Clues for differential diagnosis of acquired muscular disorders in young adults
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Periodic paralysis comprises a group of neuromuscular diseases in which the patients present with paroxysmal muscle weakness of the limbs. [1] The most common causes are thyrotoxic hypokalemic periodic paralysis (TPP) and familial hypokalemic periodic paralysis (FPP). [1]
Thyrotoxic periodic paralysis (TPP) is a medical emergency characterized by an acute and reversible attack of muscle weakness associated with the hypokalemia. [1, 2] TPP is the most common form of acquired flaccid paralysis in adults with hyperthyroidism and can occur in patients of any ethnicity, [3, 4] although it is more frequent in Asian populations. [5] TPP is the newest form of endocrine channelopathy included in the large group of periodic paralysis and should be included in the differential diagnosis of acute muscle weakness in patients seeking emergency care.
The association of loss of limb muscle strength and Graves’ disease was first published by Rosenfeld in the German literature at the beginning of the last century. [6] In English, the first report was made by Dunlap and Kepler in 1931, describing four patients. [7] In 1968, the first case of TPP diagnosed in Brazil was described by Pereira et al. [8]
TPP is more frequently described in Asian descendants, [5] but it can occur in patients of other ancestries. [3, 4] This aspect is particularly important because TPP should not be excluded in the differential diagnosis of paralysis based only on the patient’s ethnicity. Although thyrotoxicosis has a higher incidence in women, the paralysis affects predominantly men, with a male:female ratio of approximately 30:1. [2]
TPP symptoms occur in young adults, in contrast to FPP, in which the paralysis crises begin at an earlier age, usually before puberty. [1] TPP is more common between the third and fifth decades of life, which coincides with the peak incidence of thyrotoxicosis [9]. In a study performed with 35 Brazilian patients, the age at diagnosis ranged from 19 to 51 years, [2] similar to the international literature. [9, 10] Unlike the familial form, TPP appears as a sporadic disease. [11] However, rare cases of TPP with a family history of paralysis and thyrotoxicosis have been reported. [12, 13]
The paralysis crises occur only in the presence of the thyrotoxic state, regardless of its etiology. Several causes of thyrotoxicosis with paralysis have been reported, including Graves’ disease (GD), toxic adenoma, toxic multinodular goiter, amiodarone-induced thyrotoxicosis, TSH-producing pituitary tumor, lymphocytic thyroiditis, and factitious thyrotoxicosis. [2] In most of the cases, TPP is associated with the hyperthyroidism in GD, [9, 14] and the paralysis crisis may be an atypical form of initial presentation of the disease. In our studies, there are also a report of TPP in a patient who used formulations containing levothyroxine to lose weight. [2]
The methodological approach to determining the genetic susceptibility to TPP is difficult. This is due in part to the absence of a familial pattern of inheritance that allows linkage analysis by polymorphic allele markers, as almost all of the cases described in the literature are sporadic. Second, the number of cases is relatively small, making an association study to identify genetic susceptibility difficult. Thus, the first genes to be studied were the ones most commonly related to FPP (CACN1AS and SCN4A) [15], a clinical condition physiopathologically similar to the TPP. However, the investigation of these genes revealed that patients with TPP were negative for these mutations [17, 18]. Several other genes were subsequently studied, and although there were reports of patients bearing the KCNE3 mutation [18, 19], these patients were later proven to have only a polymorphic variant. [20]
More recently, after the study of Plaster et al. [21] on a familial paralysis form associated with facial dysmorphism and arrhythmias called Andersen-Twail Syndrome, a new group of candidate genes arose. Thus, the KCNJ12 gene (potassium channel Kir2.2) was included in the screening for TPP mutations. Kir2.2 became the candidate of greatest interest because of its expression in the skeletal muscle and the presence of the consensus elements (cis), the Thyroid Response Elements (TRE), in its regulatory region. Although no mutation has been found in this group of genes in TPP, during the study of the KCNJ12 gene, a novel paralog gene was discovered and called KCNJ18 (Kir2.6). [22] Four different mutations were identified, including two missense (T354M & K366R) and two nonsense (R399X & Q407X) mutations that combined are present in 33% of patients with TPP. [22] These mutations result in a defect in muscle repolarization. The high K+levels in the muscular system keep the cell in a partially depolarized state, and the membrane becomes unable to trigger a new muscle excitation-contraction coupling, resulting in flaccid paralysis. [22]
The physiopathology of TPP remains incompletely understood. Evidence suggests that TPP results from a combination of three factors: genetic, environmental, and thyrotoxicosis [1]. From this association, we hypothesized that the interaction of these factors would alter the channel dynamics of the cell membrane at the neuromuscular junction, triggering the paralysis crises only in patients genetically susceptible. [2] There are reports of a patient with history of TPP who suffered a paralysis crisis after taking excessive doses of thyroid hormone, [23, 24] which supports this hypothesis. [25]
In Figure 1, we described a theoretical model of multifactorial interactions in TPP. The genetic factors could include a defect in one of the ion channels involved in excitation-contraction coupling (Ca2+, Na+, and K+) or a defect in one of the channel’s regulatory subunits (ß, ∂, or SUR, for example). Alterations in one of these genes would be responsible for the generation of non-functional ion channels, which would define the TPP as an endocrine channelopathy. [26, 27]
Theoretical model of multifactorial interaction in TPP. Modified from Ref. [1]
The environmental factors include the excessive consumption of carbohydrate-rich foods, alcohol, or resting after intense exercise. Thyrotoxicosis would be the limiting factor and essential for the paralysis crisis. [1] In addition, several other studies have demonstrated that the activity of the Na+/K+-ATPase pump is increased in thyrotoxicosis and is more exacerbated in patients with TPP. [28, 29] The hypokalemia observed in these cases is due to the increased K+influx into a cell secondary to the increase in the activity of the Na+/K+-ATPase pump and by the hyperinsulinemic response to carbohydrate intake in patients susceptible to TPP. [25, 30] Androgens also can increase the activity of the Na+/K+-ATPase pump, which explains the higher incidence of the disease in young males. [30]
According to the mechanism illustrated in the Figure 2, we believe that during the TPP crisis, the mutated Kir2.6 potassium channel retains potassium in the sarcolemma, causing hypokalemia and flaccid paralysis.
Physiological regulation of Kir2.6 by thyroid hormone and when mutated.
Illustrative case report of TPP:
A 32-year-old mulatto male patient was brought to the emergency room at 5:00 am by relatives in a wheelchair. He reported being healthy until six months prior to presentation when episodes of muscle weakness in his lower limbs began to develop and kept him from getting out of bed and walking. He also complained of weakness of lower intensity in upper limbs. He denied pain or loss of sensation. All episodes spontaneously resolved without motor sequelae. During physical examination, a decreased in strength, especially in the lower limbs, and hypoactive deep tendon reflexes were noted. In addition, the patient also exhibited diffuse goiter, ocular proptosis, and thyrotoxicosis symptoms (tachycardia, excessive sweating, tremor of the extremities, and 10 kg weight loss). Eating several slices of pizza and soda in a restaurant was identified by the patient as the triggering factor for the crisis the following the next day.
The laboratory tests at the time of the crisis demonstrated hypokalemia (K=1.9 mEq/L; Normal Range: 3.5 to 5.1 mEq/L). The ECG demonstrated the presence of “U” waves and decreased amplitude of the T wave, and oral and intravenous potassium replacement was initiated. The paralysis crisis was resolved after the medication, and the patient was referred to the clinic for the etiologic diagnosis. During the investigation, Graves’ disease was diagnosed with TSH <0.05 mUI/L (Normal range: 0.5-4.5 mUI/L), free T4 >6.0 ng/dL (Normal range: 0.6-1.5 ng/dL), and total T3=535 ng/dL (Normal range: 30-200 ng/dL). The ultrasound revealed diffuse enlargement of the thyroid gland and increased vascularization detected by Doppler. [1, 31] I scintigraphy revealed an uptake of 21% over 2 hours (normal range from 1 to 8%) and 50% over 24 hours (normal range from 3 to 23%). Methimazole and propranolol treatments were initiated followed by the definitive hyperthyroidism therapy with radioactive iodine.
The case above illustrates the importance of a proper diagnosis to determine the specific treatment. Many patients already exhibit signs of hyperthyroidism due to Graves’ disease (goiter and exophthalmia) or thyrotoxicosis symptoms at the time of the paralysis crisis, but often the thyroid alteration is not recognized at the time and may be confused with hysteria or neuro-anxiety. Often, patients are erroneously classified as psychiatric and consequently treated with benzodiazepines.
The paralysis crises are transient and remit spontaneously, and their frequency, duration and intensity vary. [1] Because of this variability in the clinical presentation, the delayed diagnosis is not uncommon. Many patients report multiple visits to the emergency department with a sudden onset of muscle weakness of the limbs before the diagnosis.
Muscle weakness typically affects the proximal muscles of the lower limbs and is usually symmetric. [31] Some patients may present with tetraparesis or tetraplegia, which can be confused with Guillain-Barre syndrome, transverse myelitis, myasthenia gravis, or an acute spinal cord compression. However, in TPP, there is no urinary incontinence or intestinal dysfunction, nor is there a history of infection or trauma. [32] Although rare, there are reports of respiratory muscle paralysis that requires mechanical ventilation. [1, 33] It is important to distinguish TPP from other neuromuscular disorders that also presents with proximal muscle weakness inherent to thyrotoxic myopathy. In these other disease, the patients exhibit muscle atrophy and increased tendon reflexes, and the symptoms are proportional to the severity of the thyrotoxic state. [34]
TPP may be preceded by prodromal symptoms such as muscle pain, cramps, and/or stiffness of muscles of the affected limbs. [32] Frequently, the patients report that crises occur when they get up during the night or early in the morning after a day of intensive exercise and/or consumption of a large amount of food.
Sensitivity is preserved in the physical-neurological examination. However, as shown in Figure 3, the tendon reflexes are decreased or absent in the majority of the patients, [32] in contrast to the expected hyperreflexia in a thyrotoxic patient without paralysis. The duration of the crisis is variable, lasting up to 72 hours. [31] In a recently published study, the average duration of most cases was two to six hours. [2]
Patellar tendon reflex in patients with TPP, normal individuals, and individuals with thyrotoxicosis.
The confirmation of thyrotoxicosis, i.e., TSH suppressed in the presence of high levels of thyroid hormones (total and free T3 and T4), is essential for the definitive diagnosis of TPP. Hypokalemia is the primary laboratory alteration at the time of crisis. [9, 35] There are some reports of normokalemia, [36, 37] but we believe that these reports are due to errors during data collection, i.e., data collection in a late stage of the crisis after the serum concentrations of potassium have already recovered, [9] or due to improper storage of the samples, predisposing them to hemolysis. [2]
Hypokalemia results from the influx of ion into the intracellular compartment and does not indicate total depletion of the body potassium. [28] Calcium levels are normal, and creatine phosphokinase (CPK) might be elevated. [2] Some patients exhibit hypophosphatemia and hypomagnesemia, [9] both without need for replacement.
Other complementary exams, such as ultrasound, thyroid scintigraphy, and antibody measurements (anti-thyroglobulin, anti-peroxidase, and anti-TSH receptors (TRAb), may be necessary to define the etiology of hyperthyroidism. During the paralysis crisis, some patients exhibit a myopathic pattern on electromyography, which disappears in the remission period. [38] Muscle biopsy demonstrates nonspecific histological findings, and the study of the cerebrospinal fluid does not add any information to the diagnosis, both being dispensable during the investigation of TPP. [2]
We present a table 1 summarizing the major clues for differential diagnosis of acquired muscular disorders in young adults, including clinical and analytical features.
\n\t\t\t | Thyrotoxic hypokalemic periodic paralysis(TPP) | \n\t\t\tFamilial hypokalemic periodic paralysis(FPP) | \n\t\t\t\n\t\t\t\tGuillain-Barré syndrome\n\t\t\t | \n\t\t\t\n\t\t\t\tProximal myopathy\n\t\t\t | \n\t\t
Thyrotoxicosis | \n\t\t\tYes (symptoms can be very subtle) | \n\t\t\tNo | \n\t\t\tNo | \n\t\t\tYes (duration rather than severity of the thyrotoxic state is proportional to muscle weakness) | \n\t\t
Age of onset (years) | \n\t\t\t20-45 (95%) | \n\t\t\tBefore 16 (80%) | \n\t\t\tAll | \n\t\t\tAll | \n\t\t
Frequency | \n\t\t\tRare | \n\t\t\tRare | \n\t\t\tRare | \n\t\t\tCommon (67% of thyrotoxic patients) | \n\t\t
Male to female ratio | \n\t\t\t30:1 | \n\t\t\t3:1 | \n\t\t\t1.5:1 | \n\t\t\tMore common among men | \n\t\t
Muscle paralysis | \n\t\t\tYes (sporadic recurrent acute paralysis) | \n\t\t\tYes (sporadic recurrent acute paralysis) | \n\t\t\tYes (weakness and paralysis with ascending progression) | \n\t\t\tNo | \n\t\t
Ethnicity most frequently affected | \n\t\t\tEast Asian | \n\t\t\tWhite | \n\t\t\tAny | \n\t\t\tAny | \n\t\t
Family history of paralysis | \n\t\t\tNo | \n\t\t\tYes | \n\t\t\tNo | \n\t\t\tNo | \n\t\t
Precipitating factors | \n\t\t\tHeavy carbohydrate and/or salt meal, alcohol, exercise, stress | \n\t\t\tHeavy carbohydrate and/or salt meal, alcohol, exercise, dehydration | \n\t\t\tUsually preceded by an infection | \n\t\t\tNo | \n\t\t
Dysautonomia | \n\t\t\tNo | \n\t\t\tNo | \n\t\t\tYes | \n\t\t\tNo | \n\t\t
Deep tendon reflexes | \n\t\t\tUsually absent or depressed | \n\t\t\tUsually absent or depressed | \n\t\t\tAbsent or depressed | \n\t\t\tNormal and often hyperactive | \n\t\t
Severe respiratory muscle weakness | \n\t\t\tVery rare | \n\t\t\tRare | \n\t\t\t10-30% of patients | \n\t\t\tVery rare (in the acute thyrotoxic myopathy only) | \n\t\t
Facial muscles weakness | \n\t\t\tNo | \n\t\t\tNo | \n\t\t\tCommon (≥ 50%) | \n\t\t\tVery rare | \n\t\t
Duration of muscle symptoms | \n\t\t\t30 min-6h | \n\t\t\t≥ 24h | \n\t\t\tProgressive over days to 4 weeks | \n\t\t\tThroughout thyrotoxic state | \n\t\t
Potassium level during the muscle symptoms (mmol/L) | \n\t\t\t1.5-3.0 | \n\t\t\t2.8-3.5 | \n\t\t\tNormal | \n\t\t\tNormal | \n\t\t
Cerebral spinal fluid | \n\t\t\tNormal | \n\t\t\tNormal | \n\t\t\tAlbuminocytologic dissociation | \n\t\t\tNormal | \n\t\t
Nerve conduction analysis | \n\t\t\tNot specific, not necessary | \n\t\t\tNot specific | \n\t\t\tUseful and helpful for diagnosis | \n\t\t\tNot specific, not necessary | \n\t\t
Clinical course | \n\t\t\tRemission when euthyroidism is reached | \n\t\t\tChronic myopathy | \n\t\t\tRecovery; residual deficit in up to 20%; death in some patients | \n\t\t\tWeakness of proximal muscles that remits when euthyroidism is reached | \n\t\t
Genetic inheritance | \n\t\t\tMutation in KCNJ18 gene in up to 33% of patients | \n\t\t\tMutation in CACN1AS gene (80%) and SCN4A gene (15%) | \n\t\t\tNone | \n\t\t\tNone | \n\t\t
Clues for differential diagnosis of acquired muscular disorders in young adults
(Adapted with permission from reference [2])
The administration of oral and/or intravenous (IV) potassium is recommended during the paralysis crisis to accelerate the recovery and prevent a possible cardiac arrhythmia. [2] The oral use of potassium should be preferred, [39] but if a faster recovery is necessary, potassium may be slowly IV infused, usually over 2 hours. The main concern about potassium replacement is rebound hyperkalemia [40] because the potassium abnormality is not due to total potassium depletion but intracellular ion trapping. Therefore, monitoring the serum K levels during the treatment and suspending the infusion at the first sign of the muscular force recovery is recommended. [2]
Non-selective beta blockers, especially oral propranolol (80-240 mg/day), [2] may be useful in TPP treatment, especially when awaiting the FT4 and TSH results, by limiting the time of the crisis without inducing rebound hyperkalemia. [41, 42] These drugs block the adrenergic stimulation of the Na+/K+-ATPase pump activity, resulting in lower K influx to skeletal muscle.
Early treatment for the underlying cause of thyrotoxicosis is the most important procedure in patients with TPP. When euthyroidism is reached, the paralysis crises remits definitively. [34] Triggering factors such as high intake of carbohydrates, alcohol, and intense physical exercise should be avoided until the resolution of the thyroid disease. [43] In cases of thyrotoxicosis caused by excessive intake of thyroid hormones, the drug is suspended. In hyperthyroidism associated with Graves’ disease, toxic multinodular goiter, or toxic adenoma, the definitive treatment with radioactive iodine or thyroidectomy should be established immediately. Anti-thyroid drugs (methimazole or propylthiouracil) should be prescribed as adjuvant while the patient waits for the definitive therapy.
The authors’ work is supported by the Brazilian research funding agencies: CNPq (Conselho Nacional de Desenvolvimento Científico e Tecnológico), CAPES (Coordenação de Aperfeiçoamento de Pessoal de Nível Superior) and FAPESP (Fundação de Amparo à Pesquisa do Estado de São Paulo). A.L.R.R is an M.S. student from the CNPq.
Endovascular aneurysm repair is associated, in a significant proportion of cases, to a systemic inflammatory response that was denominated Postimplantation syndrome (PIS) [1]. PIS was first described in 1999 by Velazquez et al. [2] as a syndrome of fever and leukocytosis after aortic stent-graft implantation. It was incidentally noted in prior clinical studies on EVAR, but the exact origin is unknown. The authors suggested that these manifestations, comprising fatigue or other constitutional (flu-like) symptoms, fever and laboratory findings of inflammation, are a reproducible phenomenon specific to the nature of this procedure, rather than related to postoperative infections [2].
\nIn fact, experimental studies in animals had suggested a local peri-aortic inflammatory response to endovascular exclusion of aneurysms. For example, in a study in sheep that underwent to endovascular implantation of heparin-coated Dacron-covered grafts, the macroscopic examination of the arterial wall revealed significant inflammatory peri-graft response with vascular thickening and adhesions around the grafts. Microscopic examination revealed a severe foreign-body response [3].
\nSeveral publications addressing the issue have been published since 1999. However, there is still no consensus over the definition for the syndrome, its real incidence, associated factors, consequences, treatment, and eventually prophylactic therapy.
\nPIS is defined as fatigue and fever associated to a rise in inflammatory biomarkers. Which markers should be used and their cutoff values is still a matter of debate. There are several proposed combinations of fever, leukocytosis, and elevated C-reactive protein (CRP) used as definition for PIS in the literature. Some authors defined PIS as the presence of fever coinciding with an elevated serum CRP level, whereas the majority of them adapted the systemic inflammatory response syndrome (SIRS) criteria and defined PIS as the presence of fever combined with leukocytosis [1, 2, 4, 5, 6, 7, 8, 9, 10, 11].
\nArnaoutoglou et al. [10] defined PIS as the presence of fever (>38°C) and leukocytosis (>12.000/μL). However, they verified that hs-CRP values were strongly related to the presence of PIS and also emerged as an important predictor of the 30 day-outcome. Therefore, they concluded that hs-CRP probably is a better marker to inflammatory response. The reported incidence of PIS in the literature varies widely, and the lack of a universally accepted definition may be responsible for this. Reported incidence ranges from 2 to 100% (Table 1).
\nIncidence of PIS according to definition.
*Only with Incraft® endograft.
**Only with Zenith Alpha® thoracic endografts.
*** The sample only included percutaneous EVAR.
****Only with Anaconda® endograft.
aThis group defined PIS as fever and leukocytosis and abdominal and/or back pain, or other nonspecific symptoms such as malaise or loss of appetite.
Blum et al. [12], analyzed prospectively the clinical outcome after EVAR in 154 patients. All were treated with polyester-covered nitinol endograft and 87 patients (56%) developed fever (temperature, 38.0–39.7°C), that lasted for 4–10 days, without evidence of bacteremia or graft infection. All patients showed leukocytosis (range from 9.800 to 29.500/μL) in laboratory tests and an elevation of C-reactive protein concentrations (range from 4 to 34.1 mg/dL) [12].
\nTwo years after, Velazquez et al. [2] developed the first study specifically aimed at describing and understanding the postimplantation syndrome, characterized by fever and leukocytosis following endovascular stent graft repair of aortic aneurysms. They defined PIS as a syndrome that occurs after EVAR and proposed two criteria for diagnosis: fever and leukocytosis. However, the cutoffs of these criteria are not specified. In their small study, they found seven patients (58%) to have leukocyte count superior to 11.000/μL, 10 patients (83%) to have fever greater than 38°C and 8 patients (67%) superior to 38.5°C. Indeed, in eight patients, CT revealed air within the native aorta, around the stent-graft and within the thrombus of the excluded aneurysm. Physical examination, chest radiograph, urinalysis, urine culture and blood culture excluded any source of infection in 11 of 12 patients [2].
\nGabriel et al. [13] analyzed the inflammatory response after endovascular repair of abdominal, thoracic and thoracoabdominal aortic aneurysms, but they neither define PIS nor stated its incidence. They found that peak values of sedimentation velocity, CRP and interleukin-6 were observed at 7 postoperative days, elevation of leukocytes count occurred in premature phase, while lymphocyte and platelet count occurred in a late phase of follow-up. Serum levels of creatinine did not have significant variability during follow-up (3 months) and fever occurred mainly in the period between 24 and 48 h after the surgery.
\nChang et al. [14] studied the systemic inflammation, coagulopathy and acute renal insufficiency following endovascular thoracoabdominal aortic aneurysm repair (TAAA). They hypothesized that endovascular TAAA repair triggers a severe form of PIS. During the postoperative time, 18 of 38 patients (47%) developed fever (>38.0°C) and all had statistically significant changes in leukocyte and platelet counts and prothrombin time. Once again, neither the definition nor the incidence was stated.
\nGeorgiadis et al. [15] in their prospective study comparing the results of Endurant® endoprosthesis in hostile and friendly necks, pointed to a PIS incidence of 36.4% (28 patients, 9 patients in friendly neck group vs. 19 patients in hostile neck group; p = 0.032) with a mean duration of 2.02 days. However, the definition of PIS is unclear.
\nTwo other studies described PIS incidence, but they did not clarify the definition used. Mazzaccaro et al. [16] performed a retrospective study with 10 patients who underwent EVAR, but only with Incraft® endograft. They found an incidence of PIS of 30% (three patients). However, they do not specify the definition that they used. Melissano et al. [17] evaluated retrospectively the safety and efficacy of the Zenith Alpha® (Cook Medical Inc., Bloomington, IN, USA), in thoracic endovascular aortic repair of thoracic aortic aneurysms, aortic ulcers and traumatic aortic rupture on 42 patients. They do not specify the PIS definition that they used but stated a PIS incidence of 2%.
\nSeveral studies defined PIS as a combination of two criteria: leukocytosis and fever. Arnaoutoglou et al. [1] performed a prospective study with 162 patients (148 with AAA and 14 with TAAA) who underwent endovascular aneurysm repair. PIS was defined according to definition of SIRS: presence of fever (continuous temperature > 38°C) and leukocytosis (>12,000/μl) despite antibiotic therapy and negative culture results. PIS occurred in 49 patients (30.2%) and there were no significant differences in patients’ characteristics and intra-operative variables, between the two groups. In this study, the authors did not characterize the population in detail and opted to describe consequences of PIS in six cases. In a subsequent prospective study of the same authors, with 40 patients, they found a similar incidence of PIS – 35% (14 patients). They did not also verify significant differences in patients’ characteristics and intraoperative variables. Of note, a significant increase in IL-6 levels was observed only in the PIS group and the decrease in platelets count was greater in the PIS group, as was an increase in hs-CRP. The incidence of PIS varied according to the graft that was deployed, with highest incidences for Anaconda grafts (Vascutek-Terumo Cardiovascular System Corp, Ann Arbor, MI, USA) with 100% of incidence, and Zenith grafts (Cook Medical Inc., Bloomington, IN, USA), with 50% of incidence. The Talent grafts (Medtronic Vascular AVE, Medtronic Europe SA, Route du Molliau, Switzerland) had an incidence of 37% (6/16 patients) and the Excluder grafts (W.L. Gore & Associates, Inc., Flagstaff, AZ, USA) had the lowest incidence with 12% (2/17 patients) [4].
\nDosluoglu et al. [6] studied the feasibility and safety of ambulatory percutaneous EVAR in a sample of 79 patients. In this way, they compared the group in which the patients go home in the same-day of the procedure to the non-ambulatory-group and evaluate the incidence of PIS in these two groups. They defined PIS as any combination of fever >37.8°C, white blood cell count >10.000/μl, abdominal and/or back pain, or other nonspecific symptoms such as malaise or loss of appetite. PIS occurred in 23% of the patients, 19% in the same-day discharge group and in 26% in non-ambulatory group.
\nIn another study, with a retrospective design, of 118 patients who underwent EVAR but only with Anaconda endograft. These authors used the same definition of PIS with leukocytes >12.000/μl and temperature and reported an incidence of PIS of 20.3% (24 patients) [8]. Another retrospective study with 87 patients, using the same definition for PIS, found an incidence of 39%. This value was not similar between graft types, with the highest incidence for Anaconda endograft (71%) and the least incidence in Excluder grafts (13%) [18]. Arnaoutoglou et al. [10] prospectively evaluated PIS after elective EVAR in 214 patients with AAAs and investigated its association with clinical outcome during first 30 postoperative days. The diagnosis of PIS occurred in 36% patients. They also used the same criteria described above for PIS.
\nWith the same definition, Sartipy et al. [19] also investigated the impact of stent graft material on the inflammatory response, in 45 patients undergoing standard elective EVAR. The global incidence of PIS was 28%. A single-center, observational cohort study of 204 consecutive EVARs revealed an incidence of PIS of 31.4%, with the same definition [20]. In a similar way, Arnaoutoglou et al. [21] in a more recent prospective study with 182 consecutive EVARs, diagnosed PIS in 65 patients (35.7%).
\nFewer studies defined PIS with elevation of CRP instead of leukocytosis. Voûte et al. [5] compared the effect of stent graft composition in PIS. This group defined the PIS as fever (tympanic temperature > 38°C) and elevated serum CRP level (>10 mg/l). They found an incidence of PIS of 56.1% (46 patients) for the woven polyester group and 17.9% (12 patients) for the ePTFE group (p = 0.001).
\nA randomized, double-blind, placebo-controlled trial was designed to analyze the effect of a single preoperative dose of 30 mg/kg of methylprednisolone or placebo, administered 2 h before surgery, in reducing the incidence of PIS after EVAR. They used the SIRS criteria for PIS (the presence of at least two of the following criteria: temperature > 38°C or < 36°C; leukocytes >12.000/l, <4.000/ or > 10% bands; heart rate > 90; respiratory rate > 20; PaCO2 < 32 mm Hg), except the criterion of leukocytosis. Instead of leukocytosis, the criterion used was elevation of CRP > 75 mg/L. PIS with modified SIRS criteria was present in 27% in the methylprednisolone group versus 100% in the placebo group [7].
\nGorla et al. [22] developed a retrospective study and analyzed PIS incidence, but the 133 patients included underwent TEVAR due to type B acute aortic syndrome. The authors defined PIS as fever >38°C, leukocytes >12.000/mL and CRP >10 mg/dL within 72 h after TEVAR, despite negative blood cultures. PIS was diagnosed in 15.8% of patients.
\nA German group studied the effects of antibiotics in preventing PIS after aortic endoprosthesis implant. This trial included 40 patients and they did not have an aneurysmal disease. In each group, there were 18 type B dissections and 2 penetrating aortic ulcers.
\nThey compared the influence of perioperative single-shot versus prolonged (7 days) antibiotic therapy on parameters of PIS after thoracic endografting. There were no differences in parameters related to PIS, namely body temperature, leukocytes count and CRP, between two groups. They also did not find differences between the groups of acute and chronic type B dissections [23].
\nMoulakakis et al. [11] assessed the inflammatory and renal response after TEVAR in the descending thoracic aorta on 30 patients (28 aneurysms, 1 type B aortic dissection and 1 penetrating aortic ulcer). They do not evaluate the incidence of PIS but detected a significant increase in leukocytes, CRP, interleucin-6 and interleucin-10 at 24 and 48 h after endograft implantation compared to baseline; platelets were significantly decreased. This inflammatory response after TEVAR was associated to a rise in body temperature in the postprocedure period. Conversely, there were no significant differences in serum levels of interleucin-8, TNF-α, creatinine, urea or cystatin C after stent graft implantation.
\nIn conclusion, many studies do not specify the PIS definitions, many others used the definition with leukocytosis and fever and only three studies used a definition that includes CRP. The reported incidences in literature vary greatly which is possibly a consequence of variability in definitions. Hence, the obvious need for a universal definition of this syndrome.
\nThe etiology of PIS is not entirely clear. Implant composition has been identified as one of the most important determinants of the incidence and severity of PIS. [4, 5] However, the inflammatory response is not of the same magnitude in all patients treated with the same type of endograft. So, factors other than implant material must also be responsible to the occurrence of PIS. These may be patient or implant related.
\nLesion of the endothelium during implantation, bacterial translocation due to transient sigmoid ischemia, contrast medium-induced neutrophils degranulation, endovascular instrumentation of the mural thrombus and thrombosis of the aneurysm sac after aneurysm exclusion had all been proposed as factors that could trigger the pathophysiology of PIS [14, 23, 24, 25, 26] (Figure 1).
\nMultiple factors that may contribute to PIS occurrence.
This is the best investigated risk factor; several studies compared the incidence of PIS or the difference in inflammatory parameters and endograft material, mainly focusing on differences between polyester and expanded politetrafluoroethylene (ePTFE)-based structures.
\nThe majority of the studies pointed to a higher incidence of PIS or a greater increase of inflammatory markers in polyester-based endografts [4, 5, 8, 18, 20]. Voûte et al. [5] constructed a multivariable risk model for PIS, and woven polyester constitution of the endograft was the only significant factor associated with an increased risk of developing PIS (HR 5.58; p = 0.007). Kakisis et al. [18] had similar results when testing for risk factors for PIS using a multivariable model; only the type of endograft was independently associated with the development of PIS.
\nDespite the results, another three studies could not identify a difference in the incidence of PIS between polyester and ePTFE endografts. [5, 11, 19] Gerasimidis et al. compared, prospectively, the incidence of inflammatory response between endovascular aneurysm repair with polyester devices (12 patients) and ePTFE devices (10 patients). One patient in each group had PIS, according to SIRS criteria. Three patients in the polyester group had fever (>38°C) and only one patient in the PTFE group (p < 0.005). However, there were no statistically significant differences between two groups, for all endpoints, possibly due to sample size. Of note, all the patients in this study received a dose of an antihistamine (cetirizine hydrochloride 10 mg) before the surgery and nonsteroid antiinflammatory drugs (nimesulide 100 mg twice a day) during 72 h postoperatively [5]. In the study by Sartipy et al. [19] there were significant differences between the two types of graft material concerning fever and CRP, but there were no significant differences in the number of PIS events. It could also be related to sample size, with 32 patients treated with polyester grafts but only 13 patients with ePTFE grafts. They performed a sensitivity analysis that showed if three more patients in the polyester group would have developed PIS (or none instead of one patient in the PTFE group), the results would have reached significance. Lastly, Moulakakis et al. [11] assessed the inflammatory and renal response after TEVAR, and they did not observe a significant difference in inflammatory response between polyester and PTFE groups. They attributed that to small number of patients implanted with ePTFE endografts in their trial.
\nIn any case, PIS related to Anaconda® endografts had the highest incidence in published literature, except in one study by Nano et al. [8] in which the reported incidence was of only 20.3% [4, 18, 25]. In that study, however, isolated fever without any sign of infection and maintained for more than a week occurred in many patients, even after administration of corticosteroids (median duration, 11 days, (4–30 days)). In the same period in this hospital, PIS occurred with other endografts but lasted for less than 3 days or resolved completely after administration of corticosteroids [8]. Thus, it seems that in addition to the higher incidence of PIS, Anaconda® endografts are associated to a more intense syndrome, which is also more difficult to resolve.
\nApart from fabric, other components of the graft structure could be implicated. The stent structure, for example, could influence the occurrence of PIS. As discussed by Voûte et al. [5] when comparing Endurant® and Talent® endografts, the Excluder graft, which is associated to the lowest incidence of PIS, has an additional outer layer of ePTFE, covering the alloy, whereas in others, the metal and fabric are connected by stitches. Moreover, the latter have a bare top stent which constitutes an additional amount of nitinol directly exposed to the circulation and to the vessel wall. In addition to amount of alloy exposition, the exact balance between nickel and titanium (components of nitinol) or even the way of cutting and polishing may differ between manufacturers and may influence the inflammatory reaction [5]. However, it is important to note that nitinol has been widely used in coronary and peripheral arterial “bare-metal” stents and no inflammatory response have been reported in these applications [27]. In Zenith® endograft, an additional component of stainless steel can contribute for the inflammatory response, but this has not been adequately studied.
\nDelivery systems could also theoretically influence PIS. Moulakakis et al. [25] showed that the Excluder® endograft had a milder postimplantation inflammation, compared to the others. In addition to differences of material composition, the Excluder® endograft is introduced through a sheath, in contrast to other endografts. They hypothesize that this may cause less injury to endothelium. Moreover, thickness and porosity may differ between polyester endografts, as the metallic skeleton, and can justify variability in inflammatory response after EVAR [25]. Despite all the proposed mechanisms, the only component of endografts that seems to influence the incidence of PIS significantly is the fabric. Polyester, when compared to ePTFE, results in a higher inflammatory reaction both in vitro and in vivo, and this is well replicated in aortic endograft implants [28].
\nThe hypothesis that the amount of preexisting mural thrombus within the aneurysm sac could be related to PIS development derived from the finding that mural thrombus of an aortic aneurysm contains high levels of interleucin-6 [29]. In this way, it was conjectured that manipulations with endovascular material, as wires and catheters, in mural thrombus could release interleucin-6 and induce an inflammatory response. Nano et al. [8] reported an association between preoperative thrombus thickness and PIS with EVAR using the Anaconda® endograft (p = 00.1). However, Kakisis et al. [18] rebutted this hypothesis, since they found that the volume of chronic mural thrombus did not affect any parameter of PIS. In the same line, in the study by Moulakakis et al. [25] the Anaconda® endograft had the highest inflammatory response and, simultaneously, requires less thrombus manipulation with catheters and wires during implant, once it has a magnet on the contralateral limb to facilitate its cannulation. If the mural thrombus was the main source to PIS, patients treated with the Anaconda® endograft should have the lowest incidence, and the contrary is observed.
\nAnother hypothesis was that new-onset thrombus, instead of chronic mural thrombus, could be responsible for the acute inflammatory response [30]. Three authors tried to demonstrate this effect of new-onset thrombus but the results were not consistent. Kakisis et al. [18] could not find an association between the previous thrombus and PIS, but they found a significant correlation between the volume of new-onset thrombus and PIS parameters. In a multiple variable model, these authors showed that both the volume of new-onset thrombus and the type of endograft were independently associated with the development of PIS. However, Vôute et al. [5] analyzed the association between inflammatory response and new-onset thrombus after EVAR and found no significant correlation between new-onset thrombus and the rise in temperature (p = 0.08) or CRP (p = 0.17), with a larger patient sample. In the same way, Arnaoutoglou et al. [10] did not find differences regarding preoperative endoluminal thrombus or in the amount of newly formed thrombus between PIS and non-PIS patients groups. In light of the current evidence, it is not likely that chronic mural thrombus or new-onset thrombus within the aneurysm sac play a significant role in the development of PIS. It is possible that new onset thrombus may play a small role, which could not yet be clearly demonstrated due to sample size in all published studies on the subject.
\nAnother potential etiology for PIS after endovascular aneurysm repair is bacterial translocation due to transient sigmoid ischemia. Intestinal ischemia may be produced by either occlusion of a previously patent inferior mesenteric artery (IMA) or microembolization during catheter and wire manipulations. Thus, Kakisis et al. [18] analyzed the association between patency of the IMA and the postoperative temperature and inflammatory markers and found no significant correlation. Another trial, that studied the effects of antibiotic therapy in PIS after thoracic aortic stent placement, is in agreement [23]. The authors stated that there were no differences in parameters related to PIS, regardless of the duration of postoperative antibiotic therapy. Therefore, the hypothesis of bacterial translocation as a cause for PIS seems remote and there is no evidence to date to support it.
\nVidem et al. [26] suggested that contrast medium iohexol provokes neutrophil degranulation, which is greatly enhanced when combined with stent graft material, contributing to PIS occurrence. There are other recent studies that specifically analyzed inflammatory response after endovascular aortic repair; however, they did not find any correlation between contrast use or dosage and PIS parameters [5, 8, 18, 25]. As such, this theory remains to be demonstrated.
\nThe influence of several other factors in PIS parameters has also been explored, namely age, gender, aneurysm size, extent of aortic coverage, length of operation, blood loss or transfusion, intensive care unit, statin, chronic obstructive disease, ischemic heart disease and heart failure. None has been shown to be an important factor to PIS [5, 8, 9, 14, 18].
\nPIS is characterized by fever, anorexia, fatigue and lumbar pain associated to increase in leukocytes count, CRP, decrease in platelets count and/or coagulation abnormalities.
\nIt typically resolves within 2 weeks without any permanent ill effects, but in some cases may result in severe complications such as pulmonary dysfunction, cardiovascular events, renal insufficiency and multisystem organ failure [1, 14, 25].
\nThe diagnosis might be suspected in the presence of fever without clinical source of infection in the immediate postoperative period after EVAR. However, the diagnosis of PIS will depend on definition that is adopted.
\nFever is usually accompanied by a rise in laboratorial inflammatory markers and a drop in platelet count. Leukocytes count typically rises in the first postoperative day [5, 25]. CRP levels increase significantly between the first and third postoperative day [23, 31] (Figure 2).
\nEvolution of body temperature, leucocytes count and CRP since EVAR until 96 h after the procedure. Adapted by Voûte et al. [5], Gabriel et al. [13] and Akin et al. [23].
In the presence of fever and inflammatory parameters in the early postoperative period, patients usually undergo a work-up for possible infection, typically including chest radiography, urinalysis, urine culture and blood culture [32]. Some argue that this may be costly and unnecessary in clinical absence of an infection source [33]. However, since consequences of a serious postoperative infection may be devastating, at least close observation is recommended.
\nSartipy et al. [9] designed a prospective study to test the hypothesis was that procalcitonin would remain <0.5 ng/mL among patients who develop PIS after elective EVAR surgery, conversely to infectious complications. They defined PIS as a body temperature > 38°C and leukocytes >12,000/mL at any time during the observation period combined with no other detected complication or any open surgical event explaining the inflammatory response. The global incidence of PIS in this trial was 17.5% (12 patients) but this incidence was higher in patients with polyester grafts than in PTFE grafts (22.4% vs. 5%). They verified that all PIS patients had levels of procalcitonin <0.5 ng/mL, as they hypothesized, whereas all showed an elevation on CRP >100 mg/L and leukocytes >12.000/mL.
\nThus, procalcitonin appears as a good differentiator between PIS and infectious complications, probably less expensive and faster than microbiologic culture tests.
\nSeveral clinical consequences of PIS have been proposed, both in the early postoperative period and over follow-up (Table 2).
\nSummary table of the studies that favor influence of PIS in outcomes and of those that are against.
Moulakakis et al. [11] did not find any clinical adverse events related to PIS and there were no readmissions in their study. In another study that evaluated inflammatory response to Anaconda® endografts, the patients who developed this syndrome had a longer hospital-stay [8]. Other studies showed a significant prolongation of postoperative hospitalization in the PIS group compared to non-PIS group [4, 10, 20].
\nArnaoutoglou et al. [1] described six cases that required readmission, four cases due to a mild SIRS that resolves with non-steroidal anti-inflammatory drug orally, but the other two cases were a severe SIRS that required a stay in an intensive care unit and endovenous corticosteroids treatment.
\nIn a study concerning the applicability of percutaneous ambulatory EVAR, one patient was also readmitted due to severe PIS in third postoperative day (in the non-ambulatory group) and PIS was the only reason for delayed discharge in five patients [6].
\nChang et al. [14] analyzed the systemic inflammation, coagulopathy and acute renal insufficiency following endovascular TAAA repair. These authors found that patients with postoperative renal insufficiency had higher changes in leukocytes and platelets counts, as compared with those who did not develop renal failure. Indeed, the two patients who died in first postoperative month developed acute renal insufficiency in the early postoperative period. The preoperative glomerular filtration rate < 60 mL/min/1.73 m2 was not associated with the development of acute renal insufficiency (p = 0.80). They performed a univariate logistic regression analysis, which showed that each 5000 cells/μL increase in leukocytes in the postoperative period was associated with a 2.4-fold odds of postoperative renal insufficiency (p = 0.02). For platelets, each decrease of 50,000 platelets/μL was associated with a 4.0-fold odds of postoperative renal insufficiency (p = 0.02). In opposition, Moulakakis et al. [11] stated that renal function was not influenced by the inflammatory response; no correlation was recognized between the increased inflammatory markers and renal function.
\nIn a study that analyzed the influence of inflammatory reaction after endovascular aneurysm repair in 30-day outcomes, a multiple logistic regression model revealed that coronary artery disease (p = 0.01), post-operative hs-CRP (p = 0.001) and duration of fever (p = 0.02) independently predict major cardiovascular events. For every additional day of fever after the first, the chance of a cardiovascular episode increased by 67.9% (p = 0.017) and for every 10 units increase of hs-CRP, this probability increases by 15% (p = 0.001). For all adverse events studied, namely cardiovascular events, acute renal failure, readmission and death by any cause, multiple logistic regression analysis showed that postoperative hs-CRP (p = 0.004), PIS (p = 0.01), maximum temperature (p = 0.02) and smoking history (p = 0.02) were independent predictors. Postoperative hs-CRP revealed an important predictor for adverse outcomes during the first 30 days. A threshold value of 125 mg/L was highly associated with an adverse event, with a sensitivity of 72% and specificity of 75% [10].
\nIn a prospective study of 182 consecutive EVARs, patients were monitored during a year. Several adverse events are scrutinized, such as any major adverse cardiovascular events, acute renal failure, readmission and death from any cause. During the follow-up period, major adverse cardiovascular events occurred in 17.2% patients in PIS group vs. 4.3% in non PIS group and the other adverse events occurred in 18.8% of patients vs. 5.1%, respectively. Multiple logistic regression analysis showed that the occurrence of PIS was the only independent predictor of major adverse cardiovascular events (p = 0.007) or any adverse event (p = 0.005). Patients with the diagnosis of PIS were about 4–5 times more likely to suffer of a major cardiovascular event or another adverse event, than non-PIS patients [21].
\nConversely, Kwon et al. [20] stated that patients with and without PIS had similar long-term overall survival rates and other clinical outcomes, such as systemic or implant-related complications.
\nIn the study by Voûte et al. [5] the change in PIS parameters did not correlate to postoperative endoleaks. Besides prolongation of hospital stay, Nano et al. [8] also established a benign character for the PIS; no association between PIS and onset of early and long-term complications, namely endoleaks, was reported.
\nGorla et al. [22] studied a composite endpoint of major adverse events, such as aortic rupture, need for reintervention and all-cause mortality, after TEVAR of type B acute aortic syndromes. The mean follow-up was 4.0 ± 2.9 years. The major adverse events were more frequent in the PIS than in the non-PIS group (62.5 vs. 25.9%; p = 0.004).
\nKwon et al. [20] in a study with a follow-up of 44 months, PIS was significantly associated with a decreased risk of developing type II endoleaks (p = 0.044). PIS appeared to be beneficial in preventing type II endoleaks during postoperative period. Kaplan–Meier survival analysis showed that the groups (PIS and non-PIS) had similar rates of overall survival (p = 0.761) and other clinical outcomes (p = 0.562), except the rate of secondary procedures that was significantly higher in the non-PIS group (p = 0.049).
\nArnaoutoglou et al. [21] in a prospective study with 1 year-follow up, found no correlation between endoleak or any complication rates and PIS (p > 0.05).
\nThe analysis of the questionnaires on quality of life after 1 month of the surgery showed that PIS patients felt significantly more limited in their daily physical activities after surgery, as well as more emotionally discouraged and depressed/anxious about their state of health [8]. No long-term studies involving quality of life are available to date.
\nIn summary, there is a suspicion that PIS may be involved in a higher rate of early cardiovascular complications and worse early quality of life. There is no evidence to date that suggests a worse long-term outcome for patients affected, but the data are scarce.
\nThe 30 day-outcomes of patients with PIS described by Arnaoutoglou et al. [10] suggest that a specific treatment should be adopted to PIS to avoid clinical consequences. Akin et al. [23] tested the extension of antibiotherapy during the postoperative time, but it did not show any advantage in PIS incidence. In the study by Nano et al. [8] in case of PIS diagnosis, 1 g of hydrocortisone was administered intravenously on the third postoperative day, according to institutional protocol. In another study with patients who underwent percutaneous ambulatory EVAR, one patient had to be readmitted due to a severe PIS in third postoperative day. He was managed with hydration, pain control and anti-inflammatory medications and went home again after 3 days [6].
\nDe la Motte et al. [7] in a randomized, double-blind, placebo-controlled trial involving 153 patients, analyzed the effects of a single preoperative dose of 30 mg/kg of methylprednisolone or placebo, administered 2 h before surgery. For diagnosis of PIS, they used all criteria of SIRS, except for leukocytosis that was changed to CRP elevation due to the influence of corticoid therapy on leucocyte count and they obtained, with a single preoperative dose of methylprednisolone, a reduction in PIS from 100–27% [7]. The postoperative need for morphine was significantly reduced by methylprednisolone but the need for antiemetics was similar. There were no differences in 30-day medical morbidity (13 vs. 43%), surgical morbidity (20 vs. 43%), reinterventions (0 vs. 29%) or readmissions (7 vs. 14%) in the methylprednisolone versus placebo group. There was no 30-day mortality in all the patients included, and during the 3 months of follow up, there was no significant difference in mortality between the groups (3% vs. 1%, P = 1.0). Regarding adverse effects of corticosteroids, 11 potential methylprednisolone side effects occurred in 10 patients (14%). They were mainly related to infusion of the drug: metallic taste in five patients, flushing in three patients, rise in blood pressure requiring treatment in two patients and euphoria within the first 24 h in one patient. In the placebo group, rise in blood pressure was noted in one patient. Analyzing the subgroup of diabetic patients (15 patients in methylprednisolone group and 7 patients in placebo group), the intraoperative median blood glucose levels were higher in the methylprednisolone group than in the placebo (363 mg/dL vs. 298 mg/dL (p = 0.01)) and they remained higher during the first 24 h (p = 0.006). In 47% of patients in the methylprednisolone group, supplementary insulin was necessary compared to none in placebo group during the first 24 h. There were no records of adverse events relating to dysregulation of blood glucose levels. Subgroup analysis on the diabetic patients showed the same tendencies as in the entire cohort [7]. In this trial, there was a substantial difference between PIS incidence with a single preoperative dose of methylprednisolone. However, they defined PIS as having either fever or elevated CRP levels. Hence, possibly, the higher incidence of 100% in placebo group.
\nThe routine administration of drugs like steroids or nonsteroid anti-inflammatory drugs is of concern because of their side effects, mainly in patients with multiple or more severe comorbidities [1]. However, it seems reasonable to prevent this inflammatory response, once it can lead to prolonged hospitalization or a readmission and even to more severe consequences, as the authors described above.
\nUndoubtedly, future studies have to be performed to clarify the need for routine prophylaxis for this syndrome or a symptom based anti-inflammatory therapy (Figure 3).
\nSchematic diagram of prevention, diagnosis and treatment of PIS, with associated references.
The absence of a universal definition for PIS is responsible to the variability of its incidence. However, CRP seems to be a better criterion for PIS instead of leukocyte count. The etiology is still not clarified, but the majority of the studies pointed to a relevant role for endograft material. Regarding diagnosis, procalcitonin appears to be a good differentiator between PIS and infectious complications. The clinical consequences of this syndrome, in length of hospital stay, readmissions, renal function, cardiovascular events, endoleaks and quality of life, are not fully elucidated, and more studies have to be performed. However, there is evidence suggesting a prolonged hospital stay, higher risk of early cardiovascular events and worse early quality of life for affected patients. Regarding treatment, although corticosteroids and nonsteroidal anti-inflammatory drugs seem to be a reasonably effective strategy, there is a need to establish the best treatment and weather pharmaceutical prophylaxis is necessary. The routine administration of drugs like steroids or nonsteroid anti-inflammatory drugs raises concerns due to side effects, mainly in patients with more severe comorbidities.
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I am also a member of the team in charge for the supervision of Ph.D. students in the fields of development of silicon based planar waveguide sensor devices, study of inelastic electron tunnelling in planar tunnelling nanostructures for sensing applications and development of organotellurium(IV) compounds for semiconductor applications. I am a specialist in data analysis techniques and nanosurface structure. I have served as the editor for many books, been a member of the editorial board in science journals, have published many papers and hold many patents.",institutionString:null,institution:{name:"Sheffield Hallam University",country:{name:"United Kingdom"}}},{id:"54525",title:"Prof.",name:"Abdul Latif",middleName:null,surname:"Ahmad",slug:"abdul-latif-ahmad",fullName:"Abdul Latif Ahmad",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"20567",title:"Prof.",name:"Ado",middleName:null,surname:"Jorio",slug:"ado-jorio",fullName:"Ado Jorio",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Universidade Federal de Minas Gerais",country:{name:"Brazil"}}},{id:"47940",title:"Dr.",name:"Alberto",middleName:null,surname:"Mantovani",slug:"alberto-mantovani",fullName:"Alberto Mantovani",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"12392",title:"Mr.",name:"Alex",middleName:null,surname:"Lazinica",slug:"alex-lazinica",fullName:"Alex Lazinica",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/12392/images/7282_n.png",biography:"Alex Lazinica is the founder and CEO of IntechOpen. 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He is an expert in structural, absorptive, catalytic and photocatalytic properties, in structural organization and dynamic features of ionic liquids, in magnetic interactions between paramagnetic centers. The author or co-author of 3 books, over 200 articles and reviews in scientific journals and books. He is an actual member of the International EPR/ESR Society, European Society on Quantum Solar Energy Conversion, Moscow House of Scientists, of the Board of Moscow Physical Society.",institutionString:null,institution:null},{id:"62389",title:"PhD.",name:"Ali Demir",middleName:null,surname:"Sezer",slug:"ali-demir-sezer",fullName:"Ali Demir Sezer",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/62389/images/3413_n.jpg",biography:"Dr. Ali Demir Sezer has a Ph.D. from Pharmaceutical Biotechnology at the Faculty of Pharmacy, University of Marmara (Turkey). 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I received a B.Eng. degree in Computer Engineering with First Class Honors in 2008 from Prince of Songkla University, Songkhla, Thailand, where I received a Ph.D. degree in Electrical Engineering. My research interests are primarily in the area of biomedical signal processing and classification notably EMG (electromyography signal), EOG (electrooculography signal), and EEG (electroencephalography signal), image analysis notably breast cancer analysis and optical coherence tomography, and rehabilitation engineering. I became a student member of IEEE in 2008. During October 2011-March 2012, I had worked at School of Computer Science and Electronic Engineering, University of Essex, Colchester, Essex, United Kingdom. In addition, during a B.Eng. I had been a visiting research student at Faculty of Computer Science, University of Murcia, Murcia, Spain for three months.\n\nI have published over 40 papers during 5 years in refereed journals, books, and conference proceedings in the areas of electro-physiological signals processing and classification, notably EMG and EOG signals, fractal analysis, wavelet analysis, texture analysis, feature extraction and machine learning algorithms, and assistive and rehabilitative devices. I have several computer programming language certificates, i.e. Sun Certified Programmer for the Java 2 Platform 1.4 (SCJP), Microsoft Certified Professional Developer, Web Developer (MCPD), Microsoft Certified Technology Specialist, .NET Framework 2.0 Web (MCTS). I am a Reviewer for several refereed journals and international conferences, such as IEEE Transactions on Biomedical Engineering, IEEE Transactions on Industrial Electronics, Optic Letters, Measurement Science Review, and also a member of the International Advisory Committee for 2012 IEEE Business Engineering and Industrial Applications and 2012 IEEE Symposium on Business, Engineering and Industrial Applications.",institutionString:null,institution:{name:"Joseph Fourier University",country:{name:"France"}}},{id:"55578",title:"Dr.",name:"Antonio",middleName:null,surname:"Jurado-Navas",slug:"antonio-jurado-navas",fullName:"Antonio Jurado-Navas",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/55578/images/4574_n.png",biography:"Antonio Jurado-Navas received the M.S. degree (2002) and the Ph.D. degree (2009) in Telecommunication Engineering, both from the University of Málaga (Spain). He first worked as a consultant at Vodafone-Spain. 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