Absence of significant clinical benefit for a systematic routine creatine phosphokinase measurement in asymptomatic patients treated with anti-programmed death protein (ligand) 1 immune checkpoint inhibitor to screen cardiac or neuromuscular immune-related toxicities.

AIM: Despite unprecedented results of anti-programmed death protein (ligand) 1 (PD-(L)1) immune checkpoint inhibitor in the oncology's armamentarium, immune-related adverse events (irAEs) represent a therapeutic hurdle. Currently, there is no consensual recommendation on a routinely monitored biomarker to early detect irAE. Biological markers such as serum creatine phosphokinase (CPK) are commonly used to measure muscular tissue injury. The potential of routine serum CPK monitoring to predict cardiac or neuromuscular irAE in patients treated with immunotherapy remains unknown. METHODS: In this retrospective study between January 2016 and December 2018 at Gustave Roussy Cancer Campus, 1151 cancer patients treated with anti-PD-(L)1 immunotherapy were systematically monitored with serum CPK measurements before each immunotherapy cycle. We considered significant CPK increases according to Common Terminology Criteria for Adverse Events v5.0 (CTCAEV5) of grade ≥2 severity. Comparisons were performed in patients with immune-related CPK (ir-CPK) elevations symptomatic versus asymptomatic. RESULTS: Overall, 53 of 1151 (4.6%) patients showed a CPK increase. Elevations of CPK were deemed to be immunotherapy-related in 31 of 1151 (2.7%) patients. Among them, 12 of 31 (38.7%) patients experienced symptomatic cardiac or neuromuscular irAE, whereas the other 19 of 31 (61.3%) patients remained asymptomatic. In patients with symptomatic irAE, the mean ir-CPK level was higher compared with asymptomatic patients (1271 versus 771 UI/L, P value = 0.02). In the asymptomatic group, all patients experienced a spontaneous resolution of the ir-CPK increase, and none required medical intervention. CONCLUSION: Most patients with immune-related CPK increase remained asymptomatic. The CPK serum increase did not alter the clinical management of asymptomatic patients. The results of this study did not support a significant clinical interest for a systematic routine CPK monitoring in patients amenable to anti-PD-(L)1 immunotherapy.

Coenzyme Q10: Clinical Applications beyond Cardiovascular Diseases.

Coenzyme Q10 (CoQ10) is an essential cofactor in oxidative phosphorylation (OXPHOS), present in mitochondria and cell membranes in reduced and oxidized forms. Acting as an energy transfer molecule, it occurs in particularly high levels in the liver, heart, and kidneys. CoQ10 is also an anti-inflammatory and antioxidant agent able to prevent the damage induced by free radicals and the activation of inflammatory signaling pathways. In this context, several studies have shown the possible inverse correlation between the blood levels of CoQ10 and some disease conditions. Interestingly, beyond cardiovascular diseases, CoQ10 is involved also in neuronal and muscular degenerative diseases, in migraine and in cancer; therefore, the supplementation with CoQ10 could represent a viable option to prevent these and in some cases might be used as an adjuvant to conventional treatments. This review is aimed to summarize the clinical applications regarding the use of CoQ10 in migraine, neurodegenerative diseases (including Parkinson and Alzheimer diseases), cancer, or degenerative muscle disorders (such as multiple sclerosis and chronic fatigue syndrome), analyzing its effect on patients' health and quality of life.

Nocturnal Transcutaneous Blood Gas Measurements in a Pediatric Neurologic Population: A Quality Assessment.

Objective: To assess the quality of SpO2 and PCO2 recordings via transcutaneous monitoring in children with neurological conditions.Methods: Overnight transcutaneous SpO2 and PCO2 were analyzed. The presence of drift and drift correction was noted, and the rate of disrupted recordings scored (0: absence, 1; presence). The quality of recordings was also scored (0, 1, 2 for poor, medium, and high).Results: A total of 228 recordings from 64 children aged 9.7 ± 6 years were analyzed of which 42 used positive pressure respiratory support. The mean quality of the recordings was scored as 1.27 (0-2). PCO2 drift, drift correction, and disrupted recordings were present in 25%, 58%, and 26% of recordings, respectively. Satisfactory clinical decisions were taken in 91% of cases.Conclusion: The quality of transcutaneous sensor recordings was acceptable and clinical findings were deemed as satisfactory in the large majority of cases. Correction of PCO2 drift was challenging.

Measures of nocturnal oxyhemoglobin desaturation in children with neuromuscular disease or Prader-Willi syndrome.

OBJECTIVES: Evidence for nocturnal oximetry interpretation in patients with abnormal neuromuscular function is limited. We aimed to compare children with neuromuscular disease (NMD) or Prader-Willi syndrome (PWS) to otherwise healthy subjects with obstructive sleep-disordered breathing (SDB) or without respiratory disorder (controls) regarding nocturnal oximetry parameters. METHODS: We analyzed recordings from children with: (a) NMD; (b) PWS; (c) snoring and adenotonsillar hypertrophy and/or obesity (SDB); and (d) controls. Outcomes included: (a) basal SpO2 ; (b) proportions of subjects with McGill oximetry score (MOS) >1 (clusters of desaturations); and (c) desaturation index (SpO2 drops ≥3%/h-ODI3). RESULTS: Data of 12 subjects with NMD (median age, 5.2 years; IQR, 2.7, 8.2), 14 children with PWS (5 years; 2.3, 6.9), 21 children with SDB (5.8 years; 4.6, 9.6), and 20 controls (6.2 years; 5.4, 11.2) were analyzed. Children with NMD, PWS, and SDB had lower basal SpO2 than controls (95.6% [94.5%, 96.9%], 96.2% [95.1%, 97.4%], 96.1% [95.8%, 97.5%] vs 97.8% [97.2%, 97.9%], respectively; (P < .01). NMD and PWS showed the greatest negative effect on basal SpO2 (P < .05). Children with SDB or PWS had a higher risk of MOS >1 than patients with NMD (OR, 25.9 [95% CI, 3.4-200.4] and 9.5 [1.5-62.6]). NMD, PWS, and SDB were similar regarding ODI3, which was elevated compared to ODI3 in controls (P < .05). Frequent desaturations predominated in NMD, while periods of sustained desaturation were noted in NMD and PWS. CONCLUSION: PWS and NMD have a negative effect on basal SpO2 , while clusters of desaturations are prevalent in patients with PWS or obstructive SDB.

Proteomic serum biomarkers for neuromuscular diseases.

INTRODUCTION: The clinical evaluation of neuromuscular symptoms often includes the assessment of altered blood proteins or changed enzyme activities. However, the blood concentration of many muscle-derived serum markers is not specific for different neuromuscular disorders and also shows alterations in the course of these diseases. Thus, the establishment of more reliable biomarker signatures for improved muscle diagnostics is required. Areas covered: To address the lack of muscle disease-specific marker molecules, mass spectrometry-based proteomics was applied to the systematic identification and biochemical characterization of new serum biomarker candidates. This article outlines serum proteomics in relation to neuromuscular disorders and reviews the bioanalytical results from recent proteomic profiling studies of representative neuromuscular disorders, including motor neuron disease, muscular dystrophies and sarcopenia of old age. Pathophysiological changes in the skeletal muscle proteome are reflected by serum alterations in a variety of sarcomeric proteins, metabolic enzymes and signaling proteins. Expert commentary: Based on the proteomic identification of actively secreted or passively released skeletal muscle proteins following pathophysiological insults, new biomarker candidates can now be used to develop liquid biopsy procedures for superior diagnostic approaches, design novel prognostic tools and establish more reliable methods for the systematic evaluation of experimental therapies to treat neuromuscular disease.

Reduced serum myostatin concentrations associated with genetic muscle disease progression.

Myostatin is a highly conserved protein secreted primarily from skeletal muscle that can potently suppress muscle growth. This ability to regulate skeletal muscle mass has sparked intense interest in the development of anti-myostatin therapies for a wide array of muscle disorders including sarcopenia, cachexia and genetic neuromuscular diseases. While a number of studies have examined the circulating myostatin concentrations in healthy and sarcopenic populations, very little data are available from inherited muscle disease patients. Here, we have measured the myostatin concentration in serum from seven genetic neuromuscular disorder patient populations using immunoaffinity LC-MS/MS. Average serum concentrations of myostatin in all seven muscle disease patient groups were significantly less than those measured in healthy controls. Furthermore, circulating myostatin concentrations correlated with clinical measures of disease progression for five of the muscle disease patient populations. These findings greatly expand the understanding of myostatin in neuromuscular disease and suggest its potential utility as a biomarker of disease progression.

Age-dependent neuromuscular impairment in prion protein knockout mice.

INTRODUCTION: The cellular prion protein (PrP(C) ) is commonly recognized as the precursor of prions, the infectious agents of the fatal transmissible spongiform encephalopathies, or prion diseases. Despite extensive effort, the physiological role of PrP(C) is still ambiguous. Evidence has suggested that PrP(C) is involved in different cellular functions, including peripheral nerve integrity and skeletal muscle physiology. METHODS: We analyzed the age-dependent influence of PrP(C) on treadmill test-based aerobic exercise capacity and on a series of morphological and metabolic parameters using wild-type and genetically modified mice of different ages expressing, or knockout (KO) for, PrP(C) . RESULTS: We found that aged PrP-KO mice displayed a reduction in treadmill performance compared with PrP-expressing animals, which was associated with peripheral nerve demyelination and alterations of skeletal muscle fiber type. CONCLUSION: PrP-KO mice have an age-dependent impairment of aerobic performance as a consequence of specific peripheral nerve and muscle alterations.

Cramp-fasciculation syndrome in patients with and without neural autoantibodies.

INTRODUCTION: We investigated the clinical, electrophysiological and neural autoantibody characteristics in cramp-fasciculation syndrome (CFS) patients. METHODS: We reviewed Mayo Clinic records from 2000 to 2011 to identify clinically defined CFS patients who underwent neural autoantibody testing. Stored sera of patients who tested positive for antibodies to voltage-gated potassium channel complex (VGKC complex) were analyzed further for leucine-rich glioma-inactivated 1 (LGI1) or contactin-associated protein-2 immunoglobulin G (CASPR2-IgG) antibodies. RESULTS: Thirty-seven patients were identified. Twelve were seropositive for neural autoantibodies. Clinical manifestations were similar in seropositive and seronegative patients, although central and autonomic neuronal hyperexcitability symptoms were more common in seropositive cases. No patients had a malignancy. Repetitive tibial nerve stimulation at 10 Hz revealed longer afterdischarges in seropositive patients. Two of 7 patients with VGKC-complex autoimmunity demonstrated LGI1 or CASPR2-IgG antibodies. Only 2 of 12 seropositive patients required immunotherapy. CONCLUSIONS: VGKC-complex autoimmunity occurs in a minority of CFS patients. Antibody positivity was associated with extramuscular manifestations, typically without malignancy. Target antigens within the VGKC complex remain unknown in most patients.

Single-fiber electromyography in hyperCKemia: the value of fiber density.

Although persistently raised serum creatine kinase (sCK), or hyperCKemia, is considered the biological hallmark of neuromuscular diseases, pauci- or asymptomatic- or isolated-hyperCKemia can often be found. Single-fiber electromyography (SFEMG) is an electrophysiological technique of great value in the assessment of neuromuscular, neuropathic and myopathic disorders. We hypothesize that SFEMG fiber density (FD) evaluation is able to detect subclinical electrophysiological abnormalities indicating a myopathic process in subjects with hyperCKemia. Nineteen subjects with hyperCKemia without evident clinical signs of muscle involvement and 15 healthy controls were studied. Electrophysiological investigations including nerve conduction studies (NCS), quantitative EMG (QEMG), SFEMG with focus on FD measurements, and muscle biopsy were performed. NCS, QEMG, SFEMG were normal in all controls. In subjects with hyperCKemia, NCS were normal; QEMG was abnormal in 5, while both SFEMG and muscle biopsy disclosed abnormalities in 12 subjects. The mean FD value was 2.6 ± 0.5 in the control and 4 ± 1.4 (p = 0.003) in the hyperCKemia group. SFEMG revealed subclinical changes in the majority of subjects with hyperCKemia. To the best of our knowledge, this is the first study demonstrating that SFEMG FD evaluation is able to detect the presence of muscle diseases, which are in a subclinical phase and would remain unidentified otherwise. SFEMG may be used to distinguish hyperCKemia associated to asymptomatic muscle disorders from idiopathic hyperCKemia. We believe that SFEMG FD evaluation should be added to the routine examinations in the screening of idiopathic hyperCKemia.

Response of serum carboxylated and undercarboxylated osteocalcin to risedronate monotherapy and combined therapy with vitamin K(2) in corticosteroid-treated patients: a pilot study.

OBJECTIVE: The aim of this study was to investigate the responses of serum osteocalcin (OC), undercarboxylated osteocalcin (ucOC) and N-terminal telopeptide of type I collagen (NTx) to corticosteroids, and to examine the effects of risedronate therapy with or without vitamin K(2) supplementation on bone metabolic markers in corticosteroid-treated patients. METHODS: Sixteen patients on corticosteroid therapy for neuromuscular disorders were assigned randomly to 2 groups (A: risedronate monotherapy, n=8; B: combined risedronate and vitamin K(2) therapy, n=8) and treated for 1 year. Another 6 patients who received intravenous steroid pulse therapy were assigned to group C for investigation of the effects of corticosteroids on OC and ucOC 1 month after pulse therapy. RESULTS: Serial measurements revealed that significant decreases of OC, ucOC and NTx persisted with a similar time course profile during 1 year of treatment in groups A and B, and between-group analysis failed to demonstrate any additional effects of vitamin K(2) on risedronate therapy. Intravenous steroid pulse therapy induced a transient depression of OC and ucOC within 1 week in group C. CONCLUSION: These results indicate that serum concentrations of OC and ucOC become consistently low during corticosteroid administration despite risedronate therapy with or without vitamin K(2) supplementation, and the serum ucOC level may not be a reliable indicator of vitamin K status under corticosteroid administration.

Patterns of neutrophil serine protease-dependent cleavage of surfactant protein D in inflammatory lung disease.

The manuscript presents definitive studies of surfactant protein D (SP-D) in the context of inflammatory lung fluids. The extent of SP-D depletion in bronchoalveolar lavage fluid (BALF) of children affected with cystic fibrosis (CF) is demonstrated to correlate best with the presence of the active neutrophil serine protease (NSP) elastase. Novel C-terminal SP-D fragments of 27 kDa and 11 kDa were identified in patient lavage fluid in addition to the previously described N-terminal, 35-kDa fragment by the use of isoelectrofocusing, modified blotting conditions, and region-specific antibodies. SP-D cleavage sites were identified. In vitro treatment of recombinant human SP-D dodecamers with NSPs replicated the fragmentation, but unexpectedly, the pattern of SP-D fragments generated by NSPs was dependent on calcium concentration. Whereas the 35- and 11-kDa fragments were generated when incubations were performed in low calcium (200 microM CaCl(2)), incubations in physiological calcium (2 mM) with higher amounts of elastase or proteinase-3 generated C-terminal 27, 21, and 14 kDa fragments, representing cleavage within the collagen and neck regions. Studies in which recombinant SP-D cleavage by individual NSPs was quantitatively evaluated under low and high calcium conditions showed that the most potent NSP for cleaving SP-D is elastase, followed by proteinase-3, followed by cathepsin G. These relative potency findings were considered in the context of other studies that showed that active NSPs in CF BALF are in the order: elastase, followed by cathepsin G, followed by proteinase-3. The findings support a pre-eminent role for neutrophil elastase as the critical protease responsible for SP-D depletion in inflammatory lung disease.

Follow-up of a large population of asymptomatic/oligosymptomatic hyperckemic subjects.

Six years before the present study we performed a retrospective study of 114 subjects presenting with asymptomatic / oligosymptomatic hyperckemia (raised creatine kinase blood levels), a diagnosis being made in 21 of them. We now present the results of a long-term follow-up in 55 of the still undiagnosed 93 individuals. Most of them have remained asymptomatic and did not develop specific neuromuscular disorders. One subject became frankly symptomatic manifesting limb-girdle weakness. A diagnosis of dystrophinopathy carrier and one of possible type I SMA carrier were indirectly made in another two subjects. Almost all subjects still have hyperckemia, though the mean creatine kinase (CK) value is lower than before. CK levels have become normal in 12 subjects. Two died of neoplasia, and six developed non-neuromuscular disorders. We noted no follow-up differences in terms of CK modifications between subjects with pathological EMG and/or muscle biopsy findings and those with normal findings at first examination.

Diagnostic evaluation of clinically normal subjects with chronic hyperCKemia.

The authors analyzed muscle biopsy specimens of 104 patients with creatine kinase activity greater than 500 UI/L (normal 10 to 170 UI/L) without signs of muscle weakness. They achieved a definite or probable diagnosis in 55% of cases. The most frequently identified diseases were glycogen storage diseases, muscular dystrophies, and inflammatory myopathies. The probability of making a diagnosis was higher in children and when creatine kinase level was greater than 2,000 UI/L.

Asymptomatic or minimally symptomatic hyperCKemia: histopathologic correlates.

BACKGROUND: Persistent creatine kinase elevation is occasionally encountered in subjects without any clinical manifestation of a neuromuscular disorder or any condition known to be associated with increased serum CK levels. It is still unresolved whether extensive investigations and specifically a muscle biopsy should be performed in clinically normal individuals with elevated CK levels. OBJECTIVE: To study the muscle pathology of patients with asymptomatic or minimally symptomatic hyperCKemia. METHODS: The clinical and laboratory data of patients with persistent hyperCKemia and normal neurologic examination were reviewed and their muscle biopsies evaluated. RESULTS: The study group included 40 patients aged 7-67 years; the male to female ratio was 3:1. Nineteen patients were completely asymptomatic, 20 had mild non-specific myalgia, and 1 had muscle cramps. Electromyography was performed in 27 patients and showed myopathic changes in 7 (26%). Abnormal muscle biopsy findings (e.g., increased variation in fiber size, increased number of central nuclei, and occasional degenerating fibers) were detected in 22 of the 40 patients (55%). No fat or glycogen accumulation was detected. Immunohistochemistry demonstrated abnormal dystrophin staining in 3 patients (8%), resembling the pathologic changes of Becker muscular dystrophy. No abnormal findings were detected on immunohistochemical staining for merosin, dysferlin, caveolin 3, or alpha and gamma sarcoglycans. The EMG findings did not correlate with the pathologic findings. CONCLUSIONS: Abnormal muscle biopsies were found in 55% of patients with asymptomatic or minimally symptomatic hyperCKemia. Specific diagnosis of muscular dystrophy, however, was possible in only 8% of the patients.

Neuronal ganglionic acetylcholine receptor autoimmunity.

We have developed and validated an assay to detect serum antibodies specific for the ganglionic AChR. The assay uses ganglionic AChR solubilized from membranes of the human neuroblastoma cell line (IMR-32) as antigen. The ganglionic AChR is radiolabeled by complexing with 125I-epibatidine. Among patients with acquired dysautonomia, seropositivity is highly associated with the diagnosis of idiopathic or paraneoplastic autonomic neuropathy and can distinguish these disorders from other forms of autonomic dysfunction. Ganglionic AChR binding antibodies are detectable in 50% of patients with subacute autoimmune autonomic neuropathy (AAN). These patients often have a high antibody value (>0.2 nmol/L). Lower values (0.05-0.20 nmol/L) are found in approximately 10% of patients with limited AAN.

[Raised creatine-kinase serum activity: not necessarily a sign of disease]. / Verhoogde serumactiviteit van creatinekinase: meestal geen teken van ziekte.

Hyper-creatine-kinase(CK)-aemia in patients without neurological abnormalities may be sign of a subclinical neuromuscular disorder. Initial screening of patients with hyper-CK-aemia must include careful history taking and a neurological examination. Appropriate blood tests to exclude aeanthocytosis and glycogen storage disease type II must be done. The diagnostic value of a skeletal muscle biopsy and electromyography is small. A muscle biopsy to exclude dystrophinopathy is indicated if the CK activity exceeds 5 times the upper limit of the normal range. If the results of initial screening are normal, patients with idiopathic hyper-CK-aemia fare quite well at 7-year follow-up. Also, standardized exercise tests in these patients have provided no evidence of increased muscle vulnerability. Thus, in most of these patients, hyper-CK-aemia probably does not reflect disease.

Retrospective study of a large population of patients with asymptomatic or minimally symptomatic raised serum creatine kinase levels.

UNLABELLED: A retrospective evaluation of asymptomatic subjects with persistent elevation of serum creatine kinase (CK) levels (hyperCKemia) was made in order to verify the presence of subclinical myopathy or idiopathic hyperCKemia and to define the most appropriate diagnostic pathway. Persistently increased serum CK levels are occasionally encountered in healthy individuals. In 1980 Rowland coined for them the term idiopathic hyperCKemia. Despite the increase of scientific knowledge, several healthy subjects with hyperCKemia still represent a problem for the clinician. We made a retrospective evaluation of 114 asymptomatic or minimally symptomatic individuals with incidentally detected persistent hyperCKemia. They underwent neurological examination and laboratory/instrumental evaluation. Skeletal muscle biopsy was performed and thoroughly investigated. Biochemical and genetic investigations were added in selected cases. Logistic regression analysis was applied. We diagnosed a neuromuscular disorder in 21 patients (18.4%), and found, by muscle biopsy and/or EMG, pathological but not conclusive findings in 57 subjects (50%). The statistic correlation between elevated serum CK levels and the probability of making a diagnosis changed according to the age of the patient. CONCLUSIONS: Muscle biopsy is the basic tool for screening asymptomatic subjects with hyperCKemia. It allowed us to make a diagnosis of disease in 18.4% of patients, and to detect skeletal muscle abnormalities in 38.6% of the subjects. Interestingly, 31.6% of individuals had completely normal muscle findings. These best fit the "diagnosis" of idiopathic hyperCKemia.

Serum creatine kinase elevation in a medical department.

Serum creatine kinase (CK) levels are diagnostic markers for acute myocardial infarction. Many other causes however, including neuromuscular disorders, may induce serum CK elevation as well. Aim of the study was to investigate the prevalence of potential causes for serum CK elevation in a medical department. In particular we were interested in the recognition of patients in whom serum CK elevation was due to a neuromuscular disorder. Included in this prospective study were 100 consecutive patients in whom the CK level, determined at admission, was increased (> 70 IU/l in female, > 80 IU/l in male patients). After admission we looked for the presence of causes known to induce CK elevation. Patients with no potential cause for CK elevation were invited for follow-up investigations three months later. If no potential cause could be found and if CK was elevated again on this occasion, the patient was referred for a comprehensive neurological investigation. The prevalence of patients with CK elevation was 11.2%. The 100 patients (44 female, 56 male) were aged from 23 to 94 (mean 67) years. In 95% CK elevation was only up to 500 IU/l. The most frequent cause for serum CK elevation was acute myocardial infarction in 32%. Further frequent causes were drug intake (32%), fall (24%), haematoma (17%), intramuscular injection (16%) and malignancy (11%). In 61% of the cases at least two potential causes for serum CK elevation could be detected. Neuromuscular disorders were found in only 2%. This study shows that serum CK elevation occurs in 11% of patients admitted to a medical department and can be explained by acute myocardial infarction in only 32%. In almost two thirds of the patients, more than one potential cause for serum CK elevation can be found thus making CK elevation a rather unspecific finding. Neuromuscular disorders are rarely found as a cause of serum CK elevation in a medical department.