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Sunday, December 30, 2018

No Evidence of Impaired Gastric Emptying in Early Huntington‘s Disease

According to the PLOS Currents Huntington,



"No Evidence of Impaired Gastric Emptying in Early Huntington‘s Disease
November 16, 2011 · Epidemiology


Authors

Carsten Saft
Jürgen Andrich
Marc Fälker
Sarah Gauda
Sina Küchler
Dirk Woitalla
Oliver Goetze




Abstract

Background: Several factors, such as dysphagia, an increased motor activity, increased metabolic rate and a hypermetabolic state have been discussed as contributing to weight loss even at the early stages of Huntington’s Disease (HD). Aim of this pilot study was to investigate gastric emptying as a possible reason for weight loss in HD.

Methods: 11 HD participants at early stages of the disease and matched controls were investigated by using the well-established and non-invasive 13C-octanoate breath test. The “Gastroparesis Cardinal Symptom Index” and the “Short-Form Leeds Dyspepsia Questionnaire” were used for clinical evaluation of gastroparesis or dyspepsia.

Results: When compared to standard values ​​given in literature and controls all HD patients had normal breath test results. There was no evidence of gastroparesis or dyspepsia. There was a correlation of breath test results with the cognitive and functional performance of HD participants.

Conclusion: According to our data, there is no evidence of impaired gastric emptying in early HD. We can not exclude that gastric emptying contributes to weight loss at more advanced stages of the disease.

Corresponding author: PD Dr. med. Carsten Saft, Department of Neurology, Huntington-Center NRW, St. Josef Hospital, Gudrunstrasse 56, 44791 Bochum, Germany, E-mail: carsten.saft@ruhr-uni-bochum.de

§ Carsten Saft and Jürgen Andrich contributed equally to this work
Funding Statement
The study was supported by a FoRUM grant, University of Bochum (AZ: F506-2006). Oliver Götze was supported by the DFG (Gö 13582/1).
Introduction

Weight loss is a main feature in Huntington’s disease (HD) and was found to be manifest even at early stages of the disease. [1][2][3][4][5] Multifactorial causes, such as decreased caloric intake due to dysphagia and a higher energy expenditure due to increased motor activity have been discussed as being a possible reason for weight loss especially at the advanced stages of the disease. [6][7][8][9][10] Using a whole body indirect calorimetry in both early stage HD patients and the R6/2 transgenic mouse model of HD, Goodman and colleagues were able to demonstrate that patients with early HD tended to have a negative energy balance for reasons not related to their movement disorder, which was paralleled in the transgenic R6/2 mice. [4] This leads to the assumption of an increased metabolic rate as a main reason for weight loss in HD, which is supported by other experiments in the transgenic R6/2 mice. [4][11][12] In a study investigating the direct relation between the number of CAG repeats in the mutant huntingtin gene and weight loss, Aziz and colleagues found a correlation between both of these factors and discussed a hypermetabolic state as being a reason for weight loss, occurring even at early stages of the disease. [13] They discussed a hypermetabolic state as being likely to stem directly from interference of the mutant protein with cellular energy homeostasis and thus reflecting fundamental pathologic mechanisms underlying HD and not to be secondary to hyperactivity. Since mutant Huntingtin (mtHtt) is not only expressed in the brain of HD patients, but also in the gastrointestinal (GI) tract, a recently published study investigated the GI tract in the R6/2 mice model for HD. This study describes a loss of enteric neuropepitdes, a decreased mucosal thickness and villius length and also an impaired gut motility, diarrhea, and malabsorption of food, suggesting that GI dysfunction plays an important role in weight loss in HD mice. [14]

In addition, gastrointestinal dysfunction is discussed as being the main reason for weight loss in Parkinson’s disease (PD). [15] In a study using a solid meal and the 13 C-sodium octanoate breath test for measurement of gastric emptying in patients with PD, Goetze and colleagues found 88% of PD patients suufered from delayed gastric emptying when compared with controls. The severity of motor impairment was associated with gastroparesis. [16] Several other studies confirm an impaired gastric emptying in PD, some of them with a rate of 100% of PD patients. [16][17][18][19][20][21] One study describes a 60% delay in gastric half emptying time in the PD patient group after a solid test meal using the non-invasive 13 C-sodium octanoate breath test for evaluation of gastric emptying. [17] Neuropathological findings suggest enteric dysfunction to be one of the initial pathophysiological events in PD. [16][22] Central and enteric nervous system involvement in PD is discussed as being a pathophysiologic basis for this dysfunction. [15]

Autonomic nervous dysfunction was found to be present in HD, too. [23] Thus, the aim of the current study was to investigate gastric emptying in early HD patients without medication as a possible additional reason for weight loss by using the well-established 13 C-octanoate breath test. [16][17][18][19][20][21][24]
Methods





Participants

11 manifest HD patients with genetically confirmed diagnosis and without any medication in at clinically early stages of the disease (Shoulson stage I/II) and 11 controls were recruited from the HD centre Bochum, Germany. [25] Participants with known concurrent gastrointestinal diseases or previous operations of the gastro-intestinal tract were excluded, as well as patients with other severe diseases, diabetes mellitus, severe respiratory dysfunction, and malignancies. Also participants with concurrent liver diseases or excessive alcohol consumption (50 g/d of ethanol) were excluded. All participants had lab parameters for ALT, AST, LDH, cholesterol and triglycerides within the normal range, as well as normal findings for the ultrasonography of the upper abdomen. Pregnant and breast-feeding women were excluded. All HD participants underwent neurological investigation and were scored according to the UHDRS items “motor scale” (MS), “total functional capacity” (TFC) “independence scale” (IS) and the items verbal fluency test, symbol digit test, interference test, color naming and color reading which were summarized as “cognitive score” (CS). [26] Fine motor skills were additionally measured by simple (tapping; higher motor impairment leads to lower test results) and complex (pegboard; higher motor impairment leads to higher test results) instrumental movement tests. [27][28][29][30] The severity of depressive symptoms was assessed by using the Beck’s depression inventory (BDI) and Hamilton depression rating scale. [31][32] Clinical characteristics of all HD patients are given in table 1. In addition we calculated the disease burden score (DBS = [CAG repeat – 35.5] x age) for each subject. [33] The study was approved by the ethic committee of the Ruhr-University Bochum, Germany (registration-number 2719). Participants gave informed written consent according to GCP/ICH.

Parameter HD Participants Controls
Age [yr] 42.4 ± 8.4 (29-57) 48.9 ± 9.6 (38-69)
Gender (male/female) 3/8 3/8
BMI 22.5 ± 3.5 (16-30) 26.5 ± 6.4 (19-42)
Weight [kg] 63.6 ± 14.1 (42-85) 84.5 ± 22.5 (54-128)
Height [cm] 166.8 ± 10.1 (153-183) 178.2 ± 9.4 (164-190)
AO motor 39 ± 8.6 (25-51) –
AO psychiatric 38 ± 20.9 (29-50)a –
CAG expanded 45 ± 2.9 (42-51) –
Disease burden score 386.59 ± 66.06 (273-483) –
Disease duration [yr] 4.2 ± 2.5 (0.1-9) –

UHDRS MS 30.8 ± 18.7 (5-72) –
UHDRS TFC 10.2 ± 1.9 (7-12) –
UHDRS IS 81.8 ± 9.8 (70-100) –
UHDRS CS 195.1 ± 79.0 (98-346) –
Verbal fluency 22.5 ± 18.2 (4-69) –
SDMT 27.2 ± 10.6 (16-44) –
Stroop color 47.1 ± 17.1 (26-74) –
Stroop word 68.1 ± 22.8 (32-100) –
Stroop interference 29.5 ± 16.1 (10-59) –
Hamilton 12.8 ± 10.0 (1-26) –
Beck depression inventory 12.3 ± 13.4 (0-39) –

Tapping dominant 129.2 ± 44.8 (47-198) –
Tapping non dominant 99.4 ± 33 (38-161) –
Pegboard dominant [sec] 68.6 ± 24.8 (42.2-120.9) –
Pegboard non dominant [sec] 80.9 ± 40.2 (43.9-184.0) –

Table 1: Clinical characteristics of 11 HD patients and 11 matched controls; values are given as mean ± SD; range (min-max) in brackets; Abbreviations: BMI – body mass index, yr – years, AO – age at onset, a n = 6; UHDRS – unified Huntington´s disease rating scale, MS – motor score TFC – total functional capacity, IS – independence scale, CS – cognitive sum score, SDMT – symbol digit modalities test; sec – seconds. * – significant differences.






Test meal and 13C-octanoate breath test technique

The 13 C-octanoate breath test was used in the same way as described earlier. [16][17][18][34] In summary: After an overnight fasting each participant received a solid test meal consisting of an egg omelet of one egg, 60 g of white bread, 5 g of margarine and 150 ml of water (14 g of proteins, 26 g of carbohydrates and 9 g of fat, 241 kcal) labeled with 100 mg of 13C-sodiumoctanoate (chemical purity of 99,7 % and an isotopic purity of 99,1 %) at 8 AM. Breath samples, which were expired in close aluminized plastic breath bags of 50 ml content were obtained before substrate administration at baseline and after 10, 20, 30, 45, 60, 75, 90, 105, 120, 135, 150, 165, 180, 200, 220 and 240 minutes. The subjects were kept in a relaxed sitting position during the octanoate breath test (OBT). Physical activity was restricted during the test. All subjects consumed their test meal within 10 minutes. The 13 C/ 12 C isotope ratio of the breath samples was analysed by isotope-selective nondispersive infrared spectrometer (NDIRS). The results were both expressed as delta (δ) value per mil (‰) and delta over baseline (dob = δ s – δ 0 ). Definition of the δ-value: δ s = (R S /R PDB -1) x 1000 [‰] with R s = 13 C/ 12 C isotope ratio in CO 2 in breath and R PDB = 0.0112372 = isotope ratio in reference (PDB = PeeDeeBelmnite, South Carolina; δ 0 = isotope ratio at baseline).







Mathematical analysis of 13CO2 excretion curves and statistical analysis

As regards the measuring of the proportion of the 13 C-sodium octanoate given by mouth that is metabolised the results were expressed as a percentage dose of 13 C recovered (PDR) over time for each time interval from which the cumulative PDR (cPDR), obtained by numerical integration from PDR values, was calculated for each time interval. This calculation is based on the formula as proposed by Ravussin. [35] CO 2 production rate was assumed as being 300 mmol per unit of body surface area per hour. The body surface area was calculated using the Haycock weight-height formula. [36] The evaluation of the OBT for gastric emptying was done by non-linear regression analysis of the 13 CO 2 -excretion curves (PDR) with the formula PDR(t) = at b e -ct . The expression ln a, as gastric emptying coefficient (GEC) is a reliable parameter to describe the rate at which the stomach empties. The percentage of 13 CO 2 cumulative values was fit using a model given by the formula cPDR(t) = m(1-e -kt ) ß , where y is cPDR at time t in hours and m, k and ß are regression estimated constants, with m being the total amount of 13 CO 2 when time is infinite. Half gastric emptying time (t 50 ) was calculated by taking PDR(t) equal to m/2 in the PDR equation which is expressed as t 50 = (-1/k)ln (1-2 -1/ß ). The Lag phase is expressed as t lag = 1/klnß. [37] Statistical analysis was carried out as a descriptive evaluation of GEC, t 50 (min), tl ag (min) and t peak (min) and characteristics of participants (mean ± SD).







Gastroparesis Cardinal Symptom Index (GCSI) and Short-Form Leeds Dyspepsia Questionnaire (SF-LDQ)

The well-validated Gastroparesis Cardinal Symptom Index (GCSI) was used for clinical evaluation of gastroparesis symptoms. GCSI quantifies nine symptoms in the three different subscales: nausea and vomiting, postprandial fullness, and bloating. [38] In addition patients were asked about the frequency and severity of their stomach complaints, heartburn, burping and nausea symptoms according to the Short-Form Leeds Dyspepsia Questionnaire (SF-LDQ). [39]

The data analysis and statistics were performed by using the commercial software program SPSS statistics 19. All measured parameters and clinical data were first analysed descriptively and they were when presented as mean ± SD. Normality of distribution of the data was tested with the one-sample Kolmogorov-Smirnov test. Data were analyzed using the independent t-test for comparison between HD participants and controls. Pearson correlation analysis was used for exploratory statistical calculations of the normal distributed data.
Results

As expected HD participants had a lower body mass index compared to controls. One HD patient had underweight with a body mass index of 16. There were however, no significant differences between groups concerning any of the clinical data (table 1). Breath test results and clinical data showed normal distribution except for gender.

Results of the 13 C-sodium octanoate breath test are given in table 2. 13 CO 2 -excretion curves (PDR) and the percentage of 13 CO 2 cumulative values (cPDR) showed normal excretion of 13 C. For PDR only PDR max for the maximum amount of 13 CO 2 -excretion reached during testing time is listed in table 2. There were no significant differences compared to controls for the values decisive for the evaluation of gastric emptying, such as PDR max , cPDR, GEC, t 50 (min) and tl ag (min; see table 2). Compared to standard values given in literature, the most important parameters t 50 and tl ag were within normal range (t 50 < 200 min and tl ag <130 min; no data is available in literature for GEC, cPDR and PDR max ) and none of the patients had abnormal breath test results (see figure 1). [24] OBT Parameter Results HD Results Controls PDR max 9.76 ± 2.866.32 – 14.18 9.85 ± 2.615.58 – 14.09 cPDR 23.64 ± 7.92(14.72 – 37.0) 25.38 ± 7.92(15.51 – 34.94) GEC 2.96 ± 0.84(0.95 – 3.77) 2.89 ± 0.36(2.42 – 3.27) t 50 129.26 ± 38.84(77.15 – 197.60) 135.88 ± 22.27(95.74 – 167.47) t lag 85.45 ± 25.14(55.95 – 123.42) 80.74 ± 17.33(56.31 – 109.05) Table 2: 13 C-sodium octanoate breath test results; values are given as mean ± SD; range (min-max) in brackets, Abbreviations: PDR max for the maximum amount of 13 CO 2 -excretion reached during testing time [%]; cPDR – cumulative exhaled 13 CO 2 (cPDR [%]) after 240 minutes; GEC – gastric emptying coefficient; t peak – time to highest exhaled 13 CO 2 value [min]; t 50 – half gastric emptying time [min]; t lag – Lag phase [min]. * – significant differences. Fig. 1: Gastric emptying of solids measured by 13 C sodium octanoate breath test presented as individual lag phase (tl ag ) and gastric half emptying time (t50) in 11 HD participants (controls not shown). The normal t 50 range reported from literature (<200 min) is shown by the dotted line. A normal t lag range is reported to be below 130 min. [24] Gastroparesis Cardinal Symptom Index (GCSI) was 0.3855 (SEM ± 0.48; range 0 – 1.28) and Short-Form Leeds Dyspepsia Questionnaire (SF-LDQ) was 0.8182 (SEM ± 1.83; range 0 – 6) for HD participants. Thus, both questionnaire results were in line with published data from healthy controls, without clinical evidence of gastroparesis or dyspepsia. [38][39] GCSI was 0.3027 (SEM ± 0.30; range 0 – 0.83) and SF-LDQ was 2.273 (SEM ± 2.195; range 0 – 7) for controls. Differences were not significant (data not shown). Explorative correlation analysis of breath test results given in table 2 with clinical symptoms from table 1 showed no significant correlation, except for the cognitive sum score and t 50 (p 0.018, r -.692) and tl ag (p 0.019, r -.688), as well as for PDR max and the total functional capacity (TFC; p 0.014, r .712; no analysis of the cognitive subtests was done; see figure 2). Especially no correlation to motor symptoms was found. Fig. 2: A strong relation can be seen between gastric emptying of solids measured by 13 C sodium octanoate breath test A strong relation can be seen between gastric emptying of solids measured by 13 C sodium octanoate breath test, presented as individual t lag (a) and t 50 (b) in minutes and the cognitive sum score of the UHDRS (t 50 – p 0.018; r – .692 and t lag – p 0.019; r – .688), as well as for PDR max (c) and total functional capacity (TFC; p 0.014, r .712). The correlation analysis of GCSI and SF-LDQ with clinical symptoms showed no significant correlation with any of the clinical characteristics from table 1. Discussion Several factors such as dysphagia, an increased motor activity, an increased metabolic rate and hypermetabolic state have been discussed as contributing to weight loss even at early stages of HD. In addition, a recently published study also suggested gastrointestinal tract dysfunction as a reason for weight loss in a Huntington mouse model, similar to findings for Parkinson’s disease (PD). [14][15][21] Several studies describe a delay in gastric emptying for 88% or even for up to 100% of PD patients. [16][17][18][19][20][21] Contrary to this, in our pilot study on HD patients did not provide any evidence of impaired gastric emptying by using a solid meal and the 13 C-sodium octanoate breath test. There were no significant differences compared to controls and also compared to standard values given in literature all parameters were within normal range. In addition, we had no clinical evidence of gastroparesis or dyspepsia symptoms by using the “Gastroparesis Cardinal Symptom Index” and “Short-Form Leeds Dyspepsia Questionnaire” in our cohort. Thus, our data contrast with data for PD, but also with data for HD mice. As a possible explanation, gastric emptying may only contribute to weight loss more severe stages of HD. R6/2 HD mice usually show a very rapid course of the disease. A recent published study investigating the GI tract in a R6/2 mice model carrying a mean of 204 CAG-repeats describes several GI abnormalities, including an increased water content in R6/2 compared to feces in wild type mice from 8 weeks of age. The fecal output as a percentage of food intake however, was only significantly increased at 12 weeks, but not at 8 weeks. [14] This indicates that the occurrence of malabsorption of nutrients plays an important role in weight loss in HD mice only in the end stage. The study did not investigate early stages of the disease prior 8 weeks in the mice model. An earlier study from our group describes a high prevalence of gastritis or esophagitis as an accidental finding during PEG-placement, as a possible indication of gastrointestinal tract dysfunction in HD patients at advanced stages of the disease. [40] The findings in this study were also correlated with the duration and severity of the disease, also suggesting that gastrointestinal tract dysfunction might occur later in the course of the disease. We presumed that influences from the disease itself as well as secondary mechanisms like medication and general disability may contribute. [40] It was also the case in this study that the focus was not on early symptomatic patients. To summarize, the pilot data from our study suggest that impaired gastric emptying is not an early event in HD when compared to PD. We can not exclude that gastric emptying contributes to weight loss at more advanced stages of the disease. Surprisingly, we found a significant correlation for the cognitive sum score und the total functional capacity of the UHDRS and breath test results, such as t 50 (47.8% of variance), tl ag (47.4% of variance) and PDR max which usually shows the most precise quantification (50.6% of variance; see figure 2). This was not expected, since OBT results were within normal range. Cognitive decline, however, is a very early event in the course of HD. [41] In fact the cognitive sum score from our HD participants showed a broad range from 98-346 points with a mean of 195.1 points indicating a cognitive impairment in most of the patients. It is well known that the performance in UHDRS cognitive tests declined during disease progression, as did the functional capacity (TFC), which is highly dependent on cognitive tasks. [42][43] A decrement in mitochondrial function is discussed as contributing to age-dependent functional deficits in neurons and myocytes in normal aging and other neurological disorders, such as Alzheimer’s disease, accompanied with a cognitive decline. [44][45][46] Mitochondrial dysfunction is well known in HD and seems to be a relevant and early feature in the pathology. [47][48][49] Mutant htt (mtHtt) tends to aggregate in cytoplasm and nucleus of neurons as well as non-neuronal tissues including the liver. [50][51][52][53][54][55] Within the mitochondria, octanoic acid undergoes b-oxidation. Octanic acid generates acetyl coenzyme A which enters the Krebs cycle and is oxidized to CO 2 . Therefore breath tests based on octanoate, usually used to assess gastric emptying, should also reflect mitochondrial function. [56] Thus, one can speculate that a correlation of OBT results with results of cognitive tasks might reflect a parallel decline in cognitive and mitochondrial function. To our knowledge this is the first study dealing with gastrointestinal track dysfunction in HD in vivo. A limitation of our study is the relative small number of participants. To exclude drug effects we only included patients without any medication and without serious comorbidities. On the other hand, due to the fact that this is a very rare group of patients it is a strength of our study that we can exclude medication effects. Competing interests The authors declare that they have no competing interests. Ethics The local ethics committee of the university approved this study. Acknowledgements We are grateful to all patients for participation. 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Tuesday, December 18, 2018

Myasthenia Gravis










What is Myasthenia Gravis?

Myasthenia gravis is a chronic autoimmune neuromuscular disease that causes weakness in the skeletal muscles, which are responsible for breathing and moving parts of the body, including the arms and legs. The name myasthenia gravis, which is Latin and Greek in origin, means 'grave, or serious, muscle weakness.'

The hallmark of myasthenia gravis is muscle weakness that worsens after periods of activity and improves after periods of rest. Certain muscles such as those that control eye and eyelid movement, facial expression, chewing, talking, and swallowing are often (but not always) involved in the disorder. The muscles that control breathing and neck and limb movements may also be affected.

There is no known cure but with current therapies most cases of myasthenia gravis are not as 'grave' as the name implies. Available treatments can control symptoms and often allow people to have a relatively high quality of life. Most individuals with the condition have a normal life expectancy.





What Causes Myasthenia Gravis?

Myasthenia gravis is caused by an error in the transmission of nerve impulses to muscles. It occurs when normal communication between the nerve and muscle is interrupted at the neuromuscular junction—the place where nerve cells connect with the muscles they control.

Neurotransmitters are chemicals that neurons, or brain cells, use to communicate information. Normally when electrical signals or impulses travel down a motor nerve, the nerve endings release a neurotransmitter called acetylcholine. Acetylcholine travels from the nerve ending and binds to acetylcholine receptors on the muscle. The binding of acetylcholine to its receptor activates the muscle and causes a muscle contraction.

In myasthenia gravis, antibodies (immune proteins) block, alter, or destroy the receptors for acetylcholine at the neuromuscular junction, which prevents the muscle from contracting. In most individuals with myasthenia gravis, this is caused by antibodies to the acetylcholine receptor itself. However, antibodies to other proteins, such as MuSK (Muscle-Specific Kinase) protein, can also lead to impaired transmission at the neuromuscular junction.

These antibodies are produced by the body's own immune system. Myasthenia gravis is an autoimmune disease because the immune system—which normally protects the body from foreign organisms—mistakenly attacks itself.

The thymus is a gland that controls immune function and maybe associated with myasthenia gravis. Located in the chest behind the breast bone, the gland is largest in children. It grows gradually until puberty, and then gets smaller and is replaced by fat. Throughout childhood, the thymus plays an important role in the development of the immune system because it is responsible for producing T-lymphocytes or T cells, a specific type of white blood cell that protects the body from viruses and infections.

In many adults with myasthenia gravis, the thymus gland remains large. People with the disease typically have clusters of immune cells in their thymus gland similar to lymphoid hyperplasia—a condition that usually only happens in the spleen and lymph nodes during an active immune response. Some individuals with myasthenia gravis develop thymomas (tumors of the thymus gland). Thymomas are most often harmless, but they can become cancerous.

The thymus gland plays a role in myasthenia gravis, but its function is not fully understood. Scientists believe that the thymus gland may give incorrect instructions to developing immune cells, ultimately causing the immune system to attack its own cells and tissues and produce acetylcholine receptor antibodies—setting the stage for the attack on neuromuscular transmission.




Source: On Image






What are the Symptoms of Myasthenia Gravis?

Although myasthenia gravis may affect any skeletal muscle, muscles that control eye and eyelid movement, facial expression, and swallowing are most frequently affected. The onset of the disorder may be sudden and symptoms often are not immediately recognized as myasthenia gravis.

In most cases, the first noticeable symptom is weakness of the eye muscles. In others, difficulty swallowing and slurred speech may be the first signs. The degree of muscle weakness involved in myasthenia gravis varies greatly among individuals, ranging from a localized form limited to eye muscles (ocular myasthenia), to a severe or generalized form in which many muscles—sometimes including those that control breathing—are affected.



Symptoms may include:

drooping of one or both eyelids (ptosis)
blurred or double vision (diplopia) due to weakness of the muscles that control eye movements
a change in facial expression
difficulty swallowing
shortness of breath
impaired speech (dysarthria)
weakness in the arms, hands, fingers, legs, and neck.





Who gets Myasthenia Gravis?

Myasthenia gravis affects both men and women and occurs across all racial and ethnic groups. It most commonly impacts young adult women (under 40) and older men (over 60), but it can occur at any age, including childhood. Myasthenia gravis is not inherited nor is it contagious. Occasionally, the disease may occur in more than one member of the same family.

Although myasthenia gravis is rarely seen in infants, the fetus may acquire antibodies from a mother affected with myasthenia gravis—a condition called neonatal myasthenia. Generally, neonatal myasthenia gravis is temporary and the child's symptoms usually disappear within two to three months after birth. Rarely, children of a healthy mother may develop congenital myasthenia. This is not an autoimmune disorder (it is caused by defective genes that produce abnormal proteins in the neuromuscular junction) and can cause similar symptoms to myasthenia gravis.




Source:HERE





How is Myasthenia Gravis Diagnosed?


A doctor may perform or order several tests to confirm the diagnosis, including:

A physical and neurological examination. A physician will first review an individual’s medical history and conduct a physical examination. In a neurological examination, the physician will check muscle strength and tone, coordination, sense of touch, and look for impairment of eye movements.

An EDROPHONIUM test. This test uses injections of edrophonium chloride to briefly relieve weakness in people with myasthenia gravis. The drug blocks the breakdown of acetylcholine and temporarily increases the levels of acetylcholine at the neuromuscular junction. It is usually used to test ocular muscle weakness.

A blood test. Most individuals with myasthenia gravis have abnormally elevated levels of acetylcholine receptor antibodies. A second antibody—called the anti-MuSK antibody—has been found in about half of individuals with myasthenia gravis who do not have acetylcholine receptor antibodies. A blood test can also detect this antibody. However, in some individuals with myasthenia gravis, neither of these antibodies is present. These individuals are said to have seronegative (negative antibody) myasthenia.

Electrodiagnostics. Diagnostic tests include repetitive nerve stimulation, which repeatedly stimulates a person’s nerves with small pulses of electricity to tire specific muscles. Muscle fibers in myasthenia gravis, as well as other neuromuscular disorders, do not respond as well to repeated electrical stimulation compared to muscles from normal individuals. Single fiber electromyography (EMG), considered the most sensitive test for myasthenia gravis, detects impaired nerve-to-muscle transmission. EMG can be very helpful in diagnosing mild cases of myasthenia gravis when other tests fail to demonstrate abnormalities.

Diagnostic imaging. Diagnostic imaging of the chest using computed tomography (CT) or magnetic resonance imaging (MRI) may identify the presence of a thymoma.



Source: HERE




Pulmonary function testing. Measuring breathing strength can help predict if respiration may fail and lead to a myasthenic crisis.
Because weakness is a common symptom of many other disorders, the diagnosis of myasthenia gravis is often missed or delayed (sometimes up to two years) in people who experience mild weakness or in those individuals whose weakness is restricted to only a few muscles.




Source: McGraw Hill





What is a Myasthenic Crisis?

A myasthenic crisis is a medical emergency that occurs when the muscles that control breathing weaken to the point where individuals require a ventilator to help them breathe.

Approximately 15 to 20 percent of people with myasthenia gravis experience at least one myasthenic crisis. This condition usually requires immediate medical attention and may be triggered by infection, stress, surgery, or an adverse reaction to medication. However, up to one-half of people may have no obvious cause for their myasthenic crisis. Certain medications have been shown to cause myasthenia gravis. However, sometimes these medications may still be used if it is more important to treat an underlying condition.






How is Myasthenia Gravis Treated?

Today, myasthenia gravis can generally be controlled. There are several therapies available to help reduce and improve muscle weakness.

THYMECTOMY. This operation to remove the thymus gland (which often is abnormal in individuals with myasthenia gravis) can reduce symptoms and may cure some people, possibly by rebalancing the immune system. A recent NINDS-funded study found that thymectomy is beneficial both for people with thymoma and those with no evidence of the tumors. The clinical trial followed 126 people with myasthenia gravis and no visible thymoma and found that the surgery reduced muscle weakness and the need for immunosuppressive drugs.

Anticholinesterase medications
. Medications to treat the disorder include anticholinesterase agents such as MESTINON or PYRIDOSTIGMINE, which slow the breakdown of acetylcholine at the neuromuscular junction and thereby improve neuromuscular transmission and increase muscle strength.

Immunosuppressive drugs. These drugs improve muscle strength by suppressing the production of abnormal antibodies. They include prednisone, azathioprine, mycophenolate mofetil, tacrolimus, and rituximab. The drugs can cause significant side effects and must be carefully monitored by a physician.

Plasmapheresis and intravenous immunoglobulin. These therapies may be options in severe cases of myasthenia gravis. Individuals can have antibodies in their plasma (a liquid component in blood) that attack the neuromuscular junction. These treatments remove the destructive antibodies, although their effectiveness usually only lasts for a few weeks to months.

Plasmapheresis is a procedure using a machine to remove harmful antibodies in plasma and replace them with good plasma or a plasma substitute.
Intravenous immunoglobulin is a highly concentrated injection of antibodies pooled from many healthy donors that temporarily changes the way the immune system operates. It works by binding to the antibodies that cause myasthenia gravis and removing them from circulation.




Source: On Image




What is the prognosis?

With treatment, most individuals with myasthenia can significantly improve their muscle weakness and lead normal or nearly normal lives.

Sometimes the severe weakness of myasthenia gravis may cause respiratory failure, which requires immediate emergency medical care.

Some cases of myasthenia gravis may go into remission—either temporarily or permanently—and muscle weakness may disappear completely so that medications can be discontinued. Stable, long-lasting complete remissions are the goal of thymectomy and may occur in about 50 percent of individuals who undergo this procedure.





What Research is Being Done?

The mission of the National Institute of Neurological Disorders and Stroke (NINDS) is to seek fundamental knowledge about the brain and nervous system and to use that knowledge to reduce the burden of neurological disease. The NINDS is a component of the National Institutes of Health (NIH), the leading supporter of biomedical research in the world.

Although there is no cure for myasthenia gravis, management of the disorder has improved over the past 30 years. There is a greater understanding about the structure and function of the neuromuscular junction, the fundamental aspects of the thymus gland and of autoimmunity, and the disorder itself. Technological advances have led to more timely and accurate diagnosis of myasthenia gravis and new and enhanced therapies have improved treatment options. Researchers are working to develop better medications, identify new ways to diagnose and treat individuals, and improve treatment options.





Medication

Some people with myasthenia gravis do not respond favorably to available treatment options, which usually include long-term suppression of the immune system. New drugs are being tested, either alone or in combination with existing drug therapies, to see if they are effective in treating the disease.

Studies are investigating the use of therapy targeting the B cells that make antibodies (rituximab) or the process by which acetylcholine antibodies injure the neuromuscular junction (eculizumab). The drugs have shown promise in initial clinical trials.






Diagnostics and biomarkers

In addition to developing new medications, researchers are trying to find better ways to diagnose and treat this disorder. For example, NINDS-funded researchers are exploring the assembly and function of connections between nerves and muscle fibers to understand the fundamental processes in neuromuscular development. This research could reveal new therapies for neuromuscular diseases like myasthenia gravis.

Researchers are also exploring better ways to treat myasthenia gravis by developing new tools to diagnose people with undetectable antibodies and identify potential biomarkers (signs that can help diagnose or measure the progression of a disease) to predict an individual’s response to immunosuppressive drugs.





Source: McGraw Hill





New treatment options

Findings from a recent NINDS-supported study yielded conclusive evidence about the benefits of surgery for individuals without thymoma, a subject that had been debated for decades. Researchers hope that this trial will become a model for rigorously testing other treatment options, and that other studies will continue to examine different therapies to see if they are superior to standard care options.






Where can I get more information?

For more information on neurological disorders or research programs funded by the National Institute of Neurological Disorders and Stroke, contact the Institute's Brain Resources and Information Network (BRAIN) at:

BRAIN
P.O. Box 5801
Bethesda, MD 20824
800-354-9424
www.ninds.nih.gov



More information about research on myasthenia gravis supported by NINDS and other NIH Institutes and Centers can be found using NIH RePORTER (projectreporter.nih.gov), a searchable database of current and past research projects supported by NIH and other federal agencies. RePORTER also includes links to publications and resources from these projects.



Information is also available from the following organizations:

Myasthenia Gravis Foundation of America, Inc.
355 Lexington Avenue, 15th Floor
New York, NY 10017
212-297-2156
800-541-5454
www.myasthenia.org

American Autoimmune Related Diseases Association
22100 Gratiot Avenue
Eastpointe, MI 48021
586-776-3900
www.aarda.org

Muscular Dystrophy Association
222 S. Riverside Plaza, Suite 1500
Chicago, IL 60606
800-572-1717
www.mda.org

U.S. National Library of Medicine
National Institutes of Health/DHHS
8600 Rockville Pike
Bethesda, MD 20894
301-594-5983
888-346-3656
www.nlm.nih.gov

NIH Publication No. 17-768

"Myasthenia Gravis Fact Sheet", NINDS, Publication date May 2017.

NIH Publication No. 17-768

Back to Myasthenia Gravis Information Page

See a list of all NINDS publications

Publicaciones en Español

Miastenia gravis

Prepared by:

Office of Communications and Public Liaison

National Institute of Neurological Disorders and Stroke

National Institutes of Health

Bethesda, MD 20892

NINDS health-related material is provided for information purposes only and does not necessarily represent endorsement by or an official position of the National Institute of Neurological Disorders and Stroke or any other Federal agency. Advice on the treatment or care of an individual patient should be obtained through consultation with a physician who has examined that patient or is familiar with that patient's medical history.

All NINDS-prepared information is in the public domain and may be freely copied. Credit to the NINDS or the NIH is appreciated.

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Date last modified: Fri, 2018-07-06 16:21"




Source:HERE





According to the CLEVELAND CLINIC,



"What is Myasthenia Gravis?

Myasthenia gravis (MG) is a neuromuscular disease, meaning that it affects the muscles and the nerves that control them. It is caused by a disorder in the immune system that causes the body to attack the area of the muscles where the nerves connect to them.

The immune system is the body’s natural defense against disease. Normally, when bacteria or other foreign substances enter the body, the immune system produces molecules called antibodies that attack the bacteria.

In people with myasthenia gravis, the immune system produces abnormal antibodies that prevent the muscles from receiving signals from the nerves that tell them when to relax or contract. This causes muscle weakness with symptoms that can include in double vision or blurred vision (eye muscle weakness), drooping eyelids (eyelid muscle weakness), difficulty with speaking and swallowing (throat muscle weakness) and weakness of the limbs.

When the immune system acts against healthy tissue by mistake, it is called an autoimmune disorder, with “auto” meaning “self. So myasthenia gravis is a neuromuscular autoimmune disease.

Myasthenia gravis is most common in young women and older men, but people of any age or either sex can get it.




Source:HERE





What Causes Myasthenia Gravis?

Scientists do not completely understand what triggers the autoimmune reaction in myasthenia gravis, but they do know that the thymus gland plays a role in the disease.

The thymus is a small gland that lies in the front part of the chest, beneath the breastbone, and extends into the lower part of the neck. It is most important early in life during immune system development.

A baby’s thymus gland weighs between .7 and 1.1 oz. The gland continues to grow and by puberty weighs 1.1 to 1.8 oz. The thymus gland’s job is thought to be completed by puberty, and after that it decreases in size. Over time, fat replaces portions of the gland. In older people the thymus weighs only .1 to .5 oz.

Tumors of the thymus gland are called thymomas (https://my.clevelandclinic.org/health/articles/6196-thymoma-and-thymic-carcinoma). Around 10-15 percent of people with myasthenia gravis have a thymoma Another 60%, however, will have other abnormalities of the gland including thymic hyperplasia (an enlarged gland).

The original association between the thymus gland and myasthenia gravis was made back in the early 1900’s when surgeons observed that removal of a thymoma resulted in the improvement in the patient’s myasthenia gravis. Ultimately surgeons began removing of the thymus gland in myasthenic patients without thymic tumors and a similar response was noted.

Research into the causes and treatments of myasthenia gravis will help scientists learn more about the role of the thymus in the disease.




Source:HERE






How is Myasthenia Gravis Treated?

The key to treatment of myasthenia gravis begins with an accurate diagnosis. The evaluation is usually directed by a Neurologist and can involve blood tests, nerve testing and tests involving administration of medicines in order to differentiate myasthenia gravis from other disease of muscles and nerves.

Once the diagnosis has been confirmed, a treatment plan is developed with the goal of reducing the number of antibodies causing the disease and/or improving the communication between the nerves and muscles. The ultimate results is improving muscle strength.


Medical treatment options include:

Medicines that suppress antibody production or improve nerve signal transmission
Plasmapheresis, a procedure that removes antibodies from the blood
High-dose intravenous immune globulin, the infusion of normal antibodies from donated blood to temporarily modify the immune system
Surgical treatment is thymectomy, removal of the thymus gland. This is the treatment for patients with thymomas, but is also considered for patients with MG who do not have thymomas.

At Cleveland Clinic, the Thoracic Surgeons are part of the treatment team evaluating patients and identifying the most appropriate combination of therapies for each individual.






Procedure Details


What are the results of thymectomy?

The goal of a thymectomy is to remove the source of abnormal antibody production causing the disease thus leading to resolution of symptoms. The benefits of thymectomy are not realized immediately after surgery, thus patients will continue with there medical regimen after the procedure with the goal of weaning those medications over time.Individual response to thymectomy varies depending on the patient’s age, response to prior medical therapy, the severity of the disease and how long the patient has had myasthenia gravis. In general, 70 percent of patients have complete remission or significant reduction in medication needs within a year of the procedure. The other 30 percent of patients who have thymectomy experience no change in their symptoms. According to the American Association of Neurologists, patients who have thymectomy are two times as likely to experience remission as those who have medical treatment alone.





How does a doctor determine which patients with myasthenia gravis should undergo thymectomy?

Thymectomy is recommended for all patients with thymomas and for patients under 60 who have mild to moderate muscle weakness due to myasthenia gravis. Thymectomy generally is not used for treating patients with myasthenia gravis that affects only their eyes.Thymectomy appears to be most effective when it is performed six to 12 months after the onset of symptoms. It is important to talk to your doctor early in your diagnosis about thymectomy as an option for treatment.




How is thymectomy performed?

Thymectomy can be performed by several different surgical techniques:

Transsternal thymectomy: In this procedure, the incision is made in the skin over the breastbone (sternum), and the breastbone is divided (sternotomy) to expose the thymus. This approach is commonly used for heart surgery. The surgeon removes the thymus through this incision as well as any residual fat in the center of the chest which may harbor extra thymic cells. This approach is commonly used when the patient has a thymoma.

Transcervical thymectomy: In this procedure the incision is made across the lower part of the neck, just above the breastbone(sternum). The surgeon removes the thymus through this incision without dividing the sternum. This is mostly used in patients without thymoma with certain body-types.

Robotic thymectomy and Video-assisted thorascopic thymectomy (VATS): These Minimally invasive techniques use several tiny incisions in the chest. A camera is inserted through one of the incisions and the surgery is performed with video guidance. The surgeon removes the thymus by using special surgical tools inserted into the other incisions. In a robotic-assisted procedure, the surgeon uses robotic arms to perform the surgery. The goal is to provide the same result as the more invasive transsternal approach with less post-operative discomfort and a quicker recovery.





What type of thymectomy is the best for me?

The transsternal thymectomy is the most commonly performed procedure, however there are no proven differences in outcomes with less invasive approaches. Your neurologist and surgeon will guide you in making a decision about the type of thymectomy you should have. Your surgeon will make a recommendation based on whether a thymoma is present and other factors related to your history and anatomy.There currently is no scientific evidence that proves one type of thymectomy is better than the other in terms of outcomes. To make the best decision for yourself, you should be informed about the different types of thymectomy and consult with your neurologist and surgeon. You also may want to seek a second opinion.






Risks / Benefits
What are the risks of thymectomy?




Complications are rare, but the risks include:

Infection
Bleeding
Injury lung
Nerve injury
Your doctor will evaluate your personal risk based on your age and other medical conditions.





Additional Details

How can I find a doctor who can evaluate me for thymectomy or provide a second opinion?
Thymectomy is performed by a thoracic surgeon, a surgeon who operates on the chest. This is a relatively rare procedure and should be performed by a surgeon with experience specifically in this procedure. In addition, the best outcomes are achieved by a multidisciplinary team of neurologists and thoracic surgeons with a cohesive treatment plan.

Doctors who perform this surgery (https://my.clevelandclinic.org/departments/heart/depts/thoracic-surgery#doctors-tab)
Thoracic Surgery Department (https://my.clevelandclinic.org/departments/heart/depts/thoracic-surgery)
For a referral to a physician, contact us (https://my.clevelandclinic.org/departments/heart/appointments-locations) or call the Miller Family Heart & Vascular Institute Resource & Information Nurse at 216.445.9288 or toll-free at 800.289.6911. We would be happy to assist you.





Resources

If you need more information, click here to contact us (https://my.clevelandclinic.org/departments/heart/appointments-locations), chat online with a nurse (https://my.clevelandclinic.org/departments/heart/appointments-locations#resource-nurse-tab) or call the Miller Family Heart and Vascular Institute Resource & Information Nurse at 216.445.9288 or toll-free at 866.289.6911. We would be happy to help you.





Condition Information

Myasthenia Gravis (https://my.clevelandclinic.org/health/diseases/17252-myasthenia-gravis-mg-)




Treatment Guides

All Miller Family Heart & Vascular Institute Treatment Guides (https://my.clevelandclinic.org/departments/heart/patient-education/treatment-guides)



This information is provided by the Cleveland Clinic and is not intended to replace the medical advice of your doctor or healthcare provider. Please consult your healthcare provider for advice about a specific medical condition. This document was last reviewed on: 04/14/2015"












Helpful Links & Resources for Myasthenia Gravis:

http://www.myasthenia.org/CommunitySupport/SupportGroupCalendar.aspx

https://www.elderneedslaw.com/blog/elder-law-and-myasthenia-gravis

https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Myasthenia-Gravis-Fact-Sheet

https://medlineplus.gov/druginfo/meds/a682229.html

https://www.rxlist.com/mestinon-drug/patient-images-side-effects.htm#whatis

Wednesday, December 5, 2018

LINX Procedure Information for GERD

I stumbled upon this for other research I am also doing right now and thought I would write about it, because it seemed interesting to me, and that maybe it might help those who are dealing with truly horrible acid reflux. As I just said, I stumbled onto this subject but I was not really sure what the Linx System did until I read about it for this article. So, please excuse all of the block quotes. I do that when I'm not familiar with a subject and I am learning about it as I go, but I want to make sure I give you the correct information, because that's the most important, especially if it might help you in some way.


***There was a RECALL notice for certain devices as of May 2018.***

The information for it can be found here: RECALL NOTICE: https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfRES/res.cfm?id=163588


The FDA approved the LINX method in 2012, according to the documents below,


Source: http://www.toraxmedical.com/news/downloads/PR_LINXFDAApproval.pdf




I am not familiar with this medical equipment or procedure yet, so I wanted to research it for those of you out there who may not have heard of it yet, as it might help you. According to Healio Gastroenterology,

"LINX Reflux Management
Give Us a Call
For more information about LINX reflux management at MUSC,
call: Mary Johnson, RN
(843) 876-3090 or
johnsome@musc.edu

A patient suffering with gastroesophageal reflux disease (GERD) normally experiences frequent heartburn, regurgitation and/or nausea in the mid-chest region. This can cause severe discomfort and negatively impact the patient's quality of daily life.

If you are a reflux patient, 21 years of age or older, who still experiences significant GERD-related symptoms despite taking medication(s), you may be interested in the LINX® Reflux Management System.

LINX provides an option for patients who are taking acid-suppressing drugs (i.e. Prevacid®, Nexium®, Prilosec®, etc.) but are not getting their desired results. These types of medications help control acid build-up, but they cannot repair the underlying problem.

A color illustration of the lower esophagus and upper stomach showing placement of a small band of magnetized titanium beads wrapped around the lower esophageal sphincter.


What is LINX?

The LINX Reflux Management System (developed by Torax Medical, Inc.) is a permanent, drug-free treatment for GERD that consists of a small band of magnetized titanium beads wrapped around the lower esophageal sphincter (LES) located at the base of the esophagus. This band helps prevent gastric acids from pushing back up into the esophagus from the stomach, yet also safely allows the LES to open when required to allow for easy swallowing.

When a person with the LINX system installed swallows, the motion of food or drink passing through the lower esophagus overcomes the magnetic attraction between the beads permitting the contents to pass through the LES into the stomach. When the stomach reacts and reflux tries to escape up the esophagus (which would then result in heartburn), the magnetic beads keep the acid down in the same manner as a normally functioning LES.

This procedure can help patients return to a normal lifestyle unaffected by their GERD."






Source:http://ddc.musc.edu/public/surgery/laparoscopic/linx.html





Source:http://ddc.musc.edu/public/surgery/laparoscopic/linx.html




According to RefluxMD,

"Ten things you need to know about LINX
By Dr. Dengler
Last updated on November 15th, 2018 at 02:23 pm
This Article is Written and/or Reviewed by RefluxMD Medical Authors Team and Reviewers






One out of three Americans suffer from heartburn symptoms. Many of those sufferers have gastroesophageal reflux disease (GERD) and they don’t even know it.

Until recently the only cure was a surgical procedure known as 'Nissen fundoplication,' which has the potential to cause side effects that lead many to delay or avoid surgery. Last year, the Food and Drug Administration approved a new treatment device called the LINX Reflux Management System to offer a new approach to treating GERD, a disease that is increasing at a rate of 30 percent every decade.

Paul Taiganides, M.D., is the medical director of the Knox Regional Heartburn Treatment Center at Knox Community Hospital in Mount Vernon, Ohio. Dr. Taiganides and Knox Community Hospital were one of 14 locations selected to participate in the initial US clinical trials for the LINX device. Since then, Dr. Taiganides has performed more LINX procedures than any other U.S. surgeon. The center has done more than 700 Nissen fundoplication surgical procedures in the last seven years. Recently, he has trained surgeons in the LINX technique at Harvard University and Northwestern University.

'I was recommended to the LINX by Tom DeMeester [M.D.] and William Dengler [M.D.], medical advisors to RefluxMD. Dr. DeMeester is the recognized global leader on reflux disease and a senior medical advisor to Torax Medical, the innovator behind the LINX System,' said Dr. Taiganides. 'This is the first advancement in the surgical treatment of GERD in 50 years — and I believe this small titanium band will have a huge impact on how we surgically treat reflux disease.'


Here are 10 things you need to know about the LINX procedure.

No. 1: It is focused on the underlying cause of reflux disease not the side effect.
Reflux disease is a result of a damaged lower esophageal sphincter (LES). The LES is a muscle that is constantly closed, but allows food and liquid to pass into the stomach. When the LES loses its strength, acidic stomach juices can back up into the esophagus creating the painful symptom of heartburn. The LINX device wraps around the LES, augmenting it to prevent reflux.

No. 2: It is safer than the long-term use of proton pump inhibitors (PPIs).
PPIs only treat symptoms. More importantly, studies have proven that reflux disease can progress even when PPI therapy has effectively eliminated GERD symptoms. Furthermore, daily PPI use has been associated with Barrett’s Esophagus, a pre-cancerous condition, an increase in bone fractures, a higher risk of pneumonia, an increased incidence of C. difficile intestinal infections, and increased risk of heart arrhythmias.

No. 3: LINX is effective at reducing symptoms and improving quality of life.
A recent study published in the New England Journal of Medicine tracked 100 patients for three years after their LINX surgery. That study found an overall decrease in stomach contents reaching the esophagus, fewer reflux symptoms, and a substantial reduction in PPI usage.

No. 4: The side effects disappear over time in most cases.
Initially, most patients experience some discomfort, but it typically dissipates over several weeks. In addition, the most commonly reported side effect is mild difficulty swallowing, which usually subsides over time.

No. 5: The cost of the device is approximately $5,000.
Surgery costs between $12,000 and $20,000. A traditional Nissen fundoplication surgical procedure is estimated in excess of $18,000. The cost can be much less than a lifetime of PPI use: a 2010 study by Consumer Reports found once-a-day PPI use can range from $2,000 to $4,500 per year for brand name prescription PPIs.

No. 6: There are very few physicians performing the LINX procedure.
Like all surgical procedures, a surgeon’s proficiency is largely dependent upon the number of procedures performed each year. Torax Medical has been very selective in choosing their surgeons seeking the most experienced physicians available.

No. 7: This is minimally invasive and is performed as an out-patient procedure.
The LINX procedure is usually completed in less than one hour. After the use of general anesthesia, small surgical instruments and a video camera are used in this laparoscopic procedure. Within 24 hours most patients return to a normal diet although there is some difficulty getting used to a functioning LES. These difficulties typically subside in 10 to 15 days and most patients report no symptoms after two or three months.

No. 8: LINX is reversible and can be replaced.
Since the LINX band is placed around the LES, the device can be removed or replaced, if necessary. This requires a surgical procedure, and Dr. Taiganides noted that this has not been necessary for any of his patients.

No. 9: This procedure is recommended for those with continued GERD symptoms under maximum therapy prescribed by a specialist.
I agree with Dr. DeMeester that a reflux disease has defined stages. Early stages must be treated with diet and lifestyle changes along with intermittent drug therapy. When these therapies fail to manage GERD symptoms impacting daily activities or sleep, the LINX System should be considered as an option.

No. 10: LINX is not for everyone with advanced GERD.
Today LINX is not approved for those with Barrett’s Esophagus or anyone suffering from esophageal cancer. It is important for everyone suffering from advanced stages of reflux disease to explore all available options before their disease progresses to the point where options are limited.

It is important to take your heartburn symptoms seriously because it is a signal from your body that something is wrong. Since reflux disease is a progressive chronic condition, you need to make the necessary changes before you have to schedule a surgery."





Source:https://www.laparoscopyhospital.com/linx-procedure-faq.html




Business Wire says,

"Torax Medical Announces FDA Approval of a New LINX® Device Compatible with 1.5 Tesla Magnetic Resonance Imaging (MRI) Systems

New LINX Device expands patients’ diagnostic imaging options after treatment

ST. PAUL, Minn.--(BUSINESS WIRE)--Torax Medical, Inc. is pleased to announce that the U.S. Food and Drug Administration (FDA) has approved a next generation LINX® Reflux Management System that is MR conditional in magnetic resonance imaging (MRI) systems up to 1.5 Tesla (1.5T), which represents about 90% of MRI systems in use in the U.S. The LINX 1.5T design contains a different grade of magnets that have a higher resistance to being demagnetized when subjected to external magnetic fields (i.e. MRI).

'We are pleased to make this next generation LINX device available to patients seeking relief from their reflux symptoms while broadening their access to diagnostic imaging options after treatment,' said Todd Berg, President and CEO of Torax Medical.

Patients considering the LINX procedure should consult their healthcare provider regarding any questions related to MR imaging. Patients who have already received a LINX implant should consult their provider prior to undergoing any MRI tests. Information on diagnostic imaging options with LINX is also available at www.linxforlife.com and www.toraxmedical.com.



The Disease

Gastro-esophageal Reflux Disease (GERD) is a chronic, often progressive disease resulting from a weak lower esophageal sphincter that allows harmful gastric fluid to reflux into the esophagus, resulting in both pain and injury to the esophageal lining. GERD is associated with a pre-cancerous condition known as Barrett’s esophagus, which increases the risk of esophageal cancer. Symptoms of GERD include heartburn and regurgitation, often associated with chronic sleep disruption, and may also include persistent cough, excessive throat clearing, hoarseness and a feeling of a “lump” in the throat. Acid reflux medications, such as Prevacid®, Nexium®, and Prilosec®, affect gastric acid production, but do not repair the sphincter defect, allowing continued reflux. The FDA has issued a series of statements on possible side effects of long-term PPI use including: possible fracture risk, low magnesium levels, and clostridium difficile-associated diarrhea. More recently, a study out of Stanford University published in the journal PLOS ONE showed PPI use may increase the risk of heart attack.1 The alternative surgical option to LINX is Nissen fundoplication. Nissen fundoplication reconstructs a new reflux barrier using a portion of the patient’s stomach, which is wrapped around the lower portion of the esophagus.



The LINX Reflux Management System

LINX is a small implant comprised of interlinked titanium beads with magnetic cores. The magnetic attraction between the beads augments the existing esophageal sphincter’s barrier function to prevent reflux. The device is implanted using a standard minimally invasive laparoscopic procedure and is an alternative to the more anatomically disruptive fundoplication, commonly used in surgical anti-reflux procedures. The LINX Reflux Management System is indicated for those patients diagnosed with GERD as defined by abnormal pH testing, and who continue to have chronic GERD symptoms despite maximum medical therapy for the treatment of reflux.

LINX does require a surgical procedure and is associated with potential risks, contraindications and life style modifications. For more information on LINX, including a statement of risks, please visit www.linxforlife.com.



About Torax Medical

Torax Medical, Inc. is a privately-held medical device company headquartered in St. Paul, Minnesota that develops and markets products designed to treat sphincter disorders utilizing its technology platform, Magnetic Sphincter Augmentation (MSA). Torax Medical is currently marketing the LINX® Reflux Management System for the treatment of GERD in the U.S. and Europe and the FENIX® Continence Restoration System for the treatment of Fecal Incontinence (FI) in Europe. For more information, please visit www.toraxmedical.com.

1PLOS ONE DOI:10.1371/journal.pone.0124653

Contacts
Torax Medical, Inc.
Maggie Wallner, 651-361-8900
info@toraxmedical.com"






Source: https://www.swedish.org/blog/2012/05/a-new-treatment-for-gerd-the-linx-reflux-management-system







According to Sages the company who was in charge of the study,




"LINX® REFLUX MANAGEMENT SYSTEM
March 13, 2017 by SAGES Webmaster

SAGES Technology and Value Assessment Committee (TAVAC) Safety and Effectiveness Analysis
LINX® Reflux Management System (Torax Medical, Inc.)

SAGES LINX® Safety and Effectiveness Analysis Committee

Dana Telem, MD, MPH
Andrew Wright, MD
Paresh Shah, MD
TAVAC Committee Chair: Matthew Hutter, MD, MPH



About this update

The original SAGES LINX Safety and Efficacy Analysis (SEA) was completed and published online in 2013. The literature presented in this first document was based on the pre-market and the initial post-market experience that had been published in the peer reviewed literature at the time. In the 3 years that have passed since the original SAGES Technology and Value Assessment Committee (TAVAC) LINX SEA was published, sufficient new data has become available to necessitate an update and a fresh look at the SAGES recommendations with regards to this technology.



Technology Overview

The LINX® Reflux Management System (Torax Medical, Inc., Shoreview, MN, USA) is comprised of a small expandable ring of linked magnetic beads. The device is laparoscopically implanted around the esophagus at the esophagogastric junction to mechanically augment the function of the lower esophageal sphincter (LES) for the treatment of gastroesophageal reflux disease (GERD).

Each bead in the LINX device contains a neodymium iron boron magnetic core coated with biocompatible titanium. Sliding titanium wires connect each bead so that they can move independently, but they can’t completely separate. At rest, each bead is in contact with adjacent beads, minimizing compressive forces upon the esophagus. The magnetic attractive forces between each bead augment the pressure of the LES. At higher pressures, the magnetic forces are overcome and the ring expands to allow esophageal distention and the passage of a swallowed bolus or other physiologic functions, such as belching or vomiting.

The LINX Reflux Management System is based on the premise that a device placed around the LES can assist, or augment, an incompetent LES to maintain a closed position when challenged by gastric reflux. The LINX System is indicated for patients diagnosed with GERD as defined by abnormal pH testing, and who continue to have chronic GERD symptoms despite medical therapy for the treatment of reflux.

The LINX device implantation is performed laparoscopically under general anesthesia. The procedure uses standard laparoscopic ports, instruments and techniques. The device is placed at the end of the esophagus. Minimal dissection is required. A specialized sizing tool is used to measure the external esophageal circumference in the target area – allowing the surgeon to select the appropriately sized LINX device. An uncomplicated procedure can generally be performed in well under 1 hour. In contrast to fundoplication, patients are started on a solid diet soon after the procedure.

The LINX System is not intended for use in patients with suspected or known allergies to metals such as iron, nickel, titanium, or stainless steel. The immediate post-approval version of the LINX device was only compatible with a magnetic resonance imaging device (MRI) up to 0.7T (Tesla). In June of 2015, the FDA approved the next generation of the device compatible and safe with an MRI up to 1.5 Tesla. The LINX System is contraindicated in patients receiving electrical implants such as defibrillators or pacemakers or undergoing insertion of metallic implants in the abdomen.

Development of the LINX device began in 2002. Animal testing of the current device began in 2005 [1]. An FDA approved Investigational Device Exemption (IDE) feasibility trial (#G060172) enrolled 44 patients at 4 sites in the US and Europe in 2007-2008. A 100 patient pivotal trial was subsequently performed at 14 US and European sites. Enrollment occurred throughout 2008-2009. Through 2011, 2-year follow-up on the pivotal trial was available. An FDA expert panel considered the clinical data from these 2 trials in January 2012, and pre-market approval (PMA #P100049) was granted in March 2012 [2].

FDA Instructions for Use (2012)
Indications
The LINX system is labeled for use in GERD patients with abnormal pH testing who continue to have chronic symptoms despite anti-reflux therapy.



Precautions (summary)
The LINX device has not been evaluated in patients with a hiatal hernia larger than 3-cm. Use of LINX device in patients with a hiatal hernia larger than 3-cm should be considered on the basis of each patient’s medical history and severity of symptoms.
The safety and effectiveness of the LINX device has not been evaluated in patients with Barrett’s esophagus or Grade C or D (LA classification) esophagitis.
The safety and effectiveness of the LINX device has not been evaluated in patients with major motility disorders.
The safety and effectiveness of the LINX Reflux Management System has not been established for the following conditions:
Scleroderma
Suspected or confirmed esophageal or gastric cancer
Prior esophageal or gastric surgery or endoscopic intervention
Distal esophageal motility less than 35-mmHg peristaltic amplitude on wet swallows or <70% (propulsive) peristaltic sequences or a known motility disorder (such as Achalasia, Nutcracker Esophagus, and Diffuse Esophageal Spasm or Hypertensive LES). Symptoms of dysphagia more than once per week within the last 3 months. Esophageal stricture or gross esophageal anatomic abnormalities (Schatzki’s ring, obstructive lesions, etc.). Esophageal or gastric varices. Morbid obesity (BMI >35).
Age <21 1. Technology Significance Gastroesophageal reflux disease (GERD) is the most prevalent gastrointestinal disease in the United States. It is also one of the most important in terms of its chronicity, overall cost, adverse impact on quality of life, and potential for complications, such as Barrett’s esophagus and esophageal adenocarcinoma [3]. Current estimates suggest that GERD affects around 10–20% of adults in Western countries on a daily or weekly basis [4]. Up to 50% of patients with GERD may require chronic pharmacologic therapy [5]. Long term GERD pharmacotherapy is exceedingly expensive with an estimated annual cost in the US of $11 billion [6]. The most powerful and commonly prescribed acid suppression medications are proton pump inhibitors (PPIs). PPIs have been linked via retrospective studies to increased risk of enteric infections including Clostridium difficile-associated diarrhea, community-acquired pneumonia, bone fracture, nutritional deficiencies, and interference with metabolism of antiplatelet agents [7]. It is estimated that as many as 40% of patients with GERD fail to respond symptomatically to aggressive acid suppression therapy [8,9,10]. As a result, 20-40% of patients are dissatisfied with medical GERD treatment and see no viable alternative to more medications and persistent symptoms [11]. Some patients with severe GERD and associated complications undergo antireflux surgery. Despite the fact that the prevalence of GERD has increased in recent years, utilization of laparoscopic Nissen fundoplication for medically refractory GERD has declined. With literally millions of American adults continuing to suffer from GERD symptoms despite aggressive medical therapy, an estimated 24,000 Americans underwent laparoscopic Nissen fundoplication in 2003 [12]. This accounts for less than 1% of patients estimated to be dissatisfied or who suffer from persistent symptoms on acid suppression medical therapy. This discrepancy is thought to be at least partly due to concerns over side effects associated with Nissen fundoplication (dysphagia, bloating) as well as the possibility of fundoplication failure with recurrent GERD and need for acid suppression medical therapy or repeat surgery. Patients with GERD who have persistent symptoms on medical therapy who aren’t willing to consider traditional antireflux surgery (or are not referred to a surgeon to be considered) fall into what is known as the GERD treatment gap. The LINX system may be an attractive alternative to chronic medical therapy for GERD patients who are hesitant to undergo Nissen fundoplication. Following fundoplication, some patients describe difficulty belching and symptoms of bloating [13,14]. Data from the premarket trial suggests that following the LINX procedure; most patients maintain their ability to belch and frequent/continuous bloating was reported at a low rate (5% of patients 12 months following LINX implantation described frequent or continuous bloating compared to 40% at baseline) [2]. Augmentation of the esophageal sphincter with a magnetic device may provide an alternative treatment for patients with incomplete symptom relief on acid suppression medical therapy or who are reluctant to undergo surgical fundoplication.
The size differences between the Linx and a quarter
Source:https://fox4kc.com/sponsored/?prx_t=eK4CArO4NArSEKA&prx_ro=s




2. Current Clinical Practice and Alternatives

Mild to moderate cases of GERD are typically treated with lifestyle modifications, over-the-counter medications, and prescription drugs. Lifestyle changes include weight loss, avoiding certain foods, managing meal size and timing, and elevating the head of the bed. Continuous pharmacotherapy is a mainstay of GERD treatment. PPIs work by suppressing stomach acid production and subsequent reflux acidity. PPIs do not address the mechanism of regurgitation in patients with pathologic GERD. Central to the pathogenesis of GERD is a weak or incompetent LES that opens abnormally and allows the reflux of gastric contents into the esophagus.

In normal subjects, omeprazole treatment does not affect the number of reflux episodes or their duration; rather it converts acid reflux to less acid reflux, thus exposing esophagus to altered gastric juice. These observations may explain the persistence of symptoms and emergence of mucosal injury while on proton pump inhibitor therapy [15]. Limitations of PPIs include the need for daily use, high cumulative costs, and decreased efficacy over time.

Surgical procedures are typically considered in patients with symptoms despite optimal PPI therapy and in patients with severe GERD. Surgery is used, however in less than 1% of eligible GERD patients, and its usage has been decreasing over the last decade [16]. Laparoscopic fundoplication is the most commonly performed antireflux operation. The laparoscopic approach to fundoplication was introduced and popularized in the 1990’s. The surgical technique involves a complete hiatal dissection with mobilization of the esophagus and fundus, re-approximation of the diaphragmatic crura, and creation of a 360-degree wrap of fundus around the distal esophagus. Laparoscopic Nissen fundoplication can be accomplished in 2 hours or less for uncomplicated cases. Most patients stay in the hospital for 1-2 days. Many surgeons have their patients gradually transition from a soft or pureed diet to a more solid diet over the course of 2-8 weeks [17]. Relief of symptoms, especially esophageal symptoms such as heartburn and regurgitation occurs in > 90% of patients and has been demonstrated to be durable beyond 10 years for the majority of patients [18,19]. Potential surgical side effects following Nissen fundoplication include difficulty swallowing, increased flatus, bloating, early satiety, and inability to vomit or belch [20,21]. Anatomic failure of the fundoplication with recurrent GERD can occur in 2-17% of cases [22].


Source:http://pediatricfeeding.com/fundoplication/



The published outcomes of antireflux surgery are not always replicated in the community, especially for surgeons who perform laparoscopic antireflux surgery infrequently [23,24]. SAGES has published a Guidelines for Surgical Treatment of Gastroesophageal Reflux Disease. According to this document “The standardization of antireflux surgery technique is highly desirable, as it has been shown to lead to good postoperative patient outcomes (Grade A). Like any other surgical procedure, laparoscopic antireflux surgery is subject to a learning curve, which may impact patient outcomes. Therefore, surgeons with little experience in advanced laparoscopic techniques and fundoplication in particular should have expert supervision during their early experience with the procedure to minimize morbidity and improve patient outcomes (Grade B).” [25] Concerns related to potential side effects, recurrent GERD, and repeat surgery following laparoscopic Nissen fundoplication likely play a role in the fact that most patients who meet indications for antireflux surgery never undergo this procedure.

As an alternative to laparoscopic antireflux surgery, there are other commercially available, FDA approved endoscopic incisionless procedures designed to treat GERD. An exhaustive review of these technologies is outside of the scope of this document. A 2013 SAGES Statement on Endoluminal Treatments for GERD focused on 2 endoluminal devices available at the time of the review – EsophyX (Trans Oral Fundoplication or TIF, Endogastric Solutions, Redmond, WA) and Stretta (Mederi Therapeutics, Norwalk, CT) and is available for review. [26]. Direct comparisons between LINX and other commercially available products are unavailable. Experience with endoluminal GERD treatments continues to evolve.




Source:http://surgicalinstitute.com/nissen-fundoplication.html






3. Clinical Evidence Summary

Clinical studies involving the LINX system were identified via a search of the PubMed/Medline database (www.ncbi.nlm.nih.gov/pubmed) conducted in July 2016. The literature search used combinations of the keywords LINX, reflux, magnetic, magnetic sphincter augmentation, and/or GERD. Review articles without unique clinical data were excluded. Articles pertaining to the use of LINX in patients who have previously undergone bariatric surgery were considered outside the scope of this review and excluded. The bibliographies of key references were searched for relevant studies not uncovered in the PubMed search. The manufacturer’s website was also used to identify key references. Finally, summary reports for unpublished clinical data used in the approval process were identified on the FDA Web site. Patients from the feasibility and the pivotal trial are included in many other case series and case-control series. Patients from the post-market experience at numerous centers are represented several times in more recent publications included in this updated review. All references are described in detail in Appendix A.





4. Safety and Efficacy Data


Summary Paragraph:
Review of published studies suggests that magnetic sphincter augmentation is safe with no reported deaths and a 0.1% rate of intra/perioperative complications [27]. Long-term efficacy of LINX appears good for typical GERD symptoms with reduced acid exposure, improved GERD symptoms, and freedom from PPI in 85-88% at 3-5 years [28,29,30]. The most common side effect is dysphagia, the rate of which likely differs based on definition and patient population. Early dysphagia within the first few weeks is common at about 70% [31,32]. Dysphagia resolves in most patients and the incidence is roughly 10% at 1 year and 4% at 3 years [31]. The need for endoscopic dilation ranges from 6-12% [27, 33] and the primary reason for explantation appears to be persistent dysphagia with a rate in larger series from 3-6% [27,28,31]. Erosion appear to be rare, with one case reported in the 1st 1,000 patients [27], one additional published case report [34], a large series reporting 2 erosions [35], and several additional reports in the FDA MAUDE dataset (true number unknown, as multiple entries in this dataset may be made for each patient). Based on very limited literature, erosion can be successfully treated with explantation. Initially there were concerns about safety of LINX in patients who might later need an MRI. Patients who underwent LINX implantation prior to May 2015 are limited to MRI under 0.7T, while patients who have LINX subsequent to that date may have MRIs up to 1.5T (Torax website).



Publication Review
The literature search found reports on 2 FDA-approved IDE clinical studies. The initial feasibility study was a prospective, multi-center, non-randomized case series that enrolled 44 patients between February 2007 and October 2008 at 4 sites in the US and Europe (11 LINX procedures performed in the US and 33 in Europe). Four separate publications report results at 3-months [36],1 to 2 years [37], 4 years [38], and 5 years [30]. The pivotal study was a prospective, non-randomized, multi-center clinical trial enrolling 100 patients (96 US and 4 European) at 14 sites (13 US and 1 European). Data from 2-year follow-up were presented in FDA documents as part of the pre-market approval process [2]. Three-year follow-up on the pivotal trial was published at the time of the first version of this document [31]. More recently, 5-year follow-up on the pivotal study cohort was published as well [29].

Bonavina et al. [36] conducted a multicenter feasibility trial to evaluate safety and efficacy of the “magnetic sphincter augmentation device.” Patients with typical heartburn (at least partially responding to proton-pump inhibitors), abnormal esophageal acid exposure, and normal esophageal peristalsis were enrolled. Patients with hiatal hernia >3 cm were excluded from the study. Over a 1-year period, 38 out of 41 enrolled patients underwent this procedure in 3 hospitals. No operative complications were recorded. A free diet was allowed since post-operative day one, and 97%of patients were discharged within 48 h. The mean follow-up was 209 days (range 12–434 days). The GERD-HRQL score decreased from 26.0 to 1.0 (p<0.005). At 3 months postoperatively, 89% of patients were off anti-reflux medications, and 79% of patients had a normal 24-h pH test. All patients preserved the ability to belch. Mild dysphagia occurred in 45% of patients. No migrations or erosions of the device occurred. From this study, the authors suggest that in their experience laparoscopic implantation of the magnetic sphincter augmentation device is safe and well tolerated. They also propose that the short learning curve and minimal dissection required may be advantageous. Bonavina et al. [37] later conducted a 1 and 2-year evaluation of the above feasibility trial. At baseline, all 44 patients had abnormal esophageal acid exposure on 24-hour pH monitoring and improved, but persistent, typical GERD symptoms while on acid suppression therapy with PPIs. Patients were evaluated after surgery by GERD Health-Related Quality of Life symptom score, PPI usage, endoscopy, esophageal manometry, and 24-hour esophageal pH monitoring. The total mean GERD Health-Related Quality of Life symptom scores improved from a mean baseline value of 25.7 to 3.8 and 2.4 at 1 and 2-year follow-up, representing an 85% and 90% reduction, respectively (P < 0.0001). Complete cessation of PPI use was reported by 90% of patients at 1 year and by 86% of patients at 2 years. Early dysphagia occurred in 43% of the patients and self-resolved by 90 days. One device was laparoscopically explanted for persistent dysphagia without disruption of the anatomy or function of the cardia. There were no device migrations, erosions, or induced mucosal injuries. At 1 and 2 years, 77% and 90% of patients had a normal esophageal acid exposure. The mean percentage time pH was less than 4 decreased from a baseline of 11.9% to 3.1% (P < 0.0001) at 1 year and to 2.4% (P < 0.0001) at 2 years. Patient satisfaction was 87% at 1 year and 86% at 2 years. The authors conclude, “The new laparoscopically implanted sphincter augmentation device eliminates GERD symptoms without creating undue side effects and is effective at 1 and 2 years of follow-up.” Lipham et al. [38] followed this same patient cohort and evaluated these 44 patients at 3 and 4 years. Each patient’s baseline GERD status served as the control for evaluations post implant. For esophageal acid exposure, the mean total % time pH < 4 was reduced from 11.9 % at baseline to 3.8 % at 3 years, with 80 % of patients achieving pH normalization. At ≥4 years, 100 % of the patients had improved quality-of-life measures for GERD, and 80 % had complete cessation of the use of proton pump inhibitors (PPIs). There have been no reports of long-term device-related complications such as migration or erosion. The authors concluded that, “Sphincter augmentation with the LINX Reflux Management System provided long-term clinical benefits with no safety issues as demonstrated by reduced esophageal acid exposure, improved GERD-related quality of life, and cessation of dependence on PPIs, with minimal side effects and no safety issues. Patients with inadequate symptom control with acid suppression therapy may benefit from treatment with sphincter augmentation.” Saino et al recently reported the 5-year outcomes of the feasibility trial cohort [30]. Of the original 44 patients, 33 were available for follow-up at 5-years. Mean total percentage of time with pH <4 was 11.9% at baseline and 4.6% at 5 years (P < .001), with 85% of patients achieving pH normalization or at least a 50% reduction. Mean total GERD-HRQL score improved significantly from 25.7 to 2.9 (P < .001) when comparing baseline and 5 years, and 93.9% of patients had at least a 50% reduction in total score compared with baseline. Complete discontinuation of PPIs was achieved by 87.8% of patients. No complications occurred in the longer term, including no device erosions or migrations. The authors conclude that based on long-term reduction in esophageal acid, symptom improvement, and no late complications, that they have demonstrated the relative safety and efficacy of magnetic sphincter augmentation for GERD. In the FDA Summary of Safety and Effectiveness Data (SSED) document, with regards to safety, the FDA concludes: “The safety of the LINX Reflux Management System in the treatment of subjects with GERD was based on adverse event data from 100 subjects followed for up to 24 months. The 12-month data demonstrated 162 total adverse events reported in 76% of the subjects. Most adverse events resolved without sequelae. Dysphagia was the most common adverse event with 76 events being reported in 68% of the subjects, with 11% of the subjects reporting ongoing dysphagia. Eighteen (18) subjects underwent esophageal dilatation and 10 continued to have dysphagia at 24 months. Furthermore, there were several subjects who experienced symptoms of odynophagia/dysphagia that started after 180 days (182-605) and several subjects who had odynophagia and/or dysphagia that took over 180 days to resolve (maximum time noted 447 days). Overall, the incidence of dysphagia was found to be comparable to the incidence of dysphagia that is reported in patients undergoing anti-reflux surgery, such as Nissen fundoplication. Overall, the safety data from the pivotal trial supports a reasonable assurance that the LINX device is safe.”
Source: https://fox4kc.com/sponsored/?prx_t=eK4CArO4NArSEKA&prx_ro=s





With regards to effectiveness, based on the pivotal trial data the FDA concludes: “While the success criterion for the pre-specified primary objective of the study (pH normalization or a ≥ 50% reduction in distal esophageal acid exposure) was not met, there was improvement in esophageal pH. Sixty four of 100 subjects met the primary endpoint; there were 56 subjects who had normalization of pH and another 8 subjects who had a least a 50% reduction in total time that the pH < 4, however the lower limit of the 97.5% confidence interval was only 53.8% instead of the pre-specified 60%. Even more subjects had success in meeting the secondary objectives of improvement in GERD symptoms and reduction in PPI usage. The success rate for reduction in GERD symptoms was 92% at 12 months and 84% at 24 months. Similarly, reduction of at least 50% in PPI use was seen in 93% of subjects at 12 months and 86% at 24 months. The majority of these subjects, 88 at 12 months and 83 at 24 months, eliminated their use of PPIs. Although the primary objective of the study was not met, FDA considered the improvement in esophageal pH that was seen in 64% of subjects in addition to the improvement in GERD symptoms and reduction in PPI medication use demonstrated a reasonable assurance as to the effectiveness of the LINX Reflux Management System.” Ganz et al. [31] published 3-year follow-up data on the 100 patients enrolled in the pivotal trial. With regards to safety, “serious adverse events occurred in six patients and required removal of the device in four of the six. In three of the patients, the device was removed at 21, 31, and 93 days after implantation because of persistent dysphagia, with resolution in all three patients after removal, and in one patient, the device was removed at 357 days owing to intermittent vomiting of unknown cause starting 3 months after implantation, without relief after removal.” The most frequent adverse event was dysphagia, which occurred in 68% of patients postoperatively. Ongoing dysphagia was noted in 11% of patients at 1 year, in 5% at 2 years, and in 4% at 3 years. Esophageal dilation for dysphagia was allowed at the discretion of the investigator. A total of 19 patients underwent dilation, with 16 reporting improvement after the procedure. Chest radiography and endoscopy performed at 1 year and at 2 years after implantation showed no evidence of device migration or erosion. At 3 years, 2 patients reported an inability to belch or vomit. With regards to safety, the authors concluded, “Studies with larger samples and longer term follow-up are needed to confirm these early results and assess longer-term safety.” With regards to effectiveness, these investigators determined that normalization of or at least a 50% reduction in esophageal acid exposure was achieved in 64% of patients (64 of 100; 95% confidence interval [CI], 54 to 73). The secondary efficacy end point, a 50% reduction in the quality of life score, as compared with the score without proton-pump inhibitors at baseline, was achieved in 92% of patients (92 of 100; 95% CI, 85 to 97). A reduction of 50% or more in the average daily dose of proton-pump inhibitors occurred in 93% of patients (93 of 100 patients; 95% CI, 86 to 97). With regards to effectiveness, the authors concluded that the magnetic device decreased exposure to esophageal acid, improved reflux symptoms, and allowed cessation of proton-pump inhibitors in the majority of patients. Ganz and colleagues later reported the 5-year outcomes for 85 of the 100 patients enrolled in the pivotal trial [29]. Over the follow-up period, no device erosions, migrations, or malfunctions occurred. At baseline, the median GERD-HRQL scores were 27 in patients not taking proton pump inhibitors, and 11 in patients on these medications. Five years after device placement this score decreased to 4. All patients used proton pump inhibitor medications at baseline and at 5 years these medications were only used in 15%. Moderate or severe regurgitation occurred in 57% of subjects at baseline, but only 1.2% at 5 years. All patients reported the ability to belch and vomit if needed. Bothersome dysphagia was present in 5% at baseline and in 6% at 5 years. Bothersome gas-bloat was present in 52% at baseline and decreased to 8.3% at 5 years. The authors conclude that augmentation of the lower esophageal sphincter with a magnetic device provides significant and sustained control of reflux, with minimal side effects or complications. No new safety risks emerged over a 5-year follow-up period. Additional notable recent additions to the literature include a safety analysis of the first 1,000 patients implanted with a device [27]. Event rates were 0.1% intra/perioperative complications, 1.3% hospital readmissions, 5.6% endoscopic dilations, and 3.4% reoperations. All reoperations were performed non-emergently for device removal, with no complications or conversion to laparotomy. The primary reason for device removal was dysphagia. No device migrations or malfunctions were reported. Erosion of the device occurred in one patient (0.1%). The authors of this study concluded that with regards to safety, the overall event rates were low based on data from 82 institutions, and that the LINX device is a safe therapeutic option. Asti et al. [35] reported the results of a retrospective review of prospectively collected data examining the outcomes of 164 patients undergoing LINX implantation with median follow-up of 48 months. In eleven patients (6.7%), the device was ultimately removed for heartburn or regurgitation (n=5), dysphagia (n=4), or chest pain (n=2). In 2 patients, full-thickness erosion of the esophageal wall with partial endoluminal penetration of the device occurred. The estimated removal-free probability at 80 months was 0.91 [confidence interval (CI) 0.86–0.96]. The median implant duration was 20 months, with 82% of the patients being explanted between 12 and 24 months after the implant. Device removal was most commonly combined with partial fundoplication. There were no conversions to laparotomy and the postoperative course was uneventful in all patients. These authors conclude that laparoscopic removal of the LINX device “can be safely performed as a 1-stage procedure and in conjunction with fundoplication even in patients presenting with device erosion.”
Source: https://www.urmc.rochester.edu/surgery/thoracic/linx.aspx





There are several publications comparing clinical outcomes of the LINX device when compared to laparoscopic Nissen fundoplication. Louie et al. [39] compared perioperative outcomes, symptom control, side effects, adverse events, and pH studies in 34 consecutive patients who underwent LINX to 32 consecutive patients who had laparoscopic Nissen fundoplication. All patients with a hiatal hernia > 3-cm were excluded from this analysis. Operative time was longer for fundoplication. At 6 months, scores on the Gastroesophageal Reflux Disease Health Related Quality of Life scale improved from 20.6 to 5.0 for LINX vs. 22.8 to 5.1 for fundoplication. Postoperative DeMeester scores (14.2 vs. 5.1, p=0.0001) and the percentage of time pH was less than 4 (4.6 vs. 1.1; p=0.0001) were normalized in both groups. , but lower in the LINX group. LINX resulted in improved gas and bloat sensations (1.32 vs. 2.36; p=0.59) and enabled belching in 67% compared with none of the fundoplication patients. The investigators determined that LINX results in similar GERD symptom control with an improved quality of life compared to fundoplication.

Sheu et. al. [40] compared the outcomes of 12 patients to undergo LINX to 12 patients who had undergone laparoscopic Nissen fundoplication who were matched based on age, gender, and hiatal hernia size. LINX and Nissen fundoplication were both effective treatments for GERD. Severe dysphagia requiring endoscopic dilation was more common in LINX (50% vs. 0%; p=0.01). There was a non-statistically significant trend towards decreased gastrointestinal symptoms of bloating, flatulence, and diarrhea for LINX. These authors concluded that LINX and fundoplication are both effective and safe treatments for GERD. “Consideration to the distinct post-operative symptom profiles should be paid when selecting a surgical therapy for reflux disease.”

Riegler et al. [41] analyzed a prospective, multicenter registry of patients to undergo LINX and laparoscopic fundoplication for GERD. There were 202 LINX and 47 fundoplication patients with 1-year follow-up data at the time of their analysis. The fundoplication group was older with a greater frequency of large hiatal hernia and Barrett’s esophagus. GERD-health related quality of life score improved following surgery for both procedures. Moderate or severe regurgitation improved from 58.2 to 3.1% after LINX and 60.0 to 13.0% after fundoplication (p = 0.014).
Proton pump inhibitor medications were discontinued by 82% of LINX and 63.% of fundoplication patients (p = 0.009). Symptoms of excessive gas and abdominal bloating were reported by 10% of LINX and 32% of fundoplication patients (p ≤ 0.001). The authors of this study concluded that antireflux surgery should be individualized to the characteristics of each patient, taking into consideration anatomy and side effects. They felt that both LINX and fundoplication showed significant improvements in reflux control, with similar safety and reoperation rates. “In the treatment continuum of antireflux surgery, MSAD (Magnetic Sphincter Augmentation Device) should be considered as a first-line surgical option in appropriately selected patients without Barrett’s esophagus or a large hiatal hernia in order to avoid unnecessary dissection and preserve the patient’s native gastric anatomy.”

Reynolds was the lead author on 2 additional comparative studies evaluating LINX and fundoplication [42,43]. In the first comparative study to be published, from a series of 62 LINX and 117 laparoscopic Nissen fundoplications, 50 patients in both groups were matched using the “best-fit” model incorporating numerous preoperative variables. At 1 year after surgery, both groups had similar GERD Health Related Quality of Life scores and proton-pump inhibitor use. There were no patients with severe gas and bloating in the LINX group compared with 10.6% in the LNF group (p = 0.022). More fundoplication patients were unable to belch (8.5% of LINX and 25.5% of fundoplication; p = 0.028) or vomit (4.3% of LINX and 21.3% of fundoplication; p = 0.004). The incidence of postoperative dysphagia was similar between the groups. The authors concluded that analogous GERD patients had similar control of reflux symptoms with a lower incidence of gas bloat in LINX. In the second comparative trial by Reynolds et al, essentially the same cohort of patients was used to compare charges, complications, and outcome of LINX versus laparoscopic Nissen fundoplication at 1-year. There were 52 LINX and 67 fundoplication patients included. There was no significant difference between the mean charges. The fundoplication procedure was associated with a longer operative time and length of stay. Symptomatic outcomes and the ability to discontinue proton pump inhibitor medications were similar between procedures. As reported in the previously referenced publication, gas bloat as well as the ability to belch or vomit if needed was better following LINX. The authors concluded that fundoplication and LINX are comparable in symptom control, safety, and overall hospital charges.

Warren et. al. [44] published a multi-institutional retrospective cohort study of patients with GERD undergoing either LINX or laparoscopic Nissen fundoplication. Comparisons were made at 1 year for the overall group and for a propensity-matched group. There were 201 LINX and 214 fundoplication patients that were similar preoperatively with regards to age, gender, and GERD-HRQL scores. Obesity, dysphagia, higher DeMeester scores, Barrett’s esophagitis, and hiatal hernias were more prevalent in the fundoplication patients. Propensity-matched cases showed similar GERD-HRQL scores and the differences in ability to belch or vomit, and gas bloat persisted in favor of LINX. Mild dysphagia was higher for LINX (44 vs. 32 %, p=0.03). Resumption of daily PPIs was higher for LINX (24 vs. 12, p=0.02) with similar patient-reported satisfaction rates.



There was a trial at the Jacksonville, Mayo Clinic. This is what their description says,

Source: Jacksonville, FL Mayo Clinic






Asti et al published another comparative study evaluating outcomes following LINX and laparoscopic Toupet fundoplication [45]. Using the propensity score full matching method and generalized estimating equation, consecutive patients undergoing laparoscopic Toupet or LINX over the same time period were compared. Over a 7-year period, 103 patients underwent a laparoscopic Toupet and 135 a LINX procedure. All patients had a minimum 1-year follow-up. Over time, patients in both groups had similar GERD-HRQL scores, gas-related symptoms, dysphagia, and reoperation-free probability. In 2 concurrent cohorts of patients with early stage GERD undergoing laparoscopic Toupet or LINX and matched by propensity score analysis, health-related quality of life significantly improved and GERD-HRQL scores had a similar decreasing trend over time up to 7 years of follow-up. The authors conclude that laparoscopic Toupet and LINX provide similar disease-specific quality of life over time in patients with early stage GERD.

A search of the ClinicalTrials.gov website identified 8 clinical trials sponsored by Torax Medical. Five of these studies (all observational) have been completed. A post-approval study of the LINX reflux management system (NCT01940185) is active but not recruiting. The primary outcome measure of this study is a successful reduction of GERD-HRQL scores and adverse events to 60 months. The estimated study completion date is September 2019. The CALIBER Study Randomized Controlled Trial of LINX Versus Double-Dose Proton Pump Inhibitor Therapy for Reflux Disease (NCT02505945) is open for enrollment with an estimated study completion date of April 2017. This study compares mechanical sphincter augmentation (LINX Reflux Management System) to double-dose proton pump inhibitors (PPIs) for the management of reflux symptoms related to gastroesophageal reflux disease (GERD). The percentage of subjects with resolution of the GERD symptom of interest in each arm will be compared for significance. The final study is not yet recruiting. https://clinicaltrials.gov/ct2/results?term=torax+medical&cond=%22Gastroesophageal+Reflux%22 (accessed March 24, 2016)

A review of the FDA MAUDE database (3/1/12-2/29/16) revealed 141 reported adverse events (https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfMAUDE/results.cfm). All 141 reports describe device explants. Over the entire post-FDA approval interval to date, there were 72 reports of devices removed for dysphagia primarily. There were 33 reports of devices removed for recurrent or persistent GERD. A total of 14 erosions are reported in the MAUDE database at the time of this search. It is not possible to determine the incidence of device removal or erosion from the MAUDE database as the denominator is not known, some events may be reported more than 1 time, and some are likely not reported at all.

There are 3 published case reports describing device removal at the time of this review. Dysphagia [46,47] and erosion [34] were the primary indications for device removal in these reports. Lipham [27] reported 1 erosion in 1,000 patients and Asti [35] reported 2 in 164 patients.

In November of 2015, the American Medical Association awarded the LINX device a new Category 1 CPT (Current Procedural Terminology) code that will be effective January 1, 2017.






The criteria for a category 1 CPT code are as follows (https://www.ama-assn.org/ama/pub/physician-resources/solutions-managing-your-practice/coding-billing-insurance/cpt/cpt-process-faq/code-becomes-cpt.page):

All devices and drugs necessary for performance of the procedure of service have received FDA clearance or approval when such is required for performance of the procedure or service

The procedure or service is performed by many physicians or other qualified health care professionals across the United States

The procedure or service is performed with frequency consistent with the intended clinical use (i.e. a service for a common condition should have high volume)

The procedure or service is consistent with current medical practice

The clinical efficacy of the procedure or service is documented in literature that meets the requirements set forth in the CPT code change application.






5. Limitations of currently published data

Patients used repeatedly in some publications

There may be a publication bias in favor of LINX, as several studies were either funded by the manufacturer or were performed by investigators affiliated with the manufacturer.

Most studies were performed in high volume centers in highly selected patients and may not reflect broader clinical practice, which may lead to underreporting of complications

Current studies lack randomization and blinding






6. Expert Panel Recommendation


This expert panel convened by the SAGES Technology and Value Assessment Committee finds that:



With regards to safety:

Safety analyses suggest the LINX procedure was associated with few serious adverse events and no reported mortality.
The most common anticipated side effect was acute dysphagia.
The reported rate of erosion is in the range of 0.1% to 0.2%. The published literature on erosions suggests that the device can be safely removed endoscopically or laparoscopically without serious adverse outcomes.
Some devices require removal, most often for recurrent GERD or persistent and/or severe dysphagia
No new patterns of failure or complications have been reported in long-term follow-up.
Longer-term follow-up supports the FDA conclusion that the device is safe.
With regards to efficacy, the panel concludes:

LINX implant results in pH normalization, improved quality of life, and complete cessation of regular PPI use on a consistent basis. The ability to belch and vomit is maintained following implantation of LINX, and de novo moderate-severe gas-bloat is uncommon.
When compared to laparoscopic fundoplication, rates of success in alleviating GERD symptoms and dysphagia are similar following LINX. Bloating side effects may be lower.
Longer-term follow-up data demonstrates that the LINX Reflux Management System is effective in the management of GERD.
Conclusions:

Longer-term (3-5 years) experience with the LINX Reflux Management System confirms the initial safety profile that led to FDA approval of the device.

The LINX device has been demonstrated to result in long-term GERD control based on symptomatic outcomes, PPI utilization, and pH studies.
LINX is a reasonable treatment option for appropriately selected patients with GERD who meet indications for antireflux surgery. The LINX procedure is part of the armamentarium in the treatment of GERD. As such, it should be performed by surgeons familiar with the workup and different management alternatives of GERD and not offered in isolation.

Implantation of the LINX device should be covered and reimbursed by insurance for appropriate patients who meet the selection criteria as described above.

Author Financial Disclosure/Conflict of Interest Statement

Dana Telem, MD: Research funding at Cook, Consulting Fees at Ethicon and Medtronic, Honoraria at Gore

Andrew Wright, MD: Honoraria at Medtronic.

Paresh Shah, MD: Consultant at Stryker, Zmicro, Olympus, Endoevolution

Matthew Hutter, MD: Reimbursed to attend Masters in MIS Forum by Olympus.

This document underwent prescreening review prior to submission to SAGES Board of Governors for approval by SD Schwaitzberg, MD and Patricia Sylla, MD







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