Category Archive Research

What Is Lung Cancer?/Lung cancer or bronchogenic carcinoma refers to tumors originating in the lung parenchyma or within bronchi. It is one of the leading causes of cancer-related deaths in the United States. Lung cancer is responsible for more deaths in women than breast cancer. It is interesting to note that at the beginning of the 20th century, lung cancer was a relatively rare disease. Its dramatic rise in later decades is mostly attributable to the increase in smoking among both males and females[rx][rx].

Causes of Lung Cancer

Smoking is the most common cause of lung cancer. It is estimated that 90% of the cases of lung cancer are attributable to smoking. The risk is highest in males who smoke. The risk is further compounded with exposure to other carcinogens, such as asbestos. There is no correlation between lung cancer and the number of packs smoked per year due to the complex interplay between smoking and environmental and genetic factors. The risk of lung cancer by passive smoking increases by 20% to 30%. Other factors include radiation for non-lung cancer treatment, especially non-Hodgkins lymphoma and breast cancer. Exposure to metals, such as chromium, nickel, and arsenic, and polycyclic aromatic hydrocarbons also is associated with lung cancer. Lung diseases like idiopathic pulmonary fibrosis increase risk of lung cancer independent of smoking[rx].

The broad divisions of SCLC and NSCLC represent more than 95% of all lung cancers.

Small Cell Lung Cancer

• Histologically, SCLC is characterized by small cells with scant cytoplasm and no distinct nucleoli. The WHO (World Health Organization) classifies SCLC into three cell subtypes: oat cell, intermediate cell, and combined cell (SCLC with NSCLC component, squamous, or adenocarcinoma).
• SCLC is almost usually with smoking. It has a higher doubling time and metastasizes early; therefore, it is always considered a systemic disease at diagnosis. The central nervous system, liver, and bone are the most common sites. Certain tumor markers help differentiate SCLC from NSCLC. The most commonly tested tumor markers are thyroid transcription factor-1, CD56, synaptophysin, and chromogranin. Characteristically, NSCLC is associated with a paraneoplastic syndrome which could be the presenting feature of the disease

Non-Small Cell Lung Cancer

Five Types of NSCLC

• Squamous cell carcinoma – is characterized by the presence of intercellular bridges and keratinization. These NSCLCs are associated with smoking and occur predominantly in men. Squamous cell cancers can present as Pancoast tumor and hypercalcemia. Pancoast tumor is the tumor in the superior sulcus of the lung. The brain is the most common site of recurrence postsurgery in cases of Pancoast tumor.
• Adenocarcinoma –  is the most common histologic subtype of NSCLC. It is also the most common cancer in women and non-smokers. Classic histochemical markers include Napsin A, Cytokeratin-7, and thyroid transcription factor-1. Lung adenocarcinoma is further subdivided into acinar, papillary and mixed subtypes.
• Adenosquamous carcinoma – comprises 0.4 % to 4% of diagnosed NSCLC. It is defined as having more than 10% mixed glandular and squamous components. It has a poorer prognosis than either squamous and adenocarcinomas. Molecular testing is recommended for these cancers.
• Large cell carcinoma – lacks the differentiation of a small cell and glandular or squamous cells[8].
• Carcinoid tumors – include two subtypes: typical and atypical. Typical carcinoid carries relatively better prognosis and is only occasionally associated with carcinoid syndrome.
• Apart from this, there is anecdotal evidence of rare and unusual forms of non-small cell lung cancer which includes but are not limited to giant cell carcinoma of the lung and sarcomatoid carcinoma of the lung[rx][rx].

Toxicokinetics

• Multiple compounds have been implicated as the cause of lung cancer. In reality, it is hard to establish a causal relationship due to a battery of other confounding factors, such as the difference in the quantity of exposure time, smoking status.
• Among the chemicals considered responsible, asbestos is the only one that has a clear causal relationship with the development of lung cancer.

Asbestos and Lung Cancer

• The risk depends on exposure time and type of asbestos. Amphibole fibers confer a much higher risk of lung cancer than chrysotile fibers. The risk increases considerably with concurrent smoking. In non-smokers who are exposed to asbestos, there is a six-fold increase in the risk of lung cancer; whereas, in smokers, this risk is 16-fold if a minimum of 20 cigarettes smoked per day and nine-fold increase with less than 20 cigarettes per day. Other compounds that may increase the risk of lung cancer include radon, nickel, cadmium, chromium, silica, and arsenic.

Diagnosis of Lung Cancer

No specific signs and symptoms exist for lung cancer. Most patients already have advanced disease at the time of presentation. Lung cancer symptoms occur due to local effects of the tumor, such as cough due to bronchial compression by the tumor, due to distant metastasis, stroke-like symptoms secondary to brain metastasis, paraneoplastic syndrome, and kidney stones due to persistent hypercalcemia[rx]. Specifically:

• A cough, dyspnea, and hemoptysis are common presenting symptoms.
• A cough is the most common symptom, accounting for 50% to 75% of cases. It is sensitive but not specific. Squamous cell and small cell cancers usually cause a cough early due to the involvement of the central airways.
• Dyspnea or shortness of breath represents lung cancer in 25% to 40% of cases.
• Hemoptysis is an important symptom in anyone with a history of smoking. Although bronchitis is the most common cause of hemoptysis, 20% to 50% of patients with underlying lung cancer present with hemoptysis.
• Rarely, patients present with shoulder pain, Horner syndrome, and hand muscle atrophy. This constellation of symptoms is called Pancoast syndrome. It is due to lung cancers arising in the superior sulcus[rx].

Evaluation

• Lung cancer is the leading cause of death in both men and women. NSCLC accounts for 85% of diagnosed cases of lung cancer in the United States. The overall goal is timely diagnosis and accurate staging. As per the American College of Chest Physicians (ACCP) guidelines, the initial evaluation should be complete within 6 weeks in patients with tolerable symptoms and no complications. Only 26% and 8% of cancers are diagnosed at stages I and II, whereas 28% and 38% are diagnosed at stages III and IV respectively. Therefore, curative surgery is an option for a minority of patients.

Lung cancer evaluation can be divided in 2 ways:

• Radiological staging
• Invasive staging

Goals of Initial Evaluation

• Clinical extent and stage of the disease
• Optimal target site and modality of 1st tissue biopsy
• Specific histologic subtypes
• Presence of co-morbidities, para-neoplastic syndromes
• Patient values and preferences regarding therapy

Radiologic Staging

Every patient suspected of having lung cancer should undergo the following tests:

• Contrast-enhanced CT chest with extension to upper abdomen up to the level of adrenal glands
• Imaging with PET or PET-CT directed at sites of potential metastasis when symptoms or focal findings are present or when chest CT shows evidence of advanced disease

CT Scan

• Intravenous (IV) contrast enhancement is preferable as it may distinguish mediastinal invasion of the primary tumor or metastatic lymph nodes from vascular structures.
• The major advantage of CT is that it provides an accurate anatomic definition of the tumor within the thorax which helps clinicians to decide the optimal biopsy site.

CT can also identify the following:

• Tumor-related atelectasis
• Post obstructive pneumonitis
• Intra- or extrathoracic metastatic disease
• Co-existing lung disease

The main objective of a CT scan is to identify the extent of the tumor, its anatomical location, and the lymph node involvement. TNM staging relies heavily on lymph node involvement. Therefore, most of the societies in Europe and the United States agree to regard a lymph node of 1 centimeter or more in the short axis to be considered as highly suspicious for malignancy. Lymph nodes can be enlarged secondary to acute inflammation, such as with congestive heart failure exacerbation or recent viral infection. The overall sensitivity and specificity of CT scan to identify malignancy are 55% and 81% respectively. Hence, CT is not a good test for lung cancer staging.

Radiological Groups

The American College of Chest Physicians (ACCP) has proposed grouping patients based on tumor extent and lymph node involvement. Although CT is not the right staging tool, it helps the clinician select the site for tissue biopsy. In other words, based on these groups, further staging via non-invasive or invasive methods is planned.

Group A

• Patients with bulky tumor encircling/invading mediastinal structures such that remote lymph nodes cannot be distinguished from the primary tumor.
• Mediastinal invasion is implied, therefore, no need for LN sampling. Tissue diagnosis suffices.

Group B

• Patients with discrete lymph node enlargement greater than 1 centimeter such that an isolated lymph node can be distinguished from the primary tumor
• Lymph node sampling is required for pathologic confirmation before curative intent therapy.

Group C

• Patients with a central tumor and elevated risk of nodal disease despite normal-sized nodes, such as high risk for N2/3 disease.
• Lymph node sampling is needed even if CT/PET negative due to a high risk of N2/N3 disease.

Group D

• Patients with low risk of N2/3 involvement or distant metastatic disease, such as peripheral T1 tumors.
• Invasive testing is not done routinely except if suspicion of N1 disease is high or patient is not a candidate for surgery but going for Stereotactic Body Radiation Therapy (SBRT).

Invasive Staging

After CT and PET scans, the next step is to obtain tissue or pathologic confirmation of malignancy, confirm staging, and histological differentiation of cancer. One of the following procedures achieves this.[rx]

• Bronchoscopic Endobronchial Ultrasound-Transbronchial Needle Aspiration (TBNA)
• Endoscopic-TBNA
• Mediastinoscopy
• Thoracoscopy or video-assisted thoracoscopy(VATS)

CT guided a transthoracic biopsy is an option for peripheral lesions with a low risk of pneumothorax. Certain older procedures, such as the Chamberlain procedure, is sometimes required[rx].

Bronchoscopic TBNA

• Convex Probe-Endobronchial Ultrasound-guided (EBUS)-TBNA
• Radial Probe-EBUS-TBNA
• Navigation Bronchoscopy

CP-EBUS Bronchoscopy

• This is a bronchoscopic technique in which a miniature convex ultrasound of 7.5 MHZ is attached to the tip of the bronchoscope. It provides direct visualization of structures in the mediastinum or lung parenchyma through the bronchial wall. A biopsy is performed in real-time.
• It mainly is used to sample the mediastinal and hilar lymph nodes. The image can be frozen and measured, and there is also Doppler available to identify blood vessels. It is the procedure of choice for this purpose. CP-EBUS is also the procedure of choice postinduction chemotherapy before surgery to confirm complete remission. CP-EBUS can be used to sample upper and lower paratracheal nodes as well as stations 10, 11, and 12. Stations 3, 5, and 6 are not accessible via CP-EBUS.

RP-EBUS Bronchoscopy

• Instead of a convex probe, there is a miniature (20 to 30 MHz) probe. The advantages are that smaller lesions or lesions that are more peripheral can be reached, and it provides a 360-degree view of lung parenchyma. A real-time biopsy cannot be performed.

Navigation Bronchoscopy

• The concept is to construct a navigational map of airways using either CT scan or electromagnetic field. After the map is constructed, the software creates the path to reach the location of the nodule. The bronchoscopist can create the pathway, and the software then navigates the bronchoscopist to the biopsy site.

Endoscopic-TBNA

• Endoscopic ultrasonography (EUS) is becoming an increasingly useful tool for the diagnosis and staging of lung cancer. It can sample lymph nodes through the esophageal wall and provides a real-time sampling of stations 2, 4, 7, 8, and 9.
• The latter 2 stations cannot be sampled by Endobronchial ultrasound (EBUS). It has the same sensitivity and specificity of EUS, 89%, and 100% respectively. There is also a growing trend to combine EBUS and EUS as a minimally invasive technique for lung cancer staging[rx].

Mediastinoscopy

• Mediastinoscopy was formerly the gold standard for lung cancer diagnosis and staging. Now it is mainly used to sample lymph nodes after negative needle technique and when the patient is still at high risk for cancer due to lymph node size or FDG uptake on PET scan.
• Most commonly, para-tracheal lymph nodes are sampled. Alternatively, an anterior mediastinoscopy (Chamberlain procedure) can be performed to access subaortic and para-aortic nodes, stations 5 and 6 respectively. Mediastinoscopy has a sensitivity of 78% and specificity of 100%. Like all surgical procedures, mediastinoscopy has some risks. General anesthesia is required, and the procedure carries a mortality risk of 0.08%[rx][rx].

Thoracoscopy

• Traditionally, thoracoscopy was performed by dividing the ribs and opening the chest cavity. Like laparoscopic surgery, it has largely replaced open abdominal surgeries. Video-assisted thoracoscopy surgery (VATS) has replaced thoracoscopy.
• It is used to treat a number of chest wall, pleural, pulmonary, and mediastinal conditions. Mediastinal lymph node sampling, as well as full dissection during lung resection for cancer, can be performed with VATS. A newer version of VATS is called RATS (robotic-assisted thoracoscopy). There are no trials comparing VATS and RATS for mediastinal lymph node biopsy.

Treatment of Lung Cancer

Treatment of Non-Small Cell Lung Cancer

Stage I

• Surgery is the mainstay of treating stage 1 NSCLC. The procedure of choice is either lobectomy or pneumonectomy with mediastinal lymph node sampling. The 5-year survival is 78% for IA and 53% for IB disease. In patients who do not have the pulmonary reserve to tolerate pneumonectomy or lobectomy, a more conservative approach with wedge resection or segmentectomy can be done. The disadvantage is a higher local recurrence rate, but survival is the same. Local postoperative radiation therapy or adjuvant chemotherapy has not shown to improve outcomes in stage I disease.

Stage II

• The survival of stage IIA and IIB lung is 46% and 36% respectively. The preferred treatment is surgery followed by adjuvant chemotherapy.
• If the tumor has invaded the chest wall, then an en-bloc resection of the chest wall is recommended. Pancoast tumor is a unique tumor of stage II. It arises from the superior sulcus and usually diagnosed at a higher stage, IIB or IIIA. The treatment of choice in cases of Pancoast tumor is neoadjuvant chemotherapy usually with etoposide and cisplatin and concurrent radiotherapy followed by resection. Overall survival is 44% to 54% depending on postsurgery presence or absence of microscopic disease in the resected specimen.

Stage III

• This is the most heterogeneous group, consisting of a wide variation of tumor invasion as well as lymph node involvement.
• Stage IIIA disease with N1 lymph nodes surgery with curative intent is the treatment of choice. Unfortunately, a significant number of patients are found to have an N2 disease at the time of resection. The current consensus is to perform surgery as planned followed by adjuvant chemotherapy. For patients with stage IIIA tumors with N2/N3 lymph nodes, there is no agreement on treatment. If the patient has good performance status and no weigh-loss, then concurrent chemo-radiotherapy affords the best outcome. However, concurrent chemo-radiotherapy is not as tolerated and can cause severe esophagitis. Sequential therapy is better tolerated. Survival is 40% to 45% in the first two years, but five-year survival is only 20%.
• T4 tumors are usually treated exclusively with chemoradiation. Surgery may be an option in T4 N0-1 tumors with carinal involvement. The operative mortality of carinal resection is 10% to 15%, and survival is approximately 20%. If a tumor is T4 due to ipsilateral nonprimary lobe nodules with no mediastinal involvement, then surgery alone renders five-year survival of 20%
• Stage IIIB tumors are treated the same way unresectable IIIA cancers are treated, with concurrent chemoradiotherapy. For a select few patients postinduction chemoradiotherapy, surgery might be an option. The trials on the survival of patients with IIIB tumors also included inoperable IIIA tumors; therefore, the survival in IIIB patients is not known.

Stage IV

• Stage IV disease is considered incurable, and therapy is aimed at improving survival and alleviating symptoms. Only 10% to 30% of patients respond to chemotherapy, and only 1% to 3% survive 5 years after diagnosis. Single or double drug-based chemotherapy is offered to patients with functional performance status. There is a small survival benefit from chemotherapy.
• In highly select patients, non-squamous NSCLC without brain metastasis or hemoptysis might benefit from the addition of bevacizumab, a vascular endothelial growth factor (VEGF) inhibitor[rx].

Targeted therapy for NSCLC

In the early 2000s, researchers discovered that specific mutations encode for proteins that are critical for cell growth and replication. These mutations were named “driver mutations.” It was proposed that blocking these mutation’s pathways may improve survival in lung cancer patients. The current practice is to check for the following mutations in every advanced NSCLC. Each of these mutations has a specific inhibitor available:

• EGFR (epidermal growth factor receptor) is a mutation inhibited by tyrosine kinase inhibitors Erlotinib, gefitinib, and afatinib[rx].
• ALK (Anaplastic lymphoma kinase) includes the specific inhibitors crizotinib, ceritinib, and alectinib. A structurally similar mutation is ROS-1. The FDA recently approved crizotinib for treating cancers expressing ROS-1 mutation.

Immunotherapy for NSCLC

• Immunotherapy, in a simple version, boost the immune system and helps the immune system recognize cancer cells as foreign and increase its responsiveness. There are several check-points to decrease autoimmunity and autodestruction of the body’s cells by the immune system. Malignant cells co-opt these check-points and create tolerance in the immune system. Of these check-points, programmed-death receptor 1 (PD-1) is of particular interest recently. PD-1 plays an important role in down-regulating T-cells and promotes self-tolerance. However, it also renders the immune system less effective against tumor cells. PD-1 interacts with two proteins: PD-L1 and PD-L2. This binding results in the inactivation of activated T-cells.

At the moment, there are antibodies approved for PD-1 and its ligand, PD-L1 only. They inhibit the PD-1 receptor directly or bind to PD-L1 thus preventing it from inactivating the activated T-cell.

Nivolumab

• It is an IgG4 monoclonal antibody against PD-1. It is approved by the FDA for squamous and non-squamous NSCLC that has progressed after platinum-based chemotherapy. It can be used in patients with high or low PD-L1 expression status.

Pembrolizumab

• It is also an IgG4 monoclonal antibody against PD-1. It is approved for pre-treated metastatic NSCLC with greater than 50% expression of PD-L1 and does not harbor EGFR and ALK mutations. It is also used in combination with pemetrexed and carboplatin for metastatic non-squamous NSCLC with less than 50% expression of PD-L1.

Atezolizumab

• It is an IgG1 antibody against PD-L1. It is approved for use in metastatic, progressive NSCLC during or following treatment with platinum-based chemotherapy. It can be used in patients who express EGFR and ALK mutations and fail targeted therapy.

Bevacizumab

• It is not considered immune therapy. It is an anti-angiogenesis antibody that inhibits vascular endothelial growth factor A (VEGF-A). It is primarily used in combination with platinum-based chemotherapy for the treatment of non-squamous NSCLC. It is contraindicated in squamous cell NSCLC due to the risk of severe and often fatal hemoptysis. It is also used to treat breast, renal, colon, and brain cancers[rx][rx].

Small Cell Lung Cancer Treatment

• SCLC is very sensitive to chemotherapy, but unfortunately, has a very high recurrence rate. Treatment for SCLC is according to the stage of the disease.

Treatment of limited-stage small-cell lung cancer

• Stage I limited-stage small cell lung cancer (LS-SCLC) is lobectomy followed by adjuvant chemotherapy. These include SCLC presenting as peripheral nodules without mediastinal or hilar lymphadenopathy. Care should be taken in completely ruling out lymph node involvement, and this is done by PET-CT followed by lymph node sampling by EBUS bronchoscopy or mediastinoscopy even if PET-CT was negative for lymph node size or FDG uptake.
• LS-SCLC with mediastinal or hilar lymph node involvement is 4 to 6 cycles of chemotherapy followed by radiation therapy. Radiation therapy is indicated to avoid recurrence since nearly 80% of SCLC will recur locally without radiation therapy. There are multiple approaches to treatment, including concurrent and alternate chemoradiotherapy or sequential treatments. Concurrent and alternative paths have slightly better outcomes, although they are more toxic than other approaches. Sequential therapy is much better tolerated.

In patients who achieve remission, prophylactic whole brain radiation is also done. This significantly reduces symptomatic brain metastasis and increases overall survival.

Treatment of extensive-stage small-cell lung cancer (ES-SCLC)

• Extensive stage small cell lung cancer (ES-SCLC) includes distant metastasis, malignant pleural or pericardial effusions, contralateral hilar, or supraclavicular lymph node involvement.
• Treatment is with platinum-based chemotherapy. Up to 50% to 60% of patients show remission and should be offered radiation therapy followed by prophylactic whole-brain irradiation. Median survival from the time of diagnosis of ES-SCLC is only 8 to 13 months, and only about 5% of patients survive two years postdiagnosis.

Staging

Lung Cancer Staging

• After the diagnosis of lung cancer, the most crucial step is to stage the disease because the state dictates treatment options, morbidity, and survival. It is of paramount importance that this is done with utmost vigilance. Staging is primarily done for NSCLC using the TNM classification. SCLC also can be staged in the same way, but a much more straightforward approach is used for limited disease and extensive disease.

Tumor, node, metastasis staging of non-small cell lung cancer

• Tumor (T), node (N), and metastasis (M) is an internationally accepted way of staging NSCLC. It is comprehensive in defining tumor size and extent, location, and distant spread which helps clinicians draw meaningful conclusions regarding the best treatment, avoid unnecessary surgeries and provide a timely referral to palliative care if the cure is not an option. [rx].

Tumor

A primary tumor is divided into 5 categories, and each category is then further subdivided depending on the size, location and invasion of surrounding structures by the tumor.

T0

• No primary tumor
• T Carcinoma in situ

T1 (less than 3 cm)

• T1mi: minimally invasive tumor
• T1a: superficial tumor confined to central airways (tracheal or bronchial wall)
• T1a: Less than 1 cm
• T1b: Greater than 1 cm but less than 2cm
• T1C: Greater than 2 cm but less than 3cm

T2

• T2: Greater than 3 cm but less than 5 cm
• T2a: Greater than 3 cm but less than 4cm
• T2b: Greater than 4 cm but less than 5cm
• Also considered a T2 tumor if involving main bronchus but not carina, visceral pleura or causes atelectasis to the hilum

T3

• T3: Greater than 5 cm but less than 7 cm)
• T3 Inv: invasion of the chest wall, pericardium or phrenic nerve
• T3 Satell: separate tumor nodules in the same lobe
• Also considered T3 tumor if involving the pericardium, phrenic nerve, chest wall or separate tumor nodules in the same lobe

T4

• T4: Greater than 7 cm)
• T4inv: Invading above structures
• T4Ipsi nod: Nodules in an ipsilateral lobe

Also considered T4 tumor if involving heart, esophagus, trachea, carina, mediastinum, great vessels, recurrent laryngeal nerve, spine, or tumor nodules in the different ipsilateral lobe. The invasion of Diaphragm is now considered a T4 tumor as compared to a T3 tumor in the seventh edition of TNM classification25[rx].

Thoracic Lymph Nodes

• Lung cancer staging also depends upon the extension of cancer to the lymph nodes corresponding to the primary tumor as well as the opposite hemithorax. It is extremely important to rule out lymph node metastasis before attempting curative surgery. Lung resection in itself carries high morbidity and mortality, therefore, should not be attempted if a cure is not possible.

Historically, thoracic lymph nodes were first classified in the 1960s by Naruke. This map was accepted by North America, Europe, and Japan. Later, in the 1980s and early 90s, further refinements were made in response to better imaging and invasive testing improvements. Hence, two lymph node maps gained popularity in North America.

• American thoracic society (ATS-Map)
• American Joint Committee on Cancer (AJCC). This was an adaptation of the Naruke map.

In 1996, the differences in the above 2 were resolved in the form of Mountain-Dressler modification, MD-ATS Map. It was accepted in North America but only sporadically in Europe.

The International Association of Study of Lung Cancer (IASLC) attempted to resolve the differences between the MD-ATS map and the Naruke map. The IASLC lymph node map is now the most widely accepted lymph node classification system utilized all over the world.

Thoracic lymph nodes can be divided into mediastinal or N2 and hilar or N1 lymph nodes. N2 nodes are more important because they differentiate in cancer stages and, therefore, treatment options.

Much care has been taking in defining the N2 nodes in all the lymph node maps. We will attempt to explain the classification under the broad headings of Mediastinal and Hilar groups and then further explain the individual mediastinal stations as per IASLC map.

Mediastinal Lymph Nodes

They are subdivided into the following groups or stations[rx]:

• Supraclavicular nodes, station 1
• Superior mediastinal nodes, station 2 to 4
• Aortic nodes, station 3
• Inferior mediastinal lymph nodes, station 4

Supraclavicular Nodes (Station 1)

• It includes lower cervical, supraclavicular and sternal notch nodes. Lymph nodes are further divided into 1R and 1L corresponding to right and left the side of the body respectively. The distinction between 1R and 1L is an imaginary midline of trachea serves as the boundary. Below station 1, the left tracheal border is considered the boundary is differentiating between right and left-sided lymph nodes.

Superior Mediastinal Lymph Nodes (Station 2 to 4)

• These lymph nodes occupy the superior mediastinum, hence, named accordingly. They are further subdivided into the following groups:

Upperparatracheall (station 2R and 2L)

• 2R nodes extend to the left lateral border of the trachea.

From the upper border of manubrium to the intersection of the caudal margin of the innominate (left brachiocephalic) vein with the trachea.

• 2L nodes extend from the upper border of manubrium to the superior border of the aortic arch. 2L nodes are located to the left of the left lateral border of the trachea

Pre-vascular (station 3A)

• These nodes are not adjacent to the trachea like the nodes in station 2, but they are anterior to the vessels

Pre-vertebral (station 3P)

Nodes not adjacent to the trachea like the nodes in station 2, but behind the esophagus, which is pre-vertebral

Lower para-tracheal (station 4R and 4L)

• 4R nodes extend from the intersection of the caudal margin of the innominate (left brachiocephalic) vein with the trachea to the lower border of the azygos vein. 4R nodes extend from the right to the left lateral border of the trachea.
• 4L nodes extend from the upper margin of the aortic arch to the upper rim of the left main pulmonary artery

Aortic Lymph Nodes (5 and 6)

This group includes:

• Sub-aortic nodes (station 5)
• These nodes are located lateral to the aorta and pulmonary trunk in the so-called AP window

Para-aortic node (station 6)

• These are ascending aorta or phrenic nodes lying anterior and lateral to the ascending aorta and the aortic arch

Inferior Mediastinal Lymph Nodes (Station 7 to 9)

• This group includes sub-carinal and para-esophageal nodes:

Sub-carinal nodes (station 7)

• They extend in a triangular fashion from the division of carina superiorly to the lower border of the bronchus intermedius on the right and the upper border of the lower lobe bronchus on the left.

Para-esophageal nodes (station 8)

•  These nodes are situated adjacent to the right and left the side of the esophageal wall. Both, stations 7 and eight are located below the carina.
• Pulmonary Ligament (station 9) – They are located within the pulmonary ligaments extending from an inferior pulmonary vein up to the diaphragm.

Hilar Lymph Nodes (Station 10 to 14)

• These are all N1 nodes. These include nodes adjacent to the main stem bronchus and hilar vessels. On the right, they extend from the lower rim of the azygos vein to the interlobar region. On the left from the upper rim of the pulmonary artery to the inter-lobar region.

Lymph Node Classification (N)

N0: No lymph node involvement

N1: Involvement of ipsilateral hilar nodes

• N1a: single station N1 nodes
• N1b: multiple-station N1 nodes

N2: Involvement of mediastinal nodes

• N2a1: Single station N2 nodes without N1 involvement (skip metastasis)
• N2a2: Single station N2 nodes with N1 involvement
• N2b: Multiple station N2 involvement

N3: Involvement of contralateral mediastinal or hilar lymph nodes[rx]

Metastasis (M)

• M0: No distant metastasis
• M1a: Malignant pleural / pericardial effusion or nodules
• M1b: Single extra-thoracic metastasis
• M2: Multiple extra-thoracic metastases

Tumor Node Metastasis Staging of Lung Cancer

Occult cancer: TX N0 M0

Primary cancer not found. No lymph node or distant metastasis.

Stage 0

• T is N 0 M 0

Stage I

IA1

• T1mi N 0 M 0
• T1a  N 0 M 0

IA2

• T1b N 0 M 0

IA3

• T1c N 0 M 0

IB

• T2a N 0 M 0

Stage II

IIA

• T2b N 0 M 0

IIB

• T1a / T1b / T1c N 1 M 0
• T2a / T2b N 1 M 0
• T3 N 0 M 0

Stage III

IIIA

• T1a / T2b / T2c N 2 M 0
• T2a / T2b N2 M 0
• T3 N 1 M 0
• T4 N 0 / N 1 M0

IIIB

• T1a / T1b / T1c N 3 M 0
• T2a / T2b N 3 M0
• T3 N 2 M 0
• T4 N 2 M 0

IIIC

• T3 N 3 M 0
• T4 N 3 M 0

Stage IV

IVA

• Any T / Any N M1a or M1b

IV B

• Any T / Any N M1c

Staging for all Small Cell Lung Cancer

• SCLC staging can be done using the TNM system, but since SCLC is considered a systemic disease, a much more straightforward classification has been used successfully since the 1950s. There is a growing body of evidence that the TNM rating may be better in defining SCLC, but there is consensus on this approach yet.
• SCLC is classified as LS-SCLC and ES-SCLC small cell based on the Veterans Affairs Lung study group (VALSG) classification.
• LS-SCLC is confined to the ipsilateral hemithorax, and local lymph nodes, both mediastinal and hilar and supraclavicular nodes can be included in a single tolerable radiotherapy port (corresponding to TNM stages I through IIIB).
• ES-SCLC has tumors beyond the boundaries of limited disease including distant metastases, malignant pericardial, or pleural effusions, and contralateral supraclavicular and contralateral hilar involvement.[rx]

References

Physical Examination

• The presentation of myocardial infarction is variable. The patient may present fairly well-appearing or might be obviously in extremis. In every patient with chest pain, it is important to perform a focused physical exam.

 Obtain vital signs, including blood pressures in both arms.

For any patient presenting with chest pain concerning ACS, cardiac workup should be initiated, including history and exam as above, electrocardiogram (EKG), and cardiac biomarkers.

EKG

In a typical 12-lead EKG, posterior infarction is an indirect observation due to the placement of the leads. Limb leads placement is on each of the four extremities.

Precordial leads are placed on the anterior chest

• V1 – 4th intercostal space on the right margin of the sternum
• V2 – 4th intercostal space on the left margin of the sternum
• V4 – 5th intercostal space at the midclavicular line
• V3  – midway between V2 and V4
• V5 – 5th intercostal space on the anterior axillary line at the level of V4
• V6 – 5th intercostal space on the midaxillary line at the level of V4

Areas of infarction

• Inferior – II, III, aVF (RCA or LCx)
• Lateral – I, aVL, V5, V6 (LCx or diagonal branch of LAD)
• Septal – V1, V2 (LAD)
• Anterior – V2, V3, V4 (LAD)

ST-elevation is visible if there is inferior, lateral, or inferolateral involvement associated with a posterior extension. However, ST-elevation will not show on the typical EKG in isolated posterior MI, and other EKG changes may be observable. However, for further clarification, posterior leads (V7-V9) may be placed to evaluate further. [rx][rx][rx]

Posterior leads V7-V9 get placed on the posterior chest wall in the same horizontal plane as V6

• V7 – left posterior axillary line
• V8- the tip of the left scapula
• V9 – left paraspinal region

ST-elevation may be more subtle, and ST-elevation greater than 0.5 mm in one lead indicates posterior ischemia and is diagnostic for posterior ST-elevation MI (STEMI). When possible, compare to old EKGs.

Other changes that may present in posterior STEMI include

• ST-depression in the anterior leads, which may be deep (over 2 mm) and flat

• Large R-wave in V2-V3, which are larger than the S-wave

  • R-waves in V2-V3 that are greater than those in V4-V6 is an abnormal R-wave progression
• Large and upright anterior T waves
• Signs of ischemia in inferior and/or lateral territories, including possible ST elevation

• Mirror image effect of EKG regarding posterior wall ischemia

  • If turned upside down, tall anterior R-waves become deep posterior Q-waves, ST-depression becomes ST-elevation, and upright T-waves become inverted T-waves
  • If these changes are not present, it does not rule out posterior STEMI[rx][rx]

If there is an obvious posterior STEMI, and there is low suspicion of other pathology, the goal is to get the patient the lab for percutaneous intervention (PCI). There is no need to wait for lab results. IV access should be obtained, and labs sent. If there are more subtle EKG changes, but not definitive STEMI, consider serial EKGs. Sometimes on repeat EKGs, subtle ischemia evolves into STEMI.

ECG

The resting 12 lead ECG is the first-line diagnostic tool for the diagnosis of the acute coronary syndrome (ACS). It should be obtained within 10 minutes of the patient’s arrival in the emergency department.[rx] Acute MI is often associated with dynamic changes in the ECG waveform. Serial ECG monitoring can provide important clues to the diagnosis if the initial EKG is non-diagnostic at the initial presentation.[rx] Serial or continuous ECG recordings may help determine reperfusion or re-occlusion status. A large and prompt reduction in ST-segment elevation is usually seen in reperfusion.[rx]

ECG findings suggestive of ongoing coronary artery occlusion (in the absence of left ventricular hypertrophy and bundle branch block):[rx]

ST-segment elevation in two contiguous lead (measured at J-point) of

• Greater than 5 mm in men younger than 40 years, greater than 2 mm in men older than 40 years, or greater than 1.5 mm in women in leads V2-V3 and/or
• Greater than 1 mm in all other leads

ST-segment depression and T-wave changes

• New horizontal or down-sloping ST-segment depression greater than 5 mm in 2 contiguous leads and/or T inversion greater than 1 mm in two contiguous leads with prominent R waves or R/S ratio of greater than 1

The hyperacute T-wave amplitude, with prominent symmetrical T waves in two contiguous leads, maybe an early sign of acute MI that may precede the ST-segment elevation. Other ECG findings associated with myocardial ischemia include cardiac arrhythmias, intraventricular blocks, atrioventricular conduction delays, and loss of precordial R-wave amplitude (less specific finding).[14]

ECG findings alone are not sufficient to diagnose acute myocardial ischemia or acute MI as other conditions such as acute pericarditis, left ventricular hypertrophy (LVH), left bundle branch block (LBBB), Brugada syndrome, Takatsubo syndrome (TTS), and early repolarization patterns also present with ST deviation.

ECG changes associated with prior MI (in the absence of left ventricular hypertrophy and left bundle branch block)

• Any Q wave in lead V2-V3 greater than 0.02 s or QS complex in leads V2-V3
• Q wave > 03 s and greater than 1 mm deep or QS complex in leads I, II, aVL, aVF or V4-V6 in any two leads of contiguous lead grouping (I, aVL; V1-V6; II, III, aVF)
• R wave > 0.04 s in V1-V2 and R/S greater than 1 with a concordant positive T wave in the absence of conduction defect

Lab Studies

• CBC
• Metabolic profile
• Troponin
• Coagulation studies
• Consider  B-type natriuretic peptide (BNP) / NT pro-BNP

Imaging Studies

• Obtain bedside chest x-ray  – (CXR) or two-view CXR
• Consider bedside echocardiography – this is an operator-dependent skill but can be of significant value. Bedside echocardiography can evaluate for pericardial effusion, gross wall motion abnormalities, size of the ventricles, valvular abnormalities, and ejection fraction estimation. A suprasternal notch view is useful to visualize the aorta and evaluate for possible dissection. The proximal aorta is usually dilated with or without a visible intimal flap.
• Echocardiogram – Sound waves (ultrasound) create images of the moving heart. Your doctor can use this test to see how your heart’s chambers and valves are pumping blood through your heart. An echocardiogram can help identify whether an area of your heart has been damaged.
• Coronary catheterization (angiogram) – A liquid dye is injected into the arteries of your heart through a long, thin tube (catheter) that’s fed through an artery, usually in your leg or groin, to the arteries in your heart. The dye makes the arteries visible on X-ray, revealing areas of blockage.
• Cardiac CT or MRI – These tests create images of your heart and chest. Cardiac CT scans use X-rays. Cardiac MRI uses a magnetic field and radio waves to create images of your heart. For both tests, you lie on a table that slides inside a long tubelike machine. Each can be used to diagnose heart problems, including the extent of damage from heart attacks.
• Biomarker Detection of MI – Cardiac troponins (I and T) are components of the contractile apparatus of myocardial cells and expressed almost exclusively in the heart. Elevated serum levels of cardiac troponin are not specific to the underlying model of injury (ischemic vs. tension)[rx] [rx]. The rising and/or falling pattern of cardiac troponins (cTn) values with at least one value above the 99 percentile of upper reference limit (URL) associated with symptoms of myocardial ischemia would indicate an acute MI. Serial testing of cTn values at 0 hours, 3 hours, and 6 hours would give a better perspective on the severity and time course of the myocardial injury. Depending on the baseline cTn value, the rising/falling pattern is interpreted. If the cTn baseline value is markedly elevated, a minimum change of greater than 20% in follow up testing is significant for myocardial ischemia. Creatine kinase MB isoform can also be used in the diagnosis of MI, but it is less sensitive and specific than cTn level.[rx][rx]

Myocardial infarctions are generally clinically classified into ST-elevation MI (STEMI) and non-ST elevation MI (NSTEMI). These are based on changes to an ECG.^[rx] STEMIs make up about 25 – 40% of myocardial infarctions.^[rx] A more explicit classification system, based on international consensus in 2012, also exists. This classifies myocardial infarctions into five types:^[rx]

• Spontaneous MI related to plaque erosion and/or rupture fissuring, or dissection
• MI related to ischemia, such as from increased oxygen demand or decreased supply, e.g. coronary artery spasm, coronary embolism, anemia, arrhythmias, high blood pressure or low blood pressure
• Sudden unexpected cardiac death, including cardiac arrest, where symptoms may suggest MI, an ECG may be taken with suggestive changes, or a blood clot is found in a coronary artery by angiography and/or at autopsy, but where blood samples could not be obtained, or at a time before the appearance of cardiac biomarkers in the blood
• Associated with coronary angioplasty or stents
  • Associated with the percutaneous coronary intervention (PCI)
  • Associated with stent thrombosis as documented by angiography or at autopsy
• Associated with CABG
• Associated with spontaneous coronary artery dissection in young, fit women

Treatment of Acute Myocardial Infarction

In summary,

• Early diagnosis – history, EKG, cardiac troponins
• Pain relief – nitroglycerin
• Hemodynamic stability – airway, breathing, circulation
• Reperfusion – PCI vs. fibrinolysis
• Prevention of thrombosis – aspirin plus P2Y12 inhibitor – clopidogrel vs. ticagrelor depending upon the choice of reperfusion
• Preventing life-threatening arrhythmias – beta-blocker therapy
• Improve prognosis and long term mortality – statins, aspirin, clopidogrel, beta-blockers, ACE inhibitors, revascularization, cardiac rehabilitation and aggressive lifestyle/behavioral modification

Reperfusion

• The definitive management of acute posterior STEMI is reperfusion therapy. Optimally this is done via percutaneous coronary intervention (PCI), though the next option would be fibrinolytic therapy. PCI is the preferred option if it can be initiated within 120 minutes, though within 90 minutes is the goal. If PCI is not available within 120 minutes, then fibrinolytic therapy should be given within 30 minutes.

Adjunctive Therapies

LifeStyle

• Smoking cessation – is the most cost-effective secondary measure to prevent MI. Smoking has a pro-thrombotic effect, which has a strong association with atherosclerosis and myocardial infarction.[rx]
• Diet, alcohol, and weight control – A diet low in saturated fat with a focus on whole grain products, vegetables, fruits, and the fish is considered cardioprotective. The target level for bodyweight is body mass index of 20 to 25 kg/m2  and waist circumference of <94 cm for the men and <80 cm for the female.[rx]

Complications

Complications of anteroseptal MI will include the complications of any myocardial infarction including:

• Myocardial dysfunction
• Heart failure
• Mechanical complication: Septal rupture, papillary muscle rupture, free wall rupture
• Septal rupture: Apical septum rupture is a rare complication but can occur with anteroseptal MI involving LAD lesion. Prompt diagnosis is necessary, and the treatment of choice is the definitive surgery.[rx]
• Papillary muscle rupture and free wall rupture are very uncommon with anteroseptal infarction. These complications are more related to multivessel disease.[rx]
• Conduction abnormalities – Conduction disturbances are associated with anteroseptal MI. One study showed that the right bundle branch block was the most common conduction abnormality in anteroseptal MI and it progressed to complete AV block in one-third of the patients.[rx]
• Post-infarction pericarditis

References

Risk factors for coronary artery disease classify into modifiable and non-modifiable risk factors.

A 2019 article indicated that age, sex, and race captured 63 to80% of prognostic performance, while modifiable risk factors contributed only modestly. Yet, control of modifiable risk factors led to substantial reductions in CAD events.[rx] Non-modifiable risk factors are discussed first:

• Age: CAD prevalence increases after 35 years of age in both men and women.  The lifetime risk of developing CAD in men and women after 40 years of age is 49% and 32%, respectively.[rx]
• Gender: Men are at increased risk compared to women.
• Ethnicity: African Americans, Hispanics, Latinos, and Southeast Asians, are ethnic groups with an increased risk of CAD morbidity and mortality.[rx][rx][rx]
• Family history: Family history is also a significant risk factor.  Patients with a family history of premature cardiac disease younger than 50 years of age have an increased CAD mortality risk.[rx] A separate article indicated that a father or brother diagnosed with CAD before 55 years of age, and a mother or sister diagnosed before 65 years of age are considered risk factors.[rx]

Modifiable risk factors have a smaller but still significant role.[rx] Yet, only two-thirds of patients receive optimal medication interventions.[rx] If this were achieved, there would be a substantial reduction in CAD events. One study observed that those with optimal risk factor profiles had a substantially lower rate of death from cardiovascular events.[rx]

Hypertension

In addition to these traditional cardiovascular risk factors, novel risk factors have also been subject to research.  These include:

Non-alcoholic fatty liver disease (NAFLD)

Testosterone

• In 2014, the FDA released a required labeling change for low testosterone products for the use of low testosterone due to aging, due to a possible increased risk of heart attack and stroke.  Subsequent studies and reviews have not been consistent in this correlation.  Some reviews have even indicated a potential beneficial cardiovascular effect when treating low testosterone with testosterone supplementation. Further study is needed to provide more clarity on this specific topic.[rx][rx][rx][rx][rx]

Vitamin D

Socioeconomic status

• Socioeconomic status is a significant risk factor for cardiovascular disease. Upstream determinants include financial strain, lack of affordable and nutritious food, exposure to domestic violence, and inadequate housing; this is an important consideration to consider given existing cardiovascular disease risk equations do not capture this.[rx]

Women and coronary artery disease (CAD)

• Although men are at higher risk than women of coronary artery disease, it is still the leading cause of death among women.  Among women, only 54% were aware of this in 2009. Cardiovascular disease caused approximately 1 in 3 female deaths.[rx] Women were found to have non-obstructive CAD in 57% of cases, in contrast to men who more commonly had obstructive CAD. Proposed mechanisms for this include coronary microvascular dysfunction (CMD), altered endothelial tone, structural changes, and altered response to vasodilator stimuli.[rx] Estrogen is thought to have a protective role in coronary vasoreactivity and is also theorized to promote plaque stabilization via an anti-inflammatory effect on atherosclerosis.[rx]
• Lack of awareness and understanding of coronary artery disease in women has also led to a disparity in health outcomes. There has been more focus on obstructive CAD and men compared to women.[rx][rx] One 2012 article reported a decrease in CAD mortality across all age groups in men and an increase in CAD mortality among young women (< 55 years old).[rx]

Symptoms of Coronary Artery Disease

Clinical Significance of Coronary Artery Disease (CAD)

Hypertension

• The United States Preventive Services Task Force (USPSTF) gives a grade A recommendation for universal screening for hypertension in patients greater than 18 years of age and a grade I (current evidence insufficient) recommendation for screening for children and adolescents.[rx][rx]
• A systolic and diastolic blood pressure reduction of greater than 10mmHg and 5mmHg, respectively, led to a significant absolute risk reduction in CAD-related events (NNT 91).[rx]
• A systolic blood pressure reduction to a goal of 130mmHg reduced the incidence of CAD (NNT 27).[rx]
• A 2002 meta-analysis revealed that systolic blood pressure reduction of 20mmHg and diastolic blood pressure reduction of 10mmHg decreases the risk of death from coronary heart disease by about 50% between ages 40 to 49 and by about 1/3 between ages 80 to 89.[rx][rx][rx]

Hyperlipidemia

• The USPSTF recommends evaluation for statin use for the primary prevention of cardiovascular disease between 40 to 75 years of age.[rx] The USPSTF gives a grade I (current evidence insufficient) recommendation for routine screening for lipid disorders in children and adolescents.[rx]
• In 2011, the National Heart, Lung, and Blood Institute (NHLBI) recommended universal screening between 9 to 11 years of age and again at 17 to 21 years of age.  The American Academy of Pediatrics subsequently endorsed this.  Despite the publication of these guidelines, pediatric lipid screening practice patterns have not followed suit.[rx]
• An early 1994 review showed that a 10% reduction in serum cholesterol leads to a 50%, 40%, 30%, and 20% drop in CAD risk at age 20, 50, 60, and 70, respectively.[rx]
• The Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) study demonstrated that statins reduce the risk of major cardiovascular events.[rx] Treatment with a moderate-intensity statin resulted in a CAD absolute risk reduction of 2.7% (NNT 37). Treatment with a high-intensity statin resulted in a 4.1% absolute risk reduction (NNT 24).[rx]

Diabetes

• The USPSTF recommends screening for abnormal glucose in patients aged 40 to 70 years old who are overweight or obese.  Early screening for diabetes can also be a consideration for patients in higher-risk groups. This risk pool includes patients with a family history of diabetes, history of gestational diabetes or polycystic ovarian syndrome, or members of specified racial/ethnic groups (African Americans, American Indians, Alaskan Natives, Asian Americans, Hispanics or Latinos, Native Hawaiians or Pacific Islanders).[rx]
• The American Diabetes Association states that three years is a reasonable screening interval.
• A 2019 meta-analysis of 12 cardiovascular outcomes trials indicated that a 0.5% reduction in A1C conferred a 20% hazard risk reduction (95% CI 4-33%) for major cardiovascular events.  This analysis included patients on peptidase-4 inhibitors, GLP-1 agonists, and SGLT-2 inhibitors.[rx]

Diet

• The DASH, Mediterranean, and vegetarian diets have the most evidence for cardiovascular disease prevention.[rx]
• The DASH diet can reduce systolic blood pressure up to 11.5 mmHg in adults with hypertension.[rx][rx] A 2013 meta-analysis and systematic review revealed a 21% coronary artery disease risk reduction (RR 0.79, 95% CI 0.71-0.88) with the DASH diet.[rx]
• A 2017 meta-analysis and systematic review revealed an 8% risk reduction (15 studies, RR 0.92, 95% CI 0.90-0.95) of coronary artery disease for every 200 grams per day of fruits and vegetables. This effect was observable at up to 800 grams per day.[rx]
• A 2016 meta-analysis and systematic review revealed a 29% risk reduction (29 studies, RR 0.71, 95% CI 0.63-0.80) of coronary artery disease for every 28 grams per day of nut consumption.[rx]
• A 2017 narrative review revealed a decreased risk of about 20 to 25% with the Mediterranean diet on cardiovascular disease. It was also showed positive effects on endothelin function, arterial stiffness, and cardiac function.[rx]
• The American Heart Association recommends the replacement of saturated fat with polyunsaturated and monounsaturated fats.[rx] A 5% exchange in saturated fat consumption with polyunsaturated fat is associated with a 10% lower CAD risk (RR 0.90, 95% CI 0.83-0.97).[rx][rx] As noted above, a 2018 review, however, challenged the strength of the traditional link between saturated fat and higher CAD risk, compared to other nutrients.[rx] In a separate review, the lack of a significant association between saturated fat and cardiovascular disease was due to studies replacing saturated fat with highly refined carbohydrates.  If saturated fats were replaced by polyunsaturated fat, then coronary heart disease is indeed reduced.[rx]
• While it is challenging to carry out research relating to diet practices and coronary artery disease, much research has taken place in the past.[rx] The AHA/ACC guidelines recommend a diet consisting mostly of vegetables, fruits, legumes, nuts, whole grains, and fish. Dietary intake of processed meats, refined carbohydrates, and sweetened beverages should be reduced, while avoiding trans fats altogether. Saturated fats should be replaced with polyunsaturated and monounsaturated fats.[rx]
• The USPSTF recommends offering or referring adults who are obese/overweight and have one additional cardiovascular risk factor intensive behavioral counseling to promote a healthful diet and physical activity (Grade B).  The USPSTF also recommends individualizing the decision to offer or refer patients without obesity or other cardiovascular risk factors for behavioral counseling.

Smoking

• The USPSTF recommends screening for tobacco use in all adults with each clinical encounter and to provide behavioral and pharmacologic smoking cessation interventions.[rx] The USPSTF also recommends educating children and adolescents about the risks of smoking to prevent the initiation of tobacco use.
• The American Heart Association recommends a combined behavioral and pharmacologic approach to maximize quit rates.[rx]
• The risk of coronary artery disease drops to a level of lifetime nonsmokers within four years of quitting, according to the FDA, and within ten years, according to the CDC.[rx][rx]
• Behavioral interventions include motivational interviewing (Ask, Advise, Assess, Assist, Arrange for follow-up).
• Pharmacologic interventions such as nicotine replacement therapy, varenicline (Chantix), and bupropion (Wellbutrin) reduce cravings and withdrawal symptoms.
• A 2014 Cochrane review revealed that nicotine replacement therapies, such as nicotine gum and the nicotine patch increased the chances of smoking cessation by 49% (55 trials, RR 1.49, 95% CI 1.40-1.60) and 64% (43 trials, RR 1.64, 95% CI 1.52-1.78), respectively. The nicotine oral tablets/lozenges (6 trials, RR 1.95, 95% CI 1.61-2.36), inhaler (4 trials, RR 1.90, 95% CI 1.36-2.67), and nasal sprays (4 trials, RR 2.02, 95% CI 1.49-2.73) approximately doubled the chances of success.  The combination of bupropion and nicotine replacement therapy increased the likelihood of success by 24% compared to bupropion alone (4 trials, RR 1.24, 95% CI 1.06-1.45).[rx]
• Varenicline doubled the chances of smoking cessation.[rx] There have been rare reports of neuropsychiatric adverse effects with varenicline.  The FDA removed this black box warning in 2016 after noting that the risk was lower than expected.
• A 2014 Cochrane review showed that bupropion increases the chances of smoking cessation by 62% (44 trials, N=13,728, RR 1.62, 95% CI 1.48-2.78).[rx][rx]
• A 2016 Cochrane review indicated that the combined use of behavioral support and pharmacotherapy had a higher chance of success.[rx]

Obesity

• A patient’s body mass index (BMI) should be measured at each clinical encounter. The USPSTF recommends that practitioners offer obese adults a referral to a multicomponent behavioral interventionist.[rx]
• There is a large amount of evidence showing that in obese or overweight patients, even just a modest 5% body weight loss can lead to clinically significant health benefits.[rx]

Exercise

• The USPSTF recommends patients who are overweight, obese, or have CAD risk factors to intensive behavioral counseling for interventions to promote physical activity for the prevention of CAD.[rx][rx][rx]
• According to the National Health Interview Survey, only 20.9% of adults met the 2008 federal physical activity guidelines for aerobic and strengthening activity.[rx]
• Approximately 150 minutes per week of moderate-intensity aerobic activity reduces the risk of cardiovascular disease.[rx] Moderate-intensity aerobic exercise is defined as 50 to 70 percent of the patient’s maximum heart rate (220 beats per minute minus the patient’s age).  Any amount of physical activity has shown to have benefits in reducing CAD risk.[rx][rx] The most active patients have an approximately 35 to 40 percent risk reduction for coronary artery disease.
• The AHA/ACC guidelines also recommend resistance strength training to be incorporated into regular physical activity, as this can help improve physical function and ability to exercise.[rx][rx]

Aspirin in primary prevention

• Aspirin has long played a role in atherosclerotic cardiovascular disease prevention.  Although still established for secondary prevention, its use in primary prevention has more recently come into question due to a less favorable risk-benefit ratio [rx].  Recent evidence suggested a more tailored approach to the use of aspirin [rx].
• The USPSTF recommends aspirin for patients age 50 to 59 years of age, with a 10-year atherosclerotic cardiovascular disease risk, and do not have bleeding risk factors. Aspirin may be considered for those 60 to 69 years of age but may have less overall benefit and higher bleeding risk.[rx]

References

Chronic Kidney Disease (CKD)/Chronic kidney disease (CKD) is defined as the presence of kidney damage or an estimated glomerular filtration rate (eGFR) less than 60 ml/min/1.73 mt2, persisting for 3 months or more, irrespective of the cause.[rx] It is a state of progressive loss of kidney function ultimately resulting in the need for renal replacement therapy (dialysis or transplantation). Kidney damage refers to pathologic abnormalities either suggested by imaging studies or renal biopsy, abnormalities in urinary sediment, or increased urinary albumin excretion rates. The 2012 KDIGO CKD classification recommends details about the cause of the CKD and classifies into 6 categories based on glomerular filtration rate (G1 to G5 with G3 split into 3a and 3b). It also includes the staging based on three levels of albuminuria (A1, A2, and A3), with each stage of CKD being sub-categorized according to the urinary albumin-creatinine ratio in (mg/gm) or (mg/mmol) in an early morning “spot” urine sample.[rx]

The 6 categories include:

• G1: GFR 90 ml/min per 1.73 m2 and above
• G2: GFR 60 to 89 ml/min per 1.73 m2
• G3a: GFR 45 to 59 ml/min per 1.73 m2
• G3b: GFR 30 to 44 ml/min per 1.73 m2
• G4: GFR 15 to 29 ml/min per 1.73 m2
• G5: GFR less than 15 ml/min per 1.73 m2 or treatment by dialysis

The three levels of albuminuria include an albumin-creatinine ratio (ACR)

• A1: ACR less than 30 mg/gm (less than 3.4 mg/mmol)
• A2: ACR 30 to 299 mg/gm (3.4 to 34 mg/mmol)
• A3: ACR greater than 300 mg/gm (greater than 34 mg/mmol).

The improved classification of CKD has been beneficial in identifying prognostic indications related to decreased kidney function and increased albuminuria. However, a downside of the use of classification systems is the possible overdiagnosis of CKD, especially in the elderly.

Causes of Chronic Kidney Disease (CKD)

The causes of CKD vary globally, and the most common primary diseases causing CKD and ultimately end-stage renal disease (ESRD) are as follows[rx]:

• Diabetes mellitus type 2 (30% to 50%)
• Diabetes mellitus type 1 (3.9%)
• Hypertension (27.2%)
• Primary glomerulonephritis (8.2%)
• Chronic Tubulointerstitial nephritis (3.6%)
• Hereditary or cystic diseases (3.1%)
• Secondary glomerulonephritis or vasculitis (2.1%)
• Plasma cell dyscrasias or neoplasm (2.1)
• Sickle Cell Nephropathy (SCN) which accounts for less than 1% of ESRD patients in the United States[rx]

CKD may result from disease processes in any of the three categories: prerenal (decreased renal perfusion pressure), intrinsic renal (pathology of the vessels, glomeruli, or tubules-interstitium), or postrenal (obstructive).

Prerenal Disease

• Chronic prerenal disease occurs in patients with chronic heart failure or cirrhosis with persistently decreased renal perfusion, which increases the propensity for multiple episodes of an intrinsic kidney injury, such as acute tubular necrosis (ATN). This leads to progressive loss of renal function over time.

Intrinsic Renal Vascular Disease

• The most common chronic renal vascular disease is nephrosclerosis, which causes chronic damage to blood vessels, glomeruli, and tubulointerstitium.
• The other renal vascular diseases are renal artery stenosis from atherosclerosis or fibro-muscular dysplasia which over months or years, cause ischemic nephropathy, characterized by glomerulosclerosis and tubulointerstitial fibrosis.[5]

Intrinsic Glomerular Disease (Nephritic or Nephrotic)

• A nephritic pattern is suggested by abnormal urine microscopy with red blood cell (RBC) casts and dysmorphic red cells, occasionally white blood cells (WBCs), and a variable degree of proteinuria.[6] The most common causes are post-streptococcal GN, infective endocarditis, shunt nephritis, IgA nephropathy, lupus nephritis, Goodpasture syndrome, and vasculitis. [7]
• A nephrotic pattern is associated with proteinuria, usually in the nephrotic range (greater than 3.5 gm per 24 hours), and an inactive urine microscopic analysis with few cells or casts. It is commonly caused by minimal change disease, focal segmental glomerulosclerosis, membranous GN, membranoproliferative GN (Type 1 and 2 and associated with cryoglobulinemia), diabetic nephropathy, and amyloidosis.

Some patients may be assigned to one of these two categories.

Intrinsic Tubular and Interstitial Disease

• The most common chronic tubulointerstitial disease is polycystic kidney disease (PKD). Other etiologies include nephrocalcinosis (most often due to hypercalcemia and hypercalciuria), sarcoidosis, Sjogren syndrome, reflux nephropathy in children and young adults, [rx]
• There is increased recognition of the relatively high prevalence of CKD of unknown cause among agricultural workers from Central America and parts of Southeast Asia called Mesoamerican nephropathy,[rx]

Postrenal (Obstructive Nephropathy)

• Chronic obstruction may be due to prostatic disease, nephrolithiasis or abdominal/pelvic tumor with mass effect on ureter(s) are the common causes. Retroperitoneal fibrosis is a rare cause of chronic ureteral obstruction.

Epidemiology

The true incidence and prevalence of CKD are difficult to determine because of the asymptomatic nature of early to moderate CKD. The prevalence of CKD is around 10% to 14% in the general population. Similarly, albuminuria (microalbuminuria or A2) and GFR less than 60 ml/min/1.73 mt2 have a prevalence of 7% and 3% to 5%, respectively.[rx]

Worldwide, CKD accounted for 2,968,600 (1%) of disability-adjusted life-years and 2,546,700 (1% to 3%) of life-years lost in 2012.[rx]

Kidney Disease Outcomes Quality Initiative (KDOQI) mandates that for labeling of chronicity and CKD, patients should be tested on three occasions over a 3-month period with 2 of the 3 results being consistently positive.[rx]

Natural History and Progression of CKD

CKD diagnosed in the general population (community CKD) has a significantly different natural history and the course of progression compared to the CKD in patients referred to the nephrology practices (referred CKD).

Community CKD is seen mainly in the older population. These individuals have had a lifelong exposure to cardiovascular risk factors, hypertension, and diabetes which can also affect the kidneys. The average rate of decline in GFR in this population is around 0.75 to 1 ml/min/year after the age of 40 to 50 years. [rx] In a large study of community based CKD by Kshirsagar et al., only 1% and 20% of patients with CKD stages G3 and G4 required renal replacement therapy (RRT), however, 24% and 45% respectively died predominantly from cardiovascular disease (CVD), suggesting that cardiac events rather than progressing to ESRD is the predominant outcome in community-based CKD.[rx]

In contrast to community CKD, patients with referred CKD present at an early age because of hereditary (autosomal dominant polycystic kidney disease ADPKD) or acquired nephropathy (glomerulonephritis, diabetic nephropathy, or tubulointerstitial disease) causing progressive renal damage and loss of function. The rate of progression in referred CKD varies according to the underlying disease process and between individual patients. Diabetic nephropathy has shown to have a rapid rate of decline in GFR averaging around 10 ml/min/year. In nondiabetic nephropathies, the rate of progression is usually faster in patients with chronic proteinuric GN than those with a low level of proteinuria. Patients with ADPKD and renal impairment, CKD stage G3b and beyond, may have a faster rate of progression compared to other nephropathies. In patients with hypertensive nephrosclerosis, good blood pressure control and minimal proteinuria are associated with very slow progression.

Risk Factors for Progression of CKD

Non-Modifiable CKD Risk Factors

• Older age, male gender, a non-Caucasian ethnicity which includes African Americans, Afro-Caribbean individuals, Hispanics, and Asians (South Asians and Pacific Asians) all adversely affect CKD progression.
• Genetic factors that affect CKD progression have been found in different Kidney diseases. In a population-based cohort study by Luttropp et al., single nucleotide polymorphisms in the genes TCF7L2 and MTHFS were associated with diabetic nephropathy and CKD progression. In the same study, polymorphisms of genes coding for mediators of renal scarring and renin-angiotensin-aldosterone system (RAAS) were found to influence CKD progression.[rx]

Modifiable CKD Risk Factors

• These include systemic hypertension, proteinuria, and metabolic factors.[rx]
• Systemic hypertension is one of the main causes of ESRD worldwide and the second leading cause in the United States after diabetes. The transmission of systemic hypertension into glomerular capillary beds and the resulting glomerular hypertension is believed to contribute to the progression of glomerulosclerosis.[rx] Night-time and 24-hour blood pressure measurement (ABPM) appear to correlate best with the progression of CKD. Systolic rather than diastolic BP seems to be predictive of CKD progression and has also been associated with complications in CKD.
• Multiple studies in patients with diabetic and nondiabetic kidney diseases have shown that marked proteinuria (albuminuria A3) is associated with a faster rate of CKD progression. Also, a reduction in marked proteinuria by RAS blockade or by diet is associated with a better renal outcome. However, in large intervention studies like Avoiding Cardiovascular Events Through Combination Therapy in Patients Living with Systolic Hypertension (ACCOMPLISH)[rx] and Ongoing Telmisartan Alone and in Combination with Ramipril Global End Point Trial (ONTARGET),[rx] significant declines in GFR were noted despite a marked reduction in albuminuria. Therefore, moderate level albuminuria (A2) is not a reliable surrogate marker for CKD progression and reduction in albuminuria can be associated with both improving and worsening of CKD progression.
• Multiple studies have linked the RAAS system in the pathogenesis of hypertension, proteinuria, and renal fibrosis throughout CKD. Subsequently, interventions targeting RAAS have proved effective in slowing the progression of CKD. This has led to widespread use of RAAS blockers in proteinuric and diabetic kidney disease.
• Obesity and smoking have been related to the development and progression of CKD. Also, metabolic factors such as insulin resistance, dyslipidemia, and hyperuricemia have been implicated in the development and progression of CKD.[rx][rx]

Recommendations for CKD Screening

Screening, mostly targeting high-risk individuals is being implemented worldwide. The KDOQI guidelines recommend screening high-risk populations which include individuals with Hypertension, Diabetes mellitus, and those older than 65 years. This should include urinalysis, a urine albumin-creatinine ratio (ACR), measurement of serum creatinine and estimation of GFR preferably by chronic kidney disease epidemiology collaboration (CKD-EPI) equation. It is the most cost-effective approach, and there is no evidence to justify screening asymptomatic individuals in the general population for CKD.

Pathophysiology

Unlike acute kidney injury (AKI), where the healing process is complete with complete functional kidney recovery, chronic and sustained insults from chronic and progressive nephropathies evolve to progressive kidney fibrosis and destruction of the normal architecture of the kidney. This affects all the 3 compartments of the kidney, namely glomeruli, the tubules, the interstitium, and the vessels. It manifests histologically as glomerulosclerosis, tubulointerstitial fibrosis, and vascular sclerosis.

The sequence of events which lead to scarring and fibrosis are complex, overlapping, and are multistage phenomena.

• Infiltration of damaged kidneys with extrinsic inflammatory cells
• Activation, proliferation, and loss of intrinsic renal cells (through apoptosis, necrosis, mesangiolysis, and podocytopenia)
• Activation and proliferation of extracellular matrix (ECM) producing cells including myofibroblasts and fibroblasts
• Deposition of ECM replacing the normal architecture

Mechanisms of Accelerated Progression of CKD

• Systemic and intraglomerular hypertension
• Glomerular hypertrophy
• Intrarenal precipitation of calcium phosphate
• Altered prostanoid metabolism

All these mechanisms lead to a histological entity called focal segmental glomerulosclerosis.[rx]

Clinical risk factors for accelerated progression of CKD are proteinuria, hypertension, black race, and hyperglycemia. Also, environmental exposures such as lead, smoking, metabolic syndrome, possibly some analgesic agents, and obesity have also been linked to accelerated progression of CKD.[rx]

Symptoms of Chronic Kidney Disease (CKD)

Early CKD stages are asymptomatic, and symptoms manifest in stages 4 or 5. It is commonly detected by routine blood or urine testing. Some common symptoms and signs at these stages of CKD are:

• Nausea
• Vomiting
• Loss of appetite
• Fatigue and weakness
• Sleep disturbance
• Oliguria
• Decreased mental sharpness
• Muscle twitches and cramps
• Swelling of feet and ankles
• Persistent pruritus
• Chest pain due to uremic pericarditis
• Shortness of breath due to pulmonary edema from fluid overload
• Hypertension that’s difficult to control
• Physical examination is often not helpful, but patients may have
• Skin pigmentation
• Scratch marks from pruritus
• Pericardial friction rub due to uremic pericarditis
• Uremic frost, where high levels of BUN result in urea in sweat
• Hypertensive fundal changes suggesting chronicity

Diagnosis of Chronic Kidney Disease (CKD)

Establishing Chronicity

When an eGFR of less than 60 ml/min/1.73m is detected in a patient, attention needs to be paid to the previous blood and urine test results and clinical history to determine whether this is a result of AKI or CKD that has been present but asymptomatic. The following factors would be helpful.

• History of long-standing chronic hypertension, proteinuria, microhematuria, and symptoms of the prostatic disease
• Skin pigmentation, scratch marks, left ventricular hypertrophy, and hypertensive fundal changes
• Blood test results of other conditions like multiple myeloma, systemic vasculitis would be helpful.
• Low serum calcium and high phosphorus levels have little discriminatory value, but normal Parathyroid hormone levels suggest AKI rather than CKD
• Patients who have very high blood urea nitrogen (BUN) values greater than 140 mg/dl, serum creatinine greater than 13.5 mg/dl, who appear relatively well and still passing normal volumes of urine are much more likely to have CKD than acute kidney disease.

Assessment of Glomerular Filtration Rate

• For patients in whom the distinction between AKI and CKD is unclear, kidney function tests should be repeated in 2 weeks of the initial finding of low eGFR below 60 ml/min/1.73 m.
• If previous tests confirm that the low eGFR is chronic or the repeat blood test results over 3 months are consistent, CKD is confirmed.
• If eGFR based on serum creatinine is known to be less accurate, then other markers like cystatin-c or an isotope-clearance measurement can be undertaken.

Assessment of Proteinuria

• KDIGO recommends that proteinuria should be assessed by obtaining an early morning urine sample and quantifying the albumin-creatinine ratio (ACR). The degree of albuminuria is graded from A1 to A3, replacing previous terms such as microalbuminuria.
• Some patients may excrete proteins other than albumin and urine protein-creatinine ratio (PCR) may be more useful for certain conditions.[rx]

Imaging of Kidneys

• If an ultrasound – examination of kidneys shows small kidneys with reduced cortical thickness, increased echogenicity, scarring, or multiple cysts, this suggests a chronic process. It may also be helpful to diagnose chronic hydronephrosis from obstructive uropathy, cystic enlargement of the kidney in ADPKD.
• Renal ultrasound Doppler – can be used in suspected renal artery stenosis to evaluate the renal vascular flow
• Computerized tomography – A low dose of non-contrast CT is used to diagnose renal stone disease. It is also used to diagnose suspected ureteric obstruction which cannot be seen by ultrasonography.
• Renal angiography – has its role in the diagnosis of polyarteritis nodosa where multiple aneurysms and irregular areas of constriction are seen.
• Voiding cystourethrography – is mainly used when chronic vesicourethral reflux is suspected as the cause of CKD.[8] It is used to confirm the diagnosis and estimate the severity of reflux.
• Renal scans – can give sufficient information about the anatomy and function of kidneys. They are used predominantly in children as they are associated with lesser radiation exposure compared to CT scan. Radionuclide renal scans are used to measure the difference in function between the kidneys.

Establishing an Accurate Diagnosis

• An accurate cause of CKD needs to be established such as when there is an underlying treatable condition that requires appropriate management, for example, lupus nephritis, ANCA vasculitis, among others. In addition, certain diseases carry a higher frequency of recurrence in the kidney after transplantation and accurate diagnosis will influence later management. A kidney biopsy is used to diagnose the etiology of CKD, and it also gives information about the extent of fibrosis in the kidney.

Treatment of Chronic Kidney Disease (CKD)

General Management

• Adjusting drug doses for the level of estimated glomerular filtration rate (GFR)
• Preparation of renal replacement therapy by placing an arteriovenous fistula or graft

Treat the Reversible Causes of Renal Failure

• The potentially reversible causes of acute kidney injury like infection, drugs which reduce the GFR, hypotension such as from shock, instances which cause hypovolemia such as vomiting, diarrhea should be identified and intervened.
• Patients with CKD should be evaluated carefully for the use of intravenous contrast studies, and any alternatives for the contrast studies should be utilized first. Other nephrotoxic agents such as aminoglycoside antibiotics and NSAIDs should be avoided.

Retarding the Progression of CKD

• The factors which result in progression of CKD should be addressed such as hypertension, proteinuria, metabolic acidosis, and hyperlipidemia. Hypertension should be managed in CKD by establishing blood pressure goals. Similarly, proteinuria goal should be met.
• Multiple studies have shown that smoking is associated with risk of developing nephrosclerosis and smoking cessation retards the progression of CKD.[rx]
• Protein restriction has also been shown to slow the CKD progression. However, the type and amount of protein intake are yet to be determined.
• Bicarbonate supplementation for the treatment of chronic metabolic acidosis has been shown to delay the CKD progression as well. [rx] Also, intensive glucose control in diabetics has been shown to delay the development of albuminuria and also the progression of albuminuria to overt proteinuria.[rx]

Preparation and Initiation of Renal Replacement Therapy

Once the CKD progression is noted, the patient should be offered various options for renal replacement therapy.

• Hemodialysis (home or in-center)
• Peritoneal dialysis (continuous or intermittent)[rx]
• Kidney transplantation (living or deceased donor): It is the treatment of choice for ESRD given better long-term outcomes.
• Patients who do not want renal replacement therapy should be provided with information about conservative and palliative care management.
• The hemodialysis is performed after stable vascular access is placed in a nondominant arm. In this arm, intravenous cannulas are avoided to preserve the veins. The preferred vascular access is AV fistula. The other hemodialysis access options are AV graft and tunneled hemodialysis catheters. The patency rates of AV fistula is good, and infections are very infrequent. Higher flows can be achieved through AV fistula, and there is less chance of recirculation.
• Peritoneal dialysis is performed after placing a peritoneal catheter.[rx]

Indications for Renal Replacement Therapy

• Pericarditis or pleuritis (urgent indication)
• Progressive uremic encephalopathy or neuropathy, with signs such as confusion, asterixis, myoclonus, and seizures (urgent indication)
• A clinically significant bleeding diathesis is attributable to uremia (urgent indication)
• Hypertension is poorly responsive to antihypertensive medications
• Fluid overload is refractory to diuretics
• Metabolic disorders that are refractory to medical therapy such as hyperkalemia, hyponatremia, metabolic acidosis, hypercalcemia, hypocalcemia, and hyperphosphatemia
• Persistent nausea and vomiting
• Evidence of malnutrition

Renal transplantation is the best treatment option of ESRD due to its survival benefit compared to long-term dialysis therapy. The patients with CKD become eligible to be listed for Deceased donor renal transplant program when the eGFR is less than 20 ml/min/1.73m2

Conservative management of ESRD is also an option for all patients who decide not to pursue renal replacement therapy. Conservative care includes the management of symptoms, advance-care planning, and provision of appropriate palliative care. This strategy is often underutilized and needs to be considered for very frail patients with poor functional status with numerous comorbidities. For facilitating this discussion a 6-month mortality score calculator is being used which includes variables such as age, serum albumin, the presence of dementia, peripheral vascular disease, and (yes/no) answer to a question by a treating nephrologist “would I be surprised if this patient died in the next year?”

When to Refer to a Nephrologist

Patients with CKD should be referred to a nephrologist when the estimated GFR is less than 30 ml/min/1.73 mt2. This is the time to discuss the options of renal replacement therapy.

Staging

The 6 categories include:

• G1: GFR 90 ml/min per 1.73 m2 and above
• G2: GFR 60 to 89 ml/min per 1.73 m2
• G3a: GFR 45 to 59 ml/min per 1.73 m2
• G3b: GFR 30 to 44 ml/min per 1.73 m2
• G4: GFR 15 to 29 ml/min per 1.73 m2
• G5: GFR less than 15 ml/min per 1.73 m2 or treatment by dialysis

The 3 levels of albuminuria include albumin-creatinine ratio (ACR):

• A1: ACR less than 30 mg/gm (less than 3.4 mg/mmol)
• A2: ACR 30 to 299 mg/gm (3.4 to 34 mg/mmol)
• A3: ACR greater than 300 mg/gm (greater than 34 mg/mmol)

Prognosis

Significant racial and ethnic differences exist in the incidence and prevalence rates of ESRD. The highest incidence is found in African Americans; followed by American Indians and Alaska Natives; followed by Asian Americans, Native Hawaiians, and other Pacific Islanders; followed by Caucasians. Hispanics have higher incidence rates of ESRD than non-Hispanics.

Early-stage CKD and ESRD are associated with increased morbidity and health care utilization rates. A review of the USRDS 2009 annual data report suggests that the number of hospitalizations in ESRD patients is 1.9% per patient-year. In a study by Khan SS et al., the prevalence of the cardiovascular disease, cerebrovascular disease, and peripheral vascular disease in earlier stages of CKD were comparable to those in US dialysis population. It was also found that patients with CKD had 3-fold higher rates of hospitalization and hospital days spent per patient-year compared to the general US population.[rx] CKD patients are at a higher risk of hospitalization and cardiovascular diseases and the risk increases with a decline in GFR.

Patients with CKD and particularly end-stage renal disease (ESRD) are at increased risk of mortality, particularly from cardiovascular disease. Review of USRDS 2009 data suggests that 5-year survival probability in a patient on dialysis is only around 34%.

Complications

Treatment of Complications of Chronic Kidney Disease

• Patients with CKD have diminished the ability to maintain a fluid balance after a rapid sodium load and becomes more apparent in stages IV and V of CKD. These patients respond to sodium restriction and a loop diuretic. The 2012 KDIGO guidelines recommend all CKD patients should be sodium restricted to less than 2 gm per day.
• Hyperkalemia in CKD can occur specifically in oliguric patients and in whom where aldosterone secretion is diminished. Dietary intake of potassium, tissue breakdown and hypoaldosteronism could result in hyperkalemia. Drugs such as ACE inhibitors and nonselective beta-blockers could also result in hyperkalemia.
• Metabolic acidosis is a common complication of advanced CKD due to the increased tendency of kidneys in CKD to retain H. Chronic metabolic acidosis in CKD would result in osteopenia, increased protein catabolism, and secondary hyperparathyroidism. These patients should be treated with bicarbonate supplementation to target serum bicarbonate of equal to 23.
• CKD is a significant risk factor for CVD and risk increases with increased severity of the CKD. Considerable evidence indicates a significant association between Epicardial adipose tissue (EAT) thickness and the incidence of CVD events in CKD patients. In CKD patients, EAT assessment could be a reliable parameter for cardiovascular risk assessment.[rx].

Bone and Mineral Disorders

• Hyperphosphatemia is a frequent complication of CKD due to a decreased filtered load of phosphorous. This leads to increased secretion of a Parathyroid hormone (PTH) and causes secondary hyperparathyroidism. Hyperparathyroidism results in normalization of phosphorous and calcium but at the expense of bone. This results in renal osteodystrophy. Therefore, phosphorus binders along with dietary restriction of phosphorus are used to treat secondary hyperparathyroidism.
• Hypertension is a manifestation of volume expansion in CKD. Patients in CKD do not always have edema to suggest volume expansion. Therefore, all patients with CKD should have a loop diuretic added to control the blood pressure which needs to be titrated before considering an increase in antihypertensive therapy.
• Anemia in CKD is usually normocytic normochromic. It is primarily due to reduced erythropoietin production from reduced functioning renal mass and also due to reduced red cell survival. Hemoglobin should be checked at least yearly in CKD 3, every 6 months in CKD IV and V, and every 3 months in dialysis patients. Erythropoietin stimulating agents (ESA) in CKD patients should be considered when Hb is less than 10 and provided iron saturation is at least 25% and ferritin greater than 200 ng/mL. In dialysis patients, the goal Hb concentration is 10 to 11.5 gm/dl.

Treatment of Complications of ESRD

• Malnutrition in ESRD is due to anorexia and poor protein intake. The diet in ESRD should provide at least 30 to 35 Kcal/kg per day. A low plasma albumin concentration is suggestive of malnutrition.
• Uremic bleeding is a complication resulting from impaired platelet function. It results in prolonged bleeding time. Asymptomatic patients are not treated. However, correction of uremic platelet dysfunction is needed during active bleeding, need for a surgical procedure. Some interventions used are desmopressin (dDAVP), cryoprecipitate, estrogen, and initiation of dialysis.
• Uremia can present as uremic pericarditis and is an indication for initiation of dialysis. Uremic pericarditis is treated with dialysis and responds well.

Complications of Renal Transplantation

• Complications related to cardiovascular, renal, neurologic, and gastrointestinal systems.[rd][rx]
• Common complications include hypertension, dyslipidemia, coronary artery disease from new-onset diabetes mellitus and renal failure, left ventricular hypertrophy, arrhythmias,[rx] and heart failure.
• Neurologic complications include stroke and posterior reversible encephalopathy syndrome, central nervous system (CNS) infections, neuromuscular disease, seizure disorders, and neoplastic disease.
• GI complications include infection, malignancy (posttransplant lymphoproliferative disorder), mucosal injury, mucosal ulceration, perforation, biliary tract disease, pancreatitis, and diverticular disease.

References

Kidney failure, also known as end-stage kidney disease, is a medical condition in which the kidneys are functioning at less than 15% of normal. Kidney failure is classified as either acute kidney failure, which develops rapidly and may resolve; and chronic kidney failure, which develops slowly.^[rx] Symptoms may include leg swelling, feeling tired, vomiting, loss of appetite, and confusion.^[rx] Complications of acute and chronic failure include uremia, high blood potassium, and volume overload.^[rx] Complications of chronic failure also include heart disease, high blood pressure, and anemia.^[rx][rx]

The term renal failure denotes the inability of the kidneys to perform excretory function leading to retention of nitrogenous waste products from the blood. Functions of the kidney are as follows:

• Electrolyte and volume regulation
• Excretion of nitrogenous waste
• Elimination of exogenous molecules, for example, many drugs
• Synthesis of a variety of hormones, for example, erythropoietin
• Metabolism of low molecular weight proteins, for example, insulin

Types of Kidney Failure

Acute and chronic renal failure are the two kinds of kidney failure.

Acute Renal Failure (ARF)

• ARF is the syndrome in which glomerular filtration declines abruptly (hours to days) and is usually reversible. According to the KDIGO criteria in 2012, AKI can be diagnosed with any one of the following: (1) creatinine increase of 0.3 mg/dL in 48 hours, (2) creatinine increase to 1.5 times baseline within last 7 days, or (3) urine volume less than 0.5 mL/kg per hour for 6 hours. [rx] Recently the term acute kidney injury (AKI) has replaced ARF because AKI denotes the entire clinical spectrum from a mild increase in serum creatinine to overt renal failure. [rx]

Chronic Renal Failure (CRF)

• CRF or chronic kidney disease (CKD) is defined as a persistent impairment of kidney function, in other words, abnormally elevated serum creatinine for more than 3 months or calculated glomerular filtration rate (GFR) less than 60 ml per minute / 1.73m2. It often involves a progressive loss of kidney function necessitating renal replacement therapy (dialysis or transplantation). When a patient needs renal replacement therapy, the condition is called end-stage renal disease (ESRD). [rx]

CKD classified based on grade

• Grade 1: GFR greater than 90
• Grade 2: 60 to 89
• Grade 3a: 45 to 59
• Grade 3b: 30 to 44
• Grade 4: 15 to 29
• Grade 5: Less than 15

CKD classified based on stage

• Stage 1: GFR greater than 90
• Stage 2: 60 to 89
• Stage 3: 30 to 59
• Stage 4: 15 to 29
• Stage 5: Less than 15

Causes of Kidney Failure

Renal Failure Etiopathogenesis

Acute Renal Failure [rx]

• Prerenal (approximately 60%) – Hypotension, volume contraction (e.g., sepsis, hemorrhage), severe organ failure such as heart failure or liver failure, drugs like non-steroidal anti-inflammatory drugs (NSAIDs), angiotensin receptor blockers (ARB) and angiotensin-converting enzyme inhibitors (ACEI), and cyclosporine
• Intrarenal (approximately 35%) – Acute tubule necrosis (from prolonged prerenal failure, radiographic contrast material, drugs like aminoglycosides, or nephrotoxic substances), acute interstitial nephritis (drug-induced), connective tissue disorders (vasculitis), arteriolar insults, fat emboli, intrarenal deposition (seen in tumor-lysis syndrome, increased uric acid production and multiple myeloma-Bence-Jones proteins), rhabdomyolysis
• Postrenal (approximately 5%) – Extrinsic compression (prostatic hypertrophy, carcinoma), intrinsic obstruction (calculus, tumor, clot, stricture), decreased function (neurogenic bladder)

Chronic Renal Failure

• Diabetes mellitus, especially type 2 diabetes mellitus, is the most frequent cause of ESRD.
• Hypertension is the second most frequent cause.
• Glomerulonephritis
• Polycystic kidney diseases
• Renal vascular diseases
• Other known causes, like prolonged obstruction of the urinary tract, nephrolithiasis
• Vesicoureteral reflux, a condition in which urine to back up into the kidneys
• Recurrent kidney infections/ pyelonephritis
• Unknown etiology [rx]

Renal failure pathophysiology can be described by a sequence of events that happen while during acute insult in the setting of acute renal failure and also gradually over a period in cases of chronic kidney diseases.

Broadly, AKI can be classified into three groups: [rx]

• The decrease in renal blood flow (prerenal azotemia): Prerenal AKI occurs secondary to either an absolute reduction in extracellular fluid volume or a reduction in circulating volume despite a normal total fluid volume, e.g., in advanced cirrhosis, heart failure, and sepsis. Normally kidney auto-regulatory mechanism maintains intra-capillary pressure during initial phase by causing dilation of afferent arterioles and constriction of efferent arterioles. When prerenal conditions become severe, renal adaptive mechanisms fail to compensate unmasking the fall in GFR and the increase in BUN and creatinine levels.
• Intrinsic renal parenchymal diseases (renal azotemia): Intrinsic disorders can be sub-divided into those involving the glomeruli, vasculature, or tubulointerstitium respectively.
• Obstruction of urine outflow (postrenal azotemia)

The pathophysiology of CRF is related mainly to specific initiating mechanisms. Over the course of time-adaptive physiology plays a role leading to compensatory hyperfiltration and hypertrophy of remaining viable nephrons. As insult continues, sub sequentially histopathologic changes occur which include distortion of glomerular architecture, abnormal podocyte function, and disruption of filtration leading to sclerosis. [rx]

Diagnosis of Kidney Failure

The relevant history and physical examination findings associated with renal failure include:

History

• Detailed present medical illness history
• Medical history such as diabetes mellitus, hypertension
• A family history of kidney diseases
• Review of hospital records
• Previous renal function
• Medications especially start date, drug levels of nephrotoxic agents, NSAIDs
• Any use of a contrast agent or any procedure performed

Physical Examination

• Hemodynamics including blood pressure, heart rate, weight
• Volume status, look for edema, jugular venous distention, lung crackles, and S3 gallop
• Skin: check for any diffuse rash or uremic frost
• Look for signs of uremia: asterixis, lethargy, seizures, pericardial friction rub, peripheral neuropathies
• Abdomen exam: check for bladder distention, note any suprapubic fullness

Patients with renal failure have a variety of different clinical presentations as explained in the history and physical exam section. Many patients are asymptomatic and are incidentally found to have an elevated serum creatinine concentration, abnormal urine studies (such as proteinuria or microscopic hematuria), or abnormal radiologic imaging of the kidneys. The key laboratory and imaging studies to be ordered in patients with renal failure follow.

Urinalysis, dipstick, and microscopy

• Dipstick for blood and protein – microscopy for cells, casts, and crystals
• Casts – Pigmented granular/muddy brown casts-ATN; WBC casts-acute interstitial nephritis; RBC casts-glomerulonephritis

Urine electrolytes

• Fractional excretion of sodium (FENa) = [(UNa x PCr)/ (PNa x UCr)] x 100, where U is urine, P is plasma, Na is sodium, andCr is Creatinine. If FeNa less than 1, then likely prerenal; greater than 2, then likely intrarenal; greater than 4, then likely postrenal
• If the patient is on diuretics, use FEurea instead of FENa. Complete blood count, BUN, creatinine (Cr), arterial blood gases (ABGs)
• Calculate Cr clearance to ensure that medications are dosed appropriately: Cockcroft-Gault equation Cr clearance (mL/min) = (140-age) x (weight in kilograms) x (0.85 if female)/(72 x serum creatinine)

Special Labs

• Creatinine Kinase (CK)
• Immunology antibodies based on the clinical scenario

Imaging

• Renal ultrasound (US)
• Doppler-flow kidney US depending upon the clinical scenario
• An abdominal x-ray (KUB): Rules out renal calculi

More advanced imaging techniques should be considered if initial tests do not reveal etiology

• Radionucleotide renal scan, CT scan, and/or MRI
• Cystoscopy with retrograde pyelogram
• Kidney biopsy

Treatment of Kidney Failure

Treatment options for renal failure vary widely and depend on the cause of failure. Broadly options are divided into two groups: treating the cause of renal failure in acute states versus replacing the renal function in acute or chronic situations and chronic conditions. Below is a summary of renal failure treatment.

Acute Renal Failure

• The mainstay is treating the underlying cause and associated complications
• In case of oliguria and no volume, overload is noted, a fluid challenge may be appropriate with diligent monitoring for volume overload
• In the case of hyperkalemia with ECG changes, IV calcium, sodium bicarbonate, and glucose with insulin should be given. These measures drive potassium into cells and can be supplemented with polystyrene sulfonate, which removes potassium from the body. Hemodialysis is also an emergency method of removal.
• Oliguric patients should have a fluid restriction of 400 mL + the previous day’s urine output (unless there are signs of volume depletion or overload).
• If acidosis: Serum bicarbonate intravenous or per oral, versus emergency/urgent dialysis based on the clinical situation
• If obstructive etiology present treat accordingly and or if bladder outlet obstruction secondary to prostatic hypertrophy may benefit from Flomax or other selective alpha-blockers

General Measures

• First things first, always review the drug list.
• Stop nephrotoxic drugs and renally adjust others. Many supplements not approved by the FDA can be nephrotoxic.
• Always record ins and outs
• Monitor daily weights
• Watch for complications, including hyperkalemia, pulmonary edema, and acidosis-all potential reasons to start dialysis
• Ensure good cardiac output and subsequent renal blood flow.
• Pay attention to diet: total caloric intake should be 35 to 50 kcal/kg per day to avoid catabolism. Potassium intake restricted to 40 mEq per day; phosphorus restricted to 800 mg per day. If it becomes high, treat with calcium carbonate or another phosphate binder. Magnesium compounds should be avoided.
• Treat infections aggressively.

Immediate Dialysis Indications

• Severe hyperkalemia
• Acidosis
• Volume overload refractory to conservative therapy
• Uremic pericarditis
• Encephalopathy
• Alcohol and drug intoxications

Chronic Renal Failure

• Optimize control of specific causes of CKD such as diabetes mellitus and hypertension
• Measure sequentially and plot the rate of decline in GFR in all patients
• Any acceleration in the rate of decline should prompt a search for a superimposed acute or subacute process that may be reversible
• Rule out extracellular fluid volume depletion, uncontrolled hypertension, urinary tract infection, new obstructive uropathy, exposure to nephrotoxic agents (such as NSAIDs or contrast dye), reactivation or flare of the original disease such as lupus or vasculitis
• Interventions to slow the progression of CKD
• Reduce intra-glomerular filtration
• Reduce proteinuria; effective meds include ACE/ARB
• Strict glycemic control
• Prevent and treat complications of CKD
• Discuss renal replacement therapy with patients appropriately and timely
• Periodically review medications and avoid nephrotoxic medicines. Dose renally excreted medications appropriately.
• Patients with CKD should be referred to a nephrologist when eGFR is less than 30 ml per minute, as this provides enough time for adequate preparation for kidney replacement therapy.

Complications

• Volume overload
• Hyponatremia
• Hyperkalemia
• Acidosis
• Calcium and phosphate balance
• Anemia
• Consult nephrology in all cases where the patient has a drop in urine output with elevated creatinine.
  Urology consultation for obstructive nephropathies
• Relief of obstruction with retrograde ureteral catheters or percutaneous nephrostomy
• Surgical consults for placement of hemodialysis catheter

References

A plica is a band of thick, fibrotic tissue that extends from the synovial capsule of a joint. Plica can be present in multiple joints, but this article will review plica in the knee, the joints most commonly affected by plica tissue. As a result of overuse or injury, plica can become inflamed or irritated due to friction across the patella or the medial femoral condyle. When the plica becomes inflamed or irritated, it can cause plica syndrome, which is anterior knee pain due to the plica.

Plica syndrome is a condition that occurs when a plica (a vestigial extension of the protective synovial capsule of the knee) becomes irritated, enlarged, or inflamed.

Synovial plicae are synovial folds that may be found as intraarticular structures within the knee joint. They are remnants of incomplete resorption of mesenchymal tissue during fetal development. Synovial plicae, if present, are supposed to be non-pathological and asymptomatic, however, if they are exposed to special events like direct trauma or repeated activities, they may be inflamed and become fibrosed and rigid and irritates the synovium of the underlying femoral condyle resulting in secondary mechanical synovitis and chondromalacia leading to what is known as plica syndrome of the knee.

Types of Plica

In the knee, 4 types of plicae can be distinguished, depending on the anatomical location within the knee joint cavities: suprapatellar, mediopatellar, infrapatellar, and lateral plicae. The last one is rarely seen and, therefore, there is some controversy regarding its existence or its exact nature. The plicae in the knee joint can vary in both structure and size; they can be fibrous or fatty, longitudinal or crescent-shaped^[rx].

Suprapatellar plica

• The suprapatellar plica also referred to as the plica synovial suprapatellar, superior plica, superomedial plica, medial suprapatellar plica, or septum is a domed, crescent-shaped septum that generally lies between the suprapatellar bursa and the tibiofemoral joint of the knee. It runs down from the synovium at the anterior side of the femoral metaphysis, to the posterior side of the quadriceps tendon, inserting above the patella.
• Its free border appears sharp, thin, wavy, or crenated in normal conditions. This type of plica can be present as an arched or peripheral membrane around an opening, called porta. It often blends into the medial plica. As the suprapatellar plica is anteriorly attached to the quadriceps tendon, it changes dimension and orientation when moving the knee.

Based on arthroscopic investigations the suprapatellar plicae can generally be classified by location and shape into different types. Kim and Choe (1997) have distinguished the following 7 types;^[rx]

• Absent No sharp-edged fold.
• Vestigial Plica with less than 1 mm protrusion. Disappeared with external pressure
• Medial Plica lying on the medial side of the suprapatellar pouch
• Lateral Plica lying on the lateral side of the suprapatellar pouch
• Arch Plica present medially, laterally and anteriorly but not over the anterior femur
• Hole Plica extending completely across the suprapatellar pouch but with a central defect.
• Complete Plica dividing the suprapatellar pouch into two separate compartments

Medial patella plica

• The medial patellar plica is also known as plica synovial mediopatellaris, medial synovial shelf, plica alaris elongate, medial parapatellar plica, the meniscus of the patella or after its first two descriptors as Iion’s band or Aoki’s ledge. It is found along the medial wall of the joint.^[rx]
• It attaches to the lower patella and the lower femur and crosses the suprapatellar plica to insert in the synovium surrounding the infrapatellar fat pad. Its free border can have different appearances. As the medial plica is attached to the synovium covering the fat pad and ligament patellae, it also changes dimension and orientation during knee movement. The medial plica is known to be the most commonly injured plica due to its anatomical location and it is usually this plica which is implicated when describing the plica syndrome.

Similar to the suprapatellar plicae, the medial plicae has also can be classified by appearance. Kim and choe  have defined the following 6 types:^[rx]

• Absent No synovial shelf on the medial wall
• Vestigial Less than 1 mm of synovial elevation which disappears with external pressure
• Shelf A complete fold with a sharp free margin.
• Reduplicated Two or more sheves running parallel. They may be of differing sizes.
• Fenestra The shelf contains a central defect

High-Riding A shelf like structure running anterior to the posterior aspect of the patella, in a position where I could not touch the femur.
Each type is subdivided according to size and relation to femoral condyle with flexion and extension of the knee into:

• A—Narrow non touch (never makes contact with the femoral condyle).
• B—Medium touch (touches condyle with knee movement).
• C—Wide covering (covers the femoral condyle).

Infrapatellar plica

• The infrapatellar plica is also called as ligamentum mucosum, plica synovial infrapatellaris, inferior plica or anterior plica. It is a fold of synovium which originates from a narrow base in the intercondylar notch, extends distally in front of the anterior cruciate ligament (ACL), and inserts into the interior of the infrapatellar fat pad.
• It is often difficult to differentiate the infrapatellar plica from the ACL. Mostly it appears as a thin, cord-like, fibrous band. The infrapatellar plica is considered to be the most common plica in the human knee. Discussion is on-going whether this plica is structurally important to regular knee movement or whether it is redundant.^[rx]

A classification for infrapatellar plicae can be as follows:^[rx]

• Absent No synovial fold between the condyles of the femur.
• Separated A complete synovial fold that was separate from the anterior cruciate ligament (ACL).
• Split Synovial fold that is separate from the ACL but is also divided into two or more cords.
• Vertical septum A complete synovial fold that is attached to the ACL and divided the joint into medial and lateral compartments.
• Fenestra A vertical septum pattern that contains a hole or defect.

 Lateral plica

• The lateral plica is also known as plica synovialis lateralis or lateral para-patellar plica. It is longitudinal, thin and is located 1-2 cm lateral to the patella. It is formed as a synovial fold along the lateral wall above the popliteus hiatus, extending inferiorly and inserting into the synovium of the infrapatellar fat pad.
• Some authors doubt whether it is a true septal remnant from the embryological phase of development or whether it is derived from the parapatellar adipose synovial fringe. ^[rx]
  This type of plica is only seen on rare occasions; its incidence being well below 1%

Causes of Plica syndrome

• This inflammation is typically caused by the plica being caught on the femur or pinched between the femur and the patella. The most common location of plica tissue is along the medial (inside) side of the knee. The plica can tether the patella to the femur, be located between the femur and patella, or be located along the femoral condyle. If the plica tethers the patella to the femoral condyle, the symptoms may cause it to be mistaken for chondromalacia.
• The plica themselves are remnants of the fetal stage of development where the knee is divided into three compartments. The plica normally diminishes in size during the second trimester of fetal development, as the three compartments develop into the synovial capsule.
• In adults, they normally exist as sleeves of tissue called synovial folds. The plica are usually harmless and unobtrusive; plica syndrome only occurs when the synovial capsule becomes irritated, which thickens the plica themselves (making them prone to irritation/inflammation, or being caught on the femur).

Symptoms of Plica

• Symptoms of plica syndrome are often similar to many other etiologies of knee pain. As a result, the differential diagnosis can be lengthy and may include osteochondritis dissecans, patellofemoral syndrome, patellofemoral subluxation, meniscal disease, osteoarthritis, patellar tendonitis, cruciate ligament pathology, and pigmented villonodular synovitis. These differential diagnoses can be differentiated from plica syndrome as follows:

Other symptoms of knee plica syndrome can also include the following 

• a catching or locking sensation on the knee while getting up from a chair after sitting for an extended period of time,
• difficulty sitting for extended intervals,
• a cracking or clicking noise when bending or stretching the knee,
• a feeling that the knee is slowly giving out,
• a sense of instability on slopes and stairs,
• and may feel swollen plica when pushing on the knee cap.

Diagnosis of Plica

As the symptoms experienced with pathological plicae are not specific, the diagnostic procedure should keep a high level of suspicion and ideally work through exclusion, to differentiate from any other knee derangement.^[rx]

• Physical examination – not give exclusive results due to possible tenderness of the anteromedial capsule or the area around the suprapatellar pouch on direct palpation.
• Provocation test – Provocation test which simulates conditions that can lead to the occurrence of symptoms could be applied. These results will be considered positive if the symptoms resulting from the tests are similar to the symptoms the patient is usually experiencing. Yet as similar symptoms may also be associated with other conditions of the knee joint, this method will not give an unambiguous result either.
• Radiography will be of no diagnostic –  value to determine whether patients suffer from plica syndrome, as the radiograph will be negative. Yet, radiography can be helpful to rule out other syndromes where the symptoms are common with those of a plica syndrome (see differential diagnosis). If there is symptomatic plicae, it will demonstrate hypertrophy and inflammation. This will lead to thickening and eventually fibrosis. If the fibrosis is significant, changes in the articular surface and the subchondral bone may occur.
• Arthroscopy – can be helpful because plica syndrome is often confused with chondromalacia or a medial meniscal tear. Lateral pneumoarthrography and double-contrast arthrography have been used with varying success. In combination with CT, it can not only visualize the plica, but it also demonstrates whether or not impingement is present. However, currently, it has gone out of use because of problems to obtain reproducible and reliable results and the exposure to radiation.^[rx]
• Nowadays, the best results are obtained through MRI Scans –  Most cases of plica syndrome do not absolutely require MRI, but it can help to rule out other pathologies that can cause knee pain. An MRI can exclude bone bruises, meniscus tears, ligament injuries, cartilage defects, OCD lesions,… that may masquerade as plica syndrome. MRI is useful to evaluate the thickness and extension of synovial plicae and it can also detect a pathologic plica, particularly if an intra-articular effusion is present.^[rx]
• Osteochondritis dissecans – Differentiate with radiographs and MRI.
• Patellofemoral syndrome – Patellofemoral knee pain can be difficult to distinguish from plica syndrome as the symptoms overlap significantly. Other causes of patellofemoral pain, such as chondromalacia, may be apparent in history and imaging.
• Patellofemoral subluxation – Differentiate because patients with a patellofemoral subluxation will often provide a history consistent with subluxation and may have apprehension with a displacement of the lateral patella.
• Meniscus pathology – Differentiate because meniscus pathology will have tenderness in the joint line, whereas plica pain tends to localize above the joint line. Also, physical exam tests such as Apley, Thessaly, bounce home, and/or McMurray can help distinguish the 2 entities.
• Osteoarthritis – Differentiate with radiographs showing decreased joint space, osteophytes, subchondral sclerosis, subchondral cysts, among others, although this does not rule out also having symptomatic plicae.
• Patellar tendonitis – Differentiate by palpating the patellar tendon on either the proximal or distal attachment.
• Cruciate ligament dysfunction – Differentiate by physical exam techniques suggesting laxity including Lachman, anterior drawer, or posterior drawer would likely be positive in cruciate ligament injury.
• Pigmented Villonodular Synovitis (PVNS) – Differentiate via MRI.

Staging

Medial plicae are most commonly symptomatic and can be classified by the Sakakibara arthroscopic classification:

• Type A – Elevation in the synovial wall
• Type B – Appear shelf-like, but not covering the anterior surface of the medial femoral condyle
• Type C – Large, shelf-like appearance and covering the anterior surface of the medial femoral condyle
• Type D – Fenestrated plica with a central defect.

Treatment of Plica

Treatment options for plica syndrome include stretching and strengthening, intrapleural corticosteroid injections, and arthroscopy.

The Sakakibara classification system is important when considering treatment because type A and B have a low likelihood to cause pain. Type C and D, on the other hand, can impinge on the medial condyle due to their larger size. Type A and B respond much better to conservative therapies than C and D do. As a result, patients with type A and B should be encouraged to attempt conservative therapy first.

Conservative treatment for plica syndrome can either be performed at home by the patient or via formal physical therapy. Either way, this would involve lower extremity stretching and knee extension exercises with the goal of strengthening the joint capsule musculature, hamstrings, and quadriceps. NSAIDs and ice are reasonable treatments at this stage to calm down inflammation. Conservative management also includes avoiding activities that incite pain. At least 3 months of conservative treatment is recommended before advancing to more aggressive therapies. One study demonstrated that 49 of 55 patients treated conservatively returned to their prior baseline without a return of symptoms. The remaining 6 patients were also able to return to their prior baseline, but they reported an occasional return of symptoms, which were tolerable.[rx]

Often the next step if stretching and strengthening do not release symptoms is intrapleural corticosteroid injection. This is a reasonable treatment option, especially early in the disease process when conservative management has not provided relief. Research of 31 patients with medial plica syndrome treated with intrapleural steroid injection found that 73% had a full return to activity with complete pain relief.[rx]

Resection via arthroscopy is a favorable option for medial plicae that do not respond to conservative treatment. Resection is also reasonable when cartilage damage is suspected, such as in type C and D lesions, even if conservative measures have not been completed for 3 months. Another study showed that compared to conservative treatment, arthroscopy yields a greater therapeutic effect for plica syndrome and the effect is longer lasting.[rx]

Physical Therapy Management of Plica

• Conservative treatment of the synovial plica syndrome first consists of pain relief with NSAIDs and repeated cryotherapy during the day using ice packs or ice massage, to reduce the initial inflammation. Other measures will include limiting aggravating activities by changing the daily physical movements to reduce repetitive flexion and extension movements and by correcting biomechanical abnormalities (tight hamstrings, weak quads).
• Additionally, microwaves diathermy, phonophoresis, ultrasound, and/or friction massage might be considered. Friction massage is also used in this therapy to break down scar tissue. Occasionally, immobilization of the knee in the extended position for a few days can be helpful, as well as avoiding maintenance of the knee in a flexed position during longer periods.^[rx]
• Once the acute inflammation is reduced, physical therapy can be initiated, aiming at decreasing compressive forces by stretching exercises and by increasing quadriceps strength and hamstring flexibility.^[rx]
• This treatment is usually recommended for the first 6-8 weeks after the initial examination.^[rx]
• It consists of strengthening and improving the flexibility of the muscles adjacent to the knee, such as the quadriceps, hamstrings, adductors, abductors, M Gastrocnemius, and M Soleus. ^[rx][rx]

The key components of the rehabilitation program will involve flexibility, cardiovascular condition training, strengthening and return to ADL.

• An exercise to regain flexibility in extension is the supine passive knee extension exercise while placing a foam roller under the ankle. Gravity will help to stretch the knee in maximal extension. If possible you can make the exercise more difficult by putting weights on the anterior sight of the knee.^[rx]
• Quadriceps sets^[rx]
• Prone passive knee extension exercise, laying down on the belly, with knees over the bench (unsupported leg).^[rx]
• Straight leg raises^[rx]
• Leg presses^[rx]
• Also mini-squats, a walking program, the use of a recumbent or stationary bicycle, a swimming program, or possibly an elliptical machine are the most successful rehabilitation programs.^[rx]
  Rehabilitation programs will have the greatest success when focussing on strengthening the quadriceps muscles which are directly attached to the medial plica, and when avoiding activities that cause medial plica irritation.^[rx]

The most important part of the quadriceps to train is the m. vastus mediale. Full range of quadriceps training is not recommended because these create excessive patellar compression at 90°. Instead, straight leg raises and short-arc quadriceps exercises at 5°-10°, also hip adductor strengthening should be performed. Other exercises to be performed are squad, go up and down the stairs, and lunging forward.^[rx]. Other important components of this treatment are a stretching program for these muscles(quadriceps, hamstrings, and gastrocnemius) and knee extension exercises. The goal of these knee extension exercises is the strengthening of the tensor musculature of the joint capsule. But if the patient has too much pain when reaching terminal extension, then this should be avoided^[rx]. This conservative treatment is effective in most cases, but in some patients surgery is necessary. In this case, post-operative therapy is necessary. The postoperative treatment is identical to the conservative treatment and is usually started 15 days after the surgery. The main goal of physiotherapy in plica syndrome is to reduce pain, maximize the ROM, and increase the strength of the muscles.

The type of plica, the age of the patient, and the duration of symptoms will greatly influence the success rate of conservative non-operative treatment of plica syndrome. It is generally believed that infrapatellar and lateral plica syndrome is not very responsive to physical therapy and will normally require surgery. The success of conservative therapy is also more likely in younger patients with only a short duration of symptoms, as the plica will not yet have undergone morphological changes. In general, the overall success of the non-surgical treatment is relatively low and complete relief of symptoms is only rarely achieved.

Resources

Physical exploration

Clinical signs and symptoms of Achilles tendinopathy include localized pain, focal or diffuse sensitivity,  swelling, stiffness/morning pain, perceived rigidity in the Achilles tendon, positive arc sign, Royal London Hospital test, and Thompson test.

Tests used to diagnose Achilles tendinopathy

• Lateral and axial calcaneus x-rays – May detect calcifications in the proximal extension of the tendon insertion or bony prominences in the upper portion of the calcaneus. Also, x-rays can help exclude pathological bone tumors.[rx][rx][rx]
• Ultrasound – Can help assess injury to the tendon[rx]; can be used to predict the risk of tendinopathy and rupture.[rx] Ultrasound may reveal the increased thickness of the Achilles tendon with hyperemia associated with hypervascularity, a decrease in the gastrocnemius-soleus rotation angle and a decrease in the length of the Kager fat pad. Ultrasound is also useful during interventional treatment.[rx]
• Magnetic Resonance Imaging – Provides significant information about the state of joint structures with a study in multiple planes in static and dynamic views.[rx][rx] One study found that MRI had lower sensitivity than ultrasound in the detection of early changes of enthesopathy.[rx]. Another study found an excellent agreement between tendon thickness measurement between magnetic resonance and ultrasound.[rx]
• Computed Tomography (CT) – The CT scan is useful to rule out trabecular structural alterations of the calcaneus in Achilles pathology of insertion. However, it exposes the patient to radiation.[rx][rx][rx]
• Victoria Institute of Sports Assessment – Achilles (VISA-A) remains the gold standard for assessing pain and function,[rx] but it requires additional studies to increase its reliability.[rx] Nevertheless, it is an essential tool for patient post-treatment follow-up.

Differential Diagnosis

• Achilles bursitis
• Ankle fracture
• Ankle impingement syndrome
• Ankle osteoarthritis
• Ankle sprain
• Calf injuries
• Calcaneofibular ligament injury
• Calcaneus fractures
• Deep venous thrombosis (DVT)
• Exertional Compartment Syndrome
• Fascial tears
• Gastrocsoleus muscle strain or rupture
• Haglund deformity
• Plantaris tendon tear
• Psoriatic arthritis
• Reiter syndrome
• Retrocalcaneal bursitis
• Ruptured Baker cyst
• Syndesmosis
• Talofibular Ligament Injury

Treatment of Achilles Tendinopathy

Management of Achilles tendinopathy can divide into conservative and surgical. Additionally, one must consider whether it is an acute or chronic condition. Finally, for those with a full rupture, the treatment is usually surgical.

Conservative therapy:  It is the first line of management and includes the following[rx][rx][rx][rx][rx][rx]

• Reduction of activity levels
• Adaptation of footwear, manual therapy directed at local sites may enhance the rehabilitation
• Eccentric stretching exercises should comprise an integral component of physiotherapy and can achieve a 40% reduction in pain; moderate level evidence favors eccentric exercise over concentric exercise for reducing pain
• Tendon loading exercise at short- and long-term follow-up
• If unresponsive to initial management, extracorporeal shock wave therapy reduces pain by 60%, with 80% patient satisfaction, improving functionality and quality of life, with a follow-up at 4 weeks; this might be the first choice because of its safety and effectiveness
• Physiotherapy improves the pain and functionality of the Achilles tendinopathy of the middle portion; however, studies do not show preferences for any particular exercise over another – overall, use of a splint to an eccentric exercise protocol or the use of orthoses to improve pain and function are not a recommendation
• Current evidence shows a lack of efficacy on the use of platelet-rich plasma for Achilles tendinopathy

Nonoperative Management

• Braces and immobilization – with a cast or pneumatic walking boot are combined with modified activity [rx]. Immobilization is frequently used in the acute setting to control exacerbating factors, but prolonged immobilization should be avoided[rx].
• Ultrasound – is a commonly prescribed program of physical therapy. In animal studies, ultrasound could stimulate collagen synthesis in tendon fibroblasts and cell division during the period of rapid cell proliferation [rx]. Therapeutic ultrasound has been shown to reduce the swelling in the acute inflammatory phase of soft-tissue disorders, relieve pain, and increase function in patients with chronic tendon injuries and may enhance tendon healing [rx, rx].
• Low-level laser therapy (LLLT) – could reduce the expression of proinflammatory markers such as IL-6 and TNF-α in gene level [rx]. In the cellular level, LLLT may increase collagen production [rx], stimulate tenocyte proliferation [rx], downregulate MMPs, decrease the capillary flow of neovascularization, and finally preserve the resistance and elasticity of tendon [rx, rx].
• Extracorporeal shockwave therapy (ESWT) – How ESWT works is still poorly understood, but it is known to cause selective dysfunction of sensory unmyelinated nerve fibers, alteration in the dorsal root ganglia, and cavitation in interstitial and extracellular disruption, which could promote the healing response [rx].
• Deep friction massage (DFM) – and tendon mobilization may also be helpful in the treatment of Achilles tendinopathy. DFM has been advocated for tendinopathy and paratendinopathy. Friction has been shown to increase the protein output of tendon cells [rx]. In combination with stretching, deep friction massage helps to restore tissue elasticity and reduce the strain in the muscle-tendon unit [rx, rx]. Future randomized comparison studies are necessary to compare DFM in isolation with other modes of treatment.
• Cryotherapy – might play a role in reducing the increased capillary blood flow in Achilles tendinopathy, reducing the metabolic rate of the tendon, and applying for relief of pain [rx, rx]. However, recent evidence in upper limb tendinopathy indicated that the addition of ice did not offer any advantage over an exercise program consisting of eccentric and static stretching exercises [rx].

Medication

• NSAIDs – used in chronic tendinopathy is questionable because the histological examination in the tendinopathic tissue shows no inflammatory cells [rx]. The benefits of NSAIDs use are relieving pain in the acute phase and reducing the possibility of leg stiffness [rx]. However, there are some studies that indicated that the NSAIDs may inhibit tendon cell migration and proliferation and impair tendon healing [rx].
• Corticosteroid injections – are reported to reduce pain and swelling and improve the ultrasound appearance of the tendon. The mechanism behind any positive effect of local steroids on chronic Achilles tendinopathy remains unclear. Some authors have hypothesized that any beneficial effects of corticosteroids in this condition are owed to other local steroid effects rather than suppression of inflammation, including lyses of tendon and peritendon adhesions or alteration of the function of pain generating nociceptor in the region [rx].
• Platelet-rich plasma (PRP) – at the site of tendon injury is thought to facilitate healing because it contains several different growth factors and other cytokines that can stimulate the healing of soft tissue [rx]. Animal studies indicated that PRP could increase the expression of collagen types I and III and vascular endothelial growth factor and improve the healing and remodeling process of the tendon [rx, rx].
• Intratendinous hyperosmolar dextrose (prolotherapy) – is thought to produce a local inflammatory response and increase in tendon strength. Clinical results indicated that intratendinous injections of hyperosmolar dextrose could reduce the pain at rest and during tendon-loading activities in patients with chronic of the Achilles tendinopathy [rx, rx]. Moreover, after the injection of dextrose, there were reductions in the size and severity of hypoechoic regions and intratendinous tears and improvements in neovascularity [rx].
• Nitric oxide – is a small-free radical generated by a family of enzymes, the nitric oxide synthases. It can induce apoptosis in inflammatory cells and cause angiogenesis and vasodilation. Moreover, oxygen-free radicals can stimulate fibroblast proliferation [rx]. Nitric oxide can enhance tendon healing. Inhibition of nitric oxide synthase can reduce the healing process, which resulted in a decreased cross-sectional area and reduced failure load [rx].
• The sclerosing agent – that selectively targets the vascular may cause thrombosis of the vessel. As the concomitant sensory nerves have been implicated as possible pain generators, to destroy local nerves adjacent to neovessels may decrease pain [rx]. As vessel number has been shown to correlate with tendon thickness, a treatment that decreases vessel number is likely to also affect the tendon thickness. Moreover, the sclerosing agent injected at multiple sites around the tendon and neovessels initiates a local inflammatory response, which induces the proliferation of fibroblasts and the synthesis of collagen.
• Aprotinin – is a broad-spectrum serine protease inhibitor capable of blocking trypsin, plasmin, kallikrein, and a range of MMPs [rx]. Most previous studies using Aprotinin injection in the management of Achilles tendinopathy showed a trend towards improved clinical results [rx, rx]. The major potential negative of using Aprotinin is the side effect of allergy [rx], but the allergic reactions can be reduced by minimizing repeat injections and recommending a delay of at least 6 weeks between injections [rx].
• Autologous blood injections – results have not been highly encouraging and there is little evidence for their use.^[rx]

Surgery

Surgical therapy is optional for 10 to 30% of patients who fail conservative therapy after six months.[rx][rx] The success rate is higher than 70%, but reports show complication rates of 3 to 40%.[rx] The Achilles tendon should undergo reattachment with a tendon rupture of more than 50%.[rx]

Noninsertional Achilles Tendinopathy

• The goal of surgery is to resect degenerative tissue, stimulate tendon healing by means of controlled, low-grade trauma, and/or augment the Achilles tendon with grafts. It has been suggested that noninvasive treatment should be tried for at least 4 months prior to operative interventions [rx]. Conventional surgical treatment has consisted of open release of adhesions with or without resection of the paratenon. If >50% of the tendon has been debrided, augmentation or reconstruction is recommended [rx].

Insertional Achilles Tendinopathy

• Patients who do not respond to conservative treatment may need operative management [rx]. The operative strategy for insertional Achilles tendinopathy is the removal of the degenerative tendon and associated calcification, excision of the inflamed retrocalcaneal bursa, resection of the prominent posterior calcaneal prominence, reattachment of the insertion as required, and/or augmentation of the tendo-Achilles with a tendon transfer/graft [rx, rx]. Calcaneoplasty and resection of the retrocalcaneal bursa can be performed endoscopically [rx].

Complications

Re-rupture

• While newer level 1 evidence has reported no difference in re-rupture rates, prior studies have suggested a 10% to 40% re-rupture rate with nonoperative management (compared to 1% to 2% rate of re-rupture after surgery)

• Lantto et al. recently demonstrated in a randomized controlled trial of 60 patients from 2009 to 2013 at 18-month follow-up: [rx]

  • Similar Achilles tendon performance scores
  • Slightly increased calf muscle strength differences favoring the operative cohort (10% to 18% strength difference) at 18-month follow-up
  • Slightly better health-related quality of life scores in the domains of physical functioning and bodily pain favoring the operative cohort

Wound Healing Complications

• Overall, a 5-10% risk following surgery

• Risk factors for postoperative wound complications include:

  • Smoking (most common and most significant risk factor)
  • Female gender
  • Steroid use
  • Open technique (vs percutaneous procedures)

Sural Nerve Injury

• Increased rate of injury associated with the percutaneous procedure (compared to open technique)

References

Straight Leg Raising Test (SLRT) /The straight leg raise test also called the Lasegue test is a fundamental neurological maneuver during the physical examination of the patient with lower back pain aimed to assess the sciatic compromise due to lumbosacral nerve root irritation. This test which was first described by Dr. Lazarevic and wrongly attributed to Dr. Lasegue can be positive in a variety of conditions, being lumbar disc herniation the most common. Nonetheless, there are multiple causes of a positive test such as facet joint cyst or hypertrophy.[rx][rx][rx]. Overall, this test is one of the most commonly performed maneuvers across clinical practice and provides important information when making the clinical decision to refer a patient to a specialist as well as among spinal surgeons to guide therapeutic decision-making.[rx]

Lasegue sign or Straight Leg Raising Test (SLRT) is a neurodynamic exam to assess nerve root irritation in the lumbosacral area.[rx] It is an integral element to the neurological exam for patients presenting with low back pain with or without radicular pain. The other less commonly used name is Lazarevic sign.

Anatomy and Physiology of Straight Leg Raising Test (SLRT)

The Lasegue test is basically a provocation test that evidences radicular irritation in the lumbosacral region by lower limb flexion and can be due to multiple causes. Radicular symptoms are primarily produced by nerve root inflammation by surrounded structures.[rx] The foramina are formed by the pedicle superiorly and inferiorly, ligamentum flavum posteriorly, disc and vertebral body anteriorly, and this small space normally allows the nerve root excursion of 4 mm, however during the straight leg raise test this root excursion can be compromised by several factors. Mechanical compression solely does not always generate radicular symptoms as many patients have asymptomatic foraminal stenosis in MRI,[rx][rx] therefore, positive leg raise test may undergo influence by nerve root irritation secondary to inflammation as well as mechanical compression.

The straight leg raise test is attributed to Charles Lasegue, a French clinician who described two cases of sciatica aggravated by weight-bearing, hip, and knee flexion in “Thoughts of Sciatica” in 1864. Nonetheless, Dr. Lasegue did not describe the test as a provoked pain; instead, his student JJ Forst described the test in his doctoral thesis in 1881, and it was Forst who considered the pain to be produced by hamstring muscle compression to the sciatic nerve.

Nevertheless, it is believed that a Serbian neurologist, Dr. Lazar Lazarevic,[rx] was the first who documented the straight leg raise test as it is known today in the article named “Ischiac postica council”, initially published in the Serbian Archives of Medicine (1880), and republished in Vienna (1884). Dr. Lazarevic described the straight-leg-raising test by explaining sciatic pain by stretching the sciatic nerve based on his experience with six patients. Based on this misinterpretation of the original description, it is recommended to describe the maneuver as the straight leg raise test.

Indications of Straight Leg Raising Test (SLRT)

• PLID
• Low back pain
• Buttock pain
• Leg pain
• Lumbago
• Low back pain

The Technique of Straight Leg Raising Test (SLRT)

The straight leg raise test is performed with the patient in a supine position. The examiner gently raises the patient’s leg by flexing the hip with the knee in extension, and the test is considered positive when the patient experiences pain along the lower limb in the same distribution of the lower radicular nerve roots (usually L5 or S1).

Furthermore, a positive straight leg raise test is determined when pain is elicited by lower limb flexion in an angle lower than 45 degrees. During the test, if the pain is reproduced during the leg straightening, patients usually request that the examiner aborts the maneuver and by flexing the patient’s knee, the buttock pain is usually relieved(Figure 1).

Additional maneuvers have been described to enhance the sensitivity of the test such as the Bragaad’s sign, which consists of concomitant foot dorsiflexion to increase the pain while the examiner completes the leg raise.

An additional maneuver is the crossed straight leg test (crossed over Lasegue), in which the examiner passively flexes the patient’s uninvolved limb while maintaining the knee in extension. A positive test is when the patient reports pain in the involved limb at 40 degrees of hip flexion with the uninvolved limb. A crossed straight test is positive in central disc herniation in cases of severe nerve root irritation.[rx]

Currently, the following technique is popular in practice

The patient should be informed about the steps of the test, what to expect during the exam, and to describe the pain distribution. The patient should be examined in a neutral supine position with the head slightly extended. During the exam, the hips and legs should stay neutral. No hips abduction or adduction is allowed as well as no leg internal or external rotation is permitted. The affected leg is then passively and slowly raised by the ankle with the knee fully extended. Upon eliciting pain, the examiner stops further leg elevation and records the range of motion along with the area of pain distribution.[rx][rx]

It is noteworthy that ankle dorsiflexion during SLRT may exaggerate the pain, notwithstanding, it is not part of the Lasegue sign.[rx]

Causes of Pain While Performing SLRT

• Stretching of the sciatic nerve
• Displacement of the medulla and conus medullaris
• Nerve compression leads to sensitization at the dorsal root ganglion and posterior horn, which in turn leads to the lowering of the pain threshold.[rx]

Causes of Positive SLRT

• Nerve root irritation – Intervertebral disc prolapse being the most common cause
• Intraspinal tumor
• Inflammatory radiculopathy

Criteria for a true positive SLRT

• Radicular leg pain should occur (radiating below the knee).
• Pain occurs when the leg is between 30 and 60 or 70 degrees from horizontal.[rx][rx]

What findings should not qualify as a positive SLRT?

• Pain occurring in the low back alone.
• Pain occurring in the posterior thigh alone.
• Pain occurring at an angle less than 30 degrees – May indicate non-organicity or hip joint pathology.
• Pain occurring at an angle more than 70 degrees from the horizontal – More likely cause is tight hamstring or gluteal muscles.
• Pain occurs in a normal person at an angle of 80 to 90 degrees.

Issues of Concern of Straight Leg Raising Test (SLRT)

SLRT modifications and its variants: the accuracy of SLRT can be better if it is interpreted with other nerve root tension tests:

• Crossed SLRT – AKA well-leg raising test or Fajersztajn sign. When the contralateral leg is lifted, the patient experiences pain on the affected side. This test is more specific than ipsilateral SLRT.[rx][rx] It becomes positive usually in severe compression and centrally located prolapse. Fajersztajn believed that this sign is due to disc prolapse in the axilla of the root.[rx]
• Reverse SLRT – AKA femoral stretch or Ely test. While the patient is in a prone position, the leg is lifted off the table with both hip and knee joints extended. Some authors may allow knee flexion. This maneuver may reproduce radicular pain in case of upper lumbar radiculopathy, far lateral lumbar disc, or femoral neuropathy. The pain will present in the femoral nerve distribution on the side of the lesion.[rx]
• Braggard test – AKA Sciatic stretch test or Flip test. While raising the leg, the foot is held in a dorsiflexed position, so that the sciatic nerve is stretched more, thereby increasing the intensity of pain or making it possible to elicit the sign early.[rx][rx]
• Reverse flip test – While raising the leg, the foot is held in a plantar-flexed position; this will lessen the pain. But if the patient is complaining of an increase in pain, it can suggest malingering.
• Bowstring sign – Also known as the popliteal compression test or posterior tibial nerve stretch sign. The patient can be examined in sitting or in a supine position. The examiner flexes the knee and applies pressure on the popliteal fossa, evoking sciatica. Some examiners do it after SLRT by flexing the knee to relieve the buttock pain. The pain would be reproduced by a quick snap on the posterior tibial nerve in the popliteal fossa.[rx]

Less frequently used nerve root irritation tests

For the sake of completion, other tests and signs of nerve root tension or irritation are discussed succinctly below:

• Sitting SLRT (Bechterew test) – the patient is made to sit at the edge of a table with both hip and knee flexed, then made to extend the knee joint or elevate the extended knee, which reproduces the radicular pain. He/she may be able to extend each leg alone, but extending both together causes radicular pain.[rx]
• Distracted SLRT – the sitting SLRT is performed without the patient’s awareness. The patient is distracted as if the surgeon is examining the foot or pulsation, and slowly, the examiner extends the knee. If the patient is experiencing true radiculopathy, the same pain will be reproduced. Otherwise, we can assume that the patient may be malingering.
• Neri’s sign – while bending forward, the patient flexes the knee to avoid stretching the nerve.[rx]
• The buckling sign – the patient may flex the knee during SLRT to avoid sciatic nerve tension.
• Sicard sign – passive dorsiflexion of ipsilateral great toe just at the angle of SLRT will produce more pain.[rx]
• Kraus-Weber test – the patient may be able to do a sit-up with the knees flexed but not extended.
• Minor sign – the patient may rise from a seated position by supporting himself/herself on the unaffected side, bending forward, and placing one hand on the affected side of the back.
• Bonnet phenomenon – the pain may be more severe or elicited sooner if the test is carried out with the thigh and leg in a position of adduction and internal rotation.

Clinical Significance of Straight Leg Raising Test (SLRT)

Interpretation of SLRT

• Pain radiating down the buttock to the lateral thigh and medial calf – L4 nerve root irritation
• Pain radiating down the buttock to the posterior thigh and lateral calf – L5 nerve root irritation
• Pain radiating down the buttock to the posterior thigh and calf, and lateral foot – S1 nerve root irritation

Interpretation of Positive Reverse SLRT

• L2, L3 or L4 root irritation
• Femoral nerve irritation

Sensitivity and Specificity of the Test

The sensitivity of ipsilateral SLRT is 72 to 97%, and specificity is 11 to 66%; whereas the crossed SLRT  sensitivity is 23 to 42%  which is less than ipsilateral SLRT but more specific (85 to 100%).[rx]

Tests to Confirm Non-organicity While Performing SLRT

• Pain occurring at an angle less than 30 degrees
• A significant discrepancy between the supine and sitting SLRT
• Touch-me-not or Waddell sign – Widespread and excessive tenderness
• Back pain on pressing down on the top of the head
• Overreaction during testing
• Non-dermatomal and non-myotomal neurologic signs
• Pain during simulated spinal rotation: The patient’s hands remain to the sides with hips rotated. There will not be any spine rotation with this maneuver. But the patient will complain of pain.

References