The long exercise test as a functional marker of periodic paralysis.

AIMS: The aim of this study was to evaluate the sensitivity of the long exercise test (LET) in the diagnosis of periodic paralysis (PP) and assess correlations with clinical phenotypes and genotypes. METHODS: From an unselected cohort of 335 patients who had an LET we analyzed 67 patients with genetic confirmation of PP and/or a positive LET. RESULTS: 32/45 patients with genetically confirmed PP had a significant decrement after exercise (sensitivity of 71%). Performing the short exercise test before the LET in the same hand confounded results in four patients. Sensitivity was highest in patients with frequent (daily or weekly) attacks (8/8, 100%), intermediate with up to monthly attacks (15/21, 71%) and lowest in those with rare attacks (9/16, 56%) (p = .035, Mann-Whitney U-test). Patients with a positive LET without confirmed PP mutation comprised those with typical PP phenotype and a group with atypical features. DISCUSSION: In our cohort, the LET is strongly correlated with the frequency of paralytic attacks suggesting a role as a functional marker. A negative test in the context of frequent attacks makes a diagnosis of PP unlikely but it does not rule out the condition in less severely affected patients.

Acute Neuromuscular Disorders in the Pediatric Intensive Care Unit.

BACKGROUND: The neuromuscular disorders encountered in the pediatric intensive care unit (PICU) encompass a broad spectrum of pathologies. These include acute disorders (eg, Guillain-Barre syndrome), acute-on-chronic disorders (eg, myasthenia gravis), progressive disorders (eg, muscular dystrophy), and disorders that develop in the PICU (eg, critical illness myopathy/polyneuropathy). Familiarity with the presenting features of these disorders is of paramount importance in facilitating timely diagnosis. METHODS: We conducted a retrospective review of the medical records of patients admitted to the PICU or Intermediate Care Program (ICP) at a single tertiary children's hospital from 2006 to 2017 with an acute or acute-on-chronic neuromuscular disorder. We did not include patients with a known progressive neuromuscular disorder or critical illness myopathy/polyneuropathy. RESULTS: Twenty-four patients were admitted to the PICU/ICP with acute or acute-on-chronic neuromuscular disorders. Diagnosis and indication for ICU/ICP admission were Guillain-Barre syndrome (n = 6; respiratory failure: 3, respiratory monitoring: 2, autonomic instability: 1), myasthenia gravis (n = 5; airway clearance: 3, respiratory failure: 2), acute flaccid myelitis (n = 3; respiratory failure: 2, respiratory monitoring: 1), periodic paralysis (n = 3; intravenous potassium replacement), rhabdomyolysis (n = 3; monitoring for electrolyte derangements), infant botulism (n = 2; respiratory failure), chronic demyelinating polyneuropathy (n = 1; respiratory failure), and congenital myasthenic syndrome (n = 1; apnea). No patients were admitted to the PICU/ICP with a diagnosis of tick paralysis, acute intermittent porphyria, or inflammatory myopathy. CONCLUSIONS: Although acute and acute-on-chronic neuromuscular disorders are encountered relatively rarely in the PICU, familiarity with the presenting features of these disorders is important in facilitating timely diagnosis. This, in turn, enables the institution of effective management strategies, thereby avoiding complications associated with diagnostic delays.

Episodic Muscle Disorders.

PURPOSE OF REVIEW: This article reviews the episodic muscle disorders, including benign cramp-fasciculation syndrome, the periodic paralyses, and the nondystrophic myotonias. The core diagnostic criteria for a diagnosis of primary periodic paralysis, including clues to distinguish between the hypokalemic and hyperkalemic forms, and the distinctive elements that characterize Andersen-Tawil syndrome are discussed. Management of patients with these disorders is also discussed. RECENT FINDINGS: Childhood presentations of periodic paralysis have recently been described, including atypical findings. Carbonic anhydrase inhibitors, such as dichlorphenamide, have recently been approved by the US Food and Drug Administration (FDA) for the treatment of both hypokalemic and hyperkalemic forms of periodic paralysis. Muscle MRI may be a useful outcome measure in pharmacologic trials in periodic paralysis. Genetic research continues to identify additional gene mutations responsible for periodic paralysis. SUMMARY: This article will help neurologists diagnose and manage episodic muscle disorders and, in particular, the periodic paralyses and the nondystrophic myotonias.

Family with primary periodic paralysis and a mutation in MCM3AP, a gene implicated in mRNA transport.

INTRODUCTION: Primary periodic paralyses (PPs) are rare genetic neuromuscular disorders commonly caused by mutations in genes related to ion channel function. However, 10%-20% of cases remain as genetically unexplained. Herein we present a family with PP with paralytic episodes generally lasting for 1-7 days at a time, associated with a drop in K+ levels. METHODS: Screening for mutations in known disease-causing genes was negative, hence we performed whole-exome sequencing of 5 family members. RESULTS: Minichromosome maintenance 3-associated protein (MCM3AP) c.2615G>A (p.C872Y) was found to cosegregate with disease in the family and was not present in control subjects. The mutation is novel, highly conserved across multiple species, and predicted to be damaging. DISCUSSION: MCM3AP encodes germinal center-associated nuclear protein (GANP), a protein involved in the export of certain messenger RNAs from the nucleus to the cytoplasm. Our findings suggest that a novel mutation in MCM3AP is associated with hypokalemic PP. Muscle Nerve, 2019.

Long Exercise Test in Periodic Paralysis: A Bayesian Analysis.

INTRODUCTION: The long exercise test (LET) is used to assess the diagnosis of periodic paralysis (PP), but LET methodology and normal "cutoff" values vary. METHODS: To determine optimal LET methodology and cutoffs, we reviewed LET data (abductor digiti minimi motor response amplitude, area) from 55 patients with PP (32 genetically definite) and 125 controls. Receiver operating characteristic curves were constructed, and area under the curve (AUC) was calculated to compare (1) peak-to-nadir versus baseline-to-nadir methodologies and (2) amplitude versus area decrements. Using bayesian principles, we calculated optimal cutoff decrements that achieved 95% posttest probability of PP for various pretest probabilities (PreTPs). RESULTS: AUC was highest for peak-to-nadir methodology and equal for amplitude and area decrements. For PreTP ≤ 50%, optimal decrement cutoffs (peak-to-nadir) were > 40% (amplitude) or > 50% (area). DISCUSSION: For confirmation of PP, our data endorse the diagnostic utility of peak-to-nadir LET methodology using 40% amplitude or 50% area decrement cutoffs for PreTP ≤50%. Muscle Nerve 59:47-54, 2019.

Periodic paralysis with normokalemia in a patient with hyperthyroidism: A case report.

RATIONALE: Thyrotoxic periodic paralysis is characterized by a sudden onset of hypokalemia and paralysis. This condition mainly affects the lower extremities and is secondary to thyrotoxicosis. The underlying hyperthyroidism is often subtle without typical symptoms such as palpitations, tremors, anxiety, and weight loss; this causes a difficulty in early diagnosis. Here, we reported a case of periodic paralysis in a patient with hyperthyroidism whose potassium level was within the normal range. PATIENT CONCERNS: A 33-year-old Taiwanese man presented to the emergency department with bilateral limb weakness (more severe in the lower limbs than in the upper limbs). On arrival, the patient's vital status was stable with clear consciousness. He denied experiencing recent trauma, back pain, chest pain, abdominal pain, headache or dizziness, or a fever episode. Physical examination showed no specific findings. Neurological examination showed weakness in the muscles of the bilateral upper and lower limbs. Muscle weakness was more severe in the proximal site than in the distal site. DIAGNOSIS: Blood examination showed normal complete blood count, normal renal and liver function, and normal potassium (3.5 mmol/L, normal range 3.5-5.1 mmol/L), sodium, and calcium levels; however, the examination showed impaired thyroid function (thyroid stimulating hormone: 0.04 uIU/mL, normal range 0.34-5.60 uIU/mL; free T4: 1.96 ng/dL, normal range 0.61-1.12 ng/dL). Brain computed tomography without contrast showed no obvious intra-cranial lesion. INTERVENTIONS: Intravenous potassium infusion (20 mEq/L) with normal saline was prescribed for the patient. OUTCOMES: After treatment, the patient felt a decrease in limb weakness. He was discharged from our emergency department with a scheduled follow-up in the endocrine outpatient department. LESSONS: TPP should be considered as a differential diagnosis in young Asian men presenting with limb paralysis that is more severe in the proximal site and in the lower limbs than in the distal site and in the upper limbs, respectively. It is important for emergency department physicians to consider TPP as a differential diagnosis as it can occur even if the patient's potassium level is within the normal range.

What the internist should know about hereditary muscle channelopathies.

OBJECTIVES: Non-dystrophic myotonia, periodic paralysis and, to a certain extent, myotonic dystrophies are rare hereditary skeletal muscle channelopathies, charactarized by myotonia or episodic muscle weakness. This review highlights the diagnostic challenges and treatment options. RESULTS: Some of these rare skeletal muscle disorders are associated with a broad range of systemic and nonspecific muscle symptoms. Consequently, patients are often referred to the internist before seeing a neurologist. This article provides clinical clues to better diagnose an tackle these unique disorders. CONCLUSION: A increased knowledge will reduce the diagnostic delay, improve monitoring and treatment, and might even prevent potentially life-threatening conditions as seen in DM.

Review of the Diagnosis and Treatment of Periodic Paralysis.

Periodic paralyses (PPs) are rare neuromuscular disorders caused by mutations in skeletal muscle sodium, calcium, and potassium channel genes. PPs include hypokalemic paralysis, hyperkalemic paralysis, and Andersen-Tawil syndrome. Common features of PP include autosomal dominant inheritance, onset typically in the first or second decades, episodic attacks of flaccid weakness, which are often triggered by diet or rest after exercise. Diagnosis is based on the characteristic clinic presentation then confirmed by genetic testing. In the absence of an identified genetic mutation, documented low or high potassium levels during attacks or a decrement on long exercise testing support diagnosis. The treatment approach should include both management of acute attacks and prevention of attacks. Treatments include behavioral interventions directed at avoidance of triggers, modification of potassium levels, diuretics, and carbonic anhydrase inhibitors. Muscle Nerve 57: 522-530, 2018.

Is thyrotoxic periodic paralysis a disease caused by muscle membrane dysfunction?

INTRODUCTION: Thyrotoxic periodic paralysis (TPP) is characterized by recurrent episodes of reversible paralysis with hyperthyroidism. It is clinically similar to hypokalemic periodic paralysis (HOPP), which features significant ion-channel dysfunction and reduced muscle fiber conduction velocity (MFCV). However, the muscle membrane function in TPP is not known. METHODS: For 13 patients with TPP and 15 age-matched controls, clinical assessment and serial neurophysiological testing, including nerve conduction, prolonged exercise (PE) testing, and MFCV. were performed. RESULTS: MFCV values were elevated up to 1 year from the paralytic attack in TPP patients. In the group with a positive PE test, MFCV values were higher. There was no significant relationship between MFCV values and either hypokalemia or hyperthyroidism. CONCLUSIONS: Although clinical manifestations in TPP are similar to those observed in HOPP, TPP appears to feature an alternate pathogenic mechanism. Specifically, MFCV values increased rather than decreased. Further studies are needed to support these findings. Muscle Nerve, 2016 Muscle Nerve 56: 780-786, 2017.

Randomized, placebo-controlled trials of dichlorphenamide in periodic paralysis.

OBJECTIVE: To determine the short-term and long-term effects of dichlorphenamide (DCP) on attack frequency and quality of life in hyperkalemic (HYP) and hypokalemic (HOP) periodic paralysis. METHODS: Two multicenter randomized, double-blind, placebo-controlled trials lasted 9 weeks (Class I evidence), followed by a 1-year extension phase in which all participants received DCP. Forty-four HOP and 21 HYP participants participated. The primary outcome variable was the average number of attacks per week over the final 8 weeks of the double-blind phase. RESULTS: The median attack rate was lower in HOP participants on DCP than in participants on placebo (0.3 vs 2.4, p = 0.02). The 9-week mean change in the Physical Component Summary score of the Short Form-36 was also better in HOP participants receiving DCP (treatment effect = 7.29 points, 95% confidence interval 2.26 to 12.32, p = 0.006). The median attack rate was also lower in HYP participants on DCP (0.9 vs 4.8) than in participants on placebo, but the difference in median attack rate was not significant (p = 0.10). There were no significant effects of DCP on muscle strength or muscle mass in either trial. The most common adverse events in both trials were paresthesia (47% DCP vs 14% placebo, both trials combined) and confusion (19% DCP vs 7% placebo, both trials combined). CONCLUSIONS: DCP is effective in reducing the attack frequency, is safe, and improves quality of life in HOP periodic paralysis. CLASSIFICATION OF EVIDENCE: These studies provide Class I evidence that DCP significantly reduces attack frequency in HOP but lacked the precision to support either efficacy or lack of efficacy of DCP in HYP.

A recessive Nav1.4 mutation underlies congenital myasthenic syndrome with periodic paralysis.

OBJECTIVE: To determine the molecular basis of a complex phenotype of congenital muscle weakness observed in an isolated but consanguineous patient. METHODS: The proband was evaluated clinically and neurophysiologically over a period of 15 years. Genetic testing of candidate genes was performed. Functional characterization of the candidate mutation was done in mammalian cell background using whole cell patch clamp technique. RESULTS: The proband had fatigable muscle weakness characteristic of congenital myasthenic syndrome with acute and reversible attacks of most severe muscle weakness as observed in periodic paralysis. We identified a novel homozygous SCN4A mutation (p.R1454W) linked to this recessively inherited phenotype. The p.R1454W substitution induced an important enhancement of fast and slow inactivation, a slower recovery for these inactivated states, and a frequency-dependent regulation of Nav1.4 channels in the heterologous expression system. CONCLUSION: We identified a novel loss-of-function mutation of Nav1.4 that leads to a recessive phenotype combining clinical symptoms and signs of congenital myasthenic syndrome and periodic paralysis, probably by decreasing channel availability for muscle action potential genesis at the neuromuscular junction and propagation along the sarcolemma.

Reference value of long-time exercise test in the diagnosis of primary periodic paralysis.

BACKGROUND: The long-time exercise test (ET) is used to diagnose the primary periodic paralyses (PPs). However the reference values of ET are many and various. This study aimed to investigate the reference value of long-time ET in the diagnosis of PPs. METHODS: We recruited 108 healthy subjects, 68 patients with PPs, and 72 patients with other diseases for the study. The procedure of ET was made on the basis of the McManis' method. Electrical responses were recorded from right abductor digiti minimi (ADM) muscle when stimulation of the ulnar nerve at the wrist. After the compound muscle action potential (CMAP) was monitored, subjects were then asked to contract the muscle as strongly as possible for 5 minutes. CMAPs were recorded for 2 seconds immediately after cessation of exercise, then every 5 minutes for 10 minutes, and finally every 10 minutes for 50 minutes. In general, the CMAP amplitudes will fall below the pre-exercise levels in an hour. The largest decrease was calculated and used as results of ET. RESULTS: The CMAP amplitude decreases had no significant differences between groups when the healthy adults were grouped according to age, gender, height, weight and test time. Decreases in PPs patients (57.76%) were significantly more than in healthy subjects (15.21%) and other disease patients (18.10%, P < 0.001). Receiver operating characteristic (ROC) curve analysis showed that the best threshold is 35.50%. CONCLUSIONS: In the long-time exercise test, threshold of 35.50% for the CMAP amplitude decrease was identified for abnormal. The result is not influenced by age, gender, height, weight, and test time. About 7.4% of healthy subjects were abnormal in ET.

Parálisis periódica hipopotasémica. A propósito de un caso / Hypokalemic periodic paralysis. A case report

Las parálisis periódicas son un trastorno poco frecuente que cursa con episodios de debilidad muscular aguda que puede confundirse con otras enfermedades como la epilepsia o la miastenia gravis, entre otras. Dentro de ellas se incluyen las parálisis hiper e hipopotasémicas, dividiéndose estas últimas a su vez en periódicas (familiar, tirotóxica o esporádica) y no periódicas. A este respecto, presentamos un caso de parálisis periódica hipopotasémica familiar en una mujer de 18 años que había sido diagnosticada en la infancia de epilepsia y que, además, había presentado un hipotiroidismo subclínico meses atrás por el que había recibido tratamiento sustitutivo. La anamnesis, siempre fundamental, y la objetivación de hipopotasemia permitieron el diagnóstico (AU)

Periodic paralysis is a rare disorder that causes episodes of severe muscle weakness that can be confused with other diseases, including epilepsy or myasthenia gravis. Hyperkalemic and hypokalemic paralysis are included within these diseases, the latter being divided intoperiodic paralysis (familial, thyrotoxic or sporadic) and non-periodic paralysis. In this regard, we present a case of familial hypokalemic periodic paralysis in an eighteen year-old female who was diagnosed with epilepsy in childhood, as well as a subclinical hypothyroidism (for which she received replacement therapy) months ago. The diagnosis was made by the anamnesis and the confirmation of hypokalemia (AU)

Rare disease centers for periodic paralysis: China versus the United States and United Kingdom.

INTRODUCTION: We have developed a rare disease center in China. METHODS: In this study we analyzed how patients with periodic paralysis accessed centers in China vs. in the USA and UK. RESULTS: A total of 116 patients with periodic paralysis were evaluated in Beijing and Hangzhou (2003-2012). These patients traveled long distances for outpatient specialist care without an appointment or physician referral. In contrast, at the University of Rochester in the USA, >90% of patients were referred from physicians throughout the country by identifying physician expertise or by referrals from a patient advocacy group. In the UK, a single center, supported by the National Health Service, provides assessment/genetic testing for all UK patients. CONCLUSIONS: Rare disease centers in China require: (1) establishing a center for clinical characterization of the disease (e.g., periodic paralysis); (2) establishing a genetic diagnostic platform; (3) placing the center at a major city hospital; and (4) facilitating patient access through internet websites.

Muscle channelopathies and related diseases.

Muscle channelopathies and related disorders are neuromuscular disorders predominantly of genetic origin which are caused by mutations in ion channels or genes that play a role in muscle excitability. They include different forms of periodic paralysis which are characterized by acute and reversible attacks of muscle weakness concomitant to changes in blood potassium levels. These disorders may also present as distinguishable myotonic syndromes (slowed muscle relaxation) which have in common lack of involvement of dystrophic changes of the muscle, in contrast to dystrophia myotonica. Recent advances have been made in the diagnosis of these different disorders, which require, in addition to a careful clinical evaluation, detailed EMG and molecular study. Although these diseases are rare, they deserve attention since patients may benefit from drugs which can dramatically improve their condition. Patients may have atypical presentations, sometimes life-threatening, which may delay a proper diagnosis, mostly in the first months of life. The creation of specialized reference centers in the Western world has greatly benefited the proper recognition of these neuromuscular diseases.

[Clinical and molecular genetic analysis of a family with normokalemic periodic paralysis].

OBJECTIVE: Periodic paralysis (PP) is one type of skeletal muscle channelopathies characterized by episodic attacks of weakness. It is usually classified into hyperkalemic periodic paralysis (HyperPP), hypokalemic periodic paralysis (HypoPP) and normokalemic periodic paralysis (NormoPP) based on the blood potassium levels. HypoPP is the most common type of these three and NormoPP is the rarest one. The aim of this study was to explore the clinical and genetic features of a Chinese family with normokalemic periodic paralysis (NormoKPP). METHOD: Clinical features of all patients in the family with NormoKPP were analyzed. Genomic DNA was extracted from peripheral blood leukocytes and amplified with PCR. We screened all 24 exons of SCN4A gene and then sequence analysis was performed in those who showed heteroduplex as compared with unaffected controls. RESULT: (1) Fifteen members of the family were clinically diagnosed NormoKPP, and their common features are: onset within infacy, episodic attacks of weakness, the blood potassium levels were within normal ranges, high sodium diet or large dosage of normal saline could attenuate the symptom. One muscle biopsy was performed and examination of light and electronic microscopy showed occasionally degenerating myofibers. (2) Gene of 12 patients were screened and confirmed mutations of SCN4A genes--c. 2111 T > C/p. Thr704Met. CONCLUSION: The study further defined the clinical features of patients with NormoKPP, and molecular genetic analysis found SCN4A gene c. 2111 T > C/p. Thr704Met point mutation contributed to the disease. In line with the autosomal dominant inheritance laws, this family can be diagnosed with periodic paralysis, and be provided with genetic counseling. And the study may also help the clinical diagnosis, guide treatment and genetic counseling of this rare disease in China.