Classification of Idiopathic Inflammatory Myopathy
The classification of idiopathic inflammatory myopathy (IIM) has been evolving partly because of the usefulness of myositis-specific antibodies (MSAs) and the increased recognition of immune-mediated necrotizing myopathy (IMNM). These developments have led to shrinkage or omission of the category of polymyositis (PM) which was overdiagnosed for decades. Loarce-Martos et al2 sought to determine the portion of patients with PM left in a reclassified UK tertiary myositis population using both European League Against Rheumatism/American College of Rheumatology (EULAR/ACR) IIM criteria1 and expert opinion. They evaluated 37 patients previously diagnosed with PM from a cohort of 255 patients with myositis. Nine (24%) remained diagnosed as PM. Therefore, PM comprised only 3.5% of the original cohort. There were 6 women and 3 men with a mean age of 58 years. The mean serum creatine kinase (CK) level was 2447 IU/L. Electrodiagnostic testing (EDx) showed myopathic changes in 5 of the 6 examined. Magnetic resonance imaging (MRI) showed evidence of muscle edema in 3 of 5. Seven patients underwent muscle biopsy. Biopsy specimens from 4 of them had diffuse major histocompatibility complex class 1 (MHC1) upregulation. Endomysial inflammation was present in 4, and perimysial inflammation was seen in 3. One specimen showed both distributions of inflammation.2
Major alternative diagnoses were IMNM in 5/37 and connective tissue disease overlap myositis in 7/37. Other new diagnoses were unspecified myopathy, dermatomyositis (DM), cancer-associated myositis, and myofibrillar myopathy. Interestingly, none were found to have inclusion body myositis (IBM), although that diagnosis was suspected in 1 patient. The reclassification of PM included pathological features with endomysial inflammation, response to immunotherapy, and negative MSAs. The study was limited by its retrospective nature and the fact that some patients did not undergo comprehensive testing. If stricter criteria for histopathologic diagnosis of PM were used,3 the cohort of PM would be even smaller.
ASSOCIATION WITH CANCER
The diagnosis of an IIM other than IBM usually warrants an evaluation for cancer. Suspicion is highest in those with DM. A better understanding of the frequency and evolution of cancer in relationship to IIM onset can help define screening strategies. To address this issue, Dani et al4 performed a prospective case–control study in Sweden to determine the occurrence of cancer before and after diagnosis of IIM. There were 1419 patients with IIM (juvenile DM, DM, IMNM, PM, and IBM), and 7045 patients from the general population served as controls. Mean follow-up was 5.6 years. The overall odds ratio (OR) of having cancer before diagnosis of IIM was 1.5. Seventeen percent of patients were found to have cancer at the time of IIM diagnosis. The adjusted hazard ratio (AHR) for cancer after IIM diagnosis was also elevated (1.7) versus the general population.
The cancer types differed depending on whether they occurred before or after IIM diagnosis. The more common cancers found before diagnosis were colorectal [adjusted OR (AOR) of 2.1], lung (AOR 5.4), and ovarian (7.0). After diagnosis, the most common causes were oropharyngeal cancer (AOR 9.1), cervical cancer (3.8), malignant melanoma (3.2), and nonmelanoma skin cancer (3.1). Adenocarcinomas were more common before diagnosis of IIM, and squamous cell cancers occurred most commonly after IIM diagnosis. For DM, the AOR of having cancer was 2.6. Interestingly, the risk of breast cancer was not increased. The risk of developing cancer was highest up to 3 years before and 3 years after IIM diagnosis with the greatest risk occurring within a year of diagnosis, and the increased risk remained for up to 10 years. The cancer risk rose after age 50 years with an AOR of 1.7 between the ages 50–59 years and 2.4 after age 80 years.
Reported frequencies and severities of cardiac involvement in IIM vary widely. Wang et al addressed the issue of subclinical cardiac involvement in IIM. They used sophisticated methods of cardiac magnetic resonance (CMR) mapping and strain analysis in IIM patients with preserved left ventricular ejection fractions.5 Strain assesses myocardial deformation. Mapping quantitates T1 (spin–lattice) and T2 (spin–spin) relaxation times. They also evaluated late gadolinium enhancement (LGE) which provides evidence of fibrosis, and they assessed hyperintensity on dark-blood T2 inversion recovery images for edema.
The authors retrospectively evaluated 65 adult patients with IIM who underwent CMR during a 5-year period. They excluded 7 patients with other connective tissue diseases, 13 with low ejection fractions, and 7 with absent mapping sequences. The final population included 38 patients with IIM, and they compared them with normal controls. Diagnoses were DM in 61%, IMNM in 10%, and 29% were said to have PM. This is a high proportion of patients with PM. Some had MSAs, but the details were not provided.
The authors found hyperintensity on dark-blood T2 imaging in 5/38 (13.2%) and LGE in 17 (44.7%). LGE mostly occurred in the midwall and epicardium and had a nonischemic pattern in the majority. The mapping values, including T1 and T2, were higher in patients with IIM versus controls, and the strain values were significantly reduced in IIM compared with controls. The authors conclude that the more sensitive techniques of CMR mapping and strain assessment hold promise for the detection of subclinical myocardial involvement in IIM patients with preserved left ventricular ejection fraction.5 These findings should be of interest to clinicians and could impact how aggressively patients with IIM are treated.
Naaraayan et al6 sought to determine the prevalence of arrhythmia in PM/DM. They performed a retrospective cohort study using an inpatient database of 32,085 patients with PM/DM seen in the United States over a 2-year period. For comparison, there were 320,850 matched controls. They adjusted for comorbidities and common risk factors for arrhythmia and found that there was an increased prevalence of arrhythmias in patients with PM/DM who were younger than 70 years. The arrhythmias were supraventricular. Patients with arrhythmias had increased in-hospital mortality (OR 3.3; P < 0.001). It is unclear exactly which patients were included under the category of PM. The causes of the arrhythmias were not determined. The possibility of systemic inflammation and its association with atherosclerotic cardiovascular disease was raised but not further evaluated.
Myositis-specific antibodies (Abs) are useful diagnostically and are associated with certain IIM phenotypes. Anti-Mi2 Abs are usually associated with classical DM. On the other hand, Fornaro et al7 reported a cohort of Italian patients with anti-Mi2 Abs and more severe disease compared with DM patients without those Abs. Their multicenter retrospective study included 22 DM patients with anti-Mi2 Abs and 69 anti-Mi2 Ab-negative DM patients. Twelve Ab+ patients underwent muscle biopsy as did 14 of the Ab− controls. Muscle biopsies from 19 patients with IMNM were also used as disease controls. The authors found that Mi2 Ab+ patients had higher levels of serum muscle enzymes at presentation (16- vs. 3.5-fold mean elevations) and more necrotic/degenerating muscle fibers compared with the Ab− patients. The Ab+ patients tended to have more endomysial macrophages similar to biopsy specimens obtained from patients with IMNM. Despite the higher CK levels and histopathologic findings, the Ab+ patients had a trend toward less pulmonary involvement than controls, and there was no statistically significant difference in manual muscle strength testing scores.7 In addition, Ab+ patients had a typical rash and responded to immunotherapy; therefore, the presence of more severe muscle disease histologically and higher muscle enzymes did not necessarily affect clinical outcomes.
Gomez et al8 recently reported MSAs and clinical characteristics of patients with IIM in Argentina using a patient registry. There were 360 patients with DM, PM, and IBM. MSAs were determined by immunoblotting. The most frequent disease subtypes were DM (43.9%) followed by PM (30%). MSAs were present in 62.2% of the cohort. The most common MSAs were anti-Jo 1 (16%), melanoma differentiation-associated protein-5 (MDA 5) (11%), and Mi-2 (10%). Patients with MDA 5 Abs were usually amyopathic and had skin manifestations often with interstitial lung disease and Raynaud phenomenon. As in the study by Fornaro et al,7 patients with Mi-2 Abs tended to have higher CK levels.8
There were only 9 patients with IMNM. The investigators did not have a commercial kit for studying anti-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) Abs; so, it seems likely that IMNM was underrepresented, and thus, PM was overrepresented in the population. Overall, there were no major differences in MSA frequency and phenotypes in this population study versus others.8
Myositis-associated autoantibodies (MAAs) are seen in patients with myositis as well as with other autoimmune diseases including systemic lupus erythematosus, systemic sclerosis, and rheumatoid arthritis. Some MAAs are associated with distinct phenotypes. Casal-Dominguez investigated the MAA called anti-Ku to define the clinical features in patients with this Ab as well as to determine the reliability of Euroline, a line blot assay for 16 autoAbs associated with myositis.9 Anti-Ku Abs recognize a protein that binds double-stranded DNA. Positive Euroline testing for anti-Ku Abs was further evaluated using enzyme-linked immunosorbent assay (ELISA).
Seventy-two anti-Ku Ab-positive patients were found among 2475 patients enrolled in the Johns Hopkins Myositis Center longitudinal study. Of the 72 samples that were anti-Ku–positive by Euroline, only 17 (23.6%) were confirmed by ELISA and other methods. The unconfirmed positives were considered false positives. Of the false positives, there were 15 with DM, 12 with IBM, 16 with PM, and 11 who did not meet criteria for myositis. Eleven of the false positives were found to have an MSA.
To compare patients with anti-Ku Abs to others with IIM, the authors used patients with IMNM, antisynthetase syndrome, IBM, anti-U1-RNP Abs, and anti-PM/Scl Abs. Interestingly, only 38% of anti-Ku–positive patients presented with weakness. However, the majority (81%) did develop diffuse weakness during the follow-up period. In the comparison groups, only patients with IBM were more likely to develop distal weakness. Twenty-five percent of anti-Ku–positive patients had Raynaud phenomenon at presentation. Only 1 of 17 was found to have cancer. In addition, more than half of the anti-Ku–positive patients developed interstitial lung disease. Although some patients had rashes, Gottron papules and heliotrope rash were uncommon. They did not develop calcinosis. Thirty-eight percent had mechanic hands and arthritis. Muscle biopsy specimens were available for only 4 patients. In 3, there were features of a necrotizing myopathy.
The authors felt that the Ku+ patients had a unique phenotype with the presence of distal as well as proximal muscle involvement, frequent interstitial lung disease, and infrequent rash. In addition to demonstrating this unusual phenotype associated with anti-Ku Abs, the authors also highlighted the fact that commercial assays for autoAbs may have a high false-positive rate.9
MYOSITIS IN PATIENTS WITH CANCER TREATED WITH IMMUNE CHECKPOINT INHIBITORS
Neuromuscular immune-related adverse events in patients receiving immune checkpoint inhibitors (ICIs) have been the subject of an increasing number of reports mostly involving single cases or small series.10,11 One of these neuromuscular adverse events, ICI-myositis, occurs in less than 1% of ICI-treated patients.10,11 Aldrich et al12 recently reported a relatively large series of ICI-myositis patients from University of Texas MD Anderson Cancer Center. They performed a retrospective cohort study of patients who received at least 1 ICI at their Center during a 3-year period. They identified ICI-myositis if symptoms suggested myositis (fatigue, myalgia, or muscle weakness), and there was at least one of the following findings: elevation in CK or aldolase or an inflammatory infiltrate on a muscle biopsy specimen. They diagnosed overlapping myasthenia gravis (MG) if the patient also had muscle weakness with a positive acetylcholine receptor Ab or fatigable ptosis or diplopia. They also assessed for overlapping myocarditis.
Of the 9088 patients who received an ICI, 36 (0.4%) were diagnosed with ICI-myositis. Of those, 17 (47%) had myositis alone, while 19 (53%) had overlap manifestations. The overlap features were MG in 5, myocarditis in 5, and both MG and myocarditis in 9. ICI-myocarditis was more frequent in patients who received combination ICI therapy (0.94%) versus monotherapy (0.31%). Median time to symptom onset was 27 days from ICI initiation after a median of 2 doses. CK levels were elevated in 94%. Muscle biopsy specimens were obtained from 12 patients. Ten biopsy specimens showed lymphocytic inflammation with most exhibiting both CD8+ and CD4+ T cells. Muscle necrosis was present in 4 specimens. Of the 9 endomyocardial biopsy specimens, 7 had lymphocytic inflammation consistent with myocarditis.
In addition to the findings mentioned above, the authors also noted that troponin I had a moderate specificity advantage over troponin T in identifying myocarditis because troponin T cross-reacts with skeletal muscle. It was also useful to test for antistriational Abs which were found in nearly half of tested patients and were more commonly seen in patients with concomitant MG.
Treatment consisted of discontinuation of ICIs, and almost all received initial treatment with glucocorticoids. Twenty-five of 36 patients received additional therapies that usually included plasmapheresis or intravenous immunoglobulin. Smaller numbers of patients received rituximab, infliximab, tocilizumab, tacrolimus, or mycophenolate mofetil.
Although most patients required hospitalization, those with ICI-myositis alone had the best outcomes. Those with overlap MG or myocarditis fared worse. At the time of discharge, patients with ICI-myositis alone improved at a rate of 81% versus 42% with overlap syndrome. Eight patients (22%)—all with overlap syndrome—had worsening symptoms with persistent respiratory failure and died. Five patients who had resolution of ICI-myositis were rechallenged with an ICI. In 3 of these, it was the same agent. One had recurrent myositis and MG with respiratory failure requiring mechanical ventilation and recovered. The other 4 did not have a flare-up.
This is the largest reported cohort of patients with ICI-myositis to date, and it enhances our knowledge of the epidemiology and clinical features. The subject numbers were too small to draw conclusions about treatment, but it is useful to review the experience of the authors and also to note that patients with ICI-myositis alone had better outcomes than those with overlap syndromes.12
Sporadic Late-Onset Nemaline Myopathy
Sporadic late-onset nemaline myopathy (SLONM) is believed to be rare, but a recent flurry of articles on this topic seems to indicate otherwise. SLONM usually occurs after age 40 years and may or may not be associated with a monoclonal gammopathy. Patients present with proximal and often axial weakness and have findings of an irritable myopathy on electrodiagnostic studies. The diagnosis is confirmed through muscle histopathology. Sporadic nemaline myopathy has also been reported with HIV. When seen with SLONM, monoclonal gammopathy is often said to be of undetermined significance (MGUS), but patients with SLONM-MGUS tend to have worse outcomes than those with SLONM without monoclonal gammopathy. Patients with SLONM-MGUS usually receive more aggressive treatment.13
De Ridder et al14 recently reported that SLOMN may be more prevalent than previously suspected. They carefully studied a cohort of 18 patients with suspected but undiagnosed inherited myopathy of late onset and negative whole exome sequencing. They excluded patients with HMGCR Abs, and they also looked for the presence of monoclonal gammopathy. On histopathologic specimens, they searched for nemaline rods through routine stains and immunohistochemistry for myotilin, α-actinin, and other Abs, and they looked for rods through electron microscopy. Surprisingly, on their re-evaluation, 10 patients had rods as a main feature on muscle biopsy, and 4 of them had an IgG-κ monoclonal gammopathy. Rods were seen in 3%–35% of muscle fibers; 7 of 10 specimens had 5% or less. Other histopathologic features included cytoplasmic bodies, rimmed vacuoles, lobulated fibers, and hyaline inclusions and other “atypical” inclusions on Gomori trichrome staining. Inflammatory infiltrates were noted in 4 of 9. None of these had CD8+ lymphocytes. CD68+ cells (macrophages) were seen in 6 biopsies. Major histocompatibility complex class I upregulation was seen in myofibers from 5 biopsies; most had patchy reactivity.
Ages of onset ranged from 45 to 70 years. The typical pattern of weakness was proximal more than distal with some having more distal weakness. Gluteus maximus weakness was often marked. Paraspinal weakness was prominent in half, and periscapular weakness was noted in several patients. Progression was slow. On muscle MRI, selective early involvement of the vastus intermedius, adductor magnus, biceps femoris, and soleus muscles was noted. Over time, there was significant involvement of posterior thigh, lateral gastrocnemius, gluteal, and paraspinal muscles. Sartorius and gracilis muscles were preserved. Creatine kinase levels were normal to mildly elevated. Cardiomyopathy was not detected.14
The diagnosis of SLONM may be difficult. There is no blood biomarker, and the rods are nonspecific and may be difficult to find in biopsy specimens. It is conceivable that we overlook this diagnosis in some of our patients. The authors reasonably propose that a diagnosis of probable SLONM should be made on identification of rods on muscle biopsy specimens from patients with a sporadic late-onset myopathy with or without MGUS and with supportive findings of negative whole exome sequencing, a suggestive muscle MRI pattern as described above, or monoclonal gammopathy or increased kappa and lambda light chains on a free light chain assay and serologic exclusion of HMGCR myopathy. Additional biopsy features may include cytoplasmic bodies, hyaline inclusions, and endomysial inflammatory infiltrates and/or sarcolemmal MHC-I upregulation.14 As most clinicians do not routinely obtain whole exome sequencing on undiagnosed late-onset myopathy patients, these recommendations have limitations, but this report certainly should prompt us to look harder for SLONM.
Tanboon et al15 further explored histopathological findings in muscle biopsy-proven SLONM with emphasis on the inflammatory changes because there is evidence that SLONM is an autoimmune myopathy. They examined 49 muscle biopsy specimens from patients seen at tertiary care centers in Japan and Germany. Clinical features were similar to those noted by De Ridder et al,14 except that 20% of patients had cardiomyopathy. They also noted respiratory weakness in 41%.15 Thirteen patients received immunotherapy before muscle biopsy. The range of rod-containing myofibers was 1.1%–93.7%. About half of the biopsies contained up to 10% nemaline rods. There was overlap in the histological features of SLONM-MGUS and SLONM without MGUS, although there was somewhat more myofiber regeneration in the patients with SLONM-MGUS. The predominant inflammatory cells were CD68+ macrophages. T cells were not seen. MHC-1 expression and fine granular p62 (sequestosome 1) immunoreactivity were seen in 67% of SLONM without MGUS and 78% with SLONM with MGUS. The number of inflammatory cells correlated with the number of rod-containing fibers.
Although macrophage infiltration occurs nonspecifically with myofiber degeneration, the authors felt that “the presence of macrophages overall exceeded what is generally found in ‘pure’ resorptive processes.”15 This study contributes to the premise that SLONM may have an inflammatory pathogenesis and shows that there is no major difference in the histopathology in SLONM with and without monoclonal myopathy. It is unclear whether these findings have therapeutic implications.
Treatment options for SLONM with monoclonal gammopathy have included corticosteroids, intravenous immunoglobulin (IVIG), plasmapheresis, plasma cell–directed chemotherapy, and autologous stem cell transplantation. Okhovat et al16 recently reported another 4 patients with SLONM with monoclonal gammopathy and concentrated on the topic of therapy. All their patients had IgG monoclonal gammopathies; 3 had kappa light chains, whereas 1 had lambda light chains. All had proximal weakness, and 1 had severe axial weakness that was progressive over 3–8 months. One patient refused treatment; the others received corticosteroids and monthly IVIG. The treated patients had improvement on manual muscle testing and on functional scales.16
In another study, Kotchetkov et al17 used chemotherapy to treat 4 patients and reviewed 49 reported cases of treated SLONM-MGUS. The 49 patients were gleaned from 23 different publications. Median age was 55 years, and there was a slight male ponderance. All patients had an IgG type of monoclonal gammopathy, and about 52% had kappa light chains, whereas 40% had lambda light chains. In total, 25 patients were treated without chemotherapy, whereas 28 patients received chemotherapy. Among the non–chemotherapy-treated patients, 40% received corticosteroids initially while 12% received IVIG; 12% received plasmapheresis and corticosteroids; 12% received corticosteroids and steroid-sparing immunotherapy, and the others received combination therapy or only steroid-sparing immunotherapy. Some patients from the non–chemotherapy-treated group later received other agents of the types mentioned. Among the chemotherapy-treated patients, 72% received autologous stem cell transplantation only. About 14% received chemotherapy alone, and 14% received induction chemotherapy and consolidative autologous stem cell transplant. The chemotherapy alone group usually received cyclophosphamide in combination with dexamethasone and either bortezomib or thalidomide. The induction chemotherapy regimen varied between cyclophosphamide with bortezomib and dexamethasone, lenalidomide with bortezomib and dexamethasone, or bortezomib and dexamethasone.
In the nonchemotherapy group, the mean follow-up was 24 months, and survival data were available for 11 patients. In the chemotherapy group, mean follow-up was 35 months, and survival data were available for 21 patients. Neurological improvement was observed in 52% in the nonchemotherapy group with most having a mild response. None reached complete remission. In the chemotherapy group, improvement was seen in 86% of patients with 46% reaching complete remission. Survival was better in the chemotherapy group. The best neurologic improvements were seen in patients with deep hematological remission. Based on the aggressive disease course in patients with SLONM and monoclonal gammopathy, the authors feel that monoclonal gammopathy should be considered to be of clinical rather than undetermined significance. They felt that the chemotherapy approach should be the preferred option in patients with SLONM and monoclonal gammopathy based on their experience and assessment of published cases.
The analysis is limited by the retrospective nature, missing data, uneven treatment protocols, lack of blinding, etc. However, it is highly unlikely that a controlled study of this rare disease will ever take place. At this point, clinicians will need to decide about treatment options based on the available literature. The editorial that accompanied this article was written by Eskazan and Gunduz18 who also note that potential toxicities need to be taken into account when considering treatment. They agreed that SLONM with monoclonal gammopathy of clinical significance is a life-threatening paraneoplastic syndrome and chemotherapy with or without autologous stem cell therapy seems to be the preferred treatment. Further investigation or experience is sorely needed to clarify treatment options.18
In conclusion, after reviewing this group of articles, SLONM may be more common than previously believed, but diagnosis requires very careful evaluation of muscle biopsy specimens for rods. Consider this diagnosis in late-onset, proximal-predominant myopathies especially with axial weakness including head drop and also periscapular weakness, normal to mildly elevated CK, irritable EMG, and negative genetic testing. Treatment for SLONM with monoclonal gammopathy, which likely is clinically significant, probably needs to be more aggressive than in SLONM patients without monoclonal gammopathy. For aggressive therapies, we may need to enlist the assistance of our oncology colleagues.
TREATMENT OF NONDYSTROPHIC CHANNELOPATHIES
Within this category are the nondystrophic myotonic disorders, mainly myotonia congenita and paramyotonia congenita, that are caused by mutations in chloride or sodium channel genes. Mexiletine, a nonselective voltage-gated sodium channel blocker, is most used to treat symptoms of myotonia.19 Treatment regimens vary somewhat. In France, the French health authority requested additional investigations of efficacy and safety of mexiletine in nondystrophic myotonias; therefore, Vicart et al20 performed a double-blind, placebo-controlled multicenter, crossover study with treatment periods lasting up to 22 days. The objectives were to determine the safety and efficacy of mexiletine in symptomatic treatment of nondystrophic myotonias. They enrolled 13 patients with myotonia congenita and 12 patients with paramyotonia congenita. Mexiletine was started at 200 mg a day and titrated to 600 mg daily over a week. The primary end point was score of stiffness severity that was self-reported by subjects using a visual analog scale (VAS) from 0 to 100 in which 100 was maximal stiffness. They also evaluated time needed to stand up from a chair, walk around the chair, and sit down again as well as quality of life, and they assessed compound muscle action potential changes after short exercise and cooling.
There was a marked reduction in symptomatic stiffness with the median VAS score for mexiletine declining from 71 before treatment to 16 at the end of treatment without any significant change with placebo treatment. There was also improvement in quality of life measures. There were no clinically significant adverse events, but gastrointestinal disorders were more frequently reported in treated subjects (24%) versus placebo (8%). This relatively small study provided additional evidence that mexiletine is beneficial in reducing stiffness and in improving quality of life in doses up to 600 mg daily in patients with nondystrophic myotonia. It was generally well tolerated over the short treatment period.
Although mexiletine is generally well tolerated, there are some patients who have limiting gastrointestinal intolerance, and there is sometimes a concern about the possibility of arrhythmia. Alternative treatments for myotonia may include ranolazine and lamotrigine which enhance the slow inactivation of sodium channels.21,22 Ravaglia et al23 recently reported another possible compound that might be useful in treating stiffness in paramyotonia congenita. They treated 2 patients with buprenorphine, a drug that is typically used for opiate addiction often in combination with naloxone. It is a mu-opioid receptor agonist, but it also has sodium channel blocking properties. Both patients were previously treated with mexiletine, but one had intolerable gastrointestinal side effects, and the other had no clinical benefit. One also received lacosamide and ranolazine. In both patients, buprenorphine was associated with a reduction in pain scores by at least 50% as well as in levels of stiffness and weakness and hand grip/eyelid opening times. There was associated electrophysiologic change, namely improvement in decrement of the compound muscle action potential during short exercise and after cooling. Further larger, controlled studies of this regulated compound should be considered.
Acetazolamide and dichlorphenamide are used to treat primary periodic paralysis. The long-term efficacy of dichlorphenamide was recently addressed by Johnson et al.24 They performed a double-blind, placebo-controlled study of 50 mg twice a day versus placebo in 63 adults with hypokalemic or hyperkalemic primary periodic paralysis. Treatment was for 9 weeks followed by 52 weeks of open-label active drug administration. Forty-seven subjects completed the 61 weeks of treatment. The investigators reported statistically significant decreases in the frequency and severity of weekly attacks from baseline to week 61. Paresthesias were common adverse events, and cognitive disturbances occurred in about 25%. Most of these events were tolerable and managed with dose reductions. Three patients developed nephrolithiasis. The study shows that DCP is relatively safe and effective for up to 61 weeks of administration.24
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