Sandbox:Mounika

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mounika Lakhmalla, MBBS[2]

Chronic Spontaneous Urticaria

Chronic spontaneous urticaria by definition is the presence of urticaria/hives, angioedema, or sometimes both for a duration of six weeks or longer. It affects adults more than children, and women are affected more often than men.

• Diagnosis of CSU is often clinical, based on the episodic appearance of characteristic urticarial lesions, with or without angioedema, on most days of the week, for a period of six weeks or longer. In 80 to 90 percent of adults and children with CSU, no specific etiology can be identified.

• Skin biopsy is not needed for routine diagnosis of CSU, although it is indicated to exclude urticarial vasculitis if there are signs or symptoms consistent with a vasculitic process or in the rare patients with features of mastocytosis.

• Tests used in investigation of pathogenesis include the autologous serum and plasma skin tests (ASST/APST), assays for autoantibodies directed against immunoglobulin (Ig)E or Fc-epsilon-RI, and also in vitro assessments of basophil function. However, these tests lack specificity and prognostic value, are not standardized across laboratories, and are not recommended for routine clinical use.
• Several hypotheses about the pathogenesis of chronic idiopathic urticaria have been proposed, although the data for each are incomplete, and none appear to be helpful for determining treatment or prognosis. The most accepted hypothesis involves histamine-releasing factors and defects in basophil signaling and/or function.

• CSU is a self-limited disease in the vast majority of patients.Spontaneous remission occurs in 30 to 50 percent of patients by one year, and the average duration of disease is two to five years. Up to 20 percent of patients still have symptoms persisting beyond five years. Those with more severe symptoms tend to have longer-lasting disease.
• Patients with chronic spontaneous urticaria are often frustrated and anxious
• Although no external cause is identified in most patients, numerous factors can aggravate the condition.
• Understanding these triggers and learning to avoid those that are relevant to the individual patient are critical components of successful management. Education should begin as soon as the diagnosis is made.
• H1 antihistamines are recommended as initial therapy for all patients with chronic spontaneous Urticaria.
• Less-sedating, second-generation agents (eg, cetirizine, levocetirizine, fexofenadine, loratadine, desloratadine)are more recommended over older first-generation agents (eg, hydroxyzine, diphenhydramine, chlorpheniramine, or mizolastine)

Treatment Response

• Around 50% of the patients may not achieve complete control of symptoms using standard doses of second-generation H1 antihistamines alone.
• a stepwise approach to increasing therapy is appropriate for this patient group(Non Responders).
• As we increase doses or as different agents are introduced, it is important to discontinue any that have not been beneficial, so that medications do not accumulate

One or more of the following interventions are recommended for those who have persistent symptoms:

1. Increasing the dose of the second-generation H1 antihistamine to up to four times the standard dose (after which, international guidelines suggest adding Omalizumab)
2. Adding a different second-generation antihistamine
3. Adding an H2 antagonist
4. Adding a leukotriene-receptor antagonist
5. Adding a first-generation H1 antihistamine at bedtime

For patients whose symptoms persist, increasing the dose of first-generation H1 antihistamine gradually is suggested. These patients need to be informed about sedation and anticholinergic side effects.
Usage of Systemic glucocorticoids should be reserved for short-term control of refractory symptoms.
Symptoms that persist despite step 3 therapy or who are intolerant of dose advancement of first-generation H1 antihistamines are considered to have refractory disease.
Once symptoms are controlled, we continue the drug(s) required for control for a minimum of1 to 3 months before attempting to taper or discontinue medications.
We recommend extending this maintenance period even longer in patients whose symptoms were particularly difficult to suppress.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [3]; Associate Editor(s)-in-Chief: Mounika Lakhmalla, MBBS[4]

Overview

Andersen–Tawil syndrome, also called Andersen syndrome and Long QT syndrome 7, is a form of Long QT syndrome. It is a rare genetic disorder, and is inherited in an autosomal dominant pattern.

Classification

There is no established system for the classification of [disease name].

OR

[Disease name] may be classified according to [classification method] into [number] subtypes/groups: [group1], [group2], [group3], and [group4].

OR

[Disease name] may be classified into [large number > 6] subtypes based on [classification method 1], [classification method 2], and [classification method 3]. [Disease name] may be classified into several subtypes based on [classification method 1], [classification method 2], and [classification method 3].

OR

Based on the duration of symptoms, [disease name] may be classified as either acute or chronic.

OR

If the staging system involves specific and characteristic findings and features: According to the [staging system + reference], there are [number] stages of [malignancy name] based on the [finding1], [finding2], and [finding3]. Each stage is assigned a [letter/number1] and a [letter/number2] that designate the [feature1] and [feature2].

OR

The staging of [malignancy name] is based on the [staging system].

OR

There is no established system for the staging of [malignancy name].

Pathophysiology

• It is thought that Anderson Tawil disease is caused by mutation in KCNJ2 or KCNJ5 gene.
• KCNJ2 encodes the α‐subunit of the potassium channel Kir2.1 .

Kir 2.1 is responsible for inward rectifier current (IK1) in cardiomyocytes (Statland, Tawil, & Venance, 2004).

• KCNJ5 encodes the G protein‐activated inwardly rectifying potassium channel 4 (Kir3.4).

Mutations in KCNJ5 gene causes inhibitory effects on channel Kir2.1.

It is characterized by the triad: ventricular arrhythmias, periodic paralysis or muscle weakness, and skeletal dysmorphism, most commonly micrognathia, clinodactyly. However, the phenotype is various (Statland et al., 2004). Coexistence of ATS with other genetic disorder was described only in research concerning the influence of KCNH2 polymorphism NM_000238.2:c.2690A>C p.(Lys897Thr) on ATS manifestation (Jagodzińska et al., 2016).

Differentiating ((Page name)) from other Diseases

[Disease name] must be differentiated from other diseases that cause [clinical feature 1], [clinical feature 2], and [clinical feature 3], such as [differential dx1], [differential dx2], and [differential dx3].

OR

[Disease name] must be differentiated from [[differential dx1], [differential dx2], and [differential dx3].

Epidemiology and Demographics

The incidence/prevalence of [disease name] is approximately [number range] per 100,000 individuals worldwide.

OR

In [year], the incidence/prevalence of [disease name] was estimated to be [number range] cases per 100,000 individuals worldwide.

OR

In [year], the incidence of [disease name] is approximately [number range] per 100,000 individuals with a case-fatality rate of [number range]%.

Patients of all age groups may develop [disease name].

OR

The incidence of [disease name] increases with age; the median age at diagnosis is [#] years.

OR

[Disease name] commonly affects individuals younger than/older than [number of years] years of age.

OR

[Chronic disease name] is usually first diagnosed among [age group].

OR

[Acute disease name] commonly affects [age group].

There is no racial predilection to [disease name].

OR

[Disease name] usually affects individuals of the [race 1] race. [Race 2] individuals are less likely to develop [disease name].

[Disease name] affects men and women equally.

OR

[Gender 1] are more commonly affected by [disease name] than [gender 2]. The [gender 1] to [gender 2] ratio is approximately [number > 1] to 1.

The majority of [disease name] cases are reported in [geographical region].

OR

[Disease name] is a common/rare disease that tends to affect [patient population 1] and [patient population 2].

Screening

Surveillance: Annual screening of asymptomatic individuals with a KCNJ2 pathogenic variant with a 12-lead ECG and 24-hour Holter monitoring.

There is insufficient evidence to recommend routine screening for [disease/malignancy].

According to the [guideline name], screening for [disease name] is not recommended.

According to the [guideline name], screening for [disease name] by [test 1] is recommended every [duration] among patients with [condition 1], [condition 2], and [condition 3].

Natural History, Complications, and Prognosis

If left untreated, [#]% of patients with [disease name] may progress to develop [manifestation 1], [manifestation 2], and [manifestation 3].

OR

Common complications of [disease name] include [complication 1], [complication 2], and [complication 3].

OR

Prognosis is generally excellent/good/poor, and the 1/5/10-year mortality/survival rate of patients with [disease name] is approximately [#]%.

Diagnosis

Diagnostic Study of Choice

There are no established criteria for the diagnosis of ATS. Diagnosis is established in an individual with characteristic clinical and ECG findings and/or identification of a pathogenic variant in KCNJ2.

Establishing the Diagnosis

The diagnosis of ATS is established in a proband with the presence of A or B in Suggestive Findings and/or by identification of a heterozygous pathogenic variant in KCNJ2 by molecular genetic testing (see Table 1).

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of ATS is broad, individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those with a phenotype indistinguishable from many other inherited disorders with cardiac arrhythmias are more likely to be diagnosed using genomic testing (see Option 2).

Suggestive Findings

Andersen-Tawil syndrome (ATS) should be suspected in individuals with either A or B:

A. Presence of two of the following three criteria:

Periodic paralysis Symptomatic cardiac arrhythmias or electrocardiographic evidence of enlarged U-waves, ventricular ectopy, or a prolonged QTc or QUc interval Characteristic facies, dental anomalies, small hands and feet, AND at least two of the following: Low-set ears Widely spaced eyes Small mandible Fifth-digit clinodactyly Syndactyly of toes 2 and 3

B. One of the above three criteria AND at least one other family member who meets two of the three criteria [Statland et al 2018]

Supportive Findings

Individuals with either episodic weakness or cardiac symptoms require careful evaluation by a neurologist and/or cardiologist as well as measurement of serum potassium concentration (baseline and during attacks of flaccid paralysis), a 12-lead ECG, a 24-hour Holter monitor, and possibly the long exercise protocol.

Serum potassium concentration during episodes of weakness may be elevated, normal, or, most commonly, reduced (<3.5 mmol/U). Routine nerve conduction electrophysiology is normal between episodes. A more sensitive electrophysiologic study, the long exercise protocol, may reveal an immediate post-exercise increment followed by an abnormal decrement in the compound motor action potential amplitude (>40%) or area (>50%) 20-40 minutes post exercise . In a study of 11 individuals with ATS, 82% met long-exercise amplitude decrement criteria for abnormal testing . Electrocardiogram may reveal characteristic abnormalities including prominent U waves, prolonged Q-U intervals, premature ventricular contractions, polymorphic ventricular tachycardia, and bidirectional ventricular tachycardia. 24-hour Holter monitoring is important to document the presence, frequency, and duration of ventricular tachycardia (VT) and the presence or absence of associated symptoms

History and Symptoms

The majority of patients with [disease name] are asymptomatic.

OR

The hallmark of [disease name] is [finding]. A positive history of [finding 1] and [finding 2] is suggestive of [disease name]. The most common symptoms of [disease name] include [symptom 1], [symptom 2], and [symptom 3]. Common symptoms of [disease] include [symptom 1], [symptom 2], and [symptom 3]. Less common symptoms of [disease name] include [symptom 1], [symptom 2], and [symptom 3].

Physical Examination

Patients with [disease name] usually appear [general appearance]. Physical examination of patients with [disease name] is usually remarkable for [finding 1], [finding 2], and [finding 3].

OR

Common physical examination findings of [disease name] include [finding 1], [finding 2], and [finding 3].

OR

The presence of [finding(s)] on physical examination is diagnostic of [disease name].

OR

The presence of [finding(s)] on physical examination is highly suggestive of [disease name].

Laboratory Findings

An elevated/reduced concentration of serum/blood/urinary/CSF/other [lab test] is diagnostic of [disease name].

OR

Laboratory findings consistent with the diagnosis of [disease name] include [abnormal test 1], [abnormal test 2], and [abnormal test 3].

OR

[Test] is usually normal among patients with [disease name].

OR

Some patients with [disease name] may have elevated/reduced concentration of [test], which is usually suggestive of [progression/complication].

OR

There are no diagnostic laboratory findings associated with [disease name].

Electrocardiogram

There are no ECG findings associated with [disease name].

OR

An ECG may be helpful in the diagnosis of [disease name]. Findings on an ECG suggestive of/diagnostic of [disease name] include [finding 1], [finding 2], and [finding 3].

X-ray

There are no x-ray findings associated with [disease name].

OR

An x-ray may be helpful in the diagnosis of [disease name]. Findings on an x-ray suggestive of/diagnostic of [disease name] include [finding 1], [finding 2], and [finding 3].

OR

There are no x-ray findings associated with [disease name]. However, an x-ray may be helpful in the diagnosis of complications of [disease name], which include [complication 1], [complication 2], and [complication 3].

Echocardiography or Ultrasound

There are no echocardiography/ultrasound findings associated with [disease name].

OR

Echocardiography/ultrasound may be helpful in the diagnosis of [disease name]. Findings on an echocardiography/ultrasound suggestive of/diagnostic of [disease name] include [finding 1], [finding 2], and [finding 3].

OR

There are no echocardiography/ultrasound findings associated with [disease name]. However, an echocardiography/ultrasound may be helpful in the diagnosis of complications of [disease name], which include [complication 1], [complication 2], and [complication 3].

CT scan

There are no CT scan findings associated with [disease name].

OR

[Location] CT scan may be helpful in the diagnosis of [disease name]. Findings on CT scan suggestive of/diagnostic of [disease name] include [finding 1], [finding 2], and [finding 3].

OR

There are no CT scan findings associated with [disease name]. However, a CT scan may be helpful in the diagnosis of complications of [disease name], which include [complication 1], [complication 2], and [complication 3].

MRI

There are no MRI findings associated with [disease name].

OR

[Location] MRI may be helpful in the diagnosis of [disease name]. Findings on MRI suggestive of/diagnostic of [disease name] include [finding 1], [finding 2], and [finding 3].

OR

There are no MRI findings associated with [disease name]. However, a MRI may be helpful in the diagnosis of complications of [disease name], which include [complication 1], [complication 2], and [complication 3].

Other Imaging Findings

There are no other imaging findings associated with [disease name].

OR

[Imaging modality] may be helpful in the diagnosis of [disease name]. Findings on an [imaging modality] suggestive of/diagnostic of [disease name] include [finding 1], [finding 2], and [finding 3].

Other Diagnostic Studies

There are no other diagnostic studies associated with [disease name].

OR

[Diagnostic study] may be helpful in the diagnosis of [disease name]. Findings suggestive of/diagnostic of [disease name] include [finding 1], [finding 2], and [finding 3].

OR

Other diagnostic studies for [disease name] include [diagnostic study 1], which demonstrates [finding 1], [finding 2], and [finding 3], and [diagnostic study 2], which demonstrates [finding 1], [finding 2], and [finding 3].

Treatment

Medical Therapy

Treatment of manifestations: For episodic weakness: if serum potassium concentration is low (<3.0 mmol/L), administration of oral potassium (20-30 mEq/L) every 15-30 minutes (not to exceed 200 mEq in a 12-hour period) until the serum concentration normalizes; if a relative drop in serum potassium within the normal range causes episodic paralysis, an individual potassium replacement regimen with a goal of maintaining serum potassium levels in the high range of normal can be considered; if serum potassium concentration is high, ingesting carbohydrates may lower serum potassium levels. Mild exercise may shorten or reduce the severity of the attack.

Management of individuals with ATS requires the coordinated input of a neurologist familiar with the treatment of periodic paralysis and a cardiologist familiar with the treatment of cardiac arrhythmias. To date, no randomized clinical therapeutic trials have been conducted on ATS.

Management of attacks of episodic weakness depends on the associated serum potassium concentration:

If the serum potassium concentration is low (<3.0 mmol/L), administer oral potassium (20-30 mEq/L) every 15-30 minutes (not to exceed 200 mEq in a 12-hour period) until the serum concentration normalizes often shortens the attack. As dysphagia is almost never a problem during attacks of paralysis, oral potassium replacement is the safest route. If intravenous potassium replacement is needed, a 5% mannitol solution instead of a saline or glucose solution (both of which may exacerbate weakness) is recommended. Close monitoring of serum potassium concentrations and ECG is necessary during potassium replacement therapy in an emergency setting to avoid secondary hyperkalemia. Whether a relative drop in serum potassium within the normal range causes episodic paralysis is not clear. If such cases are suspected, affected individuals can work with their physician to devise an individual potassium replacement regimen, with a goal of maintaining serum potassium levels in the high range of normal. Attacks of weakness when serum potassium concentration is high usually resolve within 60 minutes. Episodes may be shortened by ingesting carbohydrates or continuing mild exercise. Intravenous calcium gluconate is rarely necessary for management in an individual seen in an emergency setting. Vasovagal syncope in individuals with ATS mandates a careful cardiology assessment.

Agents/circumstances to avoid: Medications known to prolong QT intervals; salbutamol inhalers (may exacerbate cardiac arrhythmias); thiazide and other potassium-wasting diuretics (may provoke drug-induced hypokalemia and could aggravate the QT interval prolongation).

Evaluation of relatives at risk: Molecular genetic testing if the pathogenic variant is known; if not, detailed neurologic and cardiologic evaluation, 12-lead ECG, and 24-hour Holter monitoring to reduce morbidity and mortality through early diagnosis and treatment of at-risk relatives.

Primary Prevention

Prevention of primary manifestations: Reduction in frequency and severity of episodic attacks of weakness with lifestyle/dietary modification to avoid known triggers; use of carbonic anhydrase inhibitors; daily use of slow-release potassium supplements; implantable cardioverter-defibrillator for those with tachycardia-induced syncope. Empiric treatment with flecainide should be considered for significant, frequent ventricular arrhythmias in the setting of reduced left ventricular function.

Prophylactic treatment aimed at reduction of attack frequency and severity can be achieved, as in other forms of periodic paralysis, with the following:

Lifestyle and dietary modification to avoid known triggers Use of carbonic anhydrase inhibitors (acetazolamide: adults 125-1,000 mg daily and children 5-10 mg/kg/day divided 1-2x/day or dichlorphenamide 50-200 mg/1-2x/day). Use of potassium-sparing diuretic should be individualized based on patient needs. Daily use of slow-release potassium supplements, which may also be helpful in controlling attack rates in individuals prone to hypokalemia. Elevating the serum potassium concentration (>4 mEq/L) has the added benefit of narrowing the QT interval, thus reducing the risk of LQT-associated arrhythmias. An implantable cardioverter-defibrillator in individuals with tachycardia-induced syncope [Chun et al 2004] Empiric treatment with flecainide [Bökenkamp et al 2007, Fox et al 2008, Pellizzón et al 2008] should be considered for significant, frequent ventricular arrhythmias in the setting of reduced left ventricular function [Tristani-Firouzi & Etheridge 2010]. A prospective open label study in ten individuals with ATS and a confirmed KCNJ2 pathogenic variant tested the effect of flecainide, a type 1c antiarrhythmic, for the prevention of cardiac arrhythmias [Miyamoto et al 2015]. Outcomes included a 24-hour Holter monitor before and after treatment and a treadmill exercise test. Flecainide was found to significantly reduce the number of ventricular arrhythmias seen on Holter monitor and to suppress exercise-induced ventricular arrhythmias. Individuals were then followed for a mean of 23 months and no syncope or cardiac arrest was documented. Other case studies have reported beneficial effects with flecainide [Statland et al 2018]. A recent study showed that fleicainide suppresses arrhythmogenicity through Na+/Ca2+ exchanger flux in induced pluripotent stem cells derived from patients with ATS [Kuroda et al 2017]. Thus, flecainide may reduce cardiac arrhythmias in ATS.

Secondary Prevention

Prevention of secondary complications: Cautious use of antiarrhythmic drugs (particularly class I drugs) that may paradoxically exacerbate the neuromuscular symptoms.

There are no established measures for the secondary prevention of ATS.

References

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