@Dr. Mayank Hans Your statement support? Did you ruleout Radilogically? OPG ...please share...if so Tmj view ? ENT report? Their findings? Never can go by just our clinical or their verbal versions. I would rule out one by one...
Mc cause of one sided facial swelling is a result of inflammation(soft tissue),one sided facial swelling of the face due abnormal tissue growth like tumor which may be either benign or malignant,other causes could be abscess(gingival,peritonsillar),Parotitis,lymphandenitis.
Any history of trauma??? Need not be recent.. Other possibility, if the patient had been under severe stress, it might have triggered neuralgia (herpetic). Just my opinion. Thank you.
Pobly a case or neuralgia...get a brief history n try to find out da trigger zones...after dat Tab pregabalin 100mg TDS for 2 weeks...can gradually increase to 300mg..
Presence of pain and swelling indicates inflammatory lesion. Detailed History and detailed IO examination is important followed by Radiographs.
Opg?? What's the clinical status of the teeth and mucosa in affected area
Dr mayank plz post radiographs.
If all dental, ENT & opthal causes have been ruled out. Clinically by what you have sent us, looking at the patient her nose is mildly deviated to the left, have you checked for DNS, possible inferior turbinate hypertropy? and subsequent or primary cause being the maxillary sinus? or PNSes?
Nasal endoscopy may show area of contact between Septum and turbinate or an occluded sinus ostium. CT scan of paranasal sinuses may reveal defects within sinuses. OPG may reveal unsuspected dental lesions. Have you tapped the relevant teeth and examined the TM joint ?
Opg must doc.rule out tooth pathology, look for tmj disorder.ask pt.about bruxism. Then look for neuralgic issue and look for parotid gland as well.
Cases that would interest you
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A 9 yr boy having swelling and tenderness on area where parotid glands r situated of right side for past 2 months with relapse and remission with no fever and pain at that site according to patient parents.No medications have been taken for this.Dx and Rx pls.TLC...8.97;DLC..39,51,5,3,1;AEC...470Dr. Shiv Kumar Vig3 Likes24 Answers
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Panchakarma- Five Teatments -1 Pancha Karma is the cornerstone to Ayurvedic management of disease. Pancha Karma is the process which gets to the root cause of the problem and corrects the essential balance of 'Tridosha' in body. Pancha Karma is not only good for alleviating disease but is also a useful tool in maintaining excellent health. Ayurveda advises undergoing Pancha Karma at the seasonal changes to clean the body, improve the digestion and to improve the metabolic processes. Panchakarma is a Sanskrit word that means "five actions" or "five treatments ". This age-old science of purifying the body is an ancient branch of Ayurveda, The Treatment in Ayurveda consists of two main types. One is Shaman Chikitsa, used to subdue the vitiated Doshas, due to which any ailments may be produced. It is administered by using various medicinal herbo-mineral preparations. However, if the Doshas are vitiated beyond a particular level, they give rise to various endotoxins, which have a tendency to be accumulated in the minute channels. These are beyond the level of pacification and hence need to be eliminated or removed from the body. In such cases, the second type of treatment, which is Shodhan Chikitsa or cleansing therapy, is indicated. Since it consists of the five types of main therapies, it is known as the Panchakarma Chikitsa. Panchakarma has been given a special place in all the ancient Ayurvedic texts. Aacharya Charak, the author of the most important ancient text on internal medicine, has described a wide use of Panchakarma therapy for almost all the major diseases. Two separate sections, Kalpa Sthanam, and Siddhi Sthanam in Charak Samhita describe the details of special decoctions and other preparations used for Panchakarma therapy. Panchakarma includes three parts namely: Poorva Karma (Preparatory Methods)which includes : Paachan (Digestion) Snehan (Internal and external oleation) Swedan (Fomentation) Pradhan Karma (Main methods)which includes : Vaman (Induced vomiting) Virechan (Induced purgation) Basti (Medicated enema) Nasya (Nasal medicine) Rakta Mokshan (Artificial bloodletting) Pashchat Karma (Post-Therapeutic Measures)which includes: Sansarjan Krama (Specific dietetics), DhumaPana (smoking of medicinal cigars) and some rules to follow specific activities. Purvakarma : Pre-purification Measures Before the actual operation of purification begins, there is a need to prepare the body in prescribed methods to encourage the body to let go of the toxins. The two procedures are 'snehan' and 'swedan'. Snehan is the oil massage. Oil is applied to the entire body with a particular type of massage which helps the toxins to move towards the gastro-intestinal tract. Oil massage also makes the superficial and deep tissues soft and supple. Snehan is given daily for three to seven days, as indicated. Swedan is sudation or sweating and is given every day immediately following the snehan. An herbal concoction may be added to the steam to further loosen the toxins from the individual. Swedan liquefies the toxins and increases the movement of toxins into the gastro-intestinal tract. After three to seven days of snehan and swedan, the doshas become well "ripened". A particular panchakarma method is then given according to the individual's constitution and disorder, prakruti and vikruti, respectively. Panchakarma - Five Basic Shodhans: Cleansing Methods 1) Vaman : therapeutic vomiting or emesis 2) Virechan : purgation 3) Basti : enema 4) Nasya : elimination of toxins through the nose 5) Rakta moksha : detoxification of the blood Vaman: Emesis Therapy When there is congestion in the lungs causing repeated attacks of bronchitis, colds, cough or asthma, the Ayurvedic treatment is therapeutic vomiting, vaman, to eliminate the kapha causing the excess mucus. First, after the snehan and swedan, three to four glasses of licorice or salt water is administered, then vomiting is stimulated by rubbing the tongue which triggers the vomiting center through the gag reflex. One may alternatively take two to three glasses of salt water which will also aggravate kapha and then rub the tongue to induce vomiting. Once the mucus is released the patient will feel instantly relieved. It is likely that congestion, wheezing and breathlessness will disappear and that the sinuses will become clear. Therapeutic vomiting is also indicated in chronic asthma, diabetes, chronic cold, lymphatic congestion, chronic indigestion and edema. Emetic Substances: madan-emetic nut, madhuka-yastimadhu-licorice, neem-bitter leaf, bimbi, kutaj-kurchi- conessi bark, murva-clematis, triloba-devdaru-deodar, Cedrus deodara, Salt, NaCl, ela-cardamom, nux vomica. Indications for Vaman : used for all kapha type disorders good for pitta headache, dizziness, and nausea will help to release blocked emotions respiratory congestion bronchitis chronic cold sinus congestion kaphagenic asthma Contra-Indications for Vaman : below the age of 12 or over age 65 menstruation pre-menstrual period (one week prior) pregnancy emaciation delicate or sensitive person with too much fear, grief or anxiety hypoglycemia vata prakruti vata diseases heart diseases during vata season acute fever diarrhea obesity Virechan : Purgation Therapy When excess bile, pitta, is secreted and accumulated in the gall bladder, liver and small intestine, it tends to result in rashes, skin inflammation, acne, chronic attacks of fever, biliary vomiting, nausea and jaundice. Ayurvedic literature suggests in these conditions the administration of therapeutic purgation or a therapeutic laxative. Virechan is facilitated with senna leaves, flax seeds, psyllium husks or triphala in a combination that is appropriate for the individual person. Virechan Substances: Senna, prune, bran, flaxseed husk, dandelion root, psyllium seed, cow's milk, salt, castor oil, raisins, mango juice, triphala. Indications for Virechan: allergic rash skin inflammation acne, dermatitis, eczema chronic fever ascites biliary vomiting jaundice urinary disorder enlargement of the spleen internal worms burning sensation in the eyes inflammation of the eyes conjunctivitis gout Contra-Indications for Virechan: low agni acute fever diarrhea severe constipation bleeding from rectum or lung cavities foreign body in the stomach after enema emaciation or weakness prolapsed rectum alcoholism dehydration childhood old age ulcerative colitisAyurveda-Panchakarma Basti & Nasya -2 Basti: Enema Therapy Vata's predominant site is the colon. Ayurvedic basti involves the introduction into the rectum of herbal concoctions of sesame oil, and certain herbal preparations in a liquid medium. Basti, is the most effective treatment of vata disorders, although many enemas over a prescribed period of time are usually required. It relieves constipation, distention, chronic fever, cold, sexual disorders, kidney stones, heart pain, backache, sciatica and other pains in the joints. Many other vata disorders such as arthritis, rheumatism, gout, muscle spasms and headaches may also be treated with basti. Vata is a very active principle in pathogenesis. If we can control vata through the use of basti, we have gone a long way in going to the root cause of the vast majority of diseases. Vata is the main etiological factor in the manifestation of diseases. It is the motive force behind the elimination and retention of feces, urine, bile and other excreta. There are eight main types of basti, according to traditional texts, each with their own indications and contra-indications as listed below. 1. Anuvasana (oil enema) is used in pure vata disorders and when a person is having excess hunger or dryness related to vata imbalances. 2. Niruha-Asthapana (decoction enema) is used, among other conditions, for evacuation of vata, nervous diseases, gastro-intestinal vata conditions, gout, certain fever conditions, unconsciousness, certain urinary conditions, appetite, pain, hyperacidity and heart diseases. 3. Uttara Basti (through the urethra with men or vagina with women) is used for selected semen and ovulation disorders and for some problems involving painful urination or bladder infections. This is not to be used for someone with diabetes. 4. Matra Basti (daily oil enema) is used by someone emaciated by overwork or too much exercise, too much heavy lifting, walking too long of a distance, too much sexual activity or someone with chronic vata disorders. It does not need to be accompanied by any strict dietary restriction or daily routine and can be administered, in the appropriate cases, in all seasons. It gives strength, promotes weight and helps elimination of waste products. 5. Karma Basti (schedule of 30 bastis), 6. Kala Basti (schedule of 15 bastis; 10 oil + 5 decoction) 7. Yoga Basti (schedule of 8 bastis; 5 oil + 3 decoction). 8. Bruhana Basti (nutritional enema) is used for providing deep nutrition in select conditions. Traditionally, highly nutritive substances have been used, such as warm milk, meat broth, bone marrow soup and herbs like shatavari or ashwagandha. General Indications for Basti: constipation low back ache gout rheumatism sciatica arthritis nervous disorders vata headache emaciation muscular atrophy General Contra-Indications for Basti (include but are not limited to the following): Enema therapy should not be used if the patient is suffering from diarrhea, bleeding of the rectum, chronic indigestion, breathlessness, diabetes, fever, emaciation, severe anemia, pulmonary tuberculosis, old age or for children below the age of seven years. for oil enemas: diabetes, obesity, indigestion, low agni, enlarged liver or spleen, unconsciousness, tuberculosis and cough. for decoction enemas: debility, hiccough, hemorrhoids, inflammation of anus, piles, diarrhea, pregnancy, ascites, diabetes and some conditions involving painful or difficult breathing. for nutritional enemas: diabetes, obesity, lymphatic obstruction, ascites. for urethra or vaginal enemas: diabetes Nasya: Nasal Administration The nose is the doorway to the brain and it is also the doorway to consciousness. The nasal administration of medication is called nasya. An excess of bodily humors accumulated in the sinus, throat, nose or head areas is eliminated by means of the nearest possible opening, the nose. Prana, life force as nerve energy, enters the body through the breath taken in through the nose. Prana is in the brain and maintains sensory and motor functions. Prana also governs mental activities, memory, concentration and intellectual activities. Deranged prana creates defective functioning of all these activities and produces headaches, convulsions, loss of memory and reduced sensory perception. Thus nasal administration, nasya is indicated for prana disorders, sinus congestion, migraine headaches, convulsions and certain eye and ear problems. There are six main types of nasya, as listed below. 1. Pradhamana (virechan) Nasya (cleansing nasya) uses dry powders (rather than oils) that are blown into the nose with a tube. Pradhamana nasya is mainly used for kapha types of diseases involving headaches, heaviness in the head, cold, nasal congestion, sticky eyes, hoarseness of voice due to sticky kapha, sinusitis, cervical lymph adenitis, tumors, worms, some skin diseases, epilepsy, drowsiness, Parkinsonism, inflammation of the nasal mucosa, attachment, greed and lust. Traditionally, powders such as brahmi are used. 2. Bruhana Nasya (nutrition nasya) uses ghee, oils, salt, shatavari ghee, ashwagandha ghee and medicated milk and is used mainly for vata disorders. It is said to benefit conditions resulting from vata imbalances such as vata-type headaches, migraine headache, dryness of voice, dry nose, nervousness, anxiety, fear, dizziness, emptiness, negativity, heaviness of eyelids, bursitis, stiffness in the neck, dry sinuses and loss of sense of smell. 3. Shaman Nasya (sedative nasya) is used according to which dosha is aggravated but mainly for pitta-type disorders such as thinning of hair, conjunctivitis and ringing in the ears. Generally certain herbal medicated decoctions, teas and medicated oils are used. 4. Navana Nasya (decoction nasya) is used in vata-pitta or kapha-pitta disorders and is made from decoctions and oils together. 5. Marshya Nasya (ghee or oil nasya) 6. Prati Marshya (daily oil nasya) This helps to open deep tissues and can be done every day and at any time to release stress. Substances Used in Nasya: brahmi, ginger, ghee oils, decoctions, onion, garlic, Piper longum, black pepper, curry pepper, rose, jasmine, mogra flowers and henna. Indications for Nasya: stress emotional imbalances stiffness in the neck & shoulders dryness of the nose sinus congestion hoarseness migraine headache convulsions Contra-Indications for Nasya: sinus infections pregnancy menstruation after sex, bathing, eating or drinking of alcohol should not be used below 7 years or over 80 years of age Click here to read more about 'Nasyakarma' Raktamoksha : Traditional Ayurvedic Method for Purification and Cleansing of the Blood Toxins present in the gastro-intestinal tract are absorbed into the blood and circulated throughout the body. This condition is called toxemia, which is the basic cause of repeated infections, hypertension and certain other circulatory conditions. This includes repeated attacks of skin disorders such as urticaria, rashes, herpes, eczema, acne, leukoderma, chronic itching or hives. In such conditions, along with internal medication, elimination of the toxins and purification of the blood is necessary. Raktamoksha is also indicated for cases of enlarged liver, spleen and gout. Extracting a small amount of blood from a vein relieves the tension created by the pittagenic toxins in the blood. Bloodletting also stimulates the spleen to produce antitoxic substances which helps to stimulate the immune system. Toxins are neutralized enabling radical cures in many blood born disorders. Bloodletting is contraindicated in cases of anemia, edema, extreme weakness, diabetes and in children and elderly persons. Indications for Raktamoksha: urticaria rash acne eczema scabies leukoderma chronic itching hives enlarged liver or spleen gout Contra-Indications for Raktamoksha: anemia edema weakness young children old age during pregnancy during menstruation Read more about Various Diseases and Indicated Panchakarma procedures for them > @Dr. Tapan Kumar Sau11 Likes13 Answers
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A 40 years old female,having a swelling on the right side of the shoulder for 3 days .No fever No pain OE a small round swelling not adherend to skin ,tenderness present. What should be the possible diagnosis and treatment?Pritayan Bhattacharjee1 Like12 Answers
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Septic Thrombosis of the Cavernous Sinuses:- John R. Ebright, MD; Mitchell T. Pace, MD; Asher F. Niazi, MD Author Affiliations Article Information Arch Intern Med. 2001;161(22):2671-2676. doi:10.1001/archinte.161.22.2671 Abstract Septic thrombosis of the cavernous sinuses (or cavernous sinus thrombophlebitis [CST]) is a dramatic and potentially lethal illness, which is still occasionally seen by clinicians. Before the availability of antimicrobial agents, mortality from CST was near 100%, but it markedly decreased to approximately 20% to 30% during the antibiotic era.1,2 Nevertheless, the threat of death and serious morbidity continues to necessitate early recognition, diagnosis, and treatment of CST to minimize risks to the patient. Accordingly, we reviewed the salient clinical features of this illness, with emphasis on newer aspects of diagnosis and treatment. Anatomy Two cavernous sinuses are positioned on either side of the sella turcica, which contains the pituitary gland. These sinuses are connected by intercavernous sinuses located anterior and posterior to the sella. As is true for all dural venous sinuses, the cavernous sinuses are formed by a separation of the layers of dura mater (specifically, the meningeal and periosteal layers), with trabeculae from each layer crossing the spaces, giving them a reticular or cavernous structure. Immediately below, separated by very thin bone, are the sphenoid sinuses. Of great clinical importance is the intimate relationship of cranial nerves III, IV, V, and VI, which, accompanied by the horizontal segment of the internal carotid artery, run through the lumen in the cases of the artery and abducens nerve or through the outside layers of the cavernous sinuses' lateral walls in the cases of the oculomotor, trochlear, and ophthalmic maxillary branches of the trigeminal nerves.4,5 The cavernous sinuses extend from the superior orbital fissure in front backward to the petrous portion of the temporal bone. They receive blood from the superior ophthalmic and cerebral veins and the sphenoparietal sinuses and terminate posteriorly in the superior and inferior petrosal sinuses, which drain into the transverse sinuses and internal jugular veins. In addition, the cavernous sinuses are connected by emissary veins to the pterygoid plexus, which is adjacent to the deep muscles of the face, and also communicates with the deep facial and inferior ophthalmic veins. Pathogenesis The dural sinuses and the cerebral and emissary veins have no valves, which allows blood to flow in either direction according to pressure gradients in the vascular system. This fact and the extensive direct and indirect vascular connections of the centrally located cavernous sinuses make them vulnerable to septic thrombosis resulting from infection at multiple sites. Sinusitis, especially involving the sphenoid and ethmoid sinuses, seems to be the most common primary source of infection predisposing to CST. Infections arising at other locations, such as the face, nose, tonsils, soft palate, teeth (lower and upper), and ears, are less common primary sources since antibiotic therapy has become widely available. Orbital infection is rarely complicated by CST, although the ophthalmic veins drain directly into the orbits.6 The most common signs of CST are related to damage of the nerves that traverse the cavernous sinuses (including the parasympathetic and sympathetic nerves accompanying the oculomotor nerve and the internal carotid artery, respectively) and to engorgement of the retinal and orbital vessels caused by impaired venous drainage. It has been speculated that the trabeculated sinuses act like sieves, trapping bacteria, emboli, and thrombi progressing from anterior infected sites involving the nose, sinuses, or medial third of the face, or in a retrograde fashion from lateral venous sinuses, ears, or teeth. It is possible that more indolent, subacute cases arise from initially sterile thrombi that become infected after extending into the cavernous sinuses and that fulminant, acute cases result from rapid progression of an infected thrombus or septic embolization from a primary infected focus.7 Irrespective of which mechanism is involved, the presence of enlarging infected clots within a confined cavernous sinus spreading via intercavernous sinuses to involve the opposite side is an ominous complication. Systemic effects from sepsis, local effects from direct injury to cranial nerves III through VI and impaired vascular drainage from the face and eyes, and possible extension into adjacent tissue, causing meningitis, subdural empyema, and pituitary necrosis, together may result in an overwhelming and truly catastrophic illness. Microbiologic findings The most commonly identified pathogen in patients with CST continues to be Staphylococcus aureus, identified in 60% to 70% of patients. Less frequently identified are streptococcal species, including Streptococcus pneumoniae; gram-negative bacilli; and anerobes.3 Blood cultures are commonly positive (approximately 70% of cases), especially in patients with acute, fulminant disease, whereas cerebrospinal fluid, abnormal in most patients in terms of elevated white blood cell counts and protein levels, is culture positive in only approximately 20% of cases.8 Occasionally, fungi such as Aspergillus and members of the Mucoraceae family may cause CST.9-11 Clinical presentation Multiple clinical features varying in frequency and severity have been reported, with some, such as septic infarcts of other organs, becoming uncommon since the availability of antibiotic therapy. Another variable in this condition is the timing of the onset of signs and symptoms: patients with acute, fulminant disease will manifest most signs and symptoms rapidly from the outset of illness, and patients with a more subacute course will evidence the features listed in Table 1 sequentially and over several days. Nevertheless, most patients will develop fever, ptosis, proptosis, chemosis, and external ophthalmoplegia during the course of their illness. External ophthalmoplegia, defined as paralysis of the extraocular muscles (in the case of CST, secondary to dysfunction of cranial nerves III, IV, and VI, rather than direct involvement of the extraocular muscles), usually includes all the extraocular muscles. However, it may be more limited or present at least initially with only lateral rectus muscle palsy, especially when disease spreads to the opposite eye. Spread to the opposite eye through the intercavernous sinuses, usually within 24 to 48 hours of the initial unilateral periorbital edema, is a common and characteristic feature of CST. Less frequent, but still seen in most patients, are mild papilledema (usually a late finding), retinal venous engorgement, and altered mental status consisting of lethargy or obtundation. Headaches, an early symptom resulting from either sinusitis or CST, usually are frontal, temporal, or retro-orbital and may be accompanied by tearing. Violaceous edema of the upper lid accompanying periorbital swelling also is common. Decreased visual acuity, internal ophthalmoplegia, and periorbital sensory alteration secondary to trigeminal nerve (cranial nerve V) dysfunction have been reported in less than half of the patients. Internal ophthalmoplegia, defined as paralysis of the iris and ciliary apparatus, results from dysfunction of parasympathetic nerve fibers carried through the cavernous sinuses and optic canals on the oculomotor (cranial nerve III) nerves or dysfunction of the sympathetic fibers that join them to form the short ciliary nerves. As a result, the pupils may be dilated from parasympathetic paralysis or may be smaller and immobile if both parasympathetic and sympathetic fibers are involved. Sensory alteration within the distribution of the first division of the trigeminal nerve may present as hyperesthesia or hypoesthesia possibly with a depressed corneal response. Diplopia, seizures, and hemiparesis are uncommon.3,6 The clinical presentation may be made even more complex as a result of ischemic changes or extension of infection from the cavernous sinuses or primary site of infection to involve the adjacent vascular structures or brain parenchyma. Southwick et al3 reviewed the pathologic findings of 23 patients who died or underwent surgery during the antibiotic era. Extension of the thrombosis to other venous sinuses, including petrosal, inferior sagittal, sigmoid, and lateral, was observed in 7 patients. Such extension may not only worsen headache, obtundation, and papilledema but may also result in additional findings, such as ear and neck pain, odynophagia, dysphagia, hoarseness, lateral-gaze nystagmus, seizures, and hemiplegia. In addition, the same authors7 noted 4 cases of pituitary necrosis due to contiguous spread of infection or ischemic damage, 11 cases of meningitis, and 9 cases of brain abscess or subdural empyema, primarily in the frontoparietal or temporal lobes.3 Differential diagnosis Cavernous sinus thrombophlebitis is only 1 (albeit probably the most dramatic) of many causes of painful ophthalmoplegia. The most common condition mimicking acute CST is orbital cellulitis, which commonly causes periorbital swelling, proptosis, chemosis, ophthalmoplegia, fever, decreased vision, and pain.12 However, bilateral eye involvement, papilledema, decreased periocular sensation, dilated pupils, marked systemic toxic effects, and abnormal spinal fluid are much more likely to be features of CST and aid in differentiating the two conditions. Preseptal cellulitis, which does not cause proptosis and ophthalmoplegia, generally causes little confusion. Orbital apex syndrome, a rare complication of sinusitis, results from inflammation or infection involving 2 clefts in the bony posterior orbit: (1) the superior orbital fissure, which transmits cranial nerves III, IV, and VI and branches of the ophthalmic division of cranial nerve V, and the superior ophthalmic vein, and (2) the optic canal, through which pass the ophthalmic artery and optic nerve. This condition, compared with orbital cellulitis, more typically causes visual loss and ophthalmoplegia out of proportion to or preceding signs of anterior eye involvement, such as proptosis and periorbital edema. Because the optic nerve passes through the apex but not through the cavernous sinus, impaired vision is more common with the orbital apex syndrome than with CST.13,14 Other more indolent or chronic conditions may cause painful ophthalmoplegia owing to involvement of the cavernous sinuses, including local or metastatic malignancy; aseptic thrombosis resulting from trauma, myeloproliferative diseases, or dehydration; granulomatous disease, such as tuberculosis or fungal infection, sarcoid, syphilis, or Tolosa-Hunt syndrome; aneurysm of the internal carotid artery; or carotid-cavernous fistula. Other chronic diseases that may be confused with disease involving the cavernous sinuses are endocrine exophthalmos and ophthalmoplegic migraine.15-20 Diagnosis Before the availability of computed tomography (CT) or magnetic resonance imaging (MRI), CST was diagnosed by its clinical features or at autopsy. Occasionally, cerebral angiography or the more definitive orbital venography was performed, but it was accompanied, at least in the case of orbital venography, by the possibility of serious complications. It was difficult to puncture the frontal veins in patients who were acutely ill with facial edema; in addition, there was much concern that orbital venography, accomplished by injecting contrast material under pressure, may actually disseminate the infection or cause extension of the thrombosis.21 The availability of high-resolution enhanced CT scans and, more recently, MRI has remarkably improved our ability to establish the diagnosis of CST using noninvasive technology. Although there is currently some debate regarding which of the two is the procedure of first choice, most experience is with high-resolution CT performed with a slice thickness of 3 mm or less.22 Abnormal findings include those that are direct signs of CST, consisting of enlargement and expansion of the cavernous sinus with lateral wall flattening or convexity rather than normal concavity, best visualized on coronal images. In addition, multiple irregular or single large filling defects within the enhancing cavernous sinus are highly suggestive direct evidence for thrombi. This is particularly the case when the filling defects are irregular and do not correspond to the anatomic course of neural structures or a thrombosed intracavernous section of the internal carotid artery. They also must be differentiated from intracavernous fat deposits by size (thrombi usually >7 mm), density, and signal intensity.21-24 Indirect signs, related to concomitant venous obstruction, consist of dilation of the superior ophthalmic vein, exophthalmos, soft tissue edema, and thrombi visualized in the veins and sinuses tributary to the cavernous sinus (superior ophthalmic vein and superior petrosal, inferior petrosal, and sigmoid sinuses).21-24 Magnetic resonance imaging may be of greatest value either to reexamine patients with nondiagnostic CT scans or to further assess complications involving the pituitary gland or extension of infection into adjacent meninges or brain.21,22 We report a case of probable mucormycosis in which the organism seems to have invaded the cavernous sinuses from the paranasal sinuses to illustrate these points. Management and treatment Management of patients with CST must also include treatment of primary infections, such as sinusitis, dental abscesses, and facial cellulitis, and possible complications, including brain abscesses, meningitis, and extension to other venous sinuses. Initial antibiotic choice, while awaiting culture results, might consist of nafcillin sodium, metronidazole, and ceftriaxone sodium or cefotaxime sodium to treat the patient for the most common organisms associated with this disease. Vancomycin could be substituted for nafcillin if the risk of methicillin resistance is high. Doses should be high, appropriate for critically ill patients with intravascular and possible central nervous system infections. The duration of antibiotic therapy is not standardized, but 3 to 4 weeks, consistent with management of other intravascular infections, such as endotheliitis or suppurative phlebitis, seems to be a reasonable projection, especially if signs of inflammation, toxic effects, and fever have ceased during that period.25 Surgical drainage of the cavernous sinus is almost never performed, but surgery may be essential for the management of primary sinusitis or dental infection or complicating brain abscess, orbital abscess, or subdural empyema. Similarly, reduction of inflammation and edema by administering systemic corticosteroids is not a well-supported intervention in patients with CST. In a few patients, corticosteroid use may have contributed to improving cranial nerve dysfunction3,26 or persistent orbital congestion.27 Rarely, corticosteroid use may play a critical role in caring for patients with adrenal insufficiency secondary to ischemia or necrosis of the pituitary gland.28,29 Full anticoagulation using heparin, however, is possibly beneficial in select patients. Although no randomized controlled studies have been conducted (and because of the infrequency of this disease, probably never will be conducted), recent retrospective reviews provide some support for heparin use in the absence of cortical venous infarction. Anticoagulant therapy begun early (ie, within 7 days of hospitalization for CST) may reduce morbidity rates in survivors.30 In particular, a reduction in diplopia from cranial nerve dysfunction, unilateral blindness, seizures, hemiparesis, and hypopituitarism may be observed. The review by Southwick et al3 suggests that early anticoagulant therapy in patients with unilateral CST may also reduce mortality rates. Duration of anticoagulant therapy with warfarin sodium after initial heparin therapy is unknown, but 4 to 6 weeks has been suggested.30 Morbidity and mortality Mortality has decreased from 80% to 100% in the preantibiotic era to 20% to 30% since 1940. In addition, Yarington2 points to a decrease in morbidity from 50% to 75% to only 22%. Nevertheless, the threat of temporary complications and long-term sequelae remains. In a review published early in the antibiotic era, Shaw7 described 60 patients treated with either sulfonamides or penicillin: 53 recovered, but most (77%) had complications or long-term sequelae. Twenty-five patients had metastatic infection primarily involving the lungs, with abscesses, empyema, and pneumonia. Nine patients developed orbital abscesses and 5 developed abscesses in the brain. Prolonged cranial nerve dysfunction, especially of nerves III and VI, were the most common long-term sequelae; 5 patients developed unilateral blindness, and 4 had decreased visual acuity. Prominent facial veins and spastic paresis of the arm were also noted but were unusual.7 A more recent review3 of 96 patients treated since 1940 found 29 to have long-term sequelae, including oculomotor (cranial nerve III) weakness in 16 (17%) of 95 patients, blindness in 16 (17%), pituitary insufficiency in 2 (2%), and hemiparesis in 3 (3%). The cause of blindness has been speculated to be pressure on the retinal artery and vein at the orbital apex, arteritis of the internal carotid artery, emboli to the retinal artery, or toxic neuropathy of the optic nerve.31 Pituitary insufficiency, a rare but well-documented event, results from either infarction or extension of infection into the sella turcica.29 Hemiparesis may be a consequence of internal carotid artery occlusion, cerebral abscess, or cortical vein thrombosis.30 Conclusions Although rare, CST remains a dramatic and potentially lethal complication of infections involving the sinuses, face, ears, and oral cavity. Early recognition and differentiation from other diseases that can mimic it coupled with aggressive medical and possible surgical intervention are key to reducing mortality rates and long-term sequelae. Recent improvements in imaging, especially CT and MRI, have contributed substantially to the rapid diagnosis of this conditionDr. Gaurav Chhaya3 Likes3 Answers
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✍️✍️Late Effects Of Blood And Marrow Transplantation ___________________________________________ Abstract Hematopoietic cell transplantation is a curative treatment for a variety of hematologic diseases. Advances in transplantation technology have reduced early transplant-relatedmortality and expanded application of transplantation to older patients and to a wider variety of diseases. Management of late effects after transplantation is increasingly important for a growing number of long-term survivors that is estimated to be half a million worldwide. Many studies have shown that transplant survivors suffer from significant late effects that adversely affect morbidity, mortality, working status and quality of life. Late effects include diseases of the cardiovascular, pulmonary, and endocrine systems, dysfunction of the thyroid gland, gonads, liver and kidneys, infertility, iron overload, bone diseases, infection, solid cancer, and neuropsychological effects. The leading causes of late mortality include recurrent malignancy, lung diseases, infection, secondary cancers and chronic graft-versus-host disease. The aim of this review is to facilitate better care of adult transplant survivors by summarizing accumulated evidence, new insights, and practical information about individual late effects. Further research is needed to understand the biology of late effects allowing better prevention and treatment strategies to be developed. Introduction Hematopoietic cell transplantation (HCT) is a curative treatment for a variety of hematologic diseases.1 The safety of HCT has improved over the decades,2 indications for HCT have expanded to older patients,3 and almost all patients are able to find suitable allogeneic donors by the growing use of cord blood4 and haploidentical transplantation.5 These current conditions have contributed to a growing number of HCT survivors, estimated to be half a million worldwide.6 Patients who are disease-free at two or five years after HCT have a greater than 80% subsequent 10-year survival rate,7–10 but many studies show that HCT survivors suffer from significant late effects that adversely affect morbidity, mortality, working status and quality of life.7–13 A prospective observational study of 1022 survivors who underwent HCT between 1974 and 1998 showed that 66% of the survivors had at least one chronic condition and 18% had severe or life-threatening conditions.14 A retrospective study of 1087 contemporary survivors also showed that the cumulative incidence of any non-malignant late effect at five years after HCT was 45% among autologous and 79% among allogeneic recipients, and 2.5% of autologous and 26% of allogeneic recipients had three or more late effects.15 Life expectancy among 5-year survivors remained 30% lower compared with the general population, regardless of their current ages and years since HCT.9 The leading causes of excess deaths in 5-year survivors included secondary malignancies (27%) and recurrent disease (14%), followed by infections (12%), chronic graft-versus-host disease (GvHD) (11%), cardiovascular diseases (11%), and respiratory diseases (7%).9 The aim of this review is to facilitate better care of adult HCT survivors by summarizing accumulated evidence, new insights, and practical information about individual late effects (Figure 1). Recurrent disease and chronic GvHD are not discussed and readers are referred to other reviews.16–20 Figure 1. Download figure Open in new tab Download powerpoint Figure 1. Late effects of blood and marrow transplantation. Cardiovascular diseases Cardiovascular diseases (CVD) after HCT include cardiomyopathy, congestive heart failure, valvular dysfunction, arrhythmia, pericarditis, and coronary artery disease.21 Their cumulative incidences were 5%–10% at ten years after HCT,22–24 accounting for 2%–11% of mortality among long-term survivors.8,9,25 The incidence of CVD and its associated mortality were 1.4–3.5-fold higher compared with the general population.8,9,24,25 HCT survivors are more likely to have conventional risk factors such as dyslipidemia and diabetes than the general population.26 Early diagnosis and treatment of modifiable risk factors is important. We usually treat hypertension more than 140/90 mmHg on 2 separate visits or more than 130/80 mmHg for patients with diabetes or renal disease.27 The first step is lifestyle modification including weight reduction, dietary sodium reduction and regular physical activity, followed by initiating antihypertensive drugs such as angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs). Anthracycline exposure and chest radiation are the major risk factors for CVD after HCT.21 Several studies showed that dexrazoxane, ACE inhibitors, ARBs and beta-blockers can prevent anthracycline-related cardiomyopathy in the non-HCT setting.28–32 Once cardiomyopathy is established, it is important to initiate appropriate treatment. ACE inhibitors and beta-blockers have been effective in improving left ventricular function.33 Pulmonary diseases Non-infectious late complications of the lung include bronchiolitis obliterans syndrome (BOS), cryptogenic organizing pneumonia (COP) and pulmonary hypertension. BOS represents chronic GvHD of the lung, and is characterized by the new onset of fixed airflow obstruction after allogeneic HCT.34 According to the strict 2005 National Institutes of Health (NIH) diagnostic criteria for chronic GvHD, incidence of BOS was 5.5% and its prevalence was 15% among patients with chronic GvHD.35 Symptoms of BOS include dyspnea on exertion, cough and wheezing, but early BOS may be asymptomatic until significant lung function is lost.36 One study showed rapid decline in %FEV1 during the six months before BOS diagnosis, with a lower %FEV1 at diagnosis associated with worse survival.37 In our practice, we perform pulmonary function tests every three months including %FEV1 and FEV1/FVC among patients with active chronic GvHD. When testing shows significant new airflow obstruction, we repeat testing every month until stability is confirmed.38 Plasma matrix metalloproteinase 3 levels39 and parametric response mapping from CT scans40 might be useful diagnostic tests for BOS but these have not yet entered clinical practice. Standard treatment of BOS is prednisone at 1 mg/kg per day, followed by a taper to reach a lower, alternate-day regimen.38 A multicenter prospective study showed that addition of FAM (inhaled fluticasone propionate at 440 μg twice a day, azithromycin at 250 mg taken 3 days per week, and montelukast at 10 mg nightly) to prednisone treatment stabilized pulmonary function in 70% of patients with newly diagnosed BOS and permitted systemic steroid exposure to be reduced.41 Cryptogenic organizing pneumonia is a disorder involving bronchioles, alveolar ducts, and alveoli, the lumen of which become filled with buds of granulation tissue consisting of fibroblasts.42 Clinical symptoms include dry cough, shortness of breath, and fever. Bronchoalveolar lavage is performed to exclude infection. Lung biopsy is required for definitive diagnosis, but an empiric diagnosis is often based on radiographic findings of diffuse, peripheral, fluffy infiltrates consistent with airspace consolidation. Pulmonary function testing shows restrictive changes and low diffusing capacity of the lungs for carbon monoxide. The incidence of COP is 2%–10%,43,44 and it is strongly associated with acute and chronic GvHD.45 COP usually responds within 5–7 days to prednisone at 1 mg/kg per day, which is continued for one month followed by a slow taper over five months because COP can often recur. Small case series suggest potential benefits of macrolides for treatment of COP.46 Pulmonary hypertension is an uncommon but potentially fatal complication after HCT, with a reported prevalence of 2.4%.47 The most common symptoms are hypoxia, tachypnea, dyspnea, and acute respiratory failure,48 and if untreated, pulmonary hypertension can result in a progressive increase in pulmonary vascular resistance, right ventricular failure and death. Since initial symptoms are non-specific, it is likely to be underdiagnosed after HCT. Although cardiac catheterization is the gold standard for diagnosis of pulmonary hypertension, high-resolution chest computed tomography and echocardiography are non-invasive and useful diagnostic modalities. The most common types are pulmonary arterial hypertension and pulmonary veno-occlusive disease, sometimes associated with transplant-associated microangiopathy and inherited or acquired hemolytic anemia.48 First-line therapies are supplemental oxygen and phosphodiesterase-5 inhibitors, followed by inhaled nitric oxide, diuretics, bipyridine inotropes and after-load reducing agents.48 Endocrine diseases Major late effects in the endocrine system include thyroid dysfunction, diabetes, dyslipidemia, and adrenal insufficiency. Hypothyroidism occurs in 30% of patients by 25 years after HCT.49 Risk factors include age under ten years, conditioning containing radiation, busulfan or cyclophosphamide, and hematologic malignancies.49,50 The international guidelines recommend checking serum thyroid-stimulating hormone and free thyroxine levels every year.21 For patients who received radiolabeled iodine antibody therapy, thyroid function should be checked earlier starting at three and six months after HCT, and other times as clinically indicated. Standard criteria are used to initiate replacement therapy for hypothyroidism. Some patients develop hyperthyroidism after HCT as a rare complication.51 Diabetes occurs in 8%–41% of patients after allogeneic HCT and in 3% of patients after autologous HCT.15,52,53 Its incidence after allogeneic HCT is 3.65 times higher compared with their siblings.54 Initial treatment is therapeutic lifestyle counseling, but many patients require hypoglycemic agents or insulin. Dyslipidemia occurs in 9%–61% of HCT survivors.53,55 Despite no established consensus for management of dyslipidemia after HCT, our practice is to initiate therapeutic lifestyle counseling followed by statin therapy when LDL cholesterol exceeds 130–190 mg/dL according to the estimated risk of CVD, based on the National Cholesterol Education Program Adult Treatment Panel III guidelines56 and the recently suggested approach after allogeneic HCT.57 The 2013 ACC/AHA guidelines do not specify the targeted levels for LDL cholesterol, and addition of statin therapy is based on calculated risk for future cardiovascular events.58 Addition of omega-3-acid ethyl esters or fibrate is considered when fasting triglycerides exceed 200–499 mg/dL. Adrenal insufficiency occurs in 13% of patients after allogeneic HCT and 1% of patients after autologous HCT,15 and can be confirmed by a cortisol-stimulation test. Once adrenal insufficiency is diagnosed, physiological glucocorticoid replacement and a very slow terminal taper is needed. Patients should carry notification that they have adrenal insufficiency to alert emergency medical providers. For chronic GvHD therapy, the risk of adrenal insufficiency is lower with alternate-day administration of corticosteroids than with daily dosing,59 although patients with brittle diabetes need daily dosing to allow for optimal glucose control. Male gonadal dysfunction and infertility Hypogonadism is common after HCT. Impaired spermatogenesis, erectile dysfunction, low testosterone, and low libido occur in male patients. Erectile dysfunction and low libido have been associated with both physical and psychosocial factors.60,61 Testosterone replacement may be considered for patients with low testosterone levels and has improved sexual function, libido and bone mass, although monitoring prostate-specific antigen and testosterone levels is necessary.62,63 Azoospermia occurred in 70% of male patients, and spermatogenesis recovered in 90% of patients conditioned with cyclophosphamide alone, in 50% of patients conditioned with cyclophosphamide plus busulfan or thiotepa, and in 17% of patients conditioned with total body irradiation (TBI).64 Semen banking or cryopreservation of testicular tissue should be discussed before HCT with patients desiring fertility. Female gonadal dysfunction, infertility and pregnancy Ovarian insufficiency, vaginal changes and low libido occur in female patients. A historical study showed that ovarian failure occurred in more than 90% of female patients after HCT and recovered in 92% of patients conditioned with cyclophosphamide alone, but only in 24% of patients conditioned with cyclophosphamide and TBI.65 A pilot study showed that only 10% of patients had ovarian failure after reduced-intensity allogeneic HCT.66 The use of hormone replacement therapy for premature ovarian failure should be individualized based on the patient age, severity of menopausal symptoms, low bone density, risk of breast cancer, clotting predisposition and liver abnormalities.67 Since efficacy of gonadotropin-releasing hormone agonists in preserving fertility in cancer patients is controversial,68,69 cryopreservation of oocytes, ovarian tissue, or embryos should be discussed with patients desiring fertility.70 The largest study of pregnancy after HCT showed that 0.87% of patients or their partners had pregnancies after allogeneic HCT, and 0.36% of those after autologous HCT.71 We generally recommend that women wait 2–5 years after HCT before attempting conception since rates of relapse are generally highest in the first two years after HCT. Another concern is the theoretical risk of recurrent malignancy because of disturbance of the graft-versus-leukemia effect, and some cases of recurrent chronic myeloid leukemia after conception have been reported.71 Pregnancy outcomes are generally good with no increase in the risk of fetal malformations, although these pregnancies are considered high risk because of higher maternal risks of pregnancy complications.71 Iron overload Iron overload is rare after autologous HCT72 but common after allogeneic HCT.73,74 Previous prospective studies showed that 30%–60% of long-term survivors of allogeneic HCT had elevated serum ferritin levels and 25%–50% had elevated liver iron concentration on T2* magnetic resonance imaging (MRI).73,74 Since serum ferritin does not specifically reflect iron overload and can be elevated in hepatic and systemic inflammation, additional testing is required if the ferritin is elevated. We favor transferrin saturation, which is widely available and defined as the ratio of serum iron concentration divided by total iron-binding capacity.75 Normal transferrin saturation is less than 50% in males and less than 45% in females. Patients with iron overload usually have saturation more than 60%. HFE genotyping is considered in patients with a family history of hemochromatosis and in patients of Northern or Western European ethnicity. When saturation is not elevated, other etiologies for an elevated ferritin including inflammation, metabolic syndrome, and alcoholism should be ruled out. The most accurate test of tissue iron concentration is liver biopsy, but the procedure is invasive and may cause serious complications. Thus, T2* MRI and other modalities (FerriScan and superconducting quantum interference device) have been increasingly used.76 Importantly, liver tests are often normal among long-term survivors with iron overload, so hepatitis and GvHD should also be considered when results of liver tests are elevated.77 Iron overload may cause cardiomyopathy. Studies of thalassemia patients showed that cardiomyopathy typically took more than ten years to be clinically evident,78 and that many patients improved with intensive chelation therapy.79 Although a prospective study and a meta-analysis showed no statistical association of liver iron concentration with mortality after allogeneic HCT,80,81 our practice is to start phlebotomy of 5 mL/kg or 250–300 mL every 3–4 weeks as long as hematocrit is more than 35% until serum ferritin falls below 1000 ng/mL. Deferasirox, an oral chelating agent, is considered for patients with anemia precluding phlebotomy. Liver diseases Late liver diseases include chronic hepatitis B, chronic hepatitis C, liver cirrhosis, nodular regenerative hyperplasia and focal nodular hyperplasia.77 Hepatitis B-infected patients have an increased risk of fulminant liver failure. One study reported a 35% risk of HBV reactivation after HCT even among patients with isolated anti-HBc antibodies, mostly during steroid treatment for GvHD.82 Patients treated with anti-CD20 antibodies have an increased risk of HBV reactivation. Antiviral prophylaxis using entecavir or lamivudine will prevent almost all fulminant cases if initiated before the start of conditioning regimens in patients with positive blood HBV DNA levels.83 Patients with latent HBV (i.e. anti-HBc+/HBV DNA−) should be monitored monthly with HBV DNA levels after HCT and antiviral treatment should be initiated when viremia is detected.83 Hepatitis C virus infection in HCT survivors almost always results in chronic hepatitis.84,85 Typically, asymptomatic elevation of alanine aminotransferase occurs 2–4 months after HCT, coinciding with tapering of immunosuppressive medications. There may be little liver-related mortality in the first ten years after HCT,84 but liver cirrhosis occurs later with a cumulative incidence of 4%–24% at 20 years.85,86 A large retrospective study showed that hepatitis C-infected patients had an increased risk of 2-year non-relapse mortality due to hepatic problems and bacterial infection.87 Antiviral therapy for HCV has not been given early after HCT, but may improve both oncological and hepatic outcomes after HCT.88 Ribavirin and interferon-based therapy have been used for patients who have discontinued all immunosuppressive medications without active GvHD, but it can cause pancytopenia and GvHD. Recently, highly effective and well tolerated direct acting antiviral agents with more than 90% rates of sustained virological response have been developed, and interferon-free regimens are now the treatments of choice.89,90 Nodular regenerative hyperplasia is a rare liver condition characterized by a widespread benign transformation of the hepatic parenchyma into small regenerative nodules.77 This process is usually asymptomatic unless portal hypertension develops. Focal nodular hyperplasia occurs in 12% of HCT survivors, and possibly reflects sinusoidal injury caused by myeloablative conditioning regimens.91 Kidney diseases Chronic kidney disease (CKD) is defined as an elevated serum creatinine level, or a decreased glomerular filtration rate (GFR) less than 60 mL/min/1.73 m2 for three months or longer.92 CKD occurs in approximately 20% of HCT recipients.93–95 There are three major etiologies of CKD after HCT: thrombotic microangiopathy (TMA), nephrotic syndrome and idiopathic CKD. Other etiologies include persistent acute kidney injury and BK virus nephropathy.96 Whenever possible, renal biopsy should be considered to accurately diagnose the etiology of CKD and to provide appropriate management.97 Thrombotic microangiopathy occurs in 2%–21% of patients after HCT, and is characterized by renal dysfunction, thrombocytopenia, neurological dysfunction, hemolytic anemia with schistocytes, elevated lactate dehydrogenase and decreased haptoglobin.98,99 Risk factors of TMA include TBI, calcineurin inhibitors, and acute and chronic GvHD.100–102 TMA-related kidney injury often improves with tapering or stopping calcineurin inhibitors, but full renal function is rarely restored.103 In some cases TMA did not improve until GvHD was treated.104 Efficacy of plasma exchange is limited.105 Nephrotic syndrome occurs in 6%–8% of patients after allogeneic HCT.106,107 Membranous nephropathy comprised 61% of cases, and minimal change disease comprised 22% of cases, with a median onset of 14 months and eight months after HCT, respectively.108 Mechanisms of membranous nephropathy are thought to be formation of immune complexes through allo- or auto-antibodies recognizing antigens expressed by the podocyte, while T cells are implicated with minimal change disease.109 Nephrotic syndrome after HCT is often associated with chronic GvHD and tapering of immunosuppressive medications. Initial treatment is prednisone 1 mg/kg/day in addition to calcineurin inhibitors. Complete response was observed in 90% of patients with minimal change in disease, but only in 27% of patients with membranous nephropathy.108 Refractory cases may be treated with rituximab or mycophenolate mofetil.110 Idiopathic CKD comprises most cases of CKD. Risk factors include acute GvHD, chronic GvHD, acute kidney injury, long-term use of calcineurin inhibitors and previous autologous HCT,94,111 suggesting that GvHD, accompanying treatment and inflammatory conditions may have pathogenic roles in this entity. Associations of TBI with risk of CKD have been controversial.94,112 ACE inhibitors and ARBs have been used to treat CKD and hypertension associated with CKD.113 Bone diseases Late complications of bone include osteopenia, osteoporosis and avascular necrosis (AVN).114 Osteoporosis has been reported in as many as 50% of HCT recipients.115,116 The diagnoses of osteopenia and osteoporosis are made by measuring T-scores with dual-energy X-ray absorptiometry. A T-score between −1.0 and −2.5 indicates osteopenia, and a T-score less than −2.5 or presence of a fragility fracture indicates osteoporosis.117 Multiple risk factors are implicated including chemotherapy, radiation, corticosteroids, calcineurin inhibitors, vitamin D deficiency, and gonadal failure.116,118 Bone loss occurs within 6–12 months after HCT, and recovery of bone mineral density (BMD) begins from the lumber spine, followed by a slower recovery in the femoral neck. The use of corticosteroids is the strongest risk factor for osteoporosis. General preventative recommendations include adequate intake of calcium of 1200 mg per day or over and vitamin D of 1000 IU (25 μg) per day or over, regular weight-bearing exercise, and avoidance of smoking and excessive alcohol. Bisphosphonates are the primary treatment for bone loss.119 Patients who are taking 5 mg or more daily prednisone-equivalent steroids for three months or more should have screening BMD tests for osteoporosis, and bisphosphonate treatment may be indicated until corticosteroid treatment is discontinued or for up to five years.120 Second-line treatment includes calcitonin, raloxifene, denusomab, romosozumab, and blosozumab, though their reported use in HCT recipients is limited and adverse effects may be more prominent than with the bisphosphonates. Avascular necrosis occurs in 4%–19% of HCT survivors with a cumulative incidence of 3%–10% at five years after HCT.121,122 AVN causes severe bone pain and bone destruction, causing significant impairment in quality of life. AVN typically affects the femoral heads, but sometimes affects other joints such as the knee and shoulders.21 Risk factors for AVN include corticosteroids, calcineurin inhibitors, older age and TBI conditioning.114 When AVN is suspected, diagnostic MRI should be performed. Early involvement of an orthopedic specialist is important for management of AVN, including conservative treatment, joint-preserving surgery and joint replacement surgery.21,114 Infectious diseases All HCT survivors have some degree of immunodeficiency, particularly during the first year after HCT.123 If patients are able to stop immunosuppressive medications without GvHD or recurrent disease, many recover adequate immune function by one year after HCT. Patients with chronic GvHD, however, remain immunodeficient and have a high risk of infections. Common late infections are caused by Pneumocystis jirovecii, encapsulated bacteria, fungi, varicella-zoster virus (VZV), cytomegalovirus, and respiratory viruses. Patients may report more frequent episodes of upper respiratory infections and sinusitis. All patients should receive prophylaxis against Pneumocystis jirovecii for at least one year after HCT or until 3–6 months after all immunosuppressive medication is discontinued, whichever occurs later. The preferred drug is trimethoprim-sulfamethoxazole, but dapsone or atovaquone could be substituted for patients who are allergic to or intolerant of trimethoprim-sulfamethoxazole. In particular, patients with chronic GvHD are highly susceptible to encapsulated bacteria such as Streptococcus pneumoniae, Haemophilus influenzae and Neisseria meningitidis due to low levels of opsonizing antibodies, low CD4+ T-cell counts, poor reticuloendothelial function and suppressive effects of immunosuppressive medications on phagocytosis. Vaccination against these bacteria is recommended.124 Efficacy of vaccination in increasing antibody levels has been shown in several prospective studies.125,126 Chemoprophylaxis is always recommended due to the unpredictable protection provided by vaccination. The first-line drug is trimethoprim-sulfamethoxazole, but if it is not tolerated, penicillin or azithromycin is substituted until 3–6 months after discontinuation of all immunosuppressive medications. Invasive fungal infection occurs in 1% of patients after autologous HCT and in 6%–8% of patients after allogeneic HCT.127 GvHD and long-term use of corticosteroids have been a major risk factor associated with onset of invasive fungal infection.128 As recommended in the European guidelines, mold prophylaxis with posaconazole or voriconazole may be considered for patients with GvHD requiring high-dose corticosteroid treatment.129 Varicella-zoster virus-seropositive patients should receive prophylaxis with acyclovir or valacyclovir during the first year after HCT or until six months after discontinuation of immunosuppressive medications. A standard dose of acyclovir is 800 mg twice daily,130 but some studies showed that 200 mg once daily was effective in preventing VZV reactivation.131 Acyclovir should be started empirically if the patient presents with an acute abdomen or hepatitis typical of fulminant visceral VZV infection.132 CMV monitoring in blood is continued beyond 100 days after HCT until one year for patients at risk of late CMV disease, including CMV-seropositive patients receiving high-dose corticosteroids, those who have already experienced CMV reactivation, and cord blood transplantation.133 Pre-emptive therapy is usually considered for CMV levels of 250 IU/mL or more (equivalent to ≥1000 copies/mL) or a positive antigenemia test. Community-acquired respiratory virus infections are an important cause of morbidity and mortality after HCT. The most frequent viruses include rhinovirus, respiratory syncytial virus (RSV), parainfluenza viruses (PIV), human metapneumovirus, and influenza viruses as these frequently cause lower respiratory tract disease associated with 12%–100% mortality.134 An immunodeficiency scoring index can predict severity of RSV infection.135 Aerosolized ribavirin showed efficacy in treating lower tract RSV after HCT.136 Combination therapy with immunomodulators such as intravenous immunoglobulin or palivizumab has been seen to have variable success.137 Treatment for PIV infection has not been established. Efficacy of ribavirin has been limited for patients with lower respiratory tract infection of PIV.138 Novel drugs such as a recombinant sialidase fusion protein and a hemagglutinin-neuraminidase inhibitor are under investigation.138 Solid cancers There is an increased risk of solid cancers following both autologous and allogeneic HCT compared with the general population. The cumulative incidence is 1%–6% at ten years after HCT, and continues to rise over time without a plateau.139–142 The most common sites include oral cavity, skin, breast and thyroid, but rates are also elevated in esophagus, liver, nervous system, bone and connective tissues compared with the general population.143 Myeloablative TBI, young age at HCT, chronic GvHD and prolonged immunosuppressive medications beyond two years are well-documented risk factors for many types of cancers.143 All HCT recipients should be advised of the risk of second cancers and should be encouraged to undergo recommended screening tests based on their predisposition.143 The 5-year overall survival rates after diagnosis of solid cancers varied by cancer site, with 88%–100% for thyroid, testis and melanoma, approximately 50% for breast, mouth, soft tissue and female reproductive organs, and 20% or less for bone, lower gastrointestinal tract, and central nervous system.144 These rates were similar to those of de novo cancers, except that rates were lower for female reproductive organs, bone, colorectum, and central nervous system, although further studies are warranted to confirm this observation. There is emerging evidence that human papilloma virus (HPV) is involved in the pathogenesis of squamous cell cancer after HCT.145,146 The efficacy of HPV vaccination in preventing squamous cell cancer after HCT remains to be determined in prospective studies.147 Neuropsychological effects Neuropsychological effects after HCT are being increasingly recognized and include, among others, depression, post-traumatic stress disorder, and neurocognitive deficits. Depression occurs in 12%–30% of HCT survivors and is more frequent in female patients, younger patients and those with poor social support, history of recurrent disease, chronic pain, and chronic GvHD.148 Post-traumatic stress disorder occurs in 28% of patients at six months after HCT and may persist for 5%–13% of cases, although its risk factors are not yet clear.148–150 Neurocognitive deficits, so called “chemo brain”, have adverse functional impacts on HCT survivors who return to work and daily activities that require short-term memory, information-processing speed, multitasking and co-ordination.151 Neuropsychological tests can help identify neurocognitive deficits. Most evidence is derived from studies of breast cancer survivors, with estimated rates of deficits ranging from 16% to 50% up to ten years after treatment.152,153 Potential mechanisms for chemotherapy-induced neurocognitive changes include cytokine and immune dysregulation, damage to DNA and telomere length through cytotoxic agents, oxidative stress and hormonal changes.154 In cases of HCT survivors, there may be additional deficits derived from neurological complications including nervous system infection (HHV-6, fungi, etc.), immune-mediated damage, and toxicities of calcineurin inhibitors such as TMA and posterior reversible encephalopathy syndrome. A prospective observational study showed that neurocognitive function declined substantially at 80 days after HCT, returned to pre-transplantation levels at one year, and continued to improve between one and five years after HCT, except for motor dexterity and verbal learning and retention.155 Mostly mild, neurocognitive dysfunction according to the Global Deficit Score persisted at five years in 42% of long-term survivors.155 Rehabilitation programs have succeeded in improving neurocognitive functions,156 and methylphenidate and modafinil have demonstrated variable efficacies to improve neurocognitive function in non-HCT cancer patients.157,158 Efficacies of these interventions remaine to be determined among HCT survivors. Influence of newer practices on late effects An understanding of the influence of newer practices such as cord blood transplantation, non-TBI or reduced-intensity conditioning regimens and older patients on the incidence and severity of late effects awaits longer follow up. For example, TBI is associated with an increased risk of many late effects such as cardiovascular diseases, COP, hypothyroidism, diabetes, dyslipidemia, infertility, TMA-related kidney injury, bone density loss, avascular necrosis, and secondary solid cancer.49,54,100,102,114,118,143,159,160 The use of non-TBI conditioning regimens might reduce the burden of these late effects among HCT survivors. Some studies found that cumulative incidences of late effects did not differ much after reduced-intensity regimens compared with myeloablative regimens,15,161 and reduced-intensity conditioning was associated with a higher risk of recurrent malignancy among patients with myeloid malignancy.162 One study showed that the risk of AVN was elevated after cord blood transplantation, but graft source had a limited influence on other long-term health status and QOL.163 Consensus guidelines for late effects and prevention behaviors Incidence, mortality, morbidity and management of individual late effects are summarized in Tables 1 and 2. Recognizing the importance of managing late effects after HCT, the Center for International Blood and Marrow Transplant Research (CIBMTR), the European Group for Blood and Marrow Transplantation (EBMT), and the American Society for Bone Marrow Transplantation (ASBMT) developed recommendations in 2006 for screening and prevention practices for HCT survivors.164 Consensus recommendations were up-dated in 2011 including other international transplant communities.21 The NIH convened working groups to formulate late effects initiatives in 2015.148,165–169 View inlineDownload powerpoint Table 1. Late effects after blood and marrow transplantation View inlineDownload powerpoint Table 2. Tests, preventive approaches and treatment of late effects. Despite higher levels of engagement with health care providers, HCT survivors had similar health and prevention behaviors as matched untransplanted controls, suggesting the need for further education of both HCT survivors and health practitioners.170 Major modifiable predictors of lower adherence to preventive care practices were concerns about medical costs and lack of knowledge.171 Conclusion While the number of HCT survivors is growing, there is no evidence that the burden of late effects is lessening. HCT survivors face myriad late effects that can limit their functioning, require prolonged or life-long medical treatment, reduce their quality of life and also shorten their survival. To the extent that the HCT procedure itself causes these late effects, the transplant community has a responsibility to appropriately monitor, treat and ultimately try to prevent late effects. Given the dispersion of survivors and the varied structure of health care, hematologists, oncologists, primary care physicians and medical subspecialists are all involved in providing this care. Further research is needed to understand the biology of late effects to help identify better prevention and treatment strategiesDr. Ved Srivastava3 Likes3 Answers