Ascending paralysis of gradual onset;

Poliomyelitis has disappeared from most of the world except for Afghanistan and the bordering country of Pakistan because of on going internal war and terrorism which prevented the completion of the vaccination program which has again been reinstated in Pakistan. In fact prevention of vaccination has been part of the terrorists’ acts of war. However flaccid paralysis is still seen in young people which leaves 20% disabled and 5% dead despite plasmapheresis. This Guillain–Barré syndrome, is characterized by acute areflexic paralysis with albuminocytologic dissociation (i.e., high levels of protein in the cerebrospinal fluid and normal cell counts), was described in1916. This discrepancy in the CSF is the basis of diagnosis. This is also seen in the Miller Fisher variant which can, in a small number of patients, develop into a full blown GB syndrome.

Various studies of the immuno-pathogenesis of the Guillain–Barré syndrome suggest that the disease actually encompasses a group of peripheral-nerve disorders,
each distinguished by the distribution of weakness in the limbs or cranial-nerve–
innervated muscles and underlying pathophysiology (Fig. 1).5-7 There is substantial
evidence to support an autoimmune cause of this syndrome, and the autoantibody
profile has been helpful in confirming the clinical and electrophysiological relationship of the typical Guillain–Barré syndrome to certain other peripheral-nerve conditions.

What infections may be responsible for setting off the GB syndrome?

Two thirds of cases are preceded by symptoms of upper respiratory tract infection
or diarrhea. The most frequently identified infectious agent associated with subsequent development of the Guillain–Barré syndrome is Campylobacter jejuni, and 30% of infections were attributed to C. jejuni in one meta-analysis, whereas cytomegalovirus has been identified in up to 10%. The incidence of the Guillain–Barré syndrome is estimated to be 0.25 to 0.65 per 1000 cases of C. jejuni infection, and 0.6 to 2.2 per 1000 cases of primary cytomegalovirus infection. Other infectious
agents with a well-defined relationship to the Guillain–Barré syndrome are Epstein–
Barr virus, varicella–zoster virus, and Mycoplasma pneumoniae. The immune response can be directed towards the myelin or the axon of peripheral nerve, resulting in demyelinating and axonal forms of GBS. Because of the immune response it is also known as the AIDP or acute inflammatory demyelinating polyneuropathy. The Zika virus can also be a trigger. A small percentage of patients develop GBS after another triggering event such as immunization, surgery, trauma, and bone-marrow transplantation.

The cardinal clinical features of Guillain-Barré syndrome (GBS) are progressive, fairly symmetric muscle weakness accompanied by absent or depressed deep tendon reflexes. Patients usually present a few days to a week after onset of symptoms. The weakness can vary from mild difficulty with walking to nearly complete paralysis of all extremity, facial, respiratory, and bulbar muscles.

GBS is associated with the following clinical features:

  1. The weakness usually starts in the legs, but it begins in the arms or facial muscles in about 10 percent of patients.
  2. Severe respiratory muscle weakness necessitating ventilatory support develops in 10 to 30 percent.
  3. Facial nerve palsies occur in more than 50 percent, and oropharyngeal weakness eventually occurs in 50 percent.
  4. Oculomotor weakness occurs in about 15 percent of patients.
  5. Decreased or absent reflexes in affected arms or legs are found in approximately 90 percent of patients at presentation and in all patients with disease progression.
  6. Paresthesias in the hands and feet accompany the weakness in more than 80 percent of patients, but sensory abnormalities on examination are frequently mild.
  7. Pain due to nerve root inflammation, typically located in the back and extremities, can be a presenting feature and is reported during the acute phase by two-thirds of patients with all forms of GBS.
  8. Dysautonomia occurs in approximately 70 percent of patients included diarrhea/constipation, hyponatremia, bradycardia, urinary retention, tachycardia (3 versus, reversible cardiomyopathy, and Horner syndrome. Severe autonomic dysfunction is important to recognize since this is occasionally associated with sudden death.
  9. The syndrome of inappropriate antidiuretic hormone secretion (SIADH), which may be due to autonomic involvement, is another complication of GBS.
  10. Unusual features of GBS include papilledema, facial myokymia, hearing loss, meningeal signs, vocal cord paralysis, and mental status changes. In addition, posterior reversible encephalopathy syndrome, also known as reversible posterior leukoencephalopathy syndrome (see “Reversible posterior leukoencephalopathy syndrome”), has been associated with GBS in adults and children, likely related to acute hypertension from dysautonomia.

A detailed neurologic assessment will help localizes the disease to the peripheral nerves rather than to the brain stem, spinal cord, cauda equina, neuromuscular junction, or muscles. The presence of distal paresthesia increases the likelihood that the correct diagnosis is the Guillain–Barré syndrome. If sensory involvement is absent, disorders such as poliomyelitis, myasthenia gravis, electrolyte disturbance, botulism, or acute myopathy should be considered. Hypokalemia shares some features with the Guillain–Barré syndrome but is commonly overlooked in the differential diagnosis. In patient with acute myopathy, tendon jerks are preserved and serum creatine kinase levels are increased. If paralysis develops abruptly and urinary retention is prominent, magnetic resonance imaging
of the spine should be considered, to rule out a compressive lesion.

Nerve-conduction studies help to confirm the presence, pattern, and severity of neuropathy. Consider alternative causes, such as vasculitis, beriberi, porphyria, toxic neuropathy, Lyme disease, and diphtheria.

Historically, the Guillain-Barré syndrome (GBS) was considered a single disorder. It now is recognized as a heterogeneous syndrome with several variant forms. Each form of GBS has distinguishing clinical, pathophysiologic, and pathologic features.


  1. Acute inflammatory demyelinating polyradiculoneuropathy (AIDP) is the most common form representing approximately 85 to 90 percent of cases.
  2. The clinical variant Miller Fisher syndrome (MFS), characterized by ophthalmoplegia, ataxia, and areflexia, occurs in approximately 10 percent of cases. There may be incomplete forms and Bickerstaff’s brain stem encephalitis. The presence of distal paresthesia is associated with the Miller Fisher syndrome. Careful clinical assessment and focused investigations such as brain imaging and electrophysiological examinations can rule out other conditions, such as brain-stem stroke, Wernicke’s encephalopathy, myasthenia gravis, and botulism. The disease peaks at a median of 1 week, and improvement often starts at a median of 2 weeks.4 Recovery from ataxia and recovery from ophthalmoplegia take a median of 1 and 3 months, respectively. By 6 months after the onset of neurologic symptoms, most patients have recovered from ataxia and ophthalmoplegia.
  3. Acute motor axonal neuropathy (AMAN).
  4. Acute motor and sensory axonal neuropathy (AMSAN) are primary axonal forms of GBS.

A lumbar puncture is usually performed in patients with suspected Guillain–Barré syndrome, primarily to rule out infectious diseases, such as Lyme disease, or malignant conditions, such as lymphoma. A common misconception holds that
there should always be albumino-cytologic dissociation. However, albumino-cytologic dissociation is present in no more than 50% of patients with
the Guillain–Barré syndrome during the first week of illness, although this percentage increases to 75% in the third week. Some patients with human immunodeficiency virus infection and the Guillain–Barré syndrome have pleocytosis.

Only 7% of cases recur and tend to recur after many years. Although hyporeflexia or areflexia is a hallmark of the Guillain–Barré syndrome, 10% of patients have normal or brisk reflexes during the course of the illness. Thus, the possibility of the Guillain–Barré syndrome should not be excluded in a patient with normal or brisk reflexes if all other features are supportive of the diagnosis. Clinical deterioration after initial improvement or stabilization with immunotherapy suggests that the treatment had
a transient effect or that chronic inflammatory demyelinating polyneuropathy (CIDP)is present.

The variations in the rate and extent of recovery in the Guillain–Barré syndrome make prognostication difficult. One clinical scoring system that has been developed uses the patient’s age, the presence or absence of antecedent diarrhea, and disease severity to predict whether a patient will be able to walk independently at 1, 3, or 6 months. Another prognostic scale uses the number of days between the onset of weakness and hospital admission, the presence or absence of facial or bulbar
weakness, and the severity of the limb weakness to predict the likelihood that respiratory insufficiency will develop. Both scales, validated in their respective patient populations, can be useful in the care of patients with the Guillain–Barré syndrome.

The histologic features of the Guillain–Barré syndrome support a classification that includes demyelinating and axonal subtypes — acute inflammatory demyelinating polyneuropathy and acute motor axonal neuropathy. The classification is based on nerve-conduction studies.

There are localized forms of the Guillain–Barré syndrome that are distinguished by involvement of certain muscle groups or nerves. Facial diplegia with paresthesia is a localized form of the demyelinating Guillain–Barré syndrome, where a pharyngeal–cervical–brachial weakness, which is characterized by acute weakness of the oropharyngeal, neck, and shoulder muscles, represents a localized form of the axonal Guillain–Barré syndrome.

Plasma exchange was the first treatment that was found to be effective in hastening recovery in patients with the Guillain–Barré syndrome, and it appeared to be most effective when it was started within the first 2 weeks after disease onset in
patients who were unable to walk. An electrophysiological examination is not always required for the initiation of immunotherapy. Plasma exchange nonspecifically removes antibodies and complement and appears to be associated with
reduced nerve damage and faster clinical improvement, as compared with supportive therapy alone. The usual empirical regimen is five exchanges over a period of 2 weeks, with a total exchange of 5 plasma volumes. One trial showed
that patients who could walk with or without aid but could not run benefited from two exchanges of 1.5 plasma volumes, but more severely affected patients required at least four exchanges. Treatment with intravenous immune globulin, initiated within 2 weeks after disease onset, is reported to be about as effective as plasma
exchange in patients with the Guillain–Barré syndrome who cannot walk independently. It is thought that immune globulin may act by neutralizing pathogenic antibodies and inhibiting autoantibody-mediated complement activation, resulting in reduced nerve injury and faster clinical improvement, as compared with no treatment, although no comparative studies have been performed. In general, intravenous immune globulin has replaced plasma exchange as the treatment of choice in many medical centers because of its greater convenience and availability.
According to the standard treatment regimen, immune globulin is given at a total dose of 2 g per kilogram of body weight over a period of 5 days. The pharmacokinetics of immune globulin varies among patients, and some patients have a smaller rise in serum IgG after the administration of immune globulin. These
patients are likely to have a poorer outcome, with fewer able to walk unaided at 6 months. A second course of immune globulin in severely unresponsive patients was reported to be beneficial in one study.

The combination of plasma exchange followed by a course of intravenous immune globulin is not significantly better than plasma exchange or immune globulin alone. Neither prednisolone nor methylprednisolone can significantly accelerate recovery or affect the long-term outcome in patients with the Guillain–Barré syndrome. Eculizumab, erythropoietin, and fasudil, which have been used in the treatment
of other, unrelated medical conditions, have shown promise in animal models of the Guillain–Barré syndrome, but clinical studies are lacking.

One of the differential diagnoses of AIDP is CIDP or chronic inflammatory demyelinating polyneuropathy. Typical CIDP is a fairly symmetric sensorimotor polyneuropathy with proximal and distal motor involvement that exceeds sensory involvement. The presentation is usually one of gradually progressive symptoms over the course of several months or longer. Some patients present with more rapidly progressive symptoms, resembling acute inflammatory demyelinating polyneuropathy (AIDP) and which have been termed “acute-onset CIDP”.

One variant is:

Asymmetric sensorimotor (multifocal) — The Lewis-Sumner syndrome, also known as multifocal acquired demyelinating sensory and motor neuropathy (MADSAM), is a well-described atypical variant of CIDP that accounts for 5 to 10 percent of CIDP cases. Patients present with a strikingly asymmetric, multifocal picture, indistinguishable from other forms of mononeuropathy multiplex, resulting in sensory and/or motor signs and symptoms in individual nerve distributions. Symptoms may start in any nerve distribution. Some patients may have autonomic symptoms, neuropathic pain, and cranial nerve involvement. Some patients present with focal CIDP with symptoms restricted to a single limb or nerve.

Sensory-predominant — The sensory-predominant form of CIDP is characterized clinically by symptoms and signs consistent with large fiber sensory dysfunction, including balance problems, pain, paresthesias, and dysesthesias.

Distal and sensory-predominant — Distal acquired demyelinating symmetric neuropathy (DADS) refers to a distal and sensory-predominant variant of CIDP, which is usually more slowly progressive than typical CIDP. Patients typically present with length-dependent, symmetric sensory or sensorimotor dysfunction in the lower extremities with sparing of proximal limbs, trunk, and face 

Pure motor — A pure motor variant of CIDP has been reported in a small number of cases. Involvement of motor nerves and sparing of sensory fibers is present on clinical and electrodiagnostic evaluations. Weakness tends to be relatively symmetric and may involve any part of the body, including motor cranial nerves,

Neurofascin antibody-mediated — Patients with autoantibodies to neurofascin (NF) 155 appear to be younger and more likely to have sensory ataxia and prominent tremor compared with those with antibody-negative CIDP 

Contactin 1 antibody-mediated — Autoantibodies of the IgG4 class to contactin 1 (CNTN1) or contactin-associated protein 1 (CASPR1) are found in a small subset of patients with CIDP

Lumbar puncture — Cerebrospinal fluid (CSF) analysis is recommended in most patients with suspected CIDP and particularly for patients in whom the clinical and electrophysiologic findings are inconclusive. Albuminocytologic dissociation is a hallmark of CIDP and represents supportive evidence in the EFNS/PNS diagnostic criteria

Neuroimaging — Magnetic resonance imaging (MRI) with gadolinium of the spine (including spinal roots, cauda equina), brachial plexus, lumbosacral plexus, and other nerve regions can be used to look for enlarged or enhancing nerves.

Nerve ultrasound — When appropriate expertise is available, neuromuscular ultrasound can also be used to detect nerve hypertrophy in patients with acquired and hereditary forms of chronic demyelinating neuropathies.

Nerve biopsy — The diagnostic utility of nerve biopsy (typically of the sural nerve) for suspected CIDP is controversial [68-70], and nerve biopsy is unnecessary for most patients with suspected CIDP, especially those with typical electroclinical findings. 

There is general agreement that the following criteria support the diagnosis of the classic form of CIDP:

  1. Progression over at least two months
  2. Weakness more than sensory symptoms
  3. Symmetric involvement of arms and legs
  4. Proximal muscles involved along with distal muscles
  5. Widespread reduction or loss of deep tendon reflexes
  6. Increased cerebrospinal fluid (CSF) protein without pleocytosis
  7. Nerve conduction evidence of a demyelinating neuropathy
  8. Nerve biopsy evidence of segmental demyelination with or without inflammation
  9. Gait ataxia secondary to large fiber sensory loss

Two sets of criteria, the European Federation of Neurological Societies and the Peripheral Nerve Society (EFNS/PNS) criteria (see ‘EFNS/PNS criteria’ below) and the Koski criteria (see ‘Koski criteria’ below), deserve special mention. Please look them up in Uptodate in the CIDP section.

Both clinical experience and data from retrospective studies suggest that the over-diagnosis of CIDP is common, involving one-third to nearly one-half of patients so labeled. Furthermore, many of those with an erroneous diagnosis of CIDP are exposed to the potential toxicities and costs of long-term treatment with intravenous immune globulin (IVIG) and glucocorticoids.

(This article (10.1056/NEJMra1114525) was
updated on June 14, 2012, at
N Engl J Med 2012;366:2294-304)

Patient with weakness of the legs: history taking and presentation.

This is the way the history was presented.

A 38 year old woman developed weakness of her lower limbs 2 and a 1/2 weeks ago. Two weeks later her upper limbs were affected in that her grip strength became weak too. She could dress herself, feed herself and do her hair without assistance. She developed loss of sensation in her feet because her flip-flop slippers fell off. She needed to be catheterized as she could not pass urine. She is constipated and needs an enema every three or four days. She has no cough, diarrhea, chest pain, breathlessness or fever. She has no coldness of the fingers, rash, joint pains, loss of hair. She has no significant illnesses in the past. She is a housewife with 6 children, does not menstruate because she has had an operation probably hysterectomy though she does not give a reason for this operation. Her condition since the onset of the weakness is static. She had an MRI but does not know the result nor does she have a written report. She has been given some injections in the hospital that she is admitted in but no blood transfusion or other procedure has been done on her.

Examination of the CNS showed normal higher mental functions and no cranial nerve deficits. She has a sensory level at the level of her nipples but can feel some sensation on her lower limbs in patches. the muscle tone in her lower limbs and upper limbs is normal. The power in the lower limbs is 2/4 and no reflexes can be elicited; both planters are upgoing. The initial diagnosis given by the candidate is spinal cord compression syndrome.

The questions asked were:

  1. How did she notice that her legs were weak? Did she fall down? Did she need help getting up from a squatting position or chair? Could she not walk at all and had to be carried to her bed? All these are going to make a difference in her diagnosis.
  2. How long did the weakness take to develop? Hours, minutes, days?
  3. Are her flipflops falling off because she can no longer grip them with her toes because of the weakness of her toes and not because of the loss of sensations? Patients tend to equate weakness with numbness so you need to clarify.
  4. Can she walk? What is her disability? Believe me the candidate who was presenting the case did not know.
  5. Does she have an indwelling catheter and if so why? The patient said she could feel the sensation to pass urine but no one in her house was strong enough to carry her to the toilet so the attending doctor passed a Foley catheter. She did not have retention of urine but simply a nursing problem emptying her bladder.
  6. She had been constipated all her life according to he as she passed hard stools every 2-3 days and now needed an enema as she could not squat on the toilet. She did not have a toilet seat and could not walk to the toilet.
  7. Why was she not menstruating? She had had tubal ligation and early cessation of menstruation need to be looked into as early ovarian failure.
  8. Are the nipples a useful landmark in a 38 year old woman who has breastfed 6 times? No, they will be at a much lower level so use the intercostal spaces instead.
  9. What are her abdominal reflexes like? The candidate had not checked them. Fatal.
  10. Did the patient really have a sensory level? The spurious level “at the level of the nipples”, patchy distribution of sensation which is not coinciding with either a dermatome or sensory nerve distribution and is accompanied by a withdrawal planter reflex show that the patient has an altered perception of her sensations. Fake news as Trump would say and the candidate is ignorant of the pattern of sensory loss in different diseases.
  11. Is this an upper or lower motor neuron loss of function? The candidate could not say.
  12. What is the level of the cord compression? All the way from L1,2,S1-5 to C8? Which disease is likely to fit in?
  13. In the systemic survey what is the significance of cough? A geriatric patient specially in the 80s plus may have a bout if severe coughing and fracture a vertebra but not a previously healthy 38 year old woman. Diarrhea is not connected. Trying to connect it to symptoms of SLE is also an exercise in futility. Fever does not prominently precede transvers myelitis. Fever, with night sweats. an evening rise and loss of weight happens in TB of the spine and may be mentioned.
  14. Are there any local signs or symptoms? The candidate had never once mentioned backache, direct or indirect trauma to the spine, osteoarthritis of the spine or ankylosing arthritis or any other arthritides.
  15. Was she on any drugs which might affect her bones?

You can see how many mistakes were made by a candidate who thought they had taken a comprehensive history and done a complete physical examination. How can this be improved?


A 38 year old woman was standing and washing her clothes when she realised that her legs were not supporting her weight. As she felt she might fall she clutched her washing machine and then the wall and door and dragged herself to a nearby chair. After 15 minutes of rest she called for help. Her daughter came but could not pick her up. Her husband and brother pulled her upright but had to support he as she could not stand by herself, she dragged her feet, her slippers fell off and with the help of the men she reached her bed, By the evening 6 hours later she could not stand even with support. She wanted to empty her bladder but as she could not walk a doctor was called who passed an indwelling catheter. By the next morning she could not hold a glass, cup or spoon and had to be fed. This shows the sudden onset weakness of the lower limbs which took about 12 hours or so to progress to the upper limbs. The need for the catheter is because of the limb weakness which does not allow her to walk to the toilet not because of retention of urine or loss of bladder sensation. It is essential that you understand and mention the difference. She has no backache, history of direct or indirect trauma to the back, has not suffered prominently from osteoarthritis or other arthritides affecting the spine nor does she symptoms suggestive of TB spine like fever, night sweats, weight loss. The need for the operation on her pelvic organs needs to be explored as if she might have had a hysterectomy for a malignancy then secondary deposits in the spine might be a possibility but pain would be expected.

She has a lower motor neuron paralysis i.e. marked weakness of the limbs with an ascending pattern, no increase in her muscle tone, loss of tendon reflexes and withdrawal planter reflexes. I would put my money on Guillain Barre syndrome.

Sensory Loss.

Higher cortical sensation can be examined if touch sensation remains relatively preserved and the patient is suspected of having a cortical lesion. Examination of cortical sensation includes two-point discrimination, graphesthesia, stereognosis, and extinction

Sensory loss that is confined to a part of a limb suggests injury to a peripheral nerve, nerve plexus, or spinal root (eg, mononeuropathy or radiculopathy).

Involvement of both sides of the body is consistent with a polyneuropathy or spinal cord disease, while involvement of one side is consistent with contralateral disease of the brainstem, thalamus, or cerebral cortex.

“Stocking-glove” sensory loss is most commonly seen with length-dependent axonal neuropathies, although other disorders may also present with this pattern. Diabetes mellitus for example and alcohol, vitamin B12 deficiency, syphilis, human immunodeficiency virus, Lyme disease, uremia, chemotherapy, vasculitis.

Disproportionate loss of vibration sense and proprioception, compared with pain and temperature sensation, tends to occur with diseases of the dorsal columns of the spinal cord (eg, tabes dorsalis, vitamin B12 deficiency, multiple sclerosis) and demyelinating polyneuropathy

Sensory loss of the face can result from lesions in the upper cervical spine, brainstem, thalamus, or cerebral hemispheres. With lower brainstem disease (eg, lateral medullary syndrome), the sensory loss on the face is typically opposite that of the body, although ipsilateral sensory loss has also been reported; sensory loss is on the same side of the face and body with upper brainstem, thalamic, or hemispheric disease.

Sensory neuronopathies are often idiopathic in etiology. However, they may be associated with paraneoplastic phenomenon. The latter is most commonly associated with small cell lung cancer and the presence of anti-Hu antibodies. Can occur in Sjogren’s syndrome, Guillain-Barré syndrome variant, chemotherapy-induced, especially the platinum drugs, Friedreich’s ataxia and vitamin B 6 deficiency. 

Spinal cord lesions.

Cape distribution sensory loss is an uncommon but well-described pattern of sensory loss resulting from lesions of the central cervical cord. Sensory loss occurs over the upper back, shoulders and upper limbs.

Central lesions affecting the cervical spinal cord can also present with a stocking-glove pattern of sensory loss.

Brown-Sequard syndrome — The Brown-Sequard syndrome results from a lesion involving only one side of the spinal cord. In this situation, the patient presents with diminished proprioception, diminished vibration sensation, and weakness on the side ipsilateral to the lesion, and decreased pinprick and temperature sensation on the contralateral side.

Wallenberg syndrome is probably the most well-known brainstem abnormality leading to sensory loss. It results from a lesion of the lateral medulla and was originally described as involving pain and temperature loss on the ipsilateral face and contralateral limbs and trunk. However, several other patterns of pain and temperature loss have been described in association with this syndrome, including contralateral face and bilateral face involvement.

Thalamic lesions may cause a contralateral sensory deficit that involves all sensory modalities to varying degrees. Although tumors and abscesses can involve the thalamus, typically the onset of sensory loss in thalamic lesions is acute or subacute and is the result of a lacunar infarct

Spinal cord compression syndrome/ Epidural spinal cord compression syndrome (ESCC).

The spinal cord is enclosed by a protective ring of bones comprised of the vertebral body anteriorly, the pedicles laterally, and the lamina and spinous process posteriorly. Within this ring is the thecal sac, the outermost layer of which is comprised of dura. Between the bone and dura lies the epidural space, which normally contains fat and the venous plexus.

Approximately 85 to 90 percent of cases of ESCC are due to metastatic tumor in the vertebral bones.

The cardinal clinical features of ESCC are symptomatic spinal cord or nerve root compression and mechanical instability of the spinal column. Early diagnosis of spinal metastases prevents the development of neurologic deficits and severe structural instability.

Clinical presentation — The majority of patients with ESCC have pain as the initial symptom, prior to the onset of motor or bladder dysfunction. Delayed recognition and therapy of ESCC may result in the development or progression of neurologic deficits.

ESCC most commonly arises in the thoracic spine. Approximately 60 to 70 percent of cases occur in the thoracic spine, 20 to 30 percent in the lumbosacral spine, and 10 percent in the cervical spine. These percentages are in rough proportion to the combined volumes of the vertebral bodies in each region.

Pain is usually the first symptom of ESCC, present in 80 to 95 percent of patients at the time of diagnosis. On average, pain precedes other neurologic symptoms of ESCC by seven weeks.

Affected patients usually notice a severe local back pain, at the level of the lesion, which progressively increases in intensity. Over time, the pain may develop a radicular quality. It may, for example, radiate into a limb with movement of the spine or Valsalva maneuver. Radicular pain is more common in lumbosacral lesions than in thoracic lesions.

The severity of weakness tends to be greatest in patients with compressive thoracic metastases. Unless there is profound weakness or severe pain with movement, the motor examination must include standing and walking to be complete.

When the site of compression is at or above the conus medullaris, weakness is from corticospinal tract dysfunction and has the typical pyramidal pattern, preferentially affecting the flexors in the lower extremities (ie, weakness of hip flexion, knee flexion, and ankle dorsiflexion with relative preservation of hip extension, knee extension, and plantar flexion strength). If compression is above the thoracic spine, the extensors of the upper extremities may also be affected (ie, more pronounced weakness in the triceps and wrist extensors than in the deltoid and biceps). Hyperreflexia below the level of the compression and extensor plantar responses may be seen.

Patients frequently report a pattern of ascending numbness and paresthesias if questioned and examined carefully.

When a spinal sensory level is present, it is typically one to five levels below the actual level of cord compression. Saddle sensory loss is commonly present in cauda equina lesions, while lesions above the cauda equina frequently result in sparing of sacral dermatomes to pinprick.

Bladder and bowel dysfunction due to ESCC is generally a late finding that was present in as many as one-half of patients in older series. Urinary retention as a manifestation of autonomic dysfunction is the most common finding and is rarely the sole symptom of ESCC.

New gait ataxia in the setting of back pain in a cancer patient should raise suspicion of ESCC.

Bilateral lower extremity pain is the classic presentation that raises concern for cauda equina syndrome. Bowel and bladder dysfunction may occur with compression of the lower sacral nerve roots. Elevated post-void residual volume on bladder scan may be a particularly sensitive marker of urinary retention in this setting.

Other causes of cord compression.

Degenerative spine disease – Intervertebral disc herniation, synovial cysts, and cervical or lumbar spondylosis can cause acute or subacute myelopathy and radiculopathy, along with pain. Spondylotic myelopathy is the most common cause of myelopathy in older adults. MRI of the spine in the appropriate clinical context is diagnostic. 

Vertebral compression fracture with retropulsed bone – Osteoporotic vertebral compression fractures, which most commonly occur in the thoracolumbar spine, occasionally present with spinal cord compression due to retropulsed bone fragments in the spinal canal. Symptoms vary depending on the level of the fracture and degree of compression and may include cauda equina syndrome for lumbar fractures.

Spinal epidural abscess is an important condition to recognize and distinguish from ESCC. Predisposing factors include intravenous drug use, vertebral osteomyelitis, and hematogenous infection. Tuberculosis and fungal infections in particular can mimic tumor. The leading bacterial pathogen causing spinal epidural abscess is Staphylococcus aureus, which accounts for approximately two-thirds of cases of bacterial etiology. Other infectious causes include Mycobacterium tuberculosis, which is responsible for up to 25 percent of cases.

Vascular malformations of the spinal cord, such as dural arteriovenous fistulas, can cause an acute or chronic progressive spinal cord syndrome with local back pain or radiculopathy. Spinal epidural hematoma. Nontraumatic, spontaneous spinal epidural hematomas occurring in the presence of anticoagulant therapy, arteriovenous malformations, or inherited or acquired bleeding disorders are a rare cause of spinal compression.

Intradural extramedullary tumor – Meningiomas and nerve sheath tumors can compress the spinal cord and produce radicular and myelopathic syndromes.

Extramedullary hematopoiesis – Spinal cord compression can rarely be induced by extramedullary hematopoiesis due to thalassemia or chronic myeloproliferative or myelodysplastic disorders.

Systemic inflammatory diseases – Rare cases of epidural involvement by rheumatoid arthritis, sarcoidosis, and tophaceous gout have been described

While you refresh your knowledge about cord compression (I have not included traumatic cord compression as physicians do not deal with those) and get prepared for the FCPS 2 exam I will read up and write important points of the GB Syndrome soon.

Inflammatory bowel disease.

Both ulcerative colitis and Crohn’s disease are diseases of modern life. UC has been known since 1800s and CD tends to occur more in the West than in Asia. Removing the appendix in early life reduces the incidence of UC but not CD. Diets rich in fats and sugar are predisposing to both diseases. The discovery that NOD2 variants are associated with susceptibility to Crohn’s disease opened a new era in the study of the genetic basis of inflammatory bowel disease. In studies of twins, there is stronger concordance with Crohn’s disease than with ulcerative colitis, and the identification of a large number of susceptibility loci for Crohn’s disease in early genome wide association studies suggested that genetic influences play a greater role in Crohn’s disease than in ulcerative colitis.

It has also been postulated that alterations in the composition of the gut microbiota, defects in mucosal immunity, or the two factors combined could lead to ulcerative colitis; however, supportive evidence is sparse. There is a consensus that the density of microbiota is greater in patients with ulcerative colitis or Crohn’s disease than in healthy control subjects, but whether there are reproducible, disease-specific alterations is unclear. The only ulcerative colitis–associated antibody is perinuclear antineutrophil cytoplasmic antibody (pANCA), which recognizes nuclear antigens that may cross-react with bacterial antigens. Autoimmunity may play a role in ulcerative colitis. In addition to pANCA, this disease is characterized by circulating IgG1 antibodies against a colonic epithelial antigen that is shared with the skin, eye, joints, and biliary epithelium.

Abnormalities in humoral and cellular adaptive immunity occur in ulcerative colitis. Elevated IgM, IgA, and IgG levels are common in inflammatory bowel disease, but there is a disproportionate increase in IgG1 antibodies in ulcerative colitis.

Abnormalities of adaptive immunity that differentiate ulcerative colitis from Crohn’s disease are defined by mucosal CD4+ T cells, which were initially divided into two lineages: Th1 and type 2 helper T cells (Th2). Crohn’s disease is a Th1-like condition, on the basis of evidence of increased production of interferon-γ. In contrast, ulcerative colitis represents an atypical Th2 response, as indicated by the presence of nonclassical natural killer T cells in the colon that secrete abundant interleukin-13, which mediates epithelial-cell cytotoxicity, apoptosis, and epithelial-barrier dysfunction.

Clinical Manifestations.

Bloody diarrhea with or without mucus is the hallmark of ulcerative colitis. The onset is typically gradual, often followed by periods of spontaneous remission and subsequent relapses. Active disease is manifested as mucosal inflammation commencing in the rectum (proctitis) and in some cases spreading to the rest of the colon.

Although proctitis is frequently associated with fecal urgency and the passage of fresh blood, constipation may paradoxically occur. Proctosigmoiditis, left-sided colitis, extensive colitis, or pancolitis may lead to diarrhea, frequent evacuations of blood and mucus, urgency or tenesmus, abdominal pain, fever, malaise, and weight loss, depending on the extent and severity of the disease. A small area of inflammation surrounding the appendiceal orifice (cecal patch) can be identified in patients with left-sided ulcerative colitis and in those with proctitis or proctosigmoiditis. The prognosis for patients with ulcerative colitis is generally good during the first decade after diagnosis, with a low rate of colectomy; over time, remission occurs in most patients.

Acute complications, such as severe bleeding and toxic megacolon may occur in patients with severe disease. Risk factors for cancer include a long duration of disease, regardless of clinical activity; extensive involvement; a young age at onset; severe inflammation; the presence of primary sclerosing cholangitis; and a family history of colorectal cancer.


An accurate diagnosis of ulcerative colitis involves defining the extent and severity of inflammation, and this information provides the basis for selecting the most appropriate treatment and for predicting the patient’s prognosis. Both endoscopy and biopsy are required to determine specific histologic characteristics; radiologic and ultra sonographic examinations are not critical but may be useful.

Colonoscopy shows a uniformly inflamed mucosa that starts at the anorectal verge and extends proximally, with an abrupt or a gradual transition from affected to normal mucosa. In mild ulcerative colitis, the mucosa has a granular, erythematous appearance, with friability and loss of the vascular pattern. In moderate disease, erosions or microulcerations are evident, whereas in severe ulcerative colitis, shallow ulcerations with spontaneous bleeding are generally seen. In pancolitis, inflammation stops at the ileocecal valve, with occasional limited involvement of the distal ileum, a condition known as backwash ileitis. 

Colonoscopy helps to differentiate ulcerative colitis from Crohn’s disease, which is typically characterized by rectal sparing, aphthous ulcers, skip lesions (areas of inflammation alternating with normal mucosa), a cobblestone pattern, and longitudinal, irregular ulcers.

In patients with cycles of inflammation and healing and in those with chronic, unremitting inflammation, colonoscopy may reveal pseudo polyps or mucosal bridging. If a stricture is detected, multiple biopsies are mandatory to rule out malignant disease; biopsies are also required for surveillance of dysplasia in patients who have the disease for longer than 8 years. Newer endoscopic techniques that are gaining acceptance, such as chromoendoscopy, narrow-band imaging, and auto-fluorescence imaging, may better delineate suspicious mucosal patterns and improve the detection of dysplasia.


In ulcerative colitis, inflammation is characteristically restricted to the mucosal layer, with infiltrates varying in density and composition during active disease or stages of remission. Infiltrates consist primarily of lymphocytes, plasma cells, and granulocytes; the last are being particularly prominent during acute flare-ups and accumulate in crypt abscesses. Other typical features include goblet-cell depletion, distorted crypt architecture, diminished crypt density, and ulcerations. However, epithelioid granulomas, which are typical of Crohn’s disease, are not present.

Looking for epithelial dysplasia is critical, given the risk of cancer in patients with long-standing ulcerative colitis; however, dysplasia can occur at any stage without indicating malignant transformation. There are no exact criteria for the diagnosis of ulcerative colitis, but in most cases, the presence of two or three of the aforementioned histologic features will suffice.

Laboratory measurements are helpful in assessing and monitoring disease activity and in differentiating ulcerative colitis from other forms of colitis. Blood counts and measurements of the erythrocyte sedimentation rate and the level of fecal lactoferrin or calprotectin help determine the severity of the inflammation. Stool cultures for Clostridium difficile, campylobacter species, and Escherichia coli 0157:H7 are recommended to rule out an infectious cause or complication. Patients with severe, refractory disease should be assessed for cytomegalovirus infection by means of histologic, immunochemical, serologic, culture, or DNA testing.56 A positive test for ASCA or pANCA is not diagnostic, given the limited sensitivity and specificity of the tests; when they are performed in combination, however, the results may help differentiate among ulcerative colitis, Crohn’s disease, and indeterminate colitis.

Induction of Remission

  1. Sulfasalazine and 5-aminosalicylates (mesalamine, olsalazine, and balsalazide), given orally, rectally (by means of suppository or enema), or both, represent first-line treatment for ulcerative colitis, with an expected remission rate of about 50%.  
  2. Mild-to-moderate proctitis can be treated with mesalamine suppositories (1 g per day) or enemas (2 to 4 g per day); clinical remission occurs in most patients within 2 weeks, with repeated treatments as needed.
  3. If this fails, 5-aminosalicylate enemas (2 to 4 g per day) or glucocorticoid enemas (hydrocortisone at a dose of 100 mg per day, or new preparations such as budesonide or beclomethasone) are a next step.
  4. Patients who do not have a response to rectally administered agents may be given oral glucocorticoids (up to 40 mg of prednisone or its equivalent).
  5. Mild-to-moderate left-sided colitis to extensive ulcerative colitis is initially best treated with a combination of rectal and oral 5-aminosalicylate (up to 4.8 g per day).
  6. Patients with mild-to-moderate ulcerative colitis that is refractory to rectal therapies and to oral 5-aminosalicylate are candidates for oral glucocorticoids or immunosuppressive agents (azathioprine or 6-mercaptopurine); those who do not have a response to maximal doses of 5-aminosalicylate or oral glucocorticoids should be given intravenous glucocorticoids.
  7. A good therapeutic option appears to be infliximab, a monoclonal antibody against TNF-α, administered at a dose of 5 mg per kilogram of body weight at 0, 2, and 6 weeks. Infliximab in combination with azathioprine (2.5 mg per kilogram) was reported to be superior to infliximab or azathioprine monotherapy for inducing glucocorticoid-free remission in patients with moderate-to-severe ulcerative colitis.
  8. Many specialists suggest that patients with extensive, severe disease receive a 5-day to 7-day course of intravenous glucocorticoids; if the disease is unresponsive, then intravenous cyclosporine (2 mg per kilogram) or infliximab is usually the next step. Although cyclosporine can be effective, it generally delays rather than prevents subsequent colectomy.

After remission has been achieved, the goal is to maintain the symptom-free status, which can be accomplished with various medications, with the exception of glucocorticoids, which have no place in maintenance therapy, given the marked side effects associated with their long-term use. Both oral and rectal 5-aminosalicylate have greater efficacy than placebo for maintenance of remission in patients with distal disease. Thiopurines (e.g., azathioprine at a dose of 2.5 mg per kilogram or 6-mercaptopurine at a dose of 1.5 mg per kilogram) are recommended when 5-aminosalicylate is ineffective or not tolerated or when the patient is glucocorticoid-dependent, although it may take several months before their maximal effectiveness is reached.

Unlike Crohn’s disease, ulcerative colitis may respond to probiotic therapy. For example, Escherichia coli strain Nissle 1917 (200 mg per day) is not less effective than 5-aminosalicylate (1.5 g per day) for maintaining remission, and the probiotic VSL#3 (3600 billion colony-forming units per day for 8 weeks) in conjunction with 5-aminosalicylate can help induce remission in mild-to-moderate ulcerative colitis.

Ulcerative colitis is generally easy to diagnose, and conventional step-up therapy is adequate for managing mild-to-moderate disease activity. Nevertheless, various important challenges remain. Several questions regarding the pathogenesis of ulcerative colitis remain to be answered. Why is inflammation restricted to the mucosal layer? Are colonic epithelial cells specific targets of an immune response? How does the luminal microbiota relate to the inflammatory response? Why does pouchitis develop in patients with an IPAA?

Many patients with ulcerative colitis still receive suboptimal doses of medications (particularly the aminosalicylates), continue to take glucocorticoids for exceedingly long intervals, or switch to biologic agents before immunosuppressive therapy has been optimized. In many cases, colectomy is a reasonable option, yet patients and clinicians alike remain reluctant to accept it.

 Adalimumab, a different anti-TNF-α antibody, is reported to induce remission, and antibodies such as MLN0002 and PF-00547659, which prevent homing of leukocytes to the gut, have shown preliminary efficacy in active ulcerative colitis.

Cirrhosis: evaluation and treatment.

Cirrhosis is the irreversible fibrosis of the liver. It is the end stage of a final shared pathway in chronic damage to a major vital organ. The pathophysiological features of cirrhosis involve progressive liver injury and fibrosis resulting in portal hypertension and decompensation, including ascites, spontaneous bacterial peritonitis, hepatic encephalopathy, variceal hemorrhage, the hepatorenal syndrome, and hepatocellular carcinoma. The major causes of cirrhosis include chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infection, alcoholism, and nonalcoholic steatohepatitis. HCV infection and nonalcoholic steatohepatitis are the causes that are primarily responsible for the growing burden of cirrhosis in health care. Owing to the increasing prevalence of nonalcoholic fatty liver disease, cirrhosis related to nonalcoholic steatohepatitis is predicted to surpass HCV-related cirrhosis as the most common indication for orthotopic liver transplantation. Schistosomiasis and portal vein thrombosis can also cause cirrhosis and portal hypertension.

The risk in cirrhosis of the liver.

A diagnosis of compensated cirrhosis is associated with a risk of death that is 4.7 times as high as the risk in the general population, and decompensated cirrhosis is associated with a risk that is 9.7 times as high. The average life expectancy of a patient with compensated cirrhosis is 10 to 13 years, and the average life expectancy may be as low as 2 years if there is decompensation. Among patients with alcoholic cirrhosis, 65% of the patients who abstain from drinking alcohol are alive at 3 years, as compared with 0% who continue drinking alcohol.

Algorithm for management of cirrhosis of the liver. August 25, 2016
N Engl J Med 2016; 375:767-777.

Nutrition in Cirrhosis.

Will proteins cause encephalopathy?

Malnutrition occurs in 20 to 60% of patients with cirrhosis, and current guidelines recommend a daily protein intake of 1.0 to 1.5 g per kilogram of dry body weight. High-protein diets are well tolerated and are associated with sustained improvement in mental status, whereas restriction of protein intake does not have any beneficial effect in patients with acute hepatic encephalopathy. Therefore, avoid protein restriction in patients, regardless of whether they have a history of hepatic encephalopathy.

Because of a hypermetabolic state, overnight fasting contributes to muscle depletion in patients with cirrhosis. Late-evening meals may improve nitrogen balance without exacerbating hepatic encephalopathy. A randomized trial involving patients with cirrhosis who received two cans of high-protein nutritional supplement (474 ml per can) nightly showed that nocturnal supplementation resulted in sustained increases in total body protein.

(Plank LD, Gane EJ, Peng S, et al. Nocturnal nutritional supplementation improves total body protein status of patients with liver cirrhosis: a randomized 12-month trial. Hepatology 2008;48:557-566).

A 2000-mg limit in daily sodium intake is mandatory in the treatment of ascites. Dietary counseling is particularly useful for patients and the people who cook for them. We recommend fluid restriction only when the serum sodium concentration is less than 120 mmol per liter. Successful fluid restriction requires that the fluid intake be less than urinary volume.

Antihypertensive drugs in cirrhosis.

Patients with cirrhosis who have a history of hypertension gradually become normotensive and eventually hypotensive as cirrhosis progresses. Studies of blood pressure in patients with cirrhosis and ascites showed that a mean arterial pressure of 82 mm Hg or less was the single variable that was most strongly correlated with a reduced probability of survival.

Pathophysiology of hypotension in cirrhosis. August 25, 2016
N Engl J Med 2016; 375:767-777.

In hypotension with a cardiac index below 1.5 liters per minute per square meter of body-surface area predicted the development of the hepatorenal syndrome and a decreased probability of survival among patients with cirrhosis and ascites.  Because of these hemodynamic changes, antihypertensive agents should be discontinued in patients who have decompensated cirrhosis with ascites or hypotension.

Nonselective beta-blockers reduce portal pressures and are used in the primary and secondary prophylaxis of variceal hemorrhage. However, various studies caution the use of beta-blockers in situations such as decompensated cirrhosis with refractory ascites, spontaneous bacterial peritonitis, and severe alcoholic hepatitis.

Window Hypothesis.

These studies led to the “window hypothesis,” which postulates that beta-blockers are associated with higher rates of survival only within a clinical window. In patients who have early cirrhosis without moderate-to-large varices, beta-blockers do not prevent the development of varices and also result in adverse effects so do not start beta blockers early. The clinical window opens when moderate-to-large esophageal varices develop, with or without variceal bleeding, and beta-blockers are indicated for primary and secondary prophylaxis of variceal bleeding. Increasingly, evidence suggests that the clinical window for beta-blockers closes and that they are no longer effective when refractory ascites, hypotension, the hepatorenal syndrome, spontaneous bacterial peritonitis, sepsis, or severe alcoholic hepatitis develops, owing to unfavorable hemodynamic effects in advanced cirrhosis.

In patients with stable hypotension, midodrine may improve splanchnic and systemic hemodynamic variables, renal function, and sodium excretion. The combination of octreotide and midodrine is used for the treatment of type 1 hepatorenal syndrome. In patients without the hepatorenal syndrome, midodrine was shown to increase urinary volume, urinary sodium excretion, and mean arterial pressure and was associated with a reduction in overall mortality.

The most recent Baveno VI consensus guidelines regarding portal hypertension recommend the discontinuation of beta-blockers when the systolic blood pressure is less than 90 mm Hg, the serum sodium concentration is less than 120 mmol per liter, or acute kidney injury has developed.

Pain management.

Analgesic agents must be carefully selected in patients with cirrhosis. opiates are contraindicated. Because of the risk of acute renal failure and gastrointestinal bleeding, nonsteroidal anti-inflammatory drugs are contraindicated, except for low-dose aspirin in patients in whom the severity of cardiovascular disease exceeds the severity of cirrhosis. Acetaminophen is effective and safe in patients with liver disease, provided that the patient does not drink alcohol. The Food and Drug Administration has recommended limiting the total daily dose of acetaminophen to 4 g in all patients.

Proton-pump inhibitors are vastly overprescribed in hospitalized patients with cirrhosis, often without any documented indication. A large study involving patients with cirrhosis who were hospitalized with an initial infection showed that the risk of subsequent infection was increased among patients taking proton-pump inhibitors and those receiving long-term antibiotic agents as prophylaxis for spontaneous bacterial peritonitis.

Benzodiazepines should be avoided in patients with hepatic encephalopathy. For patients with alcoholic hepatitis or cirrhosis in whom severe symptoms of acute alcohol withdrawal develop, short-acting benzodiazepines such as lorazepam and oxazepam are preferred in order to minimize the risk of over sedation. For patients with insomnia, hydroxyzine at a dose of 25 mg at bedtime may be a reasonable alternative and has been studied in a small, randomized trial. Prescribed trazodone at a dose of 100 mg at bedtime.


3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) can be safely started and continued in patients with cirrhosis. Statins have established cardiovascular benefits in the treatment of nonalcoholic fatty liver disease.


Selective vasopressin V2–receptor antagonists (vaptans) have been evaluated for use in hyponatremia and ascites. A large, placebo-controlled study involving patients with cirrhosis and ascites showed that although satavaptan alleviated hyponatremia, mortality was higher among patients with recurrent ascites who were receiving satavaptan than among those who were receiving placebo. Because of these findings as well as hepatotoxicity reported with respect to tolvaptan, the use of vaptans in patients with cirrhosis and ascites is not recommended.

Protecting the liver from harm.

The fundamental principles in the management of cirrhosis focus on education, lifestyle modification, protecting the liver from harm, and care coordination. The liver has considerable regenerative potential, and “recompensation” and reversal of cirrhosis have been described in patients with alcoholic cirrhosis who abstained from alcohol, patients with HBV infection who underwent antiviral therapy, and patients with nonalcoholic steatohepatitis who underwent bariatric surgery. A study involving patients with decompensated HCV cirrhosis who received direct-acting antiviral therapy showed that a sustained virologic response at 12 weeks after the completion of treatment was associated with decreases in the Child–Pugh class and MELD score. Antiviral therapy in patients with HBV cirrhosis may reduce the risk of hepatocellular carcinoma.

Public education efforts are needed to discourage obesity, needle sharing, and excessive alcohol consumption.

It is recommended that patients undergo endoscopy for variceal screening and subsequently follow established guidelines for endoscopic surveillance. Endoscopic band ligation is preferred in patients with medium-to-large esophageal varices. A nonselective beta-blocker can be considered if the patient does not have refractory ascites, spontaneous bacterial peritonitis, severe alcoholic hepatitis, or hypotension.

It is recommended that all patients with cirrhosis undergo surveillance for hepatocellular carcinoma with the use of abdominal ultrasonography or computed tomography every 6 months. Serum measurement of the alpha-fetoprotein level in conjunction with abdominal ultrasonography may improve the effectiveness of surveillance for hepatocellular carcinoma.

Antibiotic prophylaxis may reduce the risk of bacterial infection (including spontaneous bacterial peritonitis) and increase survival rates in selected scenarios.

Patients with alcoholism are prone to relapse because of cravings and anxiety. We recommend baclofen for the suppression of alcohol cravings. A randomized trial involving patients with alcohol dependency and cirrhosis showed that 71% of patients receiving baclofen were able to maintain abstinence, as compared with 29% of patients receiving placebo.

Patients with decompensated cirrhosis may ultimately require orthotopic liver transplantation. Evaluation for transplantation is indicated when the MELD score is 17 or more.

The MELD Score (Model for End stage Liver Disease) has been validated as predictor of survival in patients with cirrhosis, alcoholic hepatitis, acute liver failure, and in patients with acute hepatitis.

Liver Transplant: important information.

Who needs a liver transplant and who does not? What drugs can be used for immunosuppression? Remember that as the liver recovers and regenerates after a successful transplant its enzymes modify and destroy the drugs being used. Close monitoring of drug levels is essential.

In chronic liver failure the two most common reasons for a transplant are hepatocellular cancer and hepatitis C. These two may also be the causes;  alcoholic cirrhosis and nonalcoholic steatohepatitis .

In acute liver failure the outcome is either complete recovery or death so a follow up in a liver unit is justified.

In cirrhosis just the presence of cirrhosis is not a reason for a transplant but evidence of decompensation most often varices and ascites, the development of hepatorenal syndrome, which is an ominous marker and signals the need for immediate transplantation evaluation.

Development of the MELD score — MELD was originally developed to predict three-month mortality following transjugular intrahepatic portosystemic shunt (TIPS) placement and was derived using data from a population of 231 patients with cirrhosis who underwent elective TIPS placement. It is in lover transplant now used for organ allocation.

Patients with some primary liver neoplasms may be candidates for liver transplantation, provided the neoplasms meet specific criteria (eg, for patients with hepatocellular carcinoma [HCC], a single lesion ≤5 cm or up to three separate lesions all ❤ cm, no evidence of gross vascular invasion, and no regional nodal or distant metastases). In addition, there may be a role for liver transplantation in patients with neuroendocrine tumors that have metastasized to the liver, but experience in this setting is limited.

Several liver-based metabolic conditions with systemic manifestations may be treated with liver transplantation. In some cases (eg, alpha-1 antitrypsin deficiency and Wilson disease), patients are cured of the underlying disease with liver transplantation, though some clinical manifestations may not be reversible.

Other conditions that may require a liver transplant are; Familial amyloid polyneuropathy, Primary hyperoxaluria, Cystic fibrosis, Alpha-1 antitrypsin deficiency, some forms of glycogen storage disease (type I and type IV), Tyrosinemia, Hemochromatosis, Wilson disease, Acute intermittent porphyria.

The optimal Model for End-stage Liver Disease (MELD) score at which patients should undergo LDLT has yet to be determined.

Graft size constraints have generally limited the use of left lobe living donor liver transplantation (LDLT) to recipients who weigh less than 60 kg, but due to the desire for safer, smaller-scale resections with less liver removed, left lobe donation will continue to be explored in a wider range of circumstances. The right lobe accounts for approximately two-thirds of the liver mass and provides adequate tissue to support the metabolic needs of an adult recipient. The right lobe also fits correctly into the right subphrenic space, making the vascular anastomoses easier to perform.

Liver regeneration is rapid following living donor liver transplantation. In one report, the volume of small-for-size left lateral segment grafts increased by 60 to 200 percent within one month and approximated standard liver volume by about two months post-transplant. Substantial hepatic growth also occurs in the donor during the first month.

However, data regarding the benefits of HLA matching have been mixed. The degree of HLA matching was not associated with time to graft failure in patients with either autoimmune or non-autoimmune causes of liver disease. Some studies have found that perfect HLA matching (a rare occurrence) may even be deleterious by predisposing to graft-versus-host disease.

Immunobiollogy of liver transplant rejection.

Signal I: Alloantigen recognition 

Signal II: Lymphocyte activation (costimulation)

Signal III: Clonal expansion.


A major issue with the immunosuppressive agents used for liver transplant recipients (particularly calcineurin inhibitors and mechanistic target of rapamycin inhibitors) is their extensive metabolism by CYP3A4. This creates the potential for drug-drug interactions that may produce toxicity or dangerously low levels of immunosuppressive agents, leading to an increased risk of rejection. As examples, antifungal agents, some antibiotics, and many of the drugs used in the treatment of HIV inhibit CYP3A4.

Four steroid formulations are used commonly in transplantation: hydrocortisoneprednisoneprednisolone, and methylprednisolone. These drugs have different relative potencies. Steroid use varies among transplant centers, and there is no agreement on an ideal protocol. A common regimen is a 1 gram bolus of methylprednisolone during the anhepatic phase, followed by 20 mg/day intravenously. Once the patient is able to take oral medications, he/she is switched to prednisone 20 mg/day. Tapering to zero is usually achieved over three to six months, although some centers leave patients on 5 mg/day indefinitely.

Cyclosporine was initially formulated as Sandimmune, a corn oil-based preparation with inconsistent absorption, especially in the absence of bile flow. This is clearly a problem after liver transplantation, so the nonaqueous, microemulsified version (Neoral) has become the preferred formulation. Monitor blood levels frequently as the regenerating liver may destroy it. Cyclosporine can be administered intravenously, although it is usually given orally as a tablet or an oral suspension. The intravenous dose is approximately 30 percent of the oral dose because of improved bioavailability, and because it is given as a continuous infusion.

Cyclosporine versus tacrolimus — By the mid-1990s, most centers agreed that tacrolimus was associated with superior graft and patient survival. All patients received azathioprine and prednisolone.

Calcineurin inhibitors and renal failure — CNI-induced renal failure is a serious problem after orthotopic liver transplant (OLT). The problem has been exacerbated by the switch to a MELD-based organ allocation system, which is weighted towards higher serum creatinine. A lower dosing, often with the addition of an auxiliary agent like mycophenolate mofetil (MMF) or a monoclonal antibody in patients with preoperative renal impairment can be used. It is important to attain adequate tacrolimus levels quickly.

Patients with HCV infection — The availability of highly effective antiviral agents (DAAs) has greatly simplified post-OLT HCV therapy. Antiviral agents may interfere with drug metabolism because of effects on CYP3A4 and/or P-glycoprotein (gp). In addition, the rate of calcineurin inhibitor clearance may increase with a declining viral load. For these reasons, calcineurin inhibitor levels should be monitored closely after starting DAAs.

Sirolimus — Sirolimus (Rapamune), a macrolide antibiotic produced by Streptomyces hygroscopicus, is a potent immunosuppressive agent approved by the US Food and Drug Administration (FDA) for renal transplantation in 1999. Targets the same receptors as tacrolimus. It is free of nephrotoxicity and neurotoxicity but is considered second line of therapy.

Everolimus — Because prolonged use of calcineurin inhibitors (CNI), such as tacrolimus, is associated with renal disease, everolimus (EVR) has been studied as an alternative for long term immunosuppression. The FDA recommends that both mTORs, everolimus and sirolimus, not be used earlier than 30 days after liver transplantation because of an increased risk of hepatic artery thrombosis in the early post-transplantation period

Mycophenolate mofetil and mycophenolate sodium. MMF does not cause neurotoxicity or nephrotoxicity, and is widely used as a calcineurin inhibitor (CNI)- or steroid-sparing agent. The most common side effects are bone marrow suppression and gastrointestinal complaints, including abdominal pain, ileus, nausea, vomiting, and oral ulceration. These symptoms are usually dose-related and improve with temporary or permanent dose reduction. Usual dosing is 1 g twice daily. 

 Azathioprine is a prodrug of 6-mercaptopurine, which is an antimetabolite that inhibits purine synthesis. By preventing the de novo synthesis of purines, and thus interfering with RNA and DNA synthesis, azathioprine inhibits the replication of T and B cells. It is typically given at a dose of 1.5 to 2.0 mg/kg/day.

Polyclonal antibodies have been used for induction of immunosuppression or treatment of steroid-resistant rejection.

Monoclonal antibodies. Basiliximab — Basiliximab (Simulect) and daclizumab (Zenapax) are humanized monoclonal antibodies against the IL-2 receptor.

Among the newer antibodies being tried out are; Belatacept (LEA29Y) and Efalizumab.

Contraindications for liver transplant.

●Cardiopulmonary disease that cannot be corrected and is a prohibitive risk for surgery

●Acquired immunodeficiency syndrome (AIDS)

●Malignancy outside of the liver not meeting oncologic criteria for cure

●Hepatocellular carcinoma with metastatic spread

●Intrahepatic cholangiocarcinoma


●Anatomic abnormalities that preclude liver transplantation

●Uncontrolled sepsis

●Acute liver failure with a sustained intracranial pressure >50 mmHg or a cerebral perfusion pressure <40 mmHg

●Persistent nonadherence with medical care

●Lack of adequate social support


What is being practiced currently in teaching hospitals internationally. Good history presentation. Good interview technique.

Facing the Examiner in the FCPS 2 Exam in Medicine. It is time for you to be assessed in the knowledge and skills that you have acquired in the last four years of your training. Some of you underwent the training earlier maybe several years ago and have settled into a routine you use daily with your patients but shortcuts have slipped in and methods not academically acceptable are being used by you. These may appear to work but may actually be delaying the diagnosis or needing to be supplemented by a lot of tests which may be unnecessary. Unconfirmed diagnoses are being treated with shotgun therapy. So candidates who have been practicing on their own need to go back to basics so that they may be successful in the exam. What are the components of a patients history? Students are no longer taught to ask patients for a presenting complaint, they are told to ask the patient why they have come to the hospital or ER today or now. this is called “Reason for admission”. Try to write or relate one or two complaints which need admission or write down the procedure for which the patient has come.”  Writing down a list of complaints in chronological order is obsolete. It leads to confusion and does not indicate what immediate action should be taken. I give an example. Presenting complaints.
  • epigastric pain postprandial 8 months.
  • heartburn on lying down or bending  7 months.
  • bloating and belching 7 months.
  • flatulence 6 months.
  • loss of appetite  5 months.
  • vomiting of fresh blood 2 hours ago.
When this patient is admitted out of working hours and you ring up the consultant to give him/her the list of complaints it is natural to think of a chronic gastric/esophageal/duodenal problem. The consultant will schedule this patient for a routine assessment within 24 or 48 hours and forget him. If you write: Reason for admission; a fresh GI bleed with loss of a cupful of fresh and clotted blood. The response from the senior doctor will be: “send a sample for crossmatch and arrange 2 pints of blood, check his Hb and PCV, alert the gastroenterologist, surgeon and anesthetist, start an IV life line, shift the patient to the ICU. I will be there as soon as I can reach the hospital.” Where does the rest of the information go? Into the history of current illness. So we now have two components of the history:
  • Reason for current admission. This may be a procedure like a biopsy. or bronchoscopy or for observation for fits etc.
  • History of current illness. What does this include? The other complaints that you had written in the original list with some details added in, treatment taken during the 8 months of the illness, any significant tests done including their results. Ask the patient if he has the test results. Any improvement or worsening of the symptoms. Any procedures undertaken like and upper GI endoscopy or gastric biopsy. If a tentative diagnosis was given to the patient please mention this. Add any co-morbid conditions. Most illnesses even if they appear unrelated are mentioned here as well as long term medications. A neoplastic disease treated even several years ago needs to be mentioned here. Infections that have effects years later like Hep C, Hep B, HIV/AIDS acquired at any time need to be mentioned. Any disease or condition being treated by a clinician needs to be mentioned. The priority that you use in mentioning these are your own.
  • There is no such thing as a past history or rarely so. Possible one might be something like fell from the roof of his hut 12 years ago and broke his tibia. Has no disability from that. Was treated for tuberculosis when he was a teenager. The disease has been inactive since then.
  • Personal history. Geographical area where the patient lives permanently as different diseases are prevalent in different countries and areas. You should be aware what they are. Current residence may have a similar effect so mention this. Remember that in the subcontinent we have a mobile population and some people may move with the seasons. If the area has a special feature like the climate is very hot or freezing cold, or a desert area, dusty, with lots of fog or smoke or pollen then mention this. Mention the kind of house they have and access to electricity and water if you consider it relevant. Are they educated enough to communicate in writing, texting or telephone? Can they afford the treatment? What is the occupation and does it affect their health? Where you mention this depends on how significant the information is and can be mentioned in the current illness. Ask about their normal diet and dietary preferences but do not waste too much time on it. The objective is to detect a deficiency.
  • Family history. Please mention if parents are alive and if not what they died of and at what age; mention siblings, whether older or younger, if they have any disease or if any have died. If it is a strongly inherited disease like diabetes or polycystic kidneys mention any aunts, uncles, grandparents or cousins who had the disease.
When you are presenting the history do not use any headings like “this is the history of present illness;” just give the information as it becomes relevant to the diagnosis  of the disease. Remember that you are presenting the history after you have examined the patient. Because of the examination you have picked up the diagnosis. Use this information when presenting the current illness. A candidate was presenting the case of a 38 ear old woman who had swelling of her body for 21/2 months. The candidate kept insisting that her face was swollen first and that the swelling then involved the lower part of the body. This usually happens in glomerulonephritis for some reason but not always. He/she insisted there was no breathlessness or orthopnea.  They then proceeded to to do systemic survey of the liver, kidney and heart which took a few minutes. The examiner asked whether the patient knew what was wrong with her. The answer was yes. Well tell me. She has a valve lesion. Which one? She does not know. The candidate continued with the history. “In the past history 11 years ago she had become very breathless and had a PMVC.” “What is that?” “A percutaneous mitral valve commissurotomy.” “What caused the severe breathlessness 11 years ago?” the examiner answered himself “Probably pregnancy and atrial fibrillation. Am I right?” Yes said the candidate. “What medication was she put on?” “Shall I tell you the names?” “Yes of course if she knows them” ” Lasoride, Tenormin, and an intramuscular injection every month for 5 years”. Here is the story of a patient who had tight mitral stenosis 11 years ago. It was not calcified so a commissurotomy was done and penicillin prophylaxis was given for 5 years. She had two more pregnancies during this period and both were uneventful but no one seems to have given her contraceptive advice. By now the re-stenosis seems to have occurred along with AF and calcification of the valve. She now needs valve replacement, treatment for AF, anticoagulants and sound contraceptive advice. The candidate was not mentioning the events that took place 11 years ago as they thought it was “past history”. It is not past history but very much part of the current illness as the valve continued to be damaged over the years. When the candidate knew about the mitral commissurotomy and had examined the patient and heard the murmur of mitral stenosis the involvement of the mitral valve should have been mentioned at once. Please do not “hide’ information with the idea that this has to be mentioned in the past history or family history. It is fatal to say to the examiner “I will tell you later”. This is not a guessing game, it is about making a diagnosis as quickly as you can and as accurately as you can. When you tell the examiner later you will not get any marks for the information. If the patient has a strong family history of Adult Polycystic Kidney Disease then mention this early in the current illness and do not wait until you come to the family history. This is essential history which will change the course of your investigation and treatment. Try and get hold of a history from a patient who has travelled from a Western country. He will have a well written history with all the relevant information given in order of medical priority without any headings like “present illness” “past illness” family history” etc. Please remember there is no “formula” which must be followed. Rely on clinical common sense. One common cliché to remember is that common things are common. A runny nose is most likely caused by a common cold and least likely by CSF rhinorrhea! Anemia is most likely caused by either a dietary deficiency or a bleed somewhere rather than an HLTV causing a rare leukemia. Ask about the diet. The daughter of a domestic cleaner is very unlikely to eat meat, chicken and eggs daily. Ask her what the menu is on a typical day in her home. That is why a personal history becomes important in history taking. If the patient appears well fed then skip the diet. Another simple rule to impress the examiner is to talk to the patient politely and in a socially acceptable manner. Don’t shout or bark questions at them. Many trainees who come from a hospital OPD and its noisy environment tend to shout loudly. Being asked “Do you have heavy periods?” or “Do you have problems during sex since you started taking this medicine?” are not questions the patient wants the whole hall to hear. You do not have to ask detailed questions about every symptom that either you or the patient has mentioned. If the patient mentions fever ask if he or a doctor or nurse ever used a thermometer to document it but if the patient only feels feverish please do not spend time in the usual litany of “Is it in the morning or evening; is it high or low; is it with a rigor; etc.” Remember your clinical acumen is being assessed as well as your ability to evaluate the significance of the patient’s symptoms. The patient may not tell you immediately about the essential symptom because either they are afraid or do not understand the importance themselves; weight loss and poor appetite, somnolence are some that are missed unless you ask about them. Understand the relevance of the questions you ask. You may be asked why you wanted some particular information. Please refrain from asking questions just to show that you know about a disease especially if the patient does not have the disease. It may backfire. Remember the guidelines commonly used for either the diagnosis or for assessing the severity of an illness and also remember who has set the guidelines and when. You may be quoting outdated guidelines. For example there are guidelines for assessing the severity of esophageal varices and there are differences in the treatment of each grade; kidney diseases are divided into stages dependent on creatinine clearance; the severity of heart failure has its own guidelines so does COPD. There are many others. The real test is how you present the information you have gathered. You will need to edit the information that the patient has given you into a form that makes clinical sense, The trick is not to miss out an important detail. If you understand why you asked certain questions and if you understood the answers not just the language; the relationship of the question to the diagnosis and how the answer clarifies the clinical problem, then your presentation will be good. Here is where you think about why, what and how: why am I asking this question?
  • Be polite but not obsequious i.e. excessively polite.
  • Remember the answer to your questions so that you do not have to repeat everything.
  • Write down an important point but do not write down the answer to all your questions.
  • Evaluate the information you are getting from the patient and divide it in your mind into
    • essential information or the reason that the patient is seeking help. If you get this wrong you are going to get your whole diagnosis wrong.
    • information that will help in making clinical decisions like is the patient a diabetic or has renal failure or is allergic to a drug or make the diagnosis clear.
    • incidental information which may or may not influence the diagnosis and treatment.
    • When you present the history do it in the above order.
  • Why did the character of the pain or symptoms change? What difference does the answer make?
  • What is the duration of the symptoms? Is it chronic or acute? Longstanding or recent?
  • What weight-age should I give the answer?
  • How did the disease progress? Is it getting worse or is a new complication developing? Remember most patients come to us with complex diseases or more than one disease.
  • If the disease is infective pay attention to the epidemiology; where did the patient get it? Has the patient passed it on to someone else? Does the patient need to be treated in isolation? Do you or your staff need to be shielded from the disease?
  • Why did the patient take so long to come to a hospital or consult a doctor? The reason may be financial or lack of access to medical care for geographical reasons, lack of awareness or treatment by practitioners of alternate treatment or by a doctor who had got the diagnosis wrong. I once came across a 12 year boy drugged to the gills for the last 1 year, with antiepileptic drugs, so drowsy that he had stopped going to school. His episodes of hypoglycemia were giving him the fits and eventually the insulinoma was removed and he no longer had epilepsy.
  • What treatment has the patient already taken? How has this treatment modified the symptoms or the signs?
  • How am I going to present the case? Which symptom or symptom complex should I talk about first?
When you are presenting the case and want to make a good impression change the the emphasis from the written history. In the written case file, you are required to write the patient’s bio data first e.g. name, age, marital status, occupation, home address, telephone, next of kin, person to call in an emergency. Do not recite all this when you are presenting the case. During the presentation it is sufficient to give the name, age, occupation briefly and what the patient was doing at the time of onset of the symptoms if this was sudden or related to exercise and duration. Start with the most significant symptom or symptom complex. Talk about the co morbid conditions or lack of them; talk about the medication the patient is already taking. You can give the personal information after you have given the clinical information. Try to give the information in your presentation so that you are leading up to a probable diagnosis. Even if your initial diagnosis is not accurate it does not matter. You can make up for it when you are presenting the clinical findings. Just randomly presenting symptoms without leading towards any diagnosis leaves a poor impression. For example “This patient vomited blood two days ago. He has had no malena i.e. black tarry stool so it appears to have stopped. He has not had jaundice in the past, is not an alcohol drinker and has not been tested for Hep B or C.” This case may turn out to be a malignant peptic ulcer or even a bleeding disorder but you have shown clinical acumen by talking about liver disease and have scored good marks on presentation. Or another example: “This 56 year old-lady, who is a school teacher, has come in with swelling of her feet for the past 5 days. She is not breathless and has no cough. She is diabetic but has never had her urine tested for proteins. Her blood pressure is also high so her major risk is either from diabetic nephropathy or hypertensive nephrosclerosis. After assessing her renal functions she may need a renal biopsy to clarify the diagnosis”. by saying this you have pre-empted a lot of questions and have exhibited your knowledge. The examiner then has time to ask you questions about management, recent advances, research and give you a better score. Some phrases and modes of information you should avoid.
  • Avoid lists of negative symptoms or signs. Do not say “there is no any (this is incorrect English grammar) breathlessness, there is no any cough; there is no any expectoration; there is no any cyanosis; there is no any clubbing, there is no any orthopnea. 
  • “The patient is a known case of hypertension/anemia/jaundice etc.” How do you know? It is better to say that the hypertension was detected when the patient went for a physical examination for an insurance policy 3 years ago. He has been on antihypertensive therapy with captopril but has not been investigated for the cause of the hypertension. This lady was found to be hypertensive during her second pregnancy and has been hypertensive since then. Her urine was checked for proteins and she says that she had no proteinuria and her feet have never been swollen, She needs her renal function checked. Another case may be “this patient has come in with the third episode of swelling of the abdomen. He was found to be Hep B positive at his first admission. He received interferon injections for 6 months but could not afford them any more. Appears to have gone into cirrhosis of the liver” Do not say that this patient is a known case of cirrhosis of the liver.
Have fun preparing. Lots of confidence is what is needed. The examiner is not out to kill you only to help you pass.

Taking a history in the long case: do you sound like a consultant?

I had written two posts on how to take a history in the long case. Nobody bothered to read them. After all you know how to take a history. The problem is that in the exam situation (FCPS 2) in Pakistan the candidate is trying to throw themselves back to their third year days. The two examiners facing them are trying to assess that the candidate is now fit to practice as an unsupervised consultant. Remember there is no CME in Pakistan so that progress in learning and the acquisition of new clinical skills and knowledge is not assessed after the exit exam. It is perhaps equal parts luck and competition in private practice that ensures that doctors keep themselves updated in knowledge though we do have lots of examples where the doctors don’t do this.

The two examiner’s who are listening and watching and rapidly losing their esteem for the candidate’s history taking skills which goes something like this:

  1. What is your name?
  2. How old are you?
  3. What work do you do?
  4. Are you married?
  5. How many children do you have?
  6. How educated are you?
  7. What is your family income?
  8. Where do you live?
  9. Is your house airy or crowded?
  10. What food do you eat?

All very well when you are a third year student trying to establish personal information about the type of patient you are dealing with but very unlikely to get you to gain empathy or a working diagnosis. The patient is either going to be annoyed or embarrassed nor will these questions help you make decisions about what tests to do or what immediate treatment to start while you confirm your diagnosis.

A good way to help you empathise with the patient is to introduce yourself before asking for a name and a title and using the title to ask more questions. Remember that on the subcontinent people specially older ones do not like to be called by their first name alone. For more professional or educated people use ” Mrs, Mr, Sir, Madam, Miss or mohtarma, bibi, or sahib, aunty or uncle. For more conservative people apaji, Baji, Bibi, Bhai, Baray bhai, Sahib etc and for younger ones beta will do.

Ask how they are feeling, whether someone has taken care of their immediate problem and whether you can get them something i.e. water, a pain killer, an extra pillow, a sheet or blanket etc. When the patient gives you a list of complains or problems ask which one he/she would like help with first or which bothers them most. Watch their face and body language when they tell you about symptoms. It may help you decide which is more of a problem. Ask if they have been to a doctor before and what the doctor told them about their illness.

Remember these are the four things you want to do when you take the history initially: try to make a diagnosis, empathise with your patient, start planning tests in a logical sequence of tests in order of usefulness and relieve distress by starting medication which will relieve pain or breathlessness or swelling or vomiting etc. Personal history comes after you have made up your mind what is likely to be wrong with the patient,

A better way is to introduce yourself by giving your name and asking for the patient’s name. Say that you are sorry for any inconvenience but you have been asked to talk to the patient and examine them. Ask if they need anything before you start like water or some pain medication or oxygen. Would they like to be examined lying down or sitting in a chair and would they like a sheet or blanket. Then start by asking how they are feeling and what their major complaint or symptom is. Note whether there is a wheel chair, crutch, an IV cannula, CVP line and oxygen cylinder, nebuliser equipment in the cubicle or if the patient has a urinary catheter. They will be relevant to the patient’s symptoms. Then take a focused history.

A focused history means you ask for symptoms which are likely to arise from the main symptom or be linked to it. This means that you are trained to follow groups of symptoms or group recognition or pattern recognition. Most candidates can be seen to be trying to recollect these group symptoms sometimes even on their fingers! Certainly shows lack of training which is fatal.

Headache —nausea—vomiting—-visual scintillating—neck stiffness—loss of consciousness—fits—–repetition of symptoms over a period of time—- aura—-trigger–response to treatment–progression to other neurological symptoms or signs.

Fainting attacks or syncope–emotional event– physical event (standing still on parade)–environmental event like smoke, pollen–associated symptoms like palpitation or hyperventilation–recovery on lying down– vomiting–fits– headache–frequency of repetition–use of a medication which will make syncope likely.

Epigastric pain–heartburn– precipitated by bending—lying down flat after a heavy meal–sets off an attack of asthma (aspiration into the lungs)–postprandial epigastric pain–bloating, and belching and flatulence–recurrent urge to empty the bowel–pain at night–disturbance of sleep.

Weight loss– accompanied with a good appetite– think of thyrotoxicosis or type 1 diabetes– poor appetite — think of an inflammatory condition like TB, rheumatoid arthritis, SLE–think of a malignancy specially lymphoma, GI malignancy specially pancreas–duration.

Abdominal cramps and diarrhoea–ask for details of the stool– frequency–consistency– a fresh GI bleed accompanying the stool–black tarry stools–loss of appetite–fever–ask about fecal soiling of clothes may give a clue to anal fistulae.

Insomnia–is there a physical symptom which keeps them awake like pain or frequent micturition, breathlessness or polyneuropathy–do they have a proper place to sleep which is quiet and comfortable and dark–do they feel sleepy early and then wake up in the early hours of the morning–do they have a problem going to sleep and then sleep very late into the daylight hours–do they feel tired and feel like having a nap frequently during the day– do they feel tired all day long–is it affecting their work or usual life routine–do they snore very loudly? Explore sleep apnoea.

These are some examples. Make sure that you have made lists of group symptoms you encounter often. Anticipate the kinds of cases that are often presented in the examination and have your focused history present. It is not obligatory to ask questions which are altogether irrelevant to your case. If somebody has ischemic heart disease you do not have to ask about hair loss or a rash for example.

When starting with your physical examination again use focused examination if possible. Note if the patient is uncomfortable, orthopneic, dyspnoeic or in pain. Ask the examiner for appropriate help to relieve. Start with the height (ask the patient, they often know and it saves time) weight, if it is relevant work out the BMI (or do it at the end of the physical examination) next do the vital signs. These are very important. If the patient has fever or hypertension or hypotension or an irregular pulse or rapid or irregular breathing or wheezing then in each case your examination will be a little different. Note if the patient is visibly overweight or obese, has signs of recent weight loss like loose skin on the arms, face or abdomen. If you can obviously see cyanosis, jaundice, a sallow skin (more and more patients with CRF are turning up in the exams), anemia then mention them at once as also for edema, an ulcer, gangrenous toes or fingers. Tremors and abnormal movements must be mentioned at once. You can then proceed with your own routine for examining a patient.

If the BP is high or the patient has diabetes or evidence of an SOL then do the funduscopy now not at the end of the time you have been given when you will probably have to do it in a rush or not be able to do it at all. Be attentive with the pulse and look at the neck veins if needed. Look at the patient’s colour and note anemia, cyanosis, jaundice. Examine the peripheral pulses, note loss of hair on the body and scalp, note a rash or eruption. Examine the lymph nodes and thyroid. Look at the nails and do not waste too much time on looking for clubbing unless relevant from the history. Examine the nails and look for tremors. Mention anything else like an ulcer or a wound that appears to be relevant for example if there is a bandage ask if you are allowed to undo it, if so you must have the material including gloves to rebandage it. Mention an IV canula or urinary catheter or a scar specially if it is recent. Do not mention esoteric signs like Janeway lesions and Roth spots unless really relevant.

Which system to examine next? The one that is most involved in the complaints presented to you in the history. Do not go for the policy of checking out the system you find most difficult to examine if it is irrelevant. It does not look very intelligent if you examine the tendon reflexes in a patient who cannot breath from pneumonia!

Please practice the examination of the nervous system repeatedly. Remember you have to examine the higher mental functions, the cranial nerves, the cerebellar system, the motor system, the sensory system and some part of the autonomic nervous system too. You should be able to do this in 8–10 minutes not more. Practice, practice, practice.

If you have not been able to elicit from the history which system is involved like in a case of pyrexia of unknown origin, then say that I am going to elicit signs from the lymphatic system because I suspect a lymphoproliferative disorder, re-examine all the peripheral lymph nodes carefully if you left out any look, look for petechial hemorrhages or bleeding from anywhere, also look for the liver and spleen, any irregular lumps in the abdomen and complete the examination of the abdomen looking specially for the presence of ascites and enlarged kidneys. Then the respiratory system should be targeted. If there was an irregular pulse or symptoms of heart failure then examine the heart next specially looking for valvular lesions. Take clues from what you find in order to perform the next action.

For joints first just look at the natural posture that the patient is keeping the involved joint in. There is usually an angle of maximum comfort like flexion at the wrist, flexion and abduction at the knee, abduction at the hip or the patient likes to flex the hip and turn over on to that side, fingers are kept flexed. If there is a physical injury then the angle of comfort will change and help you recognize what is happening. Look for the degree of swelling, any cysts, look for limitation of movement. Join a surgical team to help you learn a proper examination of the knees, hips, spine, shoulders and elbows! Note the number of joints involved. If the hands are involved note the grip strength. When you are discussing the joint mention whether the joint is functional and if it is capable of bearing weight.

Dementia. Often begins with aggressive behavior; quarrelsome behavior, lack of anger management; confusion about major events in the family; confusion about routine events in the day like “Have I had my breakfast/dinner/bath/walk?”. They are likely to become aggressive about this. Confusion about where they sleep or live causes the tendency to wander off and get lost. Forget where the toilet is and urinate inappropriately. Insomnia with evening or night time aggression. Behavioral disturbances commonly peak in the late afternoon or evening, a phenomenon often referred to as “sundowning.” Sundowning affects up to two-thirds of patients with dementia and is closely related to disturbed circadian rhythms. Ask the patient and the caregiver what the major problem is. They tend to forget words so the vocabulary becomes limited hence conversation becomes repetitive and limited. They stop watching the TV news and plays as the words no longer make sense. Stop reading for the same reason. Need help with personal toilet and clothes. May see objects and people that are not there i.e. hallucinations and delusions. Also check with the caregiver what medications they are on and be aware of the side effects of these drugs. You will need to ask questions about all the above symptoms.

When symptoms and signs tend to involve several systems or do not clearly involve one system dominantly don’t panic. Think of diabetes, thyroid, adrenals i.e. endocrinopathies: think of connective tissue disorders: tuberculosis and other infections that can affect many systems: HIV/AIDS: lymphoproliferative and myeloproliferative disorder: diseases modified by treatment like immunosuppression. Keep asking, you will get the answer. Co back over your history; have you missed a symptom or mistaken a symptom for something else? Is the patient recovering from an illness hence the symptoms have gone away? Dig a little deeper.

At the end if you still have not come up with a diagnosis say “I am not sure what the patient has. I have several differential diagnoses. I will do the following tests and imaging processes and re-assess the patient again.” Please do not say “I will do routine tests.” Give reasons for each test that you want to do. Have some idea of false positives and false negatives and how useful each test is going to be.

Immunosuppression with drugs in renal transplant.

Let us see what we are up against once a solid organ like the kidney is transplanted into a patient after their original one has failed. Here kidney transplant will be dealt with according to a review article in the NEJM 2004.

What happens in an acute rejection reaction? Inflammatory processes are set in motion spear headed by the T lymphocytes instigated by the Antigen Presenting Cells (APCs) mainly the dendritic cells. Lets add a few details. Lymphocytes are either naive i.e. they have not encountered the antigen or be memory cells and it appears that viral antigens may resemble MHC antigens and sensitize the lymphocytes which will then react more quickly and vigorously.

What happens next is the 3 signal activation of the inflammatory reaction which primes the system to produce active T cells and alloantibody.

  1. Signal 1. These are the antigens on the dendritic cells which through the CD3 complex transduce the T cell.
  2. Signal 2. Dendritic cells provide costimulation, delivered when CD80 and CD86 on the surface of dendritic cells engage CD28 on T cells. Signals 1 and 2 activate three signal transduction pathways: the calcium–calcineurin pathway, the RAS–mitogen-activated protein (MAP) kinase pathway, and the nuclear factor-κB pathway.9 These pathways activate transcription factors that trigger the expression of many new molecules, including interleukin-2, CD154, and CD25. Interleukin-2 and other cytokines (e.g., interleukin-15)
  3. Signal 3. “Target of rapamycin” (mTOR) pathway is activated.,” This is the trigger for cell proliferation. Lymphocyte proliferation also requires nucleotide synthesis.

Proliferation and differentiation lead to the production of a large number of effector T cells.

B cells are activated when antigen engages their antigen receptors, usually in lymphoid follicles or in extrafollicular sites, such as red pulp of spleen, or possibly in the transplant, producing alloantibody against donor HLA antigens. Thus, within days the immune response generates the agents of allograft rejection, effector T cells and alloantibody.

Effector T cells that emerge from lymphoid organs infiltrate the graft and orchestrate an inflammatory response. In T-cell–mediated rejection, the graft is infiltrated by effector T cells, activated macrophages, B cells, and plasma cells and displays interferon-γ effects, increased chemokine expression, altered capillary permeability and extracellular matrix, and deterioration of parenchymal function. The diagnostic lesions of T-cell–mediated rejection reflect mononuclear cells invading the kidney tubules (tubulitis) and the intima of small arteries (arteritis). Macrophages that are activated by T cells participate through delayed-type hypersensitivity, but the injury remains antigen-specific.

Alloantibody against donor antigens that is produced systemically or locally in the graft targets capillary endothelium. Antibody-mediated rejection is diagnosed by clinical, immunologic, and histologic criteria, including a demonstration of complement factor C4d in capillaries. A failure of the graft to produce urine, a rise or failure to fall in the serum creatinine should raise a suspicion of acute rejection either immediate post -operatively or within a week of the transplant or maybe later. Ultrasound of the graft, renal scan, renal biopsy will all be required as well as a fluid and frusemide challenge and a careful follow up of the volume status and urine output.

So to sum it up the T-cell mediated response is a cellular response characterized by mononuclear cell infiltration and the antibody rejection is a vascular response damaging the endothelium of the capillaries. Both cellular and antibody responses can occur together.

How does the graft survive with immunosuppression?

Some adaptive responses take place.  Changes in the organ — a loss of donor dendritic cells and a resolution of injury — contribute to the adaptation. Regulatory T cells may also be able to control alloimmune responses, by analogy with their ability to suppress autoimmunity, although this hypothesis is unproven. The crucial element is that host T cells become less responsive to donor antigens when antigen persists and immunosuppression is maintained. 

This may be a general characteristic of T-cell responses in vivo, in which antigen persistence with inadequate costimulation triggers adaptations that limit T-cell responsiveness. The resulting partial T-cell anergy (known as “adaptive tolerance” or “in vivo anergy”) is characterized by decreased tyrosine kinase activation and calcium mobilization (signal 1) and decreased response to interleukin-2 (signal 3). Adaptation in clinical transplantation resembles in vivo anergy — for example, both can occur in the presence of calcineurin inhibitors.

What is the aim of immunosuppression?

Immunosuppressive drugs appear to restrict/ reduce antigen presentation and make T cell activation less likely.

Immunosuppressive Drugs. Site of action.

Some of the sites where drugs act. As the sites are different a combination of drugs is more effective than one drug alone.

Immunosuppression can be achieved by depleting lymphocytes, diverting lymphocyte traffic, or blocking lymphocyte response pathways.

Immunosuppressive drugs have three effects:

  1. the therapeutic effect (suppressing rejection),
  2. undesired consequences of immunodeficiency (infection or cancer),
  3. nonimmune toxicity to other tissues.

Immunodeficiency leads to characteristic infections and cancers, such as post-transplantation lymphoproliferative disease, which are related more to the intensity of immunosuppression than to the specific agent used.

Immunosuppressive drugs include small-molecule drugs, depleting and nondepleting protein drugs (polyclonal and monoclonal antibodies), fusion proteins, intravenous immune globulin, and glucocorticoids


Immunosuppressive Therapies in Organ Transplantation

Natural and synthetic glucocorticoids remain at the forefront of anti-inflammatory and immunosuppressive therapies.  However, long-term use of oral glucocorticoids is associated with serious side effects, including osteoporosis, metabolic disease and increased risk of cardiovascular disease. The glucocorticoid receptor (GR) is a DNA binding protein that regulates transcription initiation and the discovery that many of the immunosuppressive actions of glucocorticoids are mediated by interference with signalling by the key inflammatory transcriptional regulators. Although categorically distinct, the innate (the relatively non-specific immediate host defence system that provides a rapid reaction to infection and tissue damage) and adaptive (the more slowly acquired, highly antigen-specific response) immune systems interact and often overlap during an inflammatory response. Foreign antigens are taken up by antigen presenting cells; particularly dendritic cells, but also macrophages, that then migrate to draining lymph nodes where they instruct the adaptive immune system (T and B lymphocytes), shaping the subsequent immune response. Glucocorticoids inhibit many of the initial events in an inflammatory response. They also promote the resolution of inflammation although the mechanisms by which they do so have received less attention than those associated with suppression of the initial response. Acutely, glucocorticoids inhibit the vasodilation and increased vascular permeability that occurs following inflammatory insult and they decrease leukocyte emigration into inflamed sites, effects that require new protein synthesis. Glucocorticoids act as agonists of glucocorticoid receptors, but at higher doses they have receptor-independent effects.

There is no consensus on the optimal dose or maintenance schedule of glucocorticoids following kidney transplantation. As part of a triple-agent immunosuppressive regimen, it is administered as methylprednisolone at 7 mg/kg (maximum of 500 mg) intravenously in the operating room, then initiate oral prednisone at a dose of 1 mg/kg per day (maximum dose of 80 mg) for the first three days posttransplant, which is then lowered to 20 mg/day for the first week. The daily dose is then tapered every week by 5 mg, resulting in 15 mg/day for one week, 10 mg/day for one week, and then 5 mg/day. In the absence of acute rejection, it is generally usual to reduce glucocorticoids to a dose of 5 mg per day by one month following kidney transplantation.

The use of long-term glucocorticoids may vary from center to center and patient to patient. In an attempt to minimize toxicity and to decrease overall immunosuppression, slow tapering and ultimate withdrawal of glucocorticoids has also been attempted.

Small molecule immunosuppressive drugs.

Most small-molecule immunosuppressive agents are derived from microbial products and target proteins that have been highly conserved in evolution. Small-molecule immunosuppressive drugs at clinically tolerated concentrations probably do not saturate their targets. For example, cyclosporine acts by inhibiting calcineurin but only partially inhibits calcineurin as used clinically. Without target saturation, the drug’s effects are proportional to the concentration of the drug, which makes dosing and monitoring critical. Cyclosporine acts by inhibiting calcineurin but only partially inhibits calcineurin as used clinically. Without target saturation, the drug’s effects are proportional to the concentration of the drug, which makes dosing and monitoring critical.

Depleting protein immunosuppressive agents

Depleting protein immunosuppressive agents are antibodies that destroy T cells, B cells, or both. T-cell depletion is often accompanied by the release of cytokines, which produces severe systemic symptoms, especially after the first dose. The use of depleting antibodies reduces early rejection but increases the risks of infection and post-transplantation lymphoproliferative disease and can be followed by late rejection as the immune system recovers. Recovery from immune depletion takes months to years and may never be complete in older adults. 

Nondepleting protein drugs

These are monoclonal antibodies or fusion proteins that reduce responsiveness without compromising lymphocyte populations. They typically target a semi redundant mechanism such as CD25, which explains their limited efficacy but the absence of immunodeficiency complications. These drugs have low nonimmune toxicity because they target proteins that are expressed only in immune cells and trigger little release of cytokines.

Small Molecule Drugs.

Characteristics of Small-Molecule Immunosuppressive Drugs Used in Organ Transplantation or in Phase 2–3 Trials.

Azathioprine, is derived from 6-mercaptopurine, was the first immunosuppressive agent to achieve widespread use in organ transplantation. The developers of azathioprine, Gertrude Elion and George Hitchings, were acknowledged by a share of the 1988 Nobel Prize. Azathioprine is thought to act by releasing 6-mercaptopurine, which interferes with DNA synthesis. Other possible mechanisms include converting costimulation into an apoptotic signal. After cyclosporine was introduced, azathioprine became a second-line drug and largely replaced by mycophenolate mophetil.

Initial therapy following transplant: IV, Oral: 2 to 5 mg/kg once (Cristelli 2013; manufacturer labeling).

Maintenance: Oral: 1 to 3 mg/kg (usual dose: 50 to 150 mg/day) once daily or 100 mg once daily (for patients <75 kg) or 150 mg (for patients ≥75 kg) once daily (Remuzzi 2007) or 2 mg/kg/day with dose adjusted based on safety/tolerability (Cristelli 2013).

Pregnant patients: ≤2 mg/kg/day.

Most transplant centers administer mycophenolate (MMF or EC-MPS) as an antimetabolic agent to kidney transplant recipients rather than azathioprine. This practice is based upon multiple large trials and meta-analyses showing lower acute rejection rates, and possibly improved graft survival, with MMF as compared with azathioprine.

Calcineurin Inhibitors.

Cyclosporine and tacrolimus selectively inhibit calcineurin, thereby impairing the transcription of interleukin (IL)-2 and several other cytokines in T lymphocytes. Calcineurin inhibitors have been mainstays of immunosuppression in solid organ transplantation for over three decades.

Cyclosporine and tacrolimus are occasionally used in the treatment of various immune-mediated diseases. However, concerns about their long-term toxicity (especially kidney dysfunction and hypertension) and the availability of newer biologic agents have restricted the use of cyclosporine and tacrolimus to patients who have not responded to conventional treatment.

Cyclosporine, a cornerstone of immunosuppression in transplantation, is in effect a prodrug that engages cyclophilin, an intracellular protein of the immunophilin family, forming a complex that then engages calcineurin. Cyclosporine is a lipophilic cyclic peptide of 11 amino acids derived from a fungus.

Cyclosporine and tacrolimus act primarily on T helper cells, although some inhibition of T suppressor and T cytotoxic cells may also occur. Cyclosporine also increases the expression of transforming growth factor (TGF)-beta, which may be an important mechanism by which it causes renal fibrosis. Unlike some other immunosuppressive agents, such as azathioprine and the alkylating agents, cyclosporine and tacrolimus lack clinically significant myelosuppressive activity.

The adverse effects of cyclosporine, which are related to the concentration of the drug, include nephrotoxicity, hypertension, hyperlipidemia, gingival hyperplasia, hirsutism, and tremor. Cyclosporine can also induce the hemolytic–uremic syndrome and post-transplantation diabetes mellitus. Recent developments include monitoring of the peak cyclosporine levels two hours after administration to better reflect exposure to the drug. A chemically modified cyclosporine, ISA(TX)247, is under development.

Most centers start calcineurin inhibitor therapy just before transplantation or within the first 24 hours of transplantation. Some centers delay the introduction of a calcineurin inhibitor until the serum creatinine has decreased by 50 percent from the pretransplant value or the patient has significant urine output. However, there is little evidence that delayed, rather than immediate, initiation of a calcineurin inhibitor results in lower rates of delayed graft function.

Liquid cyclosporine is available in capsules, oral solution, and concentrate for injection:

●Liquid-filled capsules of 25 mg and 100 mg are stored at less than 86°F (30°C) but not frozen.

●The oral solution of 100 mg/mL in 50 mL bottles remains stable for two months after opening if stored in the original container at less than 86°F (30°C) but does not require refrigeration and should not be frozen.

●Concentrate for injection of 50 mg/mL in 5 mL ampules should be stored at less than 86°F (30°C) and protected from light and freezing. Dilutions in 5 percent glucose or normal saline are stable for 24 hours. Substantial amounts of cyclosporine may be lost during intravenous administration through plastic tubing. Polyoxyethylated castor oil that is contained in the concentration for intravenous cyclosporine infusion can cause phthalate stripping from polyvinyl chloride (PVC)-containing intravenous tubing. Thus, when intravenous nonmodified cyclosporine is administered, PVC-free intravenous fluid containers and tubing should be used.

Modified — Capsules and solution are for oral use; no parenteral formulation is available. Patients who need an intravenous formulation should be prescribed cyclosporine nonmodified concentrate for injection. Cyclosporine modified capsules or the equivalent generic product are preferred due to superior pharmacokinetic profile compared with the nonmodified formulation:

●Capsules of 25 mg and 100 mg should be stored at 68 to 77°F (20 to 25°C); some generic formulations are available in a 50 mg capsule.

●The oral solution of 100 mg/mL is available in 50 mL bottles, which remains stable for two months after opening if stored in the original container at 68 to 77°F (20 to 25°C).

Cyclosporine modified – For nonautoimmune disease, cyclosporine modified is initially dosed at 4 to 10 mg/kg/day orally in two divided doses. Most clinicians start at the lower end of the dosing range and make adjustments based upon drug concentrations. The first dose may be administered within 24 hours of transplantation. In newly transplanted patients, the initial dose of cyclosporine modified is the same as the initial dose of cyclosporine nonmodified, although cyclosporine modified is preferred.

Tacrolimus engages another immunophilin, FK506-binding protein 12 (FKBP12), to create a complex that inhibits calcineurin with greater molar potency than does cyclosporine and is a macrolide antibiotic. Initial trials indicated that there was less rejection with tacrolimus than with cyclosporine, but recent analyses suggest that in the current dosing strategies, the efficacy of cyclosporine is similar to that of tacrolimus. Tacrolimus resembles cyclosporine in that it can result in nephrotoxicity and the hemolytic–uremic syndrome, but it is less likely to cause hyperlipidemia, hypertension, and cosmetic problems and more likely to induce post-transplantation diabetes. Tacrolimus has been suspected of inducing more BK-related polyomavirus nephropathy than has cyclosporine in patients who have undergone kidney transplantation, especially when used with mycophenolate mofetil, but renal function may be better with tacrolimus. New developments include a preparation of modified-release tacrolimus to permit once-daily dosing.

The use of tacrolimus has increased steadily, and the drug is now the dominant calcineurin inhibitor, but most transplantation programs exploit the strengths of both tacrolimus and cyclosporine, depending on the risks in individual patients. Hypertension, hyperlipidemia, and the risk of rejection argue for tacrolimus, whereas a high risk of diabetes (e.g., older age or obesity) argues for cyclosporine.

Tacrolimus– Tacrolimus is typically dosed at 0.1 to 0.2 mg/kg/day orally in two divided doses. Most clinicians start at the lower end of the dosing range and make adjustments based upon drug concentrations. The product information recommends the following for tacrolimus initiation [16]:

•At 0.1 mg/kg/day in kidney transplant recipients who also receive mycophenolate mofetil plus an interleukin (IL)-2 receptor antagonist

•At 0.2 mg/kg/day in kidney transplant recipients treated with azathioprine rather than mycophenolate mofetil

•At 0.1 to 0.15 mg/kg/day in adult liver transplant recipients

•At 0.075 mg/kg/day in adult heart transplant recipients

Extended-release tacrolimus products – In patients receiving mycophenolate mofetil, glucocorticoids, and basiliximab induction, extended-release tacrolimus capsules (Astagraf XL) should be given at a dose of 0.15 to 0.2 mg/kg/day prior to reperfusion or within 48 hours of the completion of the transplant procedure. In patients treated with mycophenolate mofetil and glucocorticoids without basiliximab induction, extended-release tacrolimus capsules should be given as a single dose of 0.1 mg/kg within 12 hours prior to reperfusion, then 0.2 mg/kg at least 4 hours after the preoperative dose, and within 12 hours after reperfusion, then 0.2 mg/kg daily [13]. The recommended starting dose of extended-release tacrolimus tablets (Envarsus) in de novo kidney transplant patients is 0.14 mg/kg/day with antibody induction [20].

Drug monitoring — Therapeutic monitoring of cyclosporine and tacrolimus is complicated by the narrow margin between adequate immunosuppression and toxicity. Whole blood should be used as a sample for both drugs. A variety of assays are available, and clinicians should become familiar with the one used in their local laboratory.

Cyclosporine should be monitored using 12-hour trough (C0), two-hour post-dose (C2), or abbreviated area under the time concentration curve (AUC) . Although monitoring of C0 is common practice, there is a poor correlation with safety, efficacy, and drug exposure using this strategy. Some centers use C2 monitoring among kidney transplant recipients since these concentrations may correlate more closely with exposure, and higher C2 concentrations have been associated with decreased acute rejection rates in the first year. In one study of liver transplant patients, C2 was more closely associated with the first four-hour post-dose cyclosporine exposure (AUC0-4) than C0. C2 monitoring may be more accurate but is often more difficult and less convenient for the patient. Most centers monitor either C0 or C2 concentrations but not both. In rare circumstances, assessing both may be beneficial in a patient with absorption issues.

Tacrolimus should be monitored using 12- and 24-hour trough (C0) concentrations for the immediate-release and extended-release preparations, respectively.

Blood concentrations should be checked two to three days after starting cyclosporine or tacrolimus and after any dose change. Typically, after transplant, concentrations are measured every one or two days while hospitalized. After discharge, levels should be measured once or twice weekly for the first month, then weekly until three months posttransplantation, then every two weeks until six months posttransplant, and then monthly. Some stable, low-risk patients may have concentrations monitored every two to three months. However, if drugs that affect cyclosporine or tacrolimus metabolism are added or withdrawn, more frequent measurement of trough concentrations will be required. Tacrolimus and cyclosporine reach steady-state concentrations after four to six doses.

Inosine Monophosphate Dehydrogenase Inhibitors: mycophenolate mofetil.

 Mycophenolic acid inhibits inosine monophosphate dehydrogenase, a key enzyme in purine synthesis. Mycophenolate mofetil is a prodrug that releases mycophenolic acid, and in large-scale trials with cyclosporine, it was superior to azathioprine in preventing rejection of kidney transplants.  Protocols using mycophenolate mofetil and calcineurin inhibitors improved patient survival and graft survival and reduced early and late allograft rejection.

Renal transplantation:


CellCept: Initial: 1 g twice daily. Maintenance dose may vary based on concomitant immunosuppression. Doses >2 g/day have been associated with an increased incidence of adverse effects but may be necessary in some patients (EMMC study group 1999; TMMRT study group 1996).

Myfortic: Oral: Initial: 720 mg twice daily. Maintenance doses may vary based on concomitant immunosuppression.

IV: CellCept: See oral dosing for CellCept; IV and oral doses (of mycophenolate mofetil) are equivalent. If converting from Myfortic to IV CellCept, convert Myfortic to equivalent CellCept oral dose first. Transition to oral therapy as soon as tolerated.

Target-of-Rapamycin Inhibitors (mTOR)

Sirolimus, everolimus and temsirolimus engage FKBP12 to create complexes that engage and inhibit the target of rapamycin but cannot inhibit calcineurin. Inhibition of the target of rapamycin blocks signal 3 by preventing cytokine receptors from activating the cell cycle.

Sirolimus (rapamycin) is a macrocyclic triene antibiotic that is produced by fermentation of Streptomyces hygroscopicus. Sirolimus was discovered from a soil sample collected in Rapa Nui, which is also known as Easter Island [1]. Although it was originally developed as an antifungal agent, it was later found to have immunosuppressive (US FDA approval in 2003 for prevention of acute rejection in kidney transplantation) and antiproliferative properties that may be useful to treat or prevent proliferative diseases such as tuberous sclerosis, psoriasis, and malignancy. Temsirolimus and everolimus are both analogs of sirolimus approved for the treatment of renal cell carcinoma. In April 2010, everolimus was approved by the US FDA for prevention of acute rejection in kidney transplantation.

Sirolimus is available in a 1 mg/mL oral solution (60 mL) and a 0.5, 1, and 2 mg triangular-shaped tablet. Although the oral solution and tablet are not bioequivalent, clinical equivalence has been demonstrated [3].

Everolimus is available as a 0.25, 0.5, and 0.75 mg round, flat tablet.



Sirolimus – Sirolimus is typically administered as a tablet, although a solution is available for those who are not able to swallow.

Sirolimus oral solution should be taken in the following manner:

•Empty the medication from the amber syringe into a glass or plastic container.

•Then, it should be vigorously stirred with 2 ounces of water or orange juice.

•After immediately drinking the mixture, the container should again be filled with an equal amount of fluid and consumed immediately.

Sirolimus should not be mixed with grapefruit juice.

•The oral solution should be protected from light and stored under refrigeration at all times to prevent degradation.

Everolimus – Everolimus is administered as a tablet.

Dose — Clinical trials of initial immunosuppressive regimens after kidney transplant have included sirolimus as a component of a regimen that includes cyclosporine and glucocorticoids. In these trials, a one-time loading dose of 6 or 15 mg (three times the maintenance dose), followed by a maintenance dose of either 2 or 5 mg/day, was utilized.

An initial everolimus dose of 0.75 mg given orally twice daily is recommended for adult kidney transplant patients in combination with reduced-dose cyclosporine.

Sirolimus and everolimus were developed for use with cyclosporine, but the combination increased nephrotoxicity, the hemolytic–uremic syndrome, and hypertension. Sirolimus has been combined with tacrolimus (e.g., the Edmonton protocol for pancreatic islet transplantation) to avoid the toxicity of sirolimus–cyclosporine combinations. However, a controlled trial in renal transplantation showed that sirolimus plus tacrolimus produced more renal dysfunction and hypertension than did mycophenolate mofetil plus tacrolimus, which indicates that sirolimus potentiates tacrolimus nephrotoxicity.

The principal nonimmune toxic effects of sirolimus and everolimus include hyperlipidemia, thrombocytopenia, and impaired wound healing. Other reported effects include delayed recovery from acute tubular necrosis in kidney transplants, reduced testosterone concentrations, aggravation of proteinuria, mouth ulcers, skin lesions, and pneumonitis. However, sirolimus and everolimus may reduce cytomegalovirus disease. 

Practitioners can reduce the toxicity of the combination of a target-of-rapamycin inhibitor and a calcineurin inhibitor by withdrawing one of the drugs. For example, withdrawing cyclosporine in patients in stable condition who are receiving the sirolimus–cyclosporine combination reduces renal dysfunction and hypertension, with a small increase in rejection episodes, which suggests a strategy for avoiding the toxic effects of calcineurin inhibitors.

Dihydroorotate Dehydrogenase Inhibitors

Leflunomide is a dihydroorotate dehydrogenase inhibitor that is approved for rheumatoid arthritis. Dihydroorotate dehydrogenase is a key enzyme in pyrimidine synthesis. Its active metabolite, A77 1726, was modified to create FK778. Leflunomide is not in widespread use as an immunosuppressant in renal transplant but may be substituted for mycophenolate in the presence of BK viremia or nephropathy. FK778 may have activity against BK-related polyomavirus and have a lower incidence of gastrointestinal effects than does mycophenolate mofetil, but its nonimmune toxic effects such as anemia must be evaluated.

Non depleting and fusion antibodies

Daxiliximab and Basiliximab

The anti-CD25 monoclonal antibodies daclizumab and basiliximab are widely used in transplantation for induction in patients who have a low-to-moderate risk of rejection.

Depleting antibodies.

Polyclonal antithymocyte globulin is produced by immunizing horses or rabbits with human lymphoid cells, harvesting the IgG, and absorbing out toxic antibodies (e.g., those against platelets and erythrocytes). As an induction agent, polyclonal antithymocyte globulin is usually used for 3 to 10 days to produce “profound and durable” lymphopenia that lasts beyond one year. 

In addition to immunodeficiency complications, toxic effects of polyclonal antithymocyte globulin include thrombocytopenia, the cytokine-release syndrome, and occasional serum sickness or allergic reactions. Rabbit preparations of polyclonal antithymocyte globulin (such as Thymoglobulin and ATG-Fresenius) are favored over horse polyclonal antithymocyte globulin because of greater potency.

Muromonab-CD3, a mouse monoclonal antibody against CD3, has been used for 20 years to treat rejection and for induction. Muromonab-CD3 binds to T-cell-receptor–associated CD3 complex and triggers a massive cytokine-release syndrome before both depleting and functionally altering T cells. Humans can make neutralizing antibodies against muromonab-CD3 that terminate its effect and limit its reuse. Prolonged courses of muromonab-CD3 increase the risk of post-transplantation lymphoproliferative disease. The use of muromonab-CD3 declined when newer small-molecule immunosuppressive drugs reduced rejection episodes. A trial of a humanized anti-CD3 monoclonal antibody in kidney transplantation was stopped.

Alemtuzumab, a humanized monoclonal antibody against CD52, massively depletes lymphocyte populations. It is approved for treating refractory B-cell chronic lymphocytic leukemia but is not approved for immunosuppression in transplantation.

Rituximab (anti-CD20 monoclonal antibody) eliminates most B cells and is approved for treating refractory non-Hodgkin’s B-cell lymphomas, including some post-transplantation lymphoproliferative disease in organ-transplant recipients. Rituximab is used off-label in combination with maintenance immunosuppressive drugs, plasmapheresis, and intravenous immune globulin to suppress deleterious alloantibody responses in transplant recipients.

Renal transplant is a complex problem to deal with. New drugs are developing. Non-glucocorticoid therapies are being used. results have got better. Most patients survive at least 5 years and more if their doctor gets it right. I hope you learnt something useful.

Why and how of renal allograft rejection and why the different types of rejection need to be treated differently.

Since renal transplants took off in the 1960s the bugbear of allograft rejection hit nephrologists and their patients. It became the problem that had to be dealt with immediately and for the duration of the patient’s life.

The introduction of immunosuppression by means of powerful calcineurin inhibitors in the 1980s and better immunologic matching of recipients with donors changed the character of acute rejection. The overall risk of acute rejection within 1 year after transplantation is now less than 15%. Although the management of acute rejection has been much improved, chronic rejection and survival beyond 5 years remain problems that need attention. That attention is being given to this problem a series of conferences known as the Banff Conference, the 10th one held in Canada which I mention here.

The 10th Banff Conference on Allograft Pathology was held in Banff, Canada from August 9 to 14, 2009. A total of 263 transplant clinicians, pathologists, surgeons, immunologists and researchers discussed several aspects of solid organ transplants with a special focus on antibody mediated graft injury. The willingness of the Banff process to adapt continuously in response to new research and improve potential weaknesses, led to the implementation of six working groups on the following areas: isolated v‐lesion, fibrosis scoring, glomerular lesions, molecular pathology, polyomavirus nephropathy and quality assurance. Banff working groups will conduct multicenter trials to evaluate the clinical relevance, practical feasibility and reproducibility of potential changes to the Banff classification. There were also sessions on quality improvement in biopsy reading and utilization of virtual microscopy for maintaining competence in transplant biopsy interpretation. In addition, compelling molecular research data led to the discussion of incorporation of omics‐technologies and discovery of new tissue markers with the goal of combining histopathology and molecular parameters within the Banff working classification in the near future.

The 2017 Banff Conference was held in Barcelona, Spain. The 2019 Banff Conference was held in Pittsburgh, Pennsylvania, and the 2021 Banff Conference will be in Banff, Alberta, Canada. These are held by the Banff Foundation for Allograft Pathology – BANFF

Rejection can be:

  1. Hyperacute (occurring within minutes),
  2. Acute (occurring within days to weeks),
  3. Late acute (occurring after 3 months),
  4. Chronic (occurring months to years after transplantation).

Rejection can also be classified according to pathophysiological changes:

  1. cellular-interstitial
  2. vascular, antibody-endothelial)
  3. severity (extent of histologic inflammation and injury, as scored and graded by means of the Banff schema)
  4. response to treatment (presence or absence of glucocorticoid resistance)
  5. presence or absence of renal dysfunction (indicating acute or subclinical rejection, respectively)
  6. immunologic mechanisms (adaptive or innate immune system response).

The Innate Immune System.

Who are the culprits?

The T cells. Whenever there is innate injury pathways of inflammation are upregulated, and aggravate the rejection process either directly or indirectly through the activation and recruitment of T lymphocytes. Injured tissues express ligands of the toll-like receptor system — damage-associated molecular-pattern (DAMP) molecules — and other innate danger molecules. Toll-like receptors normally detect pathogens, but they can also sense the presence of foreign-tissue molecules and can produce factors that cause the maturation and activation of dendritic cells. Dendritic cells (DCs), named for their probing, ‘tree-like’ or dendritic shapes, are responsible for the initiation of adaptive immune responses and hence function as the ‘sentinels’ of the immune system and were initially mistaken for cutaneous nerve cells.

The complement system.

Another element of innate immunity, the complement system, produces C3a and C5a, which directly activate intragraft T cells and antigen-presenting cells. Antigenpresenting cells (APCs) are a heterogeneous group of immune cells that mediate the cellular immune response by processing and presenting antigens for recognition by certain lymphocytes such as T cells. Classical APCs include dendritic cells, macrophages, Langerhans cells and B cells.

An increase in major-histocompatibility-complex (MHC) class I peptide–related sequence A (MICA) antigens on endothelial surfaces can activate natural killer cells and CD8 T cells. Moreover, there is an association between poor graft outcomes and sensitization to the highly polymorphic MICA antigens in HLA-matched transplants.

Who are you going to chose as a donor?

Transplants obtained from a spouse, friend, or altruistic donor under optimal physiological conditions and with shorter ischemia times lead to excellent results, even when genetic and HLA differences are greater than from deceased donors, who are of older age, with the presence of hypotension or hypertension, diabetes, renal impairment, donation after cardiac death, and prolonged ischemia of the graft due to a delay in shipping.

Who has preformed antibodies?

Antibodies that can mediate rejection include those against HLA molecules, endothelial-cell antigens, and ABO blood-group antigens on endothelial cells and red cells. Most recipients do not have antibodies against HLA molecules before transplantation unless they were sensitized by exposure to alloantigens through pregnancy, blood transfusion, or previous transplantation.

Antibodies against ABO antigens. Will you use a kidney donor who is ABO incompatible?

Kidneys selected for transplantation are routinely assigned to recipients with a compatible blood group; however, ABO-incompatible kidneys have been successfully transplanted with the use of an experimental protocol that entails perioperative removal of antibodies from the recipient by means of plasmapheresis or immunoadsorption. After they have been removed, anti–blood-group antibodies can rise to pretreatment levels after transplantation, adhere to the microvasculature, and activate complement, yet they generally do not injure the endothelium. This anomaly has been attributed to “accommodation” within the kidney, but the mechanism responsible for this benign response is unknown. In contrast, injury to the graft by anti-HLA antibodies is frequently insidious, and accommodation is uncommon.

Hyper acute rejection/ activation of complement cascade in the graft.

Rejection of the renal graft that occurs almost immediately after release of the vascular cross-clamps is classified as hyperacute. Instead of “pinking up” as a result of normal reperfusion, the kidney appears flaccid and mottled, reflecting the deposition of antibodies against HLA antigens expressed on the endothelium of the glomeruli and microvasculature. Activation of the classic complement cascade within the graft is followed by endothelial necrosis, platelet deposition, and local coagulation. In these cases, the initial transplant ends with removal of the kidney.

Acute Antibody-Mediated Rejection.

Can this be delayed for weeks? Why is it necessary to recognize that it is antibody mediated?

Antibody-mediated rejection often begins within days after transplantation (or within weeks, if antilymphocyte antibody therapy was given). The main feature is rapid graft dysfunction due to inflammation. An anamnestic response engendered by previous exposure to the relevant antigen rapidly generates high titers of complement-fixing antibodies. The main targets of these “recall” antibodies are MHC antigens displayed by the endothelium of the donor peritubular and glomerular capillaries.

Is the rejection likely to be steroid resistant?

 Agonistic angiotensin II type 1 (AT1)–receptor antibodies have been associated with corticosteroid-resistant vascular rejection accompanied by malignant hypertension, but their pathogenic role remains unclear. Microthrombi, with hemorrhage and arterial-wall necrosis and infarction, occur in severe cases. Detection of potentially harmful antibodies before transplantation should prompt a search for an alternative donor or an aggressive approach to post-transplantation management.

Early diagnosis and treatment are essential for salvaging grafts undergoing acute antibody-mediated rejection. Treatments include removal of antibodies by plasmapheresis or immunoadsorption, high-dose pulses of glucocorticoids, intravenous immune globulin, and antiproliferative agents. Supplementary therapies include rituximab or antilymphocyte antibody, if there is concurrent T-cell–mediated rejection. These treatments can be useful when given as prophylaxis to highly sensitized or ABO-mismatched recipients.  Eculizumab (a monoclonal antibody that inhibits the cleavage of C5) and bortezomib (a proteasome inhibitor that can inhibit plasma cells) are new, investigational agents that have shown promise in preliminary studies of antibody-mediated acute rejection, but the results require confirmation.

T cell mediated acute rejection.

This is the most common form of acute allograft rejection. It is initiated when donor alloantigens are presented to the T lymphocytes of the recipient by antigen-presenting cells (APCs). Immature dendritic cells within the graft carry donor antigens from the transplanted organ to the recipient’s draining lymph nodes and spleen; during their journey, these antigens mature into APCs. The recipient’s antigen-presenting dendritic cells also participate and circulate through the graft. The APCs then home to lymphoid organs, where they activate the recipient’s T cells. These T cells differentiate into various subgroups and return to the graft, where they take part in destroying the transplanted organ.

Endogenous antigens are digested into peptides by proteosomes and are loaded into class I MHC. Exogenous antigens are degraded in or within endosomes and are loaded into class II MHC. Assembly of the MHC within the cell’s endoplasmic reticulum precedes its transport through the Golgi apparatus and its ultimate expression on the cell surface along with peptide, where the MHC–peptide complex interacts with CD8+ or CD4+ T lymphocytes. β2m denotes β2-microglobulin, CLIP class II-associated invariant-chain peptide, and TAP transporter associated with antigen processing.

Role of the T cells in recognizing antigens.

The T cells in graft rejection seem to be more experienced in recognizing allograft antigen (up to 10% will recognize antigens versus 1% in normal people). They pick up the antigen displayed by the APCs from the donor (direct pathway) and the recipient (indirect pathway). They have a low threshold for reacting to MHC antigens. The recipient’s APCs can also take up membrane fragments of other cells; these fragments contain MHC molecules bearing “predigested” peptides derived from the donor’s MHC glycoproteins (the semidirect pathway). APCs can present such MHC–peptide complexes to CD4 T cells, which in turn activate CD8 T cells.

This picture may help you understand the differentiated T cells and their products.

After presentation of antigen by the antigen-presenting cell (APC), naive T lymphocytes become activated, proliferate, and differentiate into subtypes with characteristic cytokine profiles. Type 1 helper T (Th1) cells drive the cellular immune response, and type 2 helper T (Th2) cells produce the humoral immune response. Regulatory T (Treg) cells can limit the rejection response, and type 17 helper T (Th17) cells can mediate glucocorticoid-resistant rejection. APC denotes antigen-presenting cell, DC donor cell, IFN-γ interferon-γ, MHC major histocompatibility complex, TCR T-cell receptor, and TGF-β transforming growth factor β.

T-cell activation requires signals other than those engendered by the MHC–peptide complex, termed costimulatory signals. T cells become anergic when presented with an antigen in the absence of these signals, and agents that block these signals are under development. Early clinical trials of agents that block costimulation were disappointing; Belatacept, a fusion protein containing CTLA-4 and the Fc fragment of IgG1, blocks T-cell stimulation engendered by the CD80–CD28 and CD86–CD28 pathways. Clinical trials are assessing this more potent inhibitor as a potential replacement for nephrotoxic calcineurin inhibitors.

How do CD8 cells physically damage the graft itself?

 Invading CD8 T lymphocytes, which have immunologic specificity for the allograft, cross the basement membrane of the tubule, where they proliferate and induce apoptosis of tubular cells. Sublethally injured tubular cells can also transform from their native epithelial phenotype into primitive mesenchymal myofibroblasts, promoting interstitial fibrosis. Necrosis of tubular epithelial cells and basement-membrane rupture cause urinary leakage, graft dysfunction, and progressive tubular atrophy.

Acute vascular rejection.

Vascular rejection is a severe condition that does not respond to glucocorticoid therapy and instead requires potent antilymphocyte-antibody therapy (muromonab-CD3 [Orthoclone OKT3, Ortho Biotech] or antithymocyte globulin).

Late acute allograft rejection

Late acute allograft rejection is often severe and difficult to reverse, with a high risk of subsequent graft loss. Its main features are active immune inflammation and chronic tubulointerstitial damage, which frequently involves graft-directed antibody. It can develop in graft recipients with high-grade immunity against the transplant or in those who receive reduced amounts of immunosuppressive therapy because of cancer, prior severe infection, or noncompliance.

Chronic allograft rejection — ongoing immune injury to the graft — is due to a failure to maintain sufficient immunosuppression to control residual antigraft lymphocytes or antibodies. Its features include a progressive decline in renal function, invasion of the renal parenchyma by T cells, and persistent infiltration of the interstitium by T cells and macrophages. Occasionally, one also sees smooth-muscle proliferation and hyperplasia in vessels, forming a neointima; focal destruction of internal elastic lamina; and finally, vascular occlusion.

What does the future hold?

Despite technical advances and improvements in management, the alloimmune response remains the primary obstacle to successful kidney transplantation. Rejection of the graft entails much more than T-cell responses. Other elements include the innate immune system of natural killer cells, macrophages, and complement; the adaptive immune system of antigen-specific T lymphocytes and B cells; and cells intrinsic to the graft, such as endothelium. Antibody-mediated rejection is increasingly recognized as a contributor to late graft injury.

Current therapies are focused on the initial stages of T-cell activation, and this strategy has minimized early acute rejection. However, we need to improve our understanding of the mechanisms underlying chronic graft dysfunction and develop better treatments to prevent loss of the graft. Protocols that are designed to induce immunologic tolerance and the transplantation of organs in highly sensitized patients (those previously exposed to alloantigens) are also likely to alter the nature and presentation of rejection.


  1. Brian J. Nankivell, M.D., Ph.D., 
  2. and Stephen I. Alexander, M.B., B.S., M.P.H.

October 7, 2010
N Engl J Med 2010; 363:1451-1462
DOI: 10.1056/NEJMra0902927

CNS complications in renal transplant long term.

If you are caring for patients with renal transplants expect complications requiring hospitalisation within the first year in the majority of patients. In this post I am going to be dealing with the most common etiologies of neurological complication after kidney transplant: infection, malignancy, medication, surgical complications, seizure, and stroke. Some of the problems with the drugs used for induction and maintenance and other neurological complications may be seen.

Neurological infections are fairly common post-operatively, and are associated with increased morbidity and mortality in this population.

Infection is of specific concern in the post-operative patient as immunosuppressive regimens alter both the typical presentation and types of organisms observed. In general, classification of post-operative infections can be divided into the first month after transplant, one to six months after transplant, and beyond 6 months. CNS infection which include meningitis, encephalitis, and abscess) have significant morbidity and mortality in renal transplant patients, and symptoms can range from non-specific (such as headache, fever, and altered mental status) to focal neurologic deficits and coma. Work-up will include CSF culture and analysis including PCR, blood cultures, and brain imaging. Other complications include malignancy, medication related, acute neuropathy, and other neurological pathology


CNS infection accounts for a significant percentage of neurological complications after solid organ transplant, including in kidney recipients. Infection is of specific concern in the post-operative patient as immunosuppressive regimens alter both the typical presentation and types of organisms observed. CNS infection (including meningitis, encephalitis, and abscess) has significant morbidity and mortality in renal transplant patients, and symptoms can range from non-specific (such as headache, fever, and altered mental status) to focal neurologic deficits and coma. When attempting to identify a causative organism, the post-surgical timeline is important as there is a correlation between time post-transplant and likely organisms (3). In general, classification of post-operative infections can be divided into the first month after transplant, one to six months after transplant, and beyond 6 months (Table 1). Management of infection in post-transplant patients typical involves initiation of empiric anti-microbial therapy (antibiotics, antivirals or anti-fungal therapy) with narrowing of agents after the causative organism is determined and decreasing or stopping entirely the immunosuppression regimen. As many symptoms of CNS infection in this population are nonspecific, determining whether these symptoms are caused by infection or a non-infectious etiology may be challenging. In general, work-up will include CSF culture and analysis including PCR, blood cultures, and brain imaging.

Table 1

Typical organisms after renal transplant by time period (36)

Time after transplantLikely organismsTypical presentationDiagnosisTreatment
First monthStreptococcus pneumoniae, Neisseria meningitidis, Listeria monocytogenes, Haemophilus influenzaNonspecific; ranging from headache, fever, meningismus, altered mental statusCSF with neutrophilic predominance, decreased glucose, elevated proteinEmpiric treatment including ceftriaxone, vancomycin, ampicillin, narrowing therapy after culture results
Aspergillus fumigatusNonspecific; seen with comorbid respiratory diseaseAntigen or antibody present in CSF, branching hyphae visualized in CSFAntifungals including voriconazole, amphotericin
Candida speciesDisseminated fungemia with CNS symptomsPseudohyphae visualized in CSF, PCR, positive cultureFluconazole
Amphotericin can be considered in severely ill or neutropenic patients
1–6 monthsMycobacterium tuberculosisNon-specific; consider in patients from endemic areas, travel or exposure history, or history of latent infectionCSF Acid Fast Bacteria stain may miss the diagnosis. Interferon-Gamma Release Assay as screen. Decreased glucose, leukocytosis with lymphocytic predominance, increased protein, and increased adenosine deaminaseMultiple drug therapy including isoniazid, rifampin, ethambutol, pyrazinamide
CytomegalovirusNon-specific, but may include symptoms of retinitis, GI manifestationsCSF PCRGanciclovir, foscarnet
Varicella Zoster VirusEncephalitis, headache, altered mental status, seizure. May or may not have skin manifestationsPCR of CSF, may require multiple samples to rule out as it can initially be negativeIntravenous acyclovir with appropriate hydration. Can consider valacyclovir prophylaxis after infection fully treated to prevent reactivation
6 months and beyondCryptococcus neoformansNonspecific; fever, headacheCSF PCR, antigen, cultureAmphotericin, flucytosine. Will need continued treatment with fluconazole for life even after CSF culture negative. Poor prognosis
Toxoplasma gondiiAltered mental status, seizure, focal neuro signsSerum toxoplasma IgG, supportive imaging findings include ring-enhancing lesionsPyrimethamine with leucovorin
Prophylaxis can include Trimethoprim-Sulfamethoxazole or pyrimethamine with leucovorin if cannot tolerate TMP-SMX
JC virusAMS, seizure, focal neuro signsCSF PCRNo treatment. Consider reducing immunosuppression. Poor prognosis

In the immediate post-operative period, CNS infection is most often caused by typical bacterial organisms although opportunistic infections from environmental organisms and reactivation of latent tuberculosis infection can occur. Typical bacteria causing neurological infection include Streptococcus pneumoniaeNeisseria meningitidisListeria monocytogenesand Haemophilus influenza. Common presentation of these patients includes headache, fever, malaise, altered mental status, and meningismus. Opportunistic infections including Mycobacterium tuberculosisAspergillus fumigatus, and Candida species can also occur. Tuberculosis is rare as a primary infection post-operatively, but immunosuppression can cause reactivation of latent infection. These patients will have similar presentation to typical bacterial meningitis but may have radiographic evidence of lesions and CSF analysis will reveal very low glucose with a lymphocytic pleocytosis (compared to neutrophilic predominance in typical bacterial infection) with positive acid fast staining and culture. 

Aspergillus fumigatus is a fungus present in the environment, and infections are associated with pre-existing respiratory disease with asthma like symptoms. CNS infection with Aspergillus is associated with multiple lesions on CT or MRI and diagnosis may be made via antigen, serology, or fungal culture. Finally, CNS infection with Candida species can be seen in patients with disseminated fungemia due to immunosuppression.

Risk of infection is highest from one to six months after transplantation as immunosuppression becomes maximally effective and dominant organisms shift to more atypical pathogens. Cytomegalovirus (CMV) is the most common opportunistic infection in kidney transplant recipients, present in up to 8% of patients. This prevalence has decreased due to improved recognition of donor and recipient seropositivity and prophylactic treatment (7). Risk is highest with donor seropositivity and recipient seronegativity, induction immunosuppression, and older donors (8). Infection may occur as a primary infection, reinfection of latent recipient infection, or most commonly donor-derived. Symptoms are generally nonspecific in CNS infection, but more characteristic systemic features include leukopenia, thrombocytopenia, and evidence of infection of other tissues with CMV such as retinitis, pneumonitis, or GI disease.

Finally, CMV infection has been implicated in case reports of post-operative Guillain Barrè syndrome. Guillain-Barre Syndrome (GBS) is an auto-immune disease affecting the peripheral nervous system. The exact mechanisms of GBS is unknown but is posited to involve humoral and cell-mediated autoimmunity in response to some antigenic trigger, infectious or otherwise. GBS typically presents as an ascending paralysis and sensory loss with areflexia and can progress to respiratory failure as symptoms spread proximally. Treatment includes respiratory support, rehabilitation, and immunotherapy with plasmapheresis and/or intravenous immunoglobulins.

Primary infection with Epstein Barr Virus (EBV) is a rare complication after renal transplant, but reactivation can occur and EBV is a significant cause of morbidity and mortality due to its association with post-transplant lymphoproliferative disorder (PTLD) discussed later in this review.

Other viruses affecting the nervous system that can sometimes be seen in this post-operative period include human herpes virus 6 (HHV6), varicella zoster (VZV), and BK Polyoma Virus.

Human polyomavirus infection may result in different disease manifestations, which depend on whether or not there is sustained viral replication although in the immunocompetent they do not cause significant disease.

  1. Progressive multifocal leukoencephalopathy (PML) is caused by high-level replication of JCPyV, mostly in oligodendrocytes, without significant inflammation is typically seen in patients with advanced AIDS who have PML and who have been treated with immunosuppressive drugs used for transplantation or the treatment of autoimmune diseases (eg, multiple sclerosis).
  2. BKPyV-associated nephropathy in kidney transplant recipients is characterized by high-level virus replication and a significant inflammatory response due to necrosis, denudation of the basement membrane, and infiltration of granulocytes and lymphocytes.
  3. Immune reconstitution inflammatory syndrome is characterized by an exaggerated inflammatory response to abundant PyV antigen upon brisk recovery of immunity. The prototypes are BKPyV-associated hemorrhagic cystitis after allogenic hematopoietic cell transplantation and the unmasking of PML after the start of antiretroviral therapy for HIV infection or following the removal of natalizumab through plasmapheresis in multiple sclerosis patients.
  4. Oncogenic effects of PyVs are characterized by viral early gene expression activating host cells, but without subsequent late gene expression and cytopathic release of progeny virus. Uncoupling from capsid protein expression, assembly, and cell lysis may also underlie BKPyV-associated urothelial cancers.

After 6 months, immunosuppressive regimens tend to decrease in intensity and overall risk of infection decreases. However, infection with rare atypical organisms can still occur with chronic immunosuppression, and organisms such as Cryptococcus neoformansToxoplasma gondii, tuberculosis, and JC virus (causing progressive multifocal leukoencephalopathy) may be seen.


Recipients of kidney transplant require immunosuppressive therapy in order to prevent rejection of the transplanted organ. Immunosuppression can be divided into induction and maintenance therapy with additional potential treatment of acute rejection. Induction therapy is given around the time of transplantation, is generally more potent with greater immunosuppression than maintenance therapy, and is done in order to prevent acute rejection. In contrast, maintenance immunosuppression is typically initiated at the time of transplant but continued long-term for the duration of the graft. Typical agents may include glucocorticoids, calcineurin inhibitors (CNIs), anti-metabolic agents, and mTOR inhibitors. Choice of agents will vary based on patients’ individual factors including risk for rejection and balancing potential side effects.

Induction therapy agents work via depletion of T-cells resulting in blunted immune response.

Medications used for induction include anti-thymocyte globulins, alemtuzumab (a humanized recombinant monoclonal antibody against CD25), and basiliximab (an IL-2R antagonist). None of these agents have specific neurotoxicities as common adverse effects so it is very unlikely that neurological complications will be seen early in the transplant scenario.

The cytokine release syndrome may give non-specific neurological symptoms. Antilymphocyte antibodies (ATG, Atgam, and alemtuzumab) may cause cytokine release syndrome, a systemic inflammatory response caused by initial immune cell activation. This is mentioned here as common symptoms (including fever, nausea, vomiting, diarrhea, tachycardia, hypotension, and seizures) are nonspecific and can mimic those of CNS infection after transplant. Basiliximab has not been associated with cytokine release syndrome and is overall well tolerated for kidney transplant induction therapy.

How are glucocorticoids used in renal transplant?

Glucocorticoids are used in both induction and maintenance therapy for their immunosuppression, as well as for the treatment of acute rejection.

How do glucocorticoids work?

These drugs function via multiple pathways, with inhibition of various cytokines including Il-1, Il-2, IL-6, TNF-A, and IFN-gamma.

Which are the commonly corticoids used?

The most commonly used glucocorticoids used for renal transplant patients are oral prednisolone, prednisone, and intravenous methylprednisolone.

Why are these agents not ideal for maintenance of immunosuppression?

These agents are not ideal for maintenance therapy because of the well characterized side effects of chronic steroid use, including multiple adverse neurological symptoms. Thankfully, most if not all neurological complications of corticosteroids are reversible with reduction or withdrawal of the offending agent. One of the most common neurological side effects of glucocorticoid use is steroid-induced myopathy.

How does steroid myopathy present?

Patients with steroid myopathy typically present with gradual onset of proximal muscle weakness with atrophy. Lower extremities are usually affected first and more severely than the upper extremities. It is usually not associated with myalgia or tenderness and there is no rise in muscle enzymes.

Glucocorticoids have a direct catabolic effect on skeletal muscle. Symptoms of the condition can begin any time from days to months after therapy begins and its incidence and severity are related to steroid dose. The diagnosis is clinical, and muscle enzymes are typically normal. The condition is surprisingly common, with previous studies showing approximately 50% of patients on steroids after solid organ transplant developing symptoms. Treatment is supportive for pain control of the myalgia and removal of steroid with full resolution taking months after discontinuation.

What are the other effects of corticosteroids on the brain?

The neuropsychiatric side effects of corticosteroid therapy are well known. Initially, steroid use is associated with elevation in mood, a potential hypomanic state, and disruption of sleep.

What will happen when the dose of steroids is increased?

Symptoms associated with higher doses for longer duration include sleep disruption, restlessness and akathesia, depression (including increased risk of suicidality), cognitive impairment, and most rarely psychosis. The majority of these symptoms are reversible with withdrawal of the agent. Risk of neuropsychiatric side effects is increased with dose, duration of therapy, age of patient, and pre-morbid psychiatric disorder.

Can steroids cause a rise in the intracranial pressure?

Finally, there have been cases of Idiopathic Intracranial Hypertension associated with long term administration of corticosteroid therapy, but these are rare and reversed with cessation of the agents.

Calcineurin inhibitors (CNIs)

The most commonly used CNIs for immunosuppression are cyclosporine and tacrolimus. The precise mechanism of CNI neurotoxicity is still unknown.

A 34 year old patient had a renal transplant donated by sibling a year ago. He now has tremor, headache, and fatigue. the tremor is a fine tremor at rest and on exertion in both hands preventing him from using his cell phone and computer. He has taken 3 days leave of absence from his work as an accountant and needs 4-8 tablets of paracetamol to keep his headache under control. His blood pressure is no longer controlled by his dose of beta blockers.

What could this be caused by?

Tacrolimus and cyclosporine can both cause it. Since he is on tacrolimus reducing or witholding the dose may help to control the symptoms.

He may have Posterior Reversible Encephalopathy Syndrome (PRES) in renal transplant recipients.

Severe neurotoxicity with tacrolimus or cyclosporine is rare in renal transplant, but seizure, polyneuropathy, encephalopathy, visual disturbances, and coma have all been reported.

Neurotoxicity associated with cyclosporine and tacrolimus can present in multiple ways ranging from more common mild symptoms to rare, but life-threatening, manifestations. Approximately half of patients will report at least one neurological symptom, with tremor, headache, and fatigue being among the most frequently observed. These symptoms are frequently associated with higher drug levels and typically resolve either with time, decrease in dose, or in some cases substitution of cyclosporine with tacrolimus or vice versa. Severe neurotoxicity with tacrolimus or cyclosporine is rare in renal transplant, but seizure, polyneuropathy, encephalopathy, visual disturbances, and coma have all been reported.

Both tacrolimus and cyclosporine are associated with development of Posterior Reversible Encephalopathy Syndrome (PRES) in renal transplant recipients. The exact mechanism of PRES is poorly understood but believed to be reversible subcortical brain edema caused by endothelial injury. Brain imaging studies reveal vasogenic edema typically (but not exclusively) of the bilateral parietal and occipital regions. Patients present initially with hypertension, headache, altered mental status, and visual disturbances, and may progress to seizures, stupor, and eventually coma. As the name of the condition suggests, most cases are reversible with supportive care including blood pressure control and discontinuation of responsible agents, but delay in diagnosis may lead to permanent deficits and death. Most cases of CNI-associated PRES presented within the first year after transplant, a majority of patients had CNI levels either elevated or high-normal, and a majority had hypertension. However, there have been cases of CNI-associated PRES with normotension, therapeutic levels of CNI, and after years of treatment.

A distinct pain syndrome has been reported with both tacrolimus and cyclosporine use. Termed Calcineurin Inhibitor Induced Pain Syndrome (CIPS), the entity is associated with bilateral, symmetric distal leg pain sparing hip areas and usually involving the feet, ankles, and knees. CIPS will affect some 2–15% of renal transplant patients on CNIs, and usually presents within the first year after kidney transplant (44). The pain is worsened with activity and improved with rest. Labs will show increased alkaline phosphatase and calcium, and imaging studies (MRI) reveal marrow edema in the regions of pain (45). CIPS is usually self-limited but can recur. . Treatment can be supportive for pain-management, removal of the CNI and replacement with non-CNI immunosuppression, or treatment with calcium channel blocking agents. There is one case report of rapid improvement in symptoms with one-time infusion of iloprost.

Other agents

Bortezomib is a small molecule proteasome inhibitor approved by the FDA for the treatment of multiple myeloma that is now finding increased usage as immunosuppressive therapy for renal transplant patients. Side effects in the renal transplant population are similar to multiple myeloma patients. The significant neurological side effect of bortezomib is a distal peripheral neuropathy and it is fairly common, affecting 20–40% of renal patients. Symptoms initially begin in a “stocking glove” distribution before spreading more proximally. The neuropathy is typically a painful, sensory polyneuropathy; motor neuropathy is rare (51). While reversible, neuropathy symptoms take a median of three months to resolve and may persist for longer. The most significant risk factor for development of neuropathy associated with bortezomib is pre-existing peripheral neuropathy. Some evidence exists suggesting reduction of incidence with concomitant dexamethasone dosing.

Acute neuropathy

Peripheral neuropathy after kidney transplant can present secondary to medications used for immunosuppression and antibiotic prophylaxis, acute neuropathy can also occur as a complication of surgery. The pathophysiology is believed to involve direct compression and ischemia of the nerve, possibly caused by steal phenomenon following anastomosis of the graft renal artery to the iliac artery.Acute femoral neuropathy (AFN) is a relatively uncommon complication, with incidence ranging 2% to 4%. Presentation of AFN can vary depending on where along the nerve’s course the damage occurs. Motor complications are more common, with the majority of patients presenting with weakness of hip flexion and knee extension either immediately after surgery or in the days following. Atrophy of these muscles can occur in severe or prolonged cases. Sensory impairment occurs less frequently and presents as numbness and/or paresthesia of the anterior-medial thigh. EMG studies confirm a femoral neuropathy. Overall prognosis of AFN is good, and recovery of neurologic function is the most frequent outcome, but symptoms may last weeks to months. Treatment includes physical therapy and medications for neuropathic pain in cases of painful sensory neuropathy.


Causes of seizure after renal transplant include drug toxicity, metabolic disorders (electrolyte disturbances), organ dysfunction, CNS infection, ischemic and hemorrhagic stroke, and PRES. Thankfully, the majority of seizures after renal transplant are isolated events and patients will not go on to develop a seizure disorder. Therapy is therefore focused on treating the underlying etiology. There is no role for primary seizure prophylaxis for all post-transplant patients, but patients who do have a seizure should be started on an anti-epileptic regimen. Levetiracetam is the drug of choice for seizure prevention, with lorazepam and fosphenytoin being used for status epilepticus. Levetiracetam is ideal due to its lack of interactions between it and the common immunosuppressive. As it is excreted renally, levetiracetam dosage must be adjusted according to renal function.Go to:


Cerebrovascular disease is seen frequently in patients who have undergone kidney transplantation, with an incidence of stroke or TIA of 5% in the first year and 9.4% in the second year. A large proportion of the incidence can be explained by frequent comorbidities of renal transplant patients; diabetes, age, post-transplant kidney function, and previous stroke are all risk factors for ischemic stroke after transplant while diabetes, PKD, and hypertension are associated with hemorrhagic stroke.

Renal patients also may develop post-transplant polycythemia and hypercoagulability which increase the risk of stroke. Prevention is aimed at control of risk factors (cholesterol, hyperglycemia, and hypertension) as well as prevention via antiplatelet agents such as aspirin. Control of cholesterol is especially important as some of the immunosuppressive regimens may cause hypercholesterolemia. Prophylactic anticoagulation is not a mainstay of therapy for all patients post-transplant.


Solid organ transplant recipients have a four-fold increased incidence of malignancy compared to the general population, and this is believed to be due to decreased immune surveillance and an increased susceptibility to oncogenic viruses due to immunosuppression. Post transplant lymphoma disorder (PTLD) is the most common malignancy seen after renal transplant. Post-operative primary CNS tumor is uncommon. While renal transplant is associated with lower rates of PTLD compared to most organ systems, a small percentage (1–2%) of kidney recipients will develop this complication. The two largest risk factors for development of PTLD after renal transplant are immunosuppression and Epstein Bar Virus serostatus. There is an increased risk (up to twenty-four fold) of PTLD among EBV-negative recipients of EBV-positive donor organs. The majority of PTLD tumors in transplant patients contain the EBV genome, suggesting a pathogenic role for the virus. However, EBV negative PTLD has been documented a minority (30%) of PTLD patients and the EBV genome can also be found in patients with this tumor who are not immunosuppressed.

Kidney transplantation is the most common solid organ transplant in the United States, with over 17,000 transplants performed annually while over 100,000 patients remain on the waiting list. This number has continued to rise over the past years as kidney transplantation offers improved survival and quality of life compared to hemodialysis for the majority of patients with end-stage renal disease, and is ultimately more cost-effective over the course of patients’ lives. However, during the first year after transplant, patients frequently encounter complications requiring hospitalization, typically due to immunosuppressive medications or infection due to chronic immunosuppression. Neurological complications are a common issue after kidney transplant, with between 30–60% of patients experiencing some neurological complication. Neurological complications are associated with increased morbidity and mortality and should be kept on the differential for all post-transplant patients. Discussed here are the most common etiologies of neurological complication after kidney transplant: infection, malignancy, medication, surgical complications, seizure, and stroke.


As immunosuppression has improved, organ transplant has become more common and safer overall. As more patients experience improved survival, the total number of patients at risk for chronic complications increases as well. Neurological symptoms are a significant contributor to morbidity and mortality after kidney transplant. Serious neurological complications result in hospitalization, and therefore physicians must be aware of the conditions unique to this population.

Aaron Shoskes and Robert W

Transl Androl Urol. 2019 Apr; 8(2): 164–172.doi: 10.21037/tau.2018.08.11