The Role of Nutrition and Physical Activity as Trigger Factors of Paralytic Attacks in Primary Periodic Paralysis.

BACKGROUND: Primary periodic paralysis (PPP) are rare inherited neuromuscular disorders including Hypokalemic periodic paralysis (HypoPP), Hyperkalemic periodic paralysis (HyperPP) and Andersen-Tawil syndrome (ATS) characterised by attacks of weakness or paralysis of skeletal muscles. Limited effective pharmacological treatments are available, and avoidance of lifestyle related triggers seems important. OBJECTIVE: Our aim was to search and assess the scientific literature for information on trigger factors related to nutrition and physical activity in PPP. METHODS: We searched Ovid Medline and Embase database for scientific papers published between January 1, 1990, to January 31, 2020. RESULTS: We did not identify published observation or intervention studies evaluating effect of lifestyle changes on attacks. Current knowledge is based on case-reports, expert opinions, and retrospective case studies with inadequate methods for description of nutrition and physical activity. In HypoPP, high carbohydrate and salt intake, over-eating, alcohol, dehydration, hard physical activity, and rest after exercise are frequently reported triggers. Regarding HyperPP, fasting, intake of potassium, alcohol, cold foods or beverages, physical activity, and rest after exercise are frequently reported triggers. No nutrition related triggers are reported regarding ATS, exercise can however induce ventricular arrhythmias. CONCLUSIONS: Our results support that dietary intake and physical activity may play a role in causing paralytic attacks in PPP, although the current scientific evidence is weak. To provide good evidence-based patient care, several lifestyle aspects need to be further assessed and described.

Pain as a significant symptom in patients with periodic paralysis-A cross-sectional survey.

INTRODUCTION: Periodic paralysis (PP) is thought to be limited to episodes of muscle weakness, but there are reports of fibromyalgia-like pain in PP. We aimed to evaluate pain and comorbid sleep, fatigue, and mood disorders in PP patients. METHODS: We administered a cross-sectional survey to PP patients at the 2019 Periodic Paralysis Conference. The survey consisted of the Brief Pain Inventory, Widespread Pain Index, Pittsburgh Sleep Quality Index, Modified Fatigue Impact Scale, and ten-question Center for Epidemiologic Studies Depression Scale (CESD-10). Descriptive statistics for PP patients were calculated and compared with earlier studies. RESULTS: Forty-four individuals with PP took the survey. Of these patients, 52.3% reported a moderate to severe interference of pain on their lives, and 45.5% met the study criteria for fibromyalgia. Patients with SCN4A mutations had higher rates of fibromyalgia than the next most prevalent gene mutation, CACNA1S. In patients with pain, there were increased rates of comorbid fatigue, depression, and poor sleep quality. DISCUSSION: Pain, akin to fibromyalgia, is a significant symptom of PP and can affect quality of life. Pain in PP was more prevalent than in the general population, at a rate comparable with other chronic neuromuscular disease groups. PP patients could benefit from a multidisciplinary approach to assess their pain, sleep, fatigue, and mood.

The clinical and genetic heterogeneity analysis of five families with primary periodic paralysis.

To explore the clinical and genetic characteristics of five families with primary periodic paralysis (PPP). We reviewed clinical manifestations, laboratory results, electrocardiogram, electromyography, muscle biopsy, and genetic analysis from five families with PPP. Five families with PPP included: hypokalemic periodic paralysis type 1 (HypoPP1, CACNA1S, 1/5), hypokalemic periodic paralysis type 2 (HypoPP2, SCN4A, 2/5), normokalemic periodic paralysis (NormoPP, SCN4A, 1/5), and Andersen-Tawil syndrome (ATS, KCNJ2, 1/5). The basic clinical manifestations of five families were consistent with PPP, presenting with paroxysmal muscle weakness, with or without abnormal serum potassium. ATS was accompanied by ventricular arrhythmias, and skeletal and craniofacial anomalies, developing with a permanent fixed myopathy later. The electromyography showed diffuse myopathic discharge, and muscle biopsy showed tubular aggregates. Genetic testing revealed five families with PPP carried CACNA1S (R1242S), SCN4A (R675Q, T704M), and KCNJ2 (R218Q) respectively. The novel heterozygous R1242S mutation in CACNA1S caused a conformational change in the protein structure, and the amino acid of this mutation site was highly conserved among different species. SCN4A mutations led to two phenotypes of HypoPP2 and NormoPP. PPPs are autosomal dominant disorders of ion channel dysfunction characterized by episodic flaccid muscle weakness secondary to abnormal sarcolemmal excitability. PPPs are caused by mutations in skeletal muscle calcium channel CaV1.1 gene (CACNA1S), sodium channel NaV1.4 gene (SCN4A), and potassium channels Kir2.1, Kir3.4 genes (KCNJ2, KCNJ5), including HypoPP1, HypoPP2, NormoPP, HyperPP, and ATS, which have significant clinical and genetic heterogeneity. Diagnosis is based on the characteristic clinical presentation then confirmed by genetic testing.

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.

The Mary Walker effect: Mary Broadfoot Walker.

Mary Broadfoot Walker (1888-1974) was the first to demonstrate the 'Mary Walker effect' describing the weakness of other muscle groups following release of the arteriovenous occlusion of an unrelated exercising muscle group in patients with myasthenia gravis, which led to the search for a circulating causative agent for myasthenia gravis. She was the first to clearly demonstrate that strength temporarily improved in patients with myasthenia gravis with physostigmine or Prostigmin (neostigmine). This dramatic treatment response has been erroneously termed the 'Mary Walker effect'. Further, she noted hypokalaemia during attacks of weakness in familial periodic paralysis, pioneering treatment with potassium chloride. Although Mary Walker practiced in a nonacademic setting and trained at a time when women were not allowed to train alongside men, she was the first to convincingly demonstrate three life-changing treatments in the field of neuromuscular medicine, a feat that few physicians of any era can claim.

Parálisis periódica hipopotasémica familiar, Instituto Hondureño de Seguridad Social / Family Hypokalemic Periodic Paralysis, Social Security Institute of Honduras, Internal Medicine Service

La parálisis periódica hipopotasémica , es una enfermedad congénita autosómica dominante; predomina en sexo masculino, con concentraciones sanguíneas de potasio bajas. Objetivo: identificar la parálisis hipopotasémica familiar como un reto clínico para el diagnóstico y tratamiento del paciente. Presentación del caso clínico: masculino, en la tercera década de la vida; sin antecedentes personales, se presenta a emergencia con tetraparesia que inicia en manos, de distal a proximal, con posterior dificultad para la deambulación. Antecedentes familiares de su madre y hermana que habían padecido cuadro similar; exámenes de laboratorio: química sanguínea, Creatin fosfocinasa 1 481, Transaminasa glutámica oxaloacetica 46 U/L, Transaminasa glutámica pirúvica 36 U/L, Sodio 143 mg/dl, Potasio 2.6 mg/dl, Calcio 9.3 mg/dl. Tratamiento al ingreso 40 mEq de cloruro de potasio y 250 cc de solución salina normal 0.9%. Se realizó prueba terapéutica con cloruro de potasio y ver recuperación progresiva de la fuerza muscular, pruebas tiroideas descartan otras causas. Conclusión: la parálisis hipopotasémica se ha vuelto un diagnóstico poco sospechado en el ingreso de pacientes con tetraparesia, aunque el tratamiento rápidamente instaurado puede mejorar los síntomas y permite un estudio posterior de la etiología...(AU)

Debilidad muscular con hipokalemia e hipertiroidismo en un adolescente con síndrome de Down / Muscle weakness with hypokalemia and hyperthyroidism in an adolescent with Down syndrome

La hipokalemia aguda es una causa poco frecuente de debilidad muscular. La parálisis periódica tirotóxica es una complicación infrecuente de la tirotoxicosis, en sus diferentes etiologías, en la cual se produce hipokalemia por un flujo masivo de potasio al compartimiento intracelular, que provoca parálisis muscular, que afecta, principalmente, la musculatura proximal de los miembros inferiores. Es importante reconocer esta entidad para instaurar un tratamiento adecuado que incluya el rápido suplemento de potasio y el uso de beta-bloqueantes no selectivos. El tratamiento del hipertiroidismo subyacente y el retorno al estado eutiroideo es imprescindible para la resolución de los episodios de parálisis periódica tirotóxica. Aquí se presenta a un paciente de 13 años de edad con síndrome de Down que consultó por debilidad muscular de los miembros inferiores y trastorno de la marcha, asociada a hipokalemia aguda, en el que se realizó el diagnóstico de hipertiroidismo por enfermedad de Graves.

Acute hypokalemic paralysis is a rare cause of acute weakness. Thyrotoxic periodic paralysis (TPP) is an unusual complication of hyperthyroidism. It is characterized by sudden onset of hypokalemia condition resulting from a shift of potassium into cells and paralysis that primarily affects the lower extremities. Failure to recognize TPP may lead to improper management. Treatment of TPP includes replacing potassium rapidly, using nonselective beta-blockers and correcting the underlying hyperthyroidism as soon as possible. TPP is curable once euthyroid state is achieved. We describe a 13-year-old male with Down syndrome who presented with acute onset of lower extremity weakness secondary to acute hypokalemia and was found to have new onset Graves' disease.

Atypical periodic paralysis and myalgia: A novel RYR1 phenotype.

OBJECTIVE: To characterize the phenotype of patients with symptoms of periodic paralysis (PP) and ryanodine receptor (RYR1) gene mutations. METHODS: Cases with a possible diagnosis of PP but additional clinicopathologic findings previously associated with RYR1-related disorders were referred for a tertiary neuromuscular clinical assessment in which they underwent detailed clinical evaluation, including neurophysiologic assessment, muscle biopsy, and muscle MRI. Genetic analysis with next-generation sequencing and/or targeted Sanger sequencing was performed. RESULTS: Three cases with episodic muscle paralysis or weakness and additional findings compatible with a RYR1-related myopathy were identified. The McManis test, used in the diagnosis of PP, was positive in 2 of 3 cases. Genetic analysis of known PP genes was negative. RYR1 analysis confirmed likely pathogenic variants in all 3 cases. CONCLUSIONS: RYR1 mutations can cause late-onset atypical PP both with and without associated myopathy. Myalgia and cramps are prominent features. The McManis test may be a useful diagnostic tool to indicate RYR1-associated PP. We propose that clinicopathologic features suggestive of RYR1-related disorders should be sought in genetically undefined PP cases and that RYR1 gene testing be considered in those in whom mutations in SCN4A, CACNA1S, and KCNJ2 have already been excluded.

Parálisis periódica hipocalémica: reporte de caso y revisión del tema / Hypokalemic periodic paralysis: A case report and a topic review

Las parálisis periódicas primarias son canalopatías poco frecuentes, de las cuales hacen parte: la parálisis periódica hipocalémica, la parálisis periódica hipercalémica y el síndrome Andersen-Tawil; son caracterizadas por ataques de debilidad muscular generalizada, con recuperación de la fuerza entre los ataques. Presentamos el caso de una mujer de 21 años con el segundo episodio de parálisis y documentación de hipocalemia, sin antecedentes de importancia, sin factores clínicos o paraclínicos que expliquen el trastorno electrolítico, con recuperación posterior de la fuerza al realizar tratamiento de la hipocalemia. Posteriormente se lleva a cabo una revisión del tema.

Primary periodic paralyses are rare channelopathies which include: hypokalemic periodic paralysis, hyperkalemic periodic paralysis, and Andersen-Tawil Syndrome. These entities are characterized by attacks of generalized muscle weakness and recovery of muscle strength between attacks. A case is presented of a 21-year-old woman who presented a second episode of paralysis and documented hypokalemia, with no important antecedents, with no clinical or diagnostic test factors which explain her electrolyte disorder, with recovery of muscle strength after receiving treatment for hypokalemia. A review of the topic was conducted.

Periodic Paralysis as a New Phenotype of Resistance to Thyroid Hormone Syndrome in a Chinese Male Adult.

CONTEXT: A majority of patients with resistance to thyroid hormone (RTH) are asymptomatic, whereas some patients show signs of hyperthyroidism, or hypothyroidism, or both. Thyrotoxic periodic paralysis is the most common form of acquired periodic paralysis. However, it has not been reported in a patient with RTH up to now. OBJECTIVE: We evaluated a 36-year-old male patient from China with elevated serum free T4 and free T3 and inappropriately high TSH who presented with periodic paralysis. STUDY DESIGN: Clinical, biochemical, and radiological assessments, as well as DNA sequencing, were performed. RESULTS: The patient's laboratory tests revealed the following: TSH, 6.14 mIU/L (0.27-4.2 mIU/L); free T3, 12.85 pmol/L (2.8-7.1 pmol/L); free T4, 33.62 pmol/L (9.05-25.5 pmol/L); and serum SHBG, 19.4 nmol/L (18.3-54.1 nmol/L). No significant suppression of TSH was observed in the rapid TSH suppression test with somatostatin analogs. Compound muscle action potential after exercise of the patient was reduced by 58%. Sequencing of thyroid hormone receptor genes confirmed a C446S mutation in the THRß gene. CONCLUSIONS: This is the first report of periodic paralysis as a new phenotype of RTH syndrome.

[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.

Thyrotoxic periodic paralysis in Chinese patients: milder thyrotoxicosis yet lower dose of (131)I should be avoided.

PURPOSE: Thyrotoxic periodic paralysis (TPP) is a complication of thyrotoxicosis mainly observed in male Asian patients. It was proposed that patients with TPP tend to have lower thyroid hormone levels. We aimed to prove this observation and to assess whether a lower I dose is feasible for prompt control of TPP. METHODS: A total of 123 male TPP patients were enrolled in this study in a 7-year period. Baseline characteristics were compared with 70 thyrotoxic patients without periodic paralysis (nTPP). Different I doses were given to 90 TPP patients with a median follow-up of 11 months, and the outcome was evaluated. RESULTS: The serum thyroid hormone levels, including total T3 and T4, and free T3 and T4, in TPP patients were slightly less elevated compared with those in nTPP patients. Patients who received lower radioactivity of I had an unsatisfactory overall remission rate of 28.6%. Longer time to remission (P = 0.004; hazard ratio, 1.846; 95% confidence interval, 1.216-2.798) was also observed in patients with lower dose. CONCLUSIONS: The serum thyroid hormone levels of TPP patients are lower than those of nTPP patients. Median/high dose of I is necessary to achieve rapid control of thyrotoxicosis.

Tentorial dural arteriovenous fistula presenting as episodic weakness mimicking periodic paralysis.

We report a rare case of episodic limb weakness caused by a tentorial dural arteriovenous fistula (DAVF) draining into the perimesencephalic veins. A middle-aged man presented with episodes of transient quadriparesis preceded by recurrent vomiting. The patient was initially suspected of having periodic paralysis but, due to the presence of recurrent vomiting and brisk reflexes, MR imaging of the brain was performed which revealed marked T2 hyperintensity of the brainstem and cervical cord along with multiple prominent flow voids. Cerebral angiography showed a Borden type 3 DAVF at the left tentorial margin which was draining into the perimesencepahlic and perimedullary veins and refluxing into the cervical epidural veins. The patient made a remarkable recovery after surgical interruption of the fistula.

Hereditary channelopathies in neurology.

Ion channelopathies are caused by malfunction or altered regulation of ion channel proteins due to hereditary or acquired protein changes. In neurology, main phenotypes include certain forms of epilepsy, ataxia, migraine, neuropathic pain, myotonia, and muscle weakness including myasthenia and periodic paralyses. The total prevalence of monogenic channelopathies in neurology is about 35:100,000. Susceptibility-related mutations further increase the relevance of channel genes in medicine considerably. As many disease mechanisms have been elucidated by functional characterization on the molecular level, the channelopathies are regarded as model disorders for pathogenesis and treatment of non-monogenic forms of epilepsy and migraine. As more than 35% of marketed drugs target ion channels, there is a high chance to identify compounds that counteract the effects of the mutations.

State of the art in hereditary muscle channelopathies.

A combination of electrophysiological and genetic studies has resulted in the identification of several skeletal muscle disorders to be caused by pathologically functioning ion channels and has led to the term channelopathies. Typical hereditary muscle channelopa thies are congenital myasthenic syndromes, non-dystrophic myotonias, periodic paralyses, malignant hyperthermia, and central core disease. Most muscle channelopathies are commonly considered to be benign diseases. However, life-threatening weakness episodes or progressive permanent weakness may make these diseases severe, particularly the periodic paralyses (PP). Even in the typical PP forms characterized by episodic occurrence of weakness, up to 60% of the patients suffer from permanent weakness and myopathy with age. In addition, some PP patients present with a predominant progressive muscle weakness phenotype. The weakness can be explained by strongly depolarized fibers that take up sodium and water and that are electrically inexcitable. Drugs that repolarize the fiber membrane can restore muscle strength and may prevent progression.

Skeletal muscle channelopathies: new insights into the periodic paralyses and nondystrophic myotonias.

PURPOSE OF REVIEW: To summarize advances in our understanding of the clinical phenotypes, genetics, and molecular pathophysiology of the periodic paralyses, the nondystrophic myotonias, and other muscle channelopathies. RECENT FINDINGS: The number of pathogenic mutations causing periodic paralysis, nondystrophic myotonias, and ryanodinopathies continues to grow with the advent of exon hierarchy analysis strategies for genetic screening and better understanding and recognition of disease phenotypes. Recent studies have expanded and clarified the role of gating pore current in channelopathy pathogenesis. It has been shown that the gating pore current can account for the molecular and phenotypic diseases observed in the muscle sodium channelopathies, and, given that homologous residues are affected in mutations of calcium channels, it is possible that pore leak represents a pathomechanism applicable to many channel diseases. Improvements in treatment of the muscle channelopathies are on the horizon. A randomized controlled trial has been initiated for the study of mexiletine in nondystrophic myotonias. The class IC antiarrhythmia drug flecainide has been shown to depress ventricular ectopy and improve exercise capacity in patients with Andersen-Tawil syndrome. SUMMARY: Recent studies have expanded our understanding of gating pore current as a disease-causing mechanism in the muscle channelopathies and have allowed new correlations to be drawn between disease genotype and phenotype.

Mutations of sodium channel alpha-subunit genes in Chinese patients with normokalemic periodic paralysis.

OBJECTIVE: In this study, we aim to investigate the clinical features and Mutations of sodium channel alpha-subunit (SCN4A) genes in Chinese patients with normokalemic periodic paralysis (normoKPP). METHODS: Six unrelated Chinese families with normoKPP were analyzed in clinical features. Genomic DNA was extracted from peripheral blood leukocytes and amplified with PCR. We screened all 24 exons of SCN4A gene with denaturing high performance liquid chromatography (DHPLC) technology, and then sequence analysis was performed in those who showed heteroduplex as compared with unaffected controls. RESULTS: The laboratory tests were within normal ranges. Electromyograms and electrocardiograms were normal. One muscle biopsy was performed with the patient in family 4 after a brief attack of normoKPP. Examination of light microscopy showed no changes, but electronic microscopy showed occasionally degenerating myofibers. The mutations of SCN4A genes were as follows: (1) Met1592Val occurred in family 1. (2) Val-781-Ile occurred with the patient and her father in family 4. (3) Both the patients had a novel mutation g2101a predicting the amino acid exchange Arg675Gln in family 5, which may be a disease-causing mutation. CONCLUSIONS: In addition to Val-781-Ile and Met1592Val, the mutation g2101a (Arg675Gln) may be the novel mutation of SCN4A genes in Chinese patients with normoKPP.

Fatal thyrotoxic periodic paralysis with normokalemia.

We present a 10-year-old girl who presented to our emergency services with difficulty in breathing of 2-days duration and progressive weakness of a month's duration. In a previous admission elsewhere, she had not been detected to have hyperthyroidism or electrolyte abnormalities. On admission, the child was in hypercapnic respiratory failure with tachycardia and hepatomegaly. A small goiter as well as signs of thyrotoxicosis were present. Laboratory investigations showed anemia, mildly elevated liver enzymes and serum potassium of 4.8mEq/L. Despite intubation and ventilation and other supportive management including propranolol, the patient could not be saved. Post-mortem biopsy of the thyroid showed diffuse hyperplasia of the follicles and muscles showed evidence of thyroid myopathy.

Caracterización electrocadiográfica en estudiantes de ciencias para la salud de Manizales, según antecedentes familiares de infarto de miocardio / Electrocardiographic characterization in students of sciences of the health of Manizales, according to familiar antecedents of myocardium infarct

Introducción: El Infarto agudo de Miocardio (IAM), constituye una de las principales causas de muerte y discapacidad en el medio, es por esto que su diagnóstico es de vital importancia. La utilización del electrocardiograma contiene un invaluable pronóstico de información relacionada con: tamaño del corazón, desviación del segmento S-T, duración de QRS y localización del infarto. Esta información sumada a la predicción clínica, debe ser valorada para facilitar la mejor opción de tratamiento -Conclusiones: En este estudio no se encontró correlación entre características electrocardiográficas que hicieran pensar en un IAM personal con antecedentes familiares de patología cardíaca posiblemente debido al período tan corto con el que se contó para realizar la investigación, sin posibilidad de realizar un seguimiento a estos pacientes...