A large left intracerebral haemorrhage due to uncontrolled hypertension with ventricular extension,midline shift and cerebral oedema . Start mannitol 8 hourly, inj Eptoin 8 hourly, urgent control oh hypertension, decompression of clot,evacuation of clot , placement of EVD . Post operative ventilatory support and supportive care with correction of fluid and electrolyte replacement including blood transfusion if required
Intracranial haemorrhage with intraventricular extension and midline shift. Neurosurgical consultation
Please clarify about neurological status 1. Concious , alert, oriented which is GCS 15/15- then medical management OR 2. E3V4M4 that is 11/15- then ventilation SOS surgery Please follow protocol of medical management http://banuprakashas.blogspot.in/2013/06/neurosurgery.html?m=1 Sms me your email I'd for complete new edition of protocol management Neurosciences Ideas comes like lightening, eureka, its not my way to greedily hang onto it be it medicine, life, politics to selfishly implement it myself, waiting for top person or stage to gain money or fame. Thats the reason of my blog. Its got pearls of my understanding of life. For after I lost two extremely intelligent friends one for infection, one in accident both perils of mismanaged society. My endeavor in AAP togive those two souls peace n assurance that not many get lost in future. Thats my shraddhanjali to them for which I would work till last breath. Few of the other posts are strong worded to give truth its due for You know im not afraid of death ensuring i live my bucket list as and when possible, but just wantu inspire as many before TO LIVE AS THOUGH YOU WILL DIE TOMORROW & LEARN AS IF YOU LIVE FOREVER preventive neurosurgery helmet, NO drink n drive, mobile phone handsfree cords avoid jerks n bumpy rides for spine health early consultation n MRI to prevent secondarily complications of diseases preventive strategy for the family members for primary prevention HEADACHE management stop smoking and alcohol, Take plenty of water, raw-vegetables,sprouts,fruits,overnight soaked nuts, butter milk,honey-ORGANIC, sunlight exposure, pranayama & ASHTANGA yoga, Music tl http://banuprakashas.blogspot.in/2013/09/health.html target="_blank">http://banuprakashas.blogspot.in/2013/09/health.html target="_blank">http://banuprakashas.blogspot.in/2013/09/health.html target="_blank">http://banuprakashas.blogspot.in/2013/09/health.html BP , Physician opinion to rule out hypertension Tab ECOSPIRIN 75 mg 0-0-1 or 1-0-1 or 1-1-1 according to weight n severity Tab crocin 500 when pain Psychiatry opinion if stress/ depression Rule out cervical/ CVJ- RA related occipital neuralgia If migraine with nausea.... T.Naxdom SOS 250mg 1-0-1 if weight<50 kgs, 500mg 1-0-1 if wt>50 kgs. when severe headache with lack of sleep patient is lean T.Tryptomer or T. profigran 10mg 0-0-1 patient is obese, T.Topema 25 mg 0-0-1 or 0-0-2 acc. to body weight If temporal arterial tenderness tab microcid. 75mg 0-1-0 or tab wysolone 10mg 1-0-0 NEUROLOGICAL EMERGENCY-UNCONCIOUS PATIENT Asses GCS, pupils, vitals, Spine Immobilisation (trauma, hanging)-spine board, head block with strap A B C D E F G H I of emergency care. physician, surgeon opinion Correct hypoglycemia, hypoxia, hypovolemia, hypercarbia, electrolyte abnormality and correct. under alcohol influence.....Check GRBS <70 dextrose 25%, inj thiamine 100mg IM if hypotension<90 mm HG take blood sample for serum Na, Hypertonic saline bolus according to GCS 100 for 14-12 , 150 for 11-13, 200 for 10-7, 250 for 8-7, 300ml for 6-3 If SBP >90 Mannitol in ml per Kg body weight STAT dose, frequency as per GCS at time of giving the dose 1.5 for 14-12 , 2 for 11-13, 5 for 7-10, 6 for 4-6, 8 for 3. If unconcious inj Valparin 20 mg/kg stat, 10mg/kg BD reassess GCS after CT scan and repeat if severe edema and no improvement . consider for EVD, surgical procedure if needed Low GCS <10, Pupillary asymmetry, severe brain edema / MLS-midline shift : intubate and ventilate. HEAD INJURY MANAGEMENT Inj eptoin 20 mg/kg in 100 ml NS over 20 min followed by 5 mg/kg/day. Inj pcm 15 mg/kg bd Iv emeset 1mg tid Iv pan 10 mg BD IVF NS+mvi @ 1ml/kg/hr adjusted according to I/O, fever, CVP Get PT, INR , group cross match, Baseline Serum electrolytes...Na under alcohol influence.....Check GRBS <70 dextrose 25%, inj thiamine 100mg IM If GCS<15 Inj mannitol 1.5ml/kg tid 3%saline 100 ml+1gm MgSO4 @ 0.5ml/kg/hr if sodium <120, 0.4<125, 0.3<130 ,0.25<135, 0.2<140, 0.15<145 monitorserum Na BD/OD. Tab minocycline 200 mg 1-0-1 If not allergic to sulfa drugs SC inj/Tab glybenclamide check GRBS General surgery opinion to rule out polytrauma, Faciomaxillary opinion SOS Abrasions H2O2, betadine, T bact oint. Laceration-debride suture under LA, IV antibiotic Music therapy , stop smoking and alcohol, pranayama & ASHTANGA yoga, physical labour, meditation and forgiveness, adeqaute water, raw-vegetables, sprouts, fruits, overnight soaked nuts, butter milk, honey-ORGANIC, sunlight exposure. http://banuprakashas.blogspot.in/2013/09/health.html HEAD & SPINE INJURY MANAGEMENT https://docs.google.com/file/d/1j7t-CyslNvJTNJPaTG_q,qO4kcFKq_i6Jvr4-0f3-L5CJUp13t7mJkcjpq9wM/edit?usp=sharing STROKE MANAGEMENT Emperical therapy Tab atorvastatin 40mg stat, HS Tab citicholine 500mg BD Tab nootropil 800mg TID Cap Minocyclin 200 BD Inj mannitol 1.5ml/kg tid if unconcious , edema Inj pcm 15mg/kg bd if headache Iv emeset 1mg tid if nausea Iv pan 10mg BD if unconcious IVF NS+MVI@ 1ml/kg/hr adjusted according to I/O, fever, CVP Get PT, INR , group cross match Serum electrolytes...Na 3%saline 100ml+1gm MgSO4 @ 0.5ml/kg/hr if sodium <120, 0.4<125, 0.3<130 ,0.25<135, 0.2<140, 0.15<145 Inj eptoin 20mg/kg in 100ml NS over 20min followed by 5mg/kg/day if cortical bleed/LOC Inj dexa 0.04mg/kg BD if severe edema, deep coma, hypothalamic/adrenal failure ISCHEMIC A) if no bleed on CT , patient had come within 4 hours of anterior circulation stroke n 12hrs of posterior circulation stroke onset.. IV thrombolysis with Alteplace or rTPA based on NIHSS score n inclusion criteria. If no improvement or beyond then attempt of intraarterial thrombolysis or recanalisation till 8 hrs in anterior 48 hrs in posterior circulation strokes https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4564430/ B) If beyond thromolysis period Inj heparin 2500 units BD HEMORRHAGIC C) If bleed keep BP <140/90. amlodepine, ACE inhibitors, labetelol, SNP Inj eptoin 20mg/kg in 100ml NS over 20min followed by 5mg/kg/day if cortical bleed/LOC If affordable Inj edaravone 30mg BD Inj cognipro 60mg OD Inj LMWH 40 units or heparin 2500 units HS for DVT prophylaxis,TED stocking, sequential compression device. vasculitis profile, lipid profile, group cross match, ECG, ECHO, carotid-vertebral doppler. Physician opinion for hypertension, diabetes, vasculitis,nephropathy, retinopathy, cardiac/mesenteric ischemia Physiotherapy Music therapy , stop smoking and alcohol, pranayama & ASHTANGA yoga, physical labour, meditation and forgiveness., adeqaute water, raw-vegetables, sprouts, fruits, overnight soaked nuts, butter milk, honey-ORGANIC, sunlight exposure http://banuprakashas.blogspot.in/2013/09/health.html . SPONDYLOSIS cervical/dorsal/Lumbar---Brace accordingly Physiotherapy Avoid potatos, oily foods, fried foods, tomatos stop smoking and alcohol, pranayama & ASHTANGA yoga, physical labour, meditation and forgiveness., adeqaute water, raw-vegetables, sprouts, fruits, overnight soaked nuts, butter milk, honey-ORGANIC, sunlight exposure http://banuprakashas.blogspot.in/2013/09/health.html Tab ECOSPIRIN 75 mg 0-0-1 or 1-0-1 or 1-1-1 according to severity Tab crocin 500 1-1-1 when pain Tab ultracet 1-0-1 Tab Nervigen (B1,B6,B12) 1-0-1x 0 days Tab. Riconia Silver (vitamin minerals) 1-0-1 x 10 days Tab Calcimax K2(Ca,Mg,D3) 1-0-1 x 10 days Tab Amitryptalline 10mg 1-0-0 x 10 days if severe pain or associated with depression symptoms vitamin D sachet 1/week If postmenopausal cap.primerose oil 1-0-1*10days Tab Neurikem-M(pregablin) 75 1-0-1 x too severe pain Music therapy physicion opinion to r/o polyarthritis if no improvement MRI If osteoporosis Tab ostiofos (alendronate) 70mg 1 tab per week in empty stomach in sitting position with plenty of water, breakfast after 30 min.....avoid in asthmatics EVD EVD is an emergency life saving procedure to be learnt by all emergency physicians like a chest tube, endotracheal tube, central line-venous cut down http://en.wikipedia.org/wiki/External_ventricular_drain the trajectory is to be perpendicular to the skull/brain surface where ever you are...Dr Ashish Pathak, PGIMER as the condition worsens with increasing edema the ventricles get chinked and shifted more medially towards the midline than from the last CT image a life saving procedure when done at the correct moment for many a situations arent stable enough for surgery and not getting better with medicines alone a factory had a celebration on year end 31.12.2009 with sweets n food distributed. few felt a little sick the evening but postponed till next day when many started complaining of stomach pain, vomiting totalling to 440 patients lying all over the floor n corridors of hospital one 30yr lady mother of 2 children with vomiting n dehydration brought o hospital on a bike sitting between the driver n pillion men, walked with support to casualty, became drowsy and non responsive so after IVF,antibiotics, antiemetics,pantoprazole she was shifted to CT which showed diffuse cerebral edema suggesting metabolic encephalopathy. mannitol, dexa given but she continued to worsen with dropping blood pressure 90 and GCS M3, little while later pupil right 3 and left 2mm. now BP 70, GCS M2 with ECG showing Ventricular tachycardia with ectopics no improvement with colloids n crystalloids intubation. a relook at the CT showed slight enlargement of rt frontal horn as compared to the left so with hot debate of pros n cons a rt frontal EVD inserted which rapidly stabilised her condition n she was concious next day MRI showed borderzone minimal infarcts n she walked back home to her children after 5-6 days ACM syrinx OBEXOSTOMY ACM is usually treated with FMD -Only bony decompression- if only there are symptoms of posterior fossa inadequacy like cough headache with bony compression in children + Dura – adults where the dura in inelastic, after bony decompression children if there appears a constriction band without a smooth funnel of posterior fossa into the spinal dura. Where in the small herniated tonsil can ascend back + arachnoid if the herniated tonsils are atrophic and elongated may be an arachnoid constriction can be there, adults where there appears a band after dural decompression and the tonsils doesn’t ascend up and posterior column of CSF not established +tonsil shrinkage /resection too long tonsils doesn’t ascend and tightly adhered in the midline obscuring the obex preventing CSF outflow from the megendie and obex to cut the arachnoid bands to ensure same +syrinx decompression if the patient has tense syrinx on MRI alone or moderate syrinx with syringomyelic syndrome then previously we had done separate incision at maximum dilatation or superficial pointing of syrinx. We did syringostomy or syringosubarachnoid shunt usually at cervical or dorsal region with mixed results of improvement, funicular pain, new weakness especially with shunt tube. Nowobexostomy can be an option if it extends till obex. 24yr student presented with paraesthesias of both hands and fingers with wasting and weakness of left hand muscles. He had dissociated sensory loss for temperature and pain in the left upper limb. MRI showed a shallow posterior fossa with tonsillar descent and cervico thoracic syrinx. Since his major symptoms were due to the syrinx we planned for a FMD and syringostomy or syringe subarachnoid shunt. Introp after opening the dura and arachnoid, the tonsils were shrunk by coagulation and megendie opened to release 4th ventricle CSF. In the obex there was a thin membrane of arachnoid/pia which I cut with scissor and probed the obex gently with ball point probe inferiorly, slow trickle of CSF like fluid came out which increased with each probing. The cord seemed decompressed so separate syringostomy was not done.post op patient had complete recovery of upper limb symptoms confirmed by post op 10th day MRI showing syrinx decompression. My first case of obexoplasty was ACM with cervico dorsal syrinx with dorsal scoliosis. There was a gush of fluid after opening the obex, I had to be sure that it was from syrinx and not the assistants irrigation or surrounding CSF. So went ahead for c5 laminectomy and durotomy to find the cord totally collapsed. Subsequent cases with syrinx have achieved good improvement but had not imaged any of them. One case of chiari 3 child with syrinx had imperforate rhombic roof with obex patent ￼ dynamic stabilisation-MOTION PRESERVATION of spine-a biomechanical possibility With routine protocol dislocation or instability is treated with rigid fixation ensuring stability at the cost of mobility. Instability in spine is like any joint due to ligamento-muscular laxity. The orthopedicians rarely fuse appendicular joints now-a-days By understanding the forces causing instability or the factors preventing its occurrence in normalcy instability can be a correctable pathology with negating the prime vector of cause or strengthening the vector to prevent it. Various methods of fusion have been done in past with improving biomechanics over the years. Using the techniques of exposure practiced for minimally invasive or functional preservation the vitality of the vectors are maintained or strengthened to stabilize the spine. If the dynamics and vectors are preserved there is no need for arthrodesis hence mobility is preserved as exemplified in all levels of instability from CVJ to LS spine. ￼ Drain removal in Lumbar fusion n Infection rate http://www.linkedin.com/groupItem?view=&gid=1725597&type=member&item=205157390&commentID=144674568&goback=%2Egde_1725597_member_250298549%2Egfl_1725597&report%2Esuccess=8ULbKyXO6NDvmoK7o030UNOYGZKrvdhBhypZ_w8EpQrrQI-BBjkmxwkEOwBjLE28YyDIxcyEO7_TA_giuRN#commentID_144674568 infection in lumbar fusion depends on the immune status of the patient, microvasculature-DM, length of surgery, loss of vitality of tissue with excessive retraction/cautery, washes, antibiotic choice- susceptibility pattern, n the duration of drain depends on the ozziness of the tissue- water logged, dependent edema, myxedema, fat necrosis, hemostasis-coagulation ability, clot retraction pattern, lymphatics n venous drainage of area..............definitely a sterile clot as in trauma gets absorbed but a clot or collection seeded with organism in low immunity is culture media........many a times blocked drains show pseudo decrease in the bag n when you pull out the dressing keeps getting soiled with discharge........its not a simple arithmetic of numbers its an instinct refined by subconscious logic based on observation of all the current facts n analysis in comparison with of the previous success n failures. SEVAKSHETRA HOSPITAL, SITA BHATEJA Hospitals charitable OASIS in the capitalistic MEDICAL DESSERT. one day we performed a pooja at home, at the end when he was asked how much to pay, he a TRUE BRAHMIN said my travelling charges are 600 and anything above it would be gracefully accepted. likewise we are offering neurosurgical care like a TRUE BRAHMIN as an act of meditation and enlightenment SARASWATHI....THE GODDESS OF KNOWLEDGE....LET US REVIVE THE RIVER the concept of let go of the beautiful work one does after its done helps to explore new paradigms of knowledge by greatest thinkers in history..... the act of expecting the benefits of efforts makes one lazy to relax n bask in the attention rather than explore new dimensions....that is what Dr Fessler n Dr Sekhar are doing.....i believe till the concept of copyright n patents r there actual science will be market controlled.........science will become equal to GOD n NATURE the day it flows like a river free for all.. https://www.facebook.com/groups/neurosurgerydoctors/ Forum Of Neurosurgery - منتدى جراحة المخ و الأعصاب Atlas of Neurosurgical Techniques: Spine and Peripheral Nerves ￼http://ublog.dd.rapidbaz.com/1ST/H565.A.o.N.T.S.a.P.N-ublog.t.k.part1.rar ￼http://ublog.dd.rapidbaz.com/1Sm/H565.A.o.N.T.S.a.P.N-ublog.t.k.part2.rar ￼http://ublog.dd.rapidbaz.com/1SF/H565.A.o.N.T.S.a.P.N-ublog.t.k.part3.rar http://neurosurgery.ucla.edu/body.cfm?id=1075 https://mega.co.nz/#!e9xhlAAb!dcrwsjxYs24605X7T3UaxFrWqxEgRekzP5DUjznhrl0 https://mega.co.nz/#!nAETFKDR!NdV9JWkAfUktChh1jEjNvByOUdsCoL8Zaaz2h9jhdx8 Password is : greenberg John Peter Paiso
Left thelamocapsuloganglionic bleed with involvement of adjacent white matter of temporal lobe ,blood in the 3rd lateral and 4th ventricle with brain edema and midline shift.Most probably hypertensive bleed
Left temporoparietal parenchymal bleed with midline shift. gcs monitoring vital monitoring iv acess dilantanization electrolytes and temperature monitoring in raised icp situation head elevation mannitol
Ich with ventricular extension &midline shift.reduce icp .antiepileptics.&brain can be decompressd&the clot can be evacuated.evd can be placed for ventrcle bleed.you didnt mention hemiparesis.
Large intraventricular haemorrhage requiring urgent neurosurgical consultation....bt first decrease the ICP by 300 ml of mannitol stat then 100 ml mannitol 8 hrly, antiepileptics nd lasix....
Left lentiform nucleus ICH with mass effect and midline shift And minimal IVH, pt might benefit from endoscopic evacuation of ICH
Possible ruptured MCA aneurysm with left temporoparietal intra parenchymal bleed with ventricular extension and mass effect
Watch out for hematoma growth and delayed detoriation, high chances, other measures as already elaborated by others.
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82 year old lady suddenly collapsed , has left sided weakness in upper and lower limb and difficulty in speaking Clinical diagnosing: stroke . following are the MRI and mr angiography reports Kindly suggest management with special emphasis on how to rehabilitate stroke patientsDr. Uttara Desai1 Like9 Answers
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25yrs old P3L3 with P0P1 delivered a healthy child by LSCS at 36weeks gestation 4 days back at some other hospital.She developed convulsions 12hrs Post delivery with disturbed conscious level presented to emergency department with C/o Left sided weakness of 0/5 power, generalized headache, difficulty in speaking. O/e - CNS -Conscious but disoriented, Withdraws to pain,Pupils 4mm RTL,no rigidity,consistent with post ictal state.GCS of 13/15,BP -180/90mmhg,P/R -98/mt,Spo2 - 100%,RR - 20/mt.KINDLY SUGGEST LINE OF TREATMENT FOR THE ABOVE CASE???Dr. Prashant Ved2 Likes17 Answers
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44 yr old lady ,not a k/c/o DM/HT/Dyslipidemia c/o dyspnoea on exertion for the past 3 yrs along with 10% weight gain. On examination bilateral pitting pedal edema present more so on the right leg (photo attached) vitals are stable and all the systemic examinations normal. Also attaching the photo of her dry,coarse skin,mostly due to hypothyroidism P.s:Can pedal edema be severe enough to cause medial deviation of the toes??(photo attached) If not what are the reasons for it??Dr. Vaibhav Suresh5 Likes25 Answers
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STURGE-WEBER SYNDROME (SWS), also called encephalotrigeminal angiomatosis, is a neurocutaneous disorder with angiomas that involve the leptomeninges (leptomeningeal angiomas [LAs]) and the skin of the face, typically in the ophthalmic (V1) and maxillary (V2) distributions of the trigeminal nerve. The hallmark of SWS is a facial cutaneous venous dilation, also referred to as a nevus flammeus or port-wine stain (PWS). ETIOLOGY : in SWS, a somatic mutation appears to cause alterations in regulation of the structure and function of blood vessels, innervation of the blood vessels, and expression of extracellular matrix and vasoactive molecules. PATHOPHYSIOLOGY: SWS is caused by residual embryonal blood vessels and their secondary effects on surrounding brain tissue. A vascular plexus develops around the cephalic portion of the neural tube, under ectoderm destined to become facial skin. Normally, this vascular plexus forms in the sixth week and regresses around the ninth week of gestation. Failure of this normal regression results in residual vascular tissue, which forms the angiomata of the leptomeninges, face, and ipsilateral eye. Neurologic dysfunction results from secondary effects on surrounding brain tissue, which include the following : Hypoxia Ischemia Venous occlusion Thrombosis Infarction Vasomotor phenomenon SIGAN AND SYMPTOMS: SWS is generally diagnosed clinically, based on the typical cutaneous(port wine stain), central nervous system (CNS), and ocular abnormalities(glaucoma ,bupthalmous ) associated with it. Neurologic signs include the following: Developmental delay/mental retardation Learning problems Attention deficit-hyperactivity disorder Factors suggesting a progressive course of cortical damage in SWS include the following: Initial focal seizures progressing to frequent, secondarily generalized seizures Increasing seizure frequency and duration despite the use of antiepileptic drugs (AEDs) Increasing duration of a transient postictal deficit Increase in focal or diffuse atrophy - Determined by serial neuroimaging Progressive increase in calcifications Development of hemiparesis Deterioration in cognitive functioning Physical signs of SWS are as follows: PWS Macrocephaly Ocular manifestations Soft-tissue hypertrophy Hemiparesis Visual loss Hemianopsia DIAGNOSIS: In young patients, examination under anesthesia or deep sedation is necessary to confirm the diagnosis of glaucoma. Careful assessment in each eye of IOP, corneal diameter, cycloplegic refraction, axial length, and optic nerve cupping, as well as gonioscopic examination, is mandatory. Cerebrospinal fluid (CSF) protein may be elevated, presumably secondary to microhemorrhage. Note that a major intracranial hemorrhage itself is rare in SWS, although microhemorrhage may be common. Besides the clinical examination, the following have historically been the procedures of choice to establish the diagnosis of SWS [1, 2] : Skull radiography Angiography Computed tomography (CT) scanning Magnetic resonance imaging (MRI) MRI with gadolinium Functional imaging - With single-photon emission computed tomography (SPECT) or positron emission tomography (PET) scanning In the diagnosis of diffuse choroidal hemangioma, A-scan and B-scan ultrasonography may be useful diagnostic aids. B-scan ultrasonography characteristically shows a solid, echogenic mass, whereas A-scan ultrasonography demonstrates high internal reflectivity. Electroencephalography (EEG) is used for the evaluation of seizure MANAGEMENT : Medical care in SWS includes anticonvulsants for seizure control, symptomatic and prophylactic therapy for headache, glaucoma treatment to reduce IOP, and laser therapy for the PWS. Anticonvulsants An anticonvulsant with efficacy in focal seizures is preferable in SWS. The chance of achieving seizure control with medical therapy in patients with SWS varies. Glaucoma medications The goal of treatment is control of IOP to prevent optic nerve injury. This can be achieved with the following agents: Beta-antagonist eye drops - Decrease the production of aqueous fluid Carbonic anhydrase inhibitors - Also decrease production of aqueous fluid Adrenergic eye drops and miotic eye drops - Promote drainage of aqueous fluid Dye laser photocoagulation Treatment of the cutaneous PWS with dye laser photocoagulation has been helpful in reducing the cosmetic blemish from the cutaneous vascular dilatation.  Physical therapy Educational therapy SURGERY : Surgery is desirable in patients with SWS who have refractory seizures, glaucoma, or specific problems related to various SWS-associated disorders, such as scoliosis.Praveen Kumar9 Likes7 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