group experienced hypersensitivity reactions, then discontinued treatment. One patient in the alglucosidase alfa group died from causes unrelated to
Society Proceedings / Clinical Neurophysiology 120 (2009) e89–e126
treatment. All evaluable patients in the alglucosidase alfa group (n = 59) developed IgG antibodies to rhGAA. A trend toward decreasing IgG titers was observed. Conclusions: In this first placebo-controlled study of rhGAA in juveniles and adults with Pompe disease, alglucosidase alfa was shown to improve walking and pulmonary outcomes as compared to placebo. This clinical trial was supported by Genzyme. Dr. Clemens received research funds from Genzyme for this study. Dr. Van Der Ploeg received research funds from Genzyme for this study. Deya Corzo, Stephen Lake, and Alison Skrinar are employees of Genzyme and hold stock in the company. Dr. Laforet is a member of the Genzyme advisory board. Dr. Pestronk is a speaker and receives license fee payments from Athena. He also received research support from Genzyme for this study. Dr. Rosenbloom was an investigator in this clinical trial sponsored by Genzyme Corporation. Dr. Escolar is an advisory board member for Orico, a medical advisor for Faust Pharmaceuticals, and an advisory board member for Acceleron. She also received research funds from Genzyme for this study. Ms. Mayhew is a consultant to Genzyme. Dr. Leshner is a speaker for Genzyme. He also received research support from Genzyme for this study. doi:10.1016/j.clinph.2008.10.114
97. Muscle strength and fatigue in patients with generalized myasthenia gravis—C.J. Symonette, B.V. Watson, W.J. Koopman, M.W. Nicolle, T.J. Doherty (London, Ont., Canada) Introduction: Patients with generalized myasthenia gravis (MG) characteristically present with fatigable muscle weakness resulting from impaired neuromuscular transmission (NMT). NMT failure is demonstrated by decrement of the compound muscle action potential with repetitive nerve stimulation (RNS). However, some patients with MG fail to show decrement despite symptoms of weakness and fatigue. Quantitative measurement of muscle strength and fatigue may provide evidence of NMT failure in the latter group despite normal RNS, or might show a pattern differentiating NMT from nonNMT causes for weakness. Objectives: To evaluate the strength and fatigue of patients with MG who present with and without decrement and to further determine whether the pattern of weakness in MG patients with normal RNS differs from those with decrement and control subjects. Methods: Subjects were divided into three groups (control subjects, nondecrementing MG, and decrementing MG) according to RNS of the spinal accessory and axillary nerves. Maximum voluntary isometric contraction (MVIC) strength and fatigue of shoulder abduction were measured. Questionnaires were used to further define the patient population in terms of additional fatigue and disease severity. Results: The decrementing MG group exhibited lower initial MVIC strength and no difference in fatigue than the nondecrementing MG and control groups. Patients with MG demonstrated greaterexperienced fatigue than the control group. Conclusion: The results indicate findings of reduced MVIC and no difference in fatigue in decrementing versus nondecrementing groups of patients with generalized MG. Greater experienced fatigue in MG may correspond to confounding variables such as physical
e117
inactivity. In addition, decrement upon RNS appears to relate best to disease severity and muscle weakness, but not to fatigue in this population. Study supported by Canada Research Chairs Program. doi:10.1016/j.clinph.2008.10.115
98. Clinical and electrophysiological characters of Lambert–Eaton syndrome—Y. Guan, L. Cui (Beijing, China) Introduction: The authors examined the symptoms and signs of Lambert-Easton myasthenic syndrome (LEMS) in 45 patients using retrospective analysis. Characteristics of electrophysiological examinations were investigated. Objectives: To analyze clinical and electrophysiological characteristic in LEMS. Methods: Forty-five LEMS patients’ records were reviewed and information gathered regarding clinical complaints, neurological symptoms, and other concomitant diseases. The records showed that repetitive nerve stimulation (RNS) and nerve conduction studies (NCSs) were performed on all of the patients. A needle electromyography (EMG) examination was performed on 30 of the 45 patients. Results: The authors identified the following three findings: (1) the two most common symptoms were weakness of lower extremities (n = 35) and a decreased or nonexistent deep tendon reflex (n = 40). (2) The types of diseases that occurred with LEMS included: small lung cell cancer (n = 9), lymphadenoma (n = 3), thymic hyperplasia (n = 2,), and other immune diseases (n = 3). Lymph node accretion in mediastina or lung without malignant tumor was found by pathology examination in 15 patients. Thirteen patients were found to have no neoplasm or autoimmune diseases. (3) RNS increased at 20 Hz when studying the abductor digiti minimi. Low frequency RNS abnormalities were found in 29 patients. Sensory NCS abnormalities or sensory and motor NCS abnormalities were found in 19 patients. Of the 30 patients who underwent a needle EMG examination, 20 had myogenic damage. Conclusions: Many abnormal electrophysiology results were found in LEMS patients, including NCS abnormalities and myopathy. These findings indicated that immune and pathological changes exceeded the neuromuscular junction and perhaps included the peripheral nerve and muscle. doi:10.1016/j.clinph.2008.10.116
99. Autoimmunity – myasthenia gravis, Graves’ disease and vitiligo: A case report—V. Serban (San Diego, CA, USA) Introduction: Myasthenia gravis (MG) is an autoimmune neuromuscular disease that is rarely associated with other autoimmune conditions. Epidemiologic studies report 5–10% occurrence of autoimmune thyroid disease (autoimmune thyroiditis and Graves’ disease) in patients with MG, whereas MG occurs in only 0.2% of patients with autoimmune thyroid disease. The clinical presentation of MG associated with autoimmune thyroid disease is frequently restricted to the eye muscles. There are few cases with the rare association of ocular MG, Graves’ disease and vitiligo. The reason for this is unknown, but hypothesized that it involves an immunological cross-reactivity of the epitopes. Case report: A 20-year-old right-handed man presented with diplopia, variable ptosis, and severely restricted eye movements.