Myelodysplastic Syndromes. Not yet a leukemia but can be fatal.

In 1982, “myelodysplasia” was used by the French–American–British (FAB) group to describe the morphologic abnormalities of the myeloid cell lines of hematopoiesis in preleukemic conditions, which were named myelodysplastic syndromes (MDS). MDS occur mainly, but not exclusively, in patients with a median age of about 70 years, and the crude incidence is 4 to 5 cases per 100,000 persons per year. Probably under reported. Hematopoeitic stem cells cloSeveral mutation-driver genes, belonging to different biologic pathways, can lead to MDS, and most patients have combinations of pathway mutations, accounting for the heterogeneity of these, usually one clone having a developmental advantage. Chromosome 5 seems to be affected with a C to T conversion by spontaneous deamination of cytosine. The deletion on the long arm of chromosome 5 is the initiating driver mutation that leads to haploinsufficiency of multiple genes and, in turn, to clinical manifestations.

It is the growth and spread of a somatically mutated clone represent the pathophysiological process that leads to MDS. Several mutation-driver genes, belonging to different biologic pathways, can lead to MDS, and most patients have combinations of pathway mutations, accounting for the heterogeneity of these disorders.

When most of the bone marrow hematopoietic cells are clonally derived, the disease is clinically manifested as cytopenia and morphologic dysplasia. After the common causes of cytopenia have been ruled out a bone marrow aspiration biopsy is done to detect morphologic dysplasia and blasts, bone marrow biopsy to assess marrow cellularity and fibrosis, and conventional cytogenetics to detect nonrandom chromosomal abnormalities.

Clinical manifestations.

Anemia is the most common cytopenia associated with MDS and it may be manifest as fatigue, weakness, exercise intolerance, angina, dizziness, cognitive impairment, or an altered sense of well-being. Fatigue is nearly ubiquitous and often may be out of proportion to the degree of anemia. Less commonly, complications associated with leukopenia (eg, infections, gingivitis) or thrombocytopenia (eg, easy bruising, bleeding) are present. Systemic symptoms such as fever, sweats, or weight loss are uncommon and generally represent late manifestations of MDS or transformation to acute leukemia. Physical findings of MDS are nonspecific but may include pallor, petechiae, purpura, mucosal ulceration/gingivitis, or stigmata of infections. Hepatomegaly, splenomegaly, and lymphadenopathy are uncommon.

Patients with MDS may develop infections related to neutropenia and granulocyte dysfunction (eg, impaired chemotaxis and microbial killing). Bacterial infections predominate, with the skin being the most common site involved.

The most common autoimmune conditions in patients with MDS are chronic rheumatic heart disease (7 percent), rheumatoid arthritis (6 percent), pernicious anemia (6 percent), psoriasis (2 percent), and polymyalgia rheumatica (2 percent). 

 Other autoimmune abnormalities include Sweet syndrome, pericarditis, pleural effusions, skin ulcerations, iritis, myositis, peripheral neuropathy, and pure red cell aplasia. Sweet syndrome (acute febrile neutrophilic dermatosis) may herald transformation to acute leukemia


Complete blood count — Complete blood count (CBC) with leukocyte differential usually demonstrates anemia, but neutropenia and thrombocytopenia are more variable. While isolated anemia is often seen, few patients present with isolated neutropenia, thrombocytopenia, or monocytosis without anemia. Pancytopenia (ie, anemia, leukopenia, and thrombocytopenia) is present in up to half of patients at the time of diagnosis. Thrombocytosis may be associated with abnormalities of chromosome 5q and in MDS/MPN with ring sideroblasts and thrombocytosis,

The peripheral blood smear usually demonstrates dysplasia in the red and white blood cell series and may reveal platelet abnormalities

Bone marrow examination is an essential component of the evaluation, diagnosis, and classification of MDS.

Characteristic morphologic features of MDS in the bone marrow examination include:

  1. Blasts – Myeloblasts are increased, but by definition, the blast percentage is <20 percent.
  2. Myeloid cells – Impaired myeloid maturation is often readily apparent; there may be a variable percentage of granulocytic precursors and a relative maturation arrest at the myelocyte stage.
  3. Erythroid cells – Although erythroid hyperplasia (associated with ineffective erythropoiesis) is usually seen, red cell aplasia and/or hypoplasia also rarely occur.
  4. Megakaryocytes are usually normal or increased in number and sometimes occur in clusters. Abnormal megakaryocytes, including large or very small mononuclear forms.
  5. Other lineages – Reactive lymphocytosis, lymphoid aggregates, increased histiocytes, and/or pseudo-Gaucher histiocytes may be seen. Increases of mast cells or spindled or clustered mast cells may be a manifestation of systemic mastocytosis, which may accompany MDS and other myeloid neoplasms (ie, systemic mastocytosis with associated hematologic neoplasm)
  6. Flow cytometry — Multiparameter flow cytometry is not required for the diagnosis of MDS but can be useful for assessing diagnostic and prognostic features of MDS.

MDS with ring sideroblasts — MDS with ring sideroblasts (MDS-RS) was previously called refractory anemia with ring sideroblasts. This category is further characterized by the number of dysplastic lineages (ie, single lineage versus multilineage).

The differential diagnosis of dysplasia also includes nonmalignant causes, including nutritional deficiencies, toxic exposures, and medications. Deficiency of vitamin B12, folic acid, or copper, or zinc excess should be excluded by clinical evaluation and laboratory testing.

Idiopathic cytopenia of undetermined significance (ICUS) and clonal cytopenia of undetermined significance (CCUS) – ICUSrefers to persistent cytopenias without significant dysplasia, evidence of other hematologic or nonhematologic cause for cytopenia, and none of the specific cytogenetic abnormalities that are considered presumptive evidence of MDS. 


The treatment of choice or definitive treatment is allogeneic stem cell transplant. Whereas only a portion of patients with lower-risk MDS are potential candidates for transplantation at the clinical onset of disease, all patients with higher-risk MDS should be assessed for eligibility at the time of diagnosis. Patients with good performance status and no or few coexisting conditions are the best candidates for transplantation, whereas those with poor performance status or multiple coexisting conditions should be preferentially considered for medical treatments. A complete blood count should be performed every 3 to 6 months, with a marrow examination once a year or whenever there is a clinically significant drop in blood counts.

Managing anemia.

Administration of erythropoiesis-stimulating agents can increase red-cell production and ameliorate anemia in patients with lower-risk MDS; this is the first therapeutic option for most such patients with anemia. A serum erythropoietin level below 200 mU per milliliter is the most reliable predictor of a response, whereas a high transfusion requirement predicts treatment failure.

Lenalidomide induces transfusion independence in about two thirds of patients with lower-risk MDS and isolated del(5q), and many patients with a response to lenalidomide have a cytogenetic remission, clearly indicating that this is a true targeted therapy.

Luspatercept is a recombinant fusion protein that binds transforming growth factor β superfamily ligands to enhance late-stage erythropoiesis. In a study involving transfusion-dependent patients who had MDS with ring sideroblasts, luspatercept treatment resulted in transfusion independence in 38% of cases.

In a subgroup of transfusion-dependent patients with hypoplastic MDS, transfusion independence can be achieved with immunosuppressive therapy, primarily antithymocyte globulin combined with cyclosporine. 

The vast majority of patients with MDS become dependent on regular red-cell transfusions during their clinical course.Although a hemoglobin level of 8 g per deciliter is generally used as a transfusion threshold, a more liberal regimen may promote a better quality of life. Transfusion dependence can lead to parenchymal iron overload and its clinical consequences. so chelation therapy is required.

Several drugs can modulate myelodysplastic hematopoiesis, but available treatments fail to eradicate it, mainly because their selective pressure leads to the emergence of resistant subclones.

The use of a hypomethylating agent, azacitidine or decitabine, currently represents the most common initial treatment in patients with higher-risk MDS who are ineligible for transplantation. About half the patients treated with azacitidine have a hematologic response, including some with a complete response. Treatment is associated with prolonged survival, although the survival benefit observed in real-life studies is on the order of a few months, which is shorter than the survival in the registration study.

With the advent of hypomethylating agents, AML-type chemotherapy is used less frequently in patients with MDS. Nonetheless, it may be considered in patients below the age of 60 years who have 10% or more bone marrow blasts without adverse cytogenetic characteristics and are ineligible for transplantation.

Identifying neurological deficits.

When a disease can cause multiple neurological deficits it more important to identify the site of the deficits than to just diagnose the disease as in multiple sclerosis.

Case 1. A 28 year old patient comes in to the hospital complaining of blurring of vision. He is known to have had an episode of paraplegia 5 years ago, diagnosed as multiple sclerosis. What is happening now and what is the lesion?

Case 2. A 43 year old woman who had recently been taken off disease modifying drugs for multiple sclerosis reports to her doctor with double vision on looking to the left. She says her left eye becomes wobbly whenever she looks to the left. What is the lesion?

Case 3. A 20 year old woman reports to her doctor with weakness in the left leg for several hours. Her doctor examines her and finds 3/5 weakness in the left lower limb, hypertonia, increased reflexes and an up going planter. There is no pain or sensory loss. What has happened?

Clinically isolated syndromes suggestive of MS such as optic neuritis, long tract symptoms/signs (eg, numbness, paresthesia, or weakness), a brainstem syndrome (eg, internuclear ophthalmoplegia), or a spinal cord syndrome (eg, transverse myelitis) are common presentations. Please remember that UMN lesions of one or more limbs are caused by demyelination of the long tracts which, after a crossover in the medulla oblongata go down on the contralateral side of the spinal cord. Hence monocrural or brachial monoplegia or a paraplegia or quadriplegia are caused by demyelinating lesions in the spinal cord.

What happens when the cerebral cortex (specially the motor cortex) is damaged? Not a simple UMN lesion but some or all of the following:

  1. Limb rigidity, not spasticity
  2. Bradykinesia or clumsy limb
  3. Postural instability
  4. Falls
  5. Abnormal gait
  6. Hyperreflexia
  7. Axial rigidity
  8. Tremor
  9. Limb dystonia
  10. Myoclonus
  11. Cognitive decline is a prominent feature 
  12. Dysarthria is prominent and usually an early feature of motor cortex damage. Characteristics are mixed and varied. Approximately one-third of patients have the hypokinetic form, similar to the type seen in idiopathic Parkinson disease, that is characterized by reduced volume, monotone pitch, fluctuating speech articulation, shallow inhalations, and a slow rate of speech punctuated with rapid burst.
  13. Aphasia and limb alienation are 2 other features.

In a particular exam students thought that this is 20 year old woman had lesions in her periventricular white matter. Periventricular leukomalacia occurs in lesions in premature infants, cerebral palsy and in adults in normal pressure hydrocephalus and vascular dementia. Small periventricular white matter lesions may occur in aggressive MS when a likely diagnosis of PML is more accurate.

Progressive multifocal leukoencephalopathy (PML) is a severe demyelinating disease of the central nervous system. PML is caused by reactivation of the polyomavirus JC. PML was initially described in patients with lymphoproliferative and myeloproliferative diseases such as chronic lymphocytic leukemia, chronic myeloid leukemia, Hodgkin lymphoma, and non-Hodgkin lymphoma. Malignancy is the most common predisposing condition among PML cases. PML is also seen in HIV, organ transplant and after the use of immunomodulatory therapy as in MS.

PML usually manifests with subacute neurologic deficits including altered mental status, motor deficits (hemiparesis or monoparesis), limb ataxia, gait ataxia, and visual symptoms such as hemianopia and diplopia. PML typically spares the optic nerves and the spinal cord.  

In patients with multiple sclerosis (MS), particularly those being treated with natalizumab, who are therefore at increased risk for PML, it may be difficult to distinguish recurrent attacks of MS from PML based upon clinical and radiologic findings. However, certain neuroimaging features may be useful in this regard:

  1. PML lesions after natalizumab therapy are usually unifocal if detected early on MRI, located at the gray-white junction of the frontal and parieto-occipital lobes, and are larger than typical foci of demyelination in MS. In contrast, MS lesions are more often small, multifocal, and predominate in the periventricular white matter.
  2. MS lesions usually have an ovoid shape and are oriented perpendicular to the corpus callosum (the abutting calloso-septal margin) or long axis on the lateral ventricles (Dawson finger pattern); PML lesions do not follow this pattern.
  3. PML lesions may be hyperintense on trace diffusion-weighted MRI, whereas MS lesions are usually not.

Optic neuritis usually presents as acute or subacute unilateral eye pain that is accentuated by ocular movements. There may be a scotoma, usually in the center of the field of vision. What will the optic disc look like? If the lesion is retrobulbar the disc may look normal or there may be edema resembling papillitis or there may be optic atrophy. A bitemporal or binasal homonymous field defect is rare in MS and should suggest a mass lesion pressing down on the optic pathways. In optic neuritis site recovers in a few weeks though some dimness and reduction in the brightness of red color may persist. A number of studies have found that reduced axial diffusivity on diffusion tensor MRI (DTI) correlates with prolonged latency of visual evoked potentials and worse visual outcome on follow-up.

There is a 35% chance of recurrence in 10 years in one or both eyes. Treatment is with IV glucocorticoids. Oral steroids are not used. Alternative treatments used for acute neuro-immunologic disease include intravenous immune globulin (IVIG) and plasma exchange. These do not have established efficacy in the treatment of optic neuritis.

Dalfampridine (4-aminopyridine; fampridine), a potassium channel blocker, may improve axonal function in patients with demyelinating disease. In one randomized crossover study in 20 patients with optic neuritis of at least six months duration, five weeks of treatment with 4-aminopyridine was associated with improved measures on visual evoked potentials.

All patients with a CIS who meet diagnostic criteria for MS should be started on a DMT. The recombinant human interferon beta agents or glatiramer acetate are first-line choices for high-risk patients with a CIS. Glatiramer acetate, administered by subcutaneous injection, is dosed at 20 mg daily or 40 mg three times a week. Teriflunomide is an alternative for patients who prefer oral therapy, but its use is contraindicated for women who are pregnant or trying to conceive because of the risk of teratogenicity, and frequent monitoring is required due to the risk of hepatoxicity. 

Transverse myelitis is an inflammatory disorder that presents with acute or subacute spinal cord dysfunction resulting in weakness, sensory alterations, and autonomic impairment (eg, bowel, bladder, and sexual dysfunction) below the level of the lesion. Transverse myelitis can occur as an independent entity, usually as a postinfectious complication, but transverse myelitis also exists on a continuum of neuro-inflammatory disorders:

  1. Transverse myelitis can occur as part of the spectrum of MS
  2. Transverse myelitis manifesting as a longitudinally extensive spinal cord lesion spanning three or more vertebral segments is one of the characteristic manifestations, along with bilateral optic neuritis, of NMOSD. ( “Neuromyelitis optica spectrum disorder).
  3. Transverse myelitis may be seen in patients with acute disseminated encephalomyelitis. (ADEM) which follows a viral infection or vaccination.

Eye movement abnormalities in MS.

Abnormalities of voluntary gaze (very common) and include internuclear ophthalmoplegia, ocular dysmetria and gaze impersistence, horizontal gaze palsy, one-and-a-half syndrome, dorsal midbrain syndrome, skew deviation. Nystagmus (very common) which may be horizontal and vertical or pendular, periodic alternating.

Abnormalities of slow phase eye movements (common) such as disordered smooth pursuit: paroxysmal disorders of eye movements (less common) such as ocular flutter, square wave jerks, opsoclonus

Isolated ocular motor nerve palsies are uncommon.

Internuclear ophthalmoplegia (INO) refers to abnormal horizontal ocular movements with lost or delayed adduction and horizontal nystagmus of the abducting eye. INO is caused by a lesion of the medial longitudinal fasciculus in the brainstem on the side of diminished adduction. Convergence is typically preserved.

In patients with MS, paraparesis or paraplegia are more common than isolated upper extremity weakness due to the frequent occurrence of lesions in the descending motor tracts of the spinal cord. Severe spasticity can occur, such that extensor spasms of the legs and sometimes the trunk may be provoked by active or passive attempts to rise from a bed or wheelchair.

Physical findings include spasticity, usually more marked in the legs than in the arms. The deep tendon reflexes are exaggerated, sustained clonus may be elicited, and extensor plantar responses are observed. All of these manifestations are commonly asymmetrical.

Occasionally, deep tendon reflexes are decreased due to lesions interrupting the reflex arc at a segmental level, and an inverted triceps reflex may be observed. In it, the triceps contraction is lost and the efferent component is represented by a contraction of the biceps muscle. The Achilles reflex can be absent due to lesions of the sacral segments of the spinal cord, with or without concomitant sphincter and sexual problems. Occasionally, reduced reflexes reflect hypotonia resulting from cerebellar pathway lesions.

Gait imbalance, difficulty in performing coordinated actions with the arms and hands, and slurred speech often occur as a result of impairment of cerebellar pathways. Cerebellar signs are usually mixed with pyramidal (corticospinal) tract signs.

I hope some of this information helps to clarify why and when neurological signs appear in MS and closely related diseases in which demyelination occurs in the CNS.

COPD and related problems.

COPD is an umbrella term for various clinical entities with multiple causes resulting in airflow limitation that is not fully reversible. COPD is better defined as a clinical syndrome characterized by chronic respiratory symptoms, structural pulmonary abnormalities (airways disease, emphysema, or both), lung function impairment (primarily airflow limitation that is poorly reversible), or any combination of these. Early definitions of COPD distinguished different types (ie, chronic bronchitis, emphysema, asthma), a distinction that is not included in the current definition.

It is the third highest cause of death. Although in most areas men suffer more from this disease in other areas women are it’s major target. For a period there is an interaction between the environment and genetic susceptibility. Logically this is the period when prevention strategies should be instigated.

In persons without obstruction who are exposed to cigarette smoking, the presence of cough, sputum, and dyspnea and the detection of a low diffusing capacity of the lung for carbon monoxide (DLco) are associated with an increase in the risk of COPD.

Similarly, in persons without obstruction who have a baseline value for forced expiratory volume in 1 second (FEV1 ) at the low end of the normal range, a reduction in FEV1 that exceeds 40 ml per year (normal rate of loss after the third decade of life, <25 ml per year) over an 18-month period is associated with an increase by a factor of 36 in the risk that COPD will develop in the next 5 years. Patients in this “silent” stage constitute a group that can be labeled as having “pre-COPD.”

COPD remains underdiagnosed, primarily because it usually is considered to be a disease of the elderly. The disorder should be recognized at an earlier age because earlier interventions, such as smoking cessation, can normalize lung-function decline. Improving the quality of air in many cities and early use of bronchodilators i.e. before the age of fifty may prevent obstruction in the lungs. The treatment of younger patients who have mild disease (i.e., earlier treatment) may provide the greatest benefit over time.

  • Who is at risk?
  1. Cigarettes’ exposure. Those who smoked cigarettes throughout a 25 year observation period were more likely than never smokers to develop COPD (36 versus 8 percent) . Smoking tobacco through a Chinese water pipe (narghile or hookah or sheesha) is also associated with an increased risk of COPD. Smoking both tobacco and marijuana synergistically increases the risk of COPD and respiratory symptoms.
  2. Environmental exposure to particulate matter, dusts, vapors, fumes, or organic antigens may also be a risk factor for COPD. Why have women become more likely to develop COPD? Women are exposed to biosmoke when, in poor areas. they cook on wood smoke, cow dung, peat and coal. Occupational exposure to chemical disinfectants (eg, glutaraldehyde, bleach, hydrogen peroxide, alcohol, and quaternary ammonium compounds) is associated with an increased risk of COPD among nurses; women tend to have more atopy but less smoking. Check this out against smoking in rural Asia and the subcontinent among women.
  3. Atopy and asthma are predictors of COPD specially when they develop at a young age.
  4. Antioxidant deficiency — There are limited data suggesting that a deficiency of antioxidant vitamins (eg, vitamins C and E) may be a risk factor for COPD.
  5. Pulmonary tuberculosis may contribute to airflow obstruction via endobronchial infection and subsequent bronchostenosis or via lung parenchymal destruction with loss of airway tethering. In a study of 8784 Chinese subjects aged 50 or older, radiographic evidence of prior pulmonary tuberculosis was associated with an increased risk for airflow obstruction, independent of cigarette smoking, biomass fuel exposure, and prior diagnosis of asthma.
  6. Antioxidant related enzymes — Genetic variation in antioxidant enzyme function or regulation may affect risk for COPD. In particular, the genes for glutathione S-transferases P1 and M1, glutamate cysteine ligase, and superoxide dismutase appear to be involved.
  7. Family history. Patients with COPD are more likely to have first degree relatives who have bronchorespiratory hyper responsiveness to smoke.
  8. Respiratory symptoms. The three cardinal symptoms of COPD are dyspnea, chronic cough, and sputum production and the most common early symptom is exertional dyspnea. Less common symptoms include wheezing and chest tightness 
  9. Combination of symptoms. Those who present with episodes of increased cough, purulent sputum, wheezing, fatigue, and dyspnea that occur intermittently, with or without fever. Diagnosis can be problematic in such patients. The combination of wheezing plus dyspnea may lead to an incorrect diagnosis of asthma. Conversely, other illnesses with similar manifestations are often incorrectly diagnosed as a COPD exacerbation (eg, heart failure, bronchiectasis, bronchiolitis).
  10. COPD derives from various lifelong, dynamic, and cumulative gene–environment interactions (e.g., smoking, inhalation of other pollutants, prematurity, respiratory infections, and dietary insufficiency

Preventive strategies.

  1. Implement, monitor, and enforce strict control of airborne exposure in the workplace
  2. Initiate intensive and continuing education of workers, managers, clinicians, and legislators
  3. Promote smoking cessation since smoking aggravates exposure to other particles and gases
  4. Improve ventilation in areas where biomass fuels are used for cooking and promote use of clean fuels

When is the disease established and advanced?

  1. Once such airflow limitation occurs, the diagnosis of COPD is confirmed.
  2. FEV1, expressed as a proportion of reference values, defines the severity of airflow limitation.
  3. The intensity of dyspnea.
  4. The presence or absence of cachexia.
  5. An assessment of the capacity to perform activities of daily life, provides additional prognostic information.
  6. A history of exacerbations, especially two or more in a year or an episode requiring hospitalization, predicts future exacerbations and poor outcomes,

What else should we look for?

Patients with COPD often have certain coexisting conditions, including ischemic heart disease, atrial fibrillation, heart failure, osteoporosis, lung cancer, gastroesophageal reflux, anxiety, and depression. Most of these disorders are characteristically seen in the elderly, but in patients with COPD they occur at younger ages.

How does a CT scan of the chest help?

Chest CT detects and quantitates the emphysema phenotype, classically known as
the “pink puffer” phenotype but better defined as the MOLT (multiorgan loss of tissue) phenotype, which is frequently associated with loss of mesenchymal tissue (bone, muscle, and fat). Patients with this phenotype are at increased
risk for lung cancer.

What else will a CT scan tell us?

  1. The presence of heterogeneous, predominantly upper-lobe emphysema identifies good candidates for bronchoscopic or surgical lung-volume reduction.
  2. CT also detects airway luminal narrowing and wall thickening associated with cough, phlegm production or discoloration, and exacerbations of COPD.
  3. It can identify bronchiectasis,
  4. early-stage lung cancer,
  5. interstitial lung abnormalities,
  6. coronary calcifications, cardiomegaly,
  7. enlargement of the pulmonary vasculature,
  8. thoracic-wall and mediastinal abnormalities, osteoporosis, sarcopenia, and hiatal hernia, all of which affect health status and could be the target of specific therapies.

First measure the resting oxygen saturation. A resting oxygen saturation of less than 90% should prompt measurement of arterial blood gases to determine whether supplemental oxygen is needed. In patients with dyspnea on exertion, physiological testing can be informative.

Hyperinflation is determined by measuring lung volumes, with air trapping indicated by a ratio of residual volume to total lung capacity that exceeds the normal value of 0.35. A low ratio of inspiratory to total lung capacity (<0.25) is associated with an increased risk of death and, when accompanied by dynamic hyperinflation, is a determinant of the severity of dyspnea.

A low DLco (an indirect measure of emphysema) is a good predictor of oxygen desaturation, coexisting pulmonary hypertension, and lung cancer.

A 6-minute walking distance of less than 350 m is associated with increased mortality. Cardiopulmonary exercise testing helps differentiate cardiac from respiratory compromise and can be used to guide pulmonary rehabilitation.

The multidimensional BODE index, which consists of the integration of four variables (body-mass index, degree of airflow obstruction, degree of dyspnea, and exercise capacity [6-minute walking distance]), provides better prognostic information (higher scores indicate a greater risk of death) than the FEV1 alone.

The initial Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines used the forced expiratory volume in one second (FEV1; expressed as a percentage of predicted) to stage disease severity.

Endotypes, Biomarkers, and Treatable Traits

An endotype is a disease subtype defined functionally and pathologically by a molecular mechanism or by treatment response. Endotypes should be identified by means of validated biomarkers. Currently, only two blood tests meet this criterion for COPD endotypes that constitute treatable traits.

  1. The first test is the serum level of alpha1 -antitrypsin, which should be measured in all patients. A low level indicates a genetically determined COPD endotype that responds to long-term replacement of the missing protein.
  2. The second test is the blood eosinophil count. In patients with frequent exacerbations despite appropriate bronchodilator treatment, the blood eosinophil count helps predict the response to inhaled glucocorticoids. Eosinophil counts higher than 300 per cubic millimeter indicate a good response, values between 100 and 300 per cubic millimeter suggest a moderate response, and a low eosinophil count (<100 per cubic millimeter) is associated with minimal benefit and an increase in the risk of pneumonia.

Primary and Secondary Prevention.

  1. Stop smoking.
  2. Reduce ambient pollution.
  3. Vaccines for influenza
  4. Improve and change methods of cooking.

How to begin treatment?

Assess the Modified Medical Research Council dyspnea scale score or COPD Assessment Test

Most patients with mild symptoms (a score of 0 or 1 on the modified Medical Research Council dyspnea scale [scores range from 0 to 4, with higher scores indicating more severe dyspnea] or a score of <10 on the COPD Assessment Test [scores range from 0 to 40, with higher scores indicating greater severity of symptoms]) and fewer than two exacerbations per year do well with exposure control, increased physical activity, vaccinations, and use of long-acting bronchodilators.

The presence of more intense symptoms and the occurrence of more frequent exacerbations should prompt a more detailed evaluation and specialized management, with consideration of a referral for pulmonary rehabilitation, which improves health status, reduces dyspnea, and increases exercise capacity.


The Global Initiative for Chronic Obstructive Lung Disease suggests an initial approach based on the intensity of symptoms and the history of exacerbations, with a subsequent algorithm that includes a blood eosinophil count for adjustment.
of therapy.

  1. A long-acting muscarinic antagonist (LAMA) such as  ipratropium, triotropium ,  umeclidinium, aclidinium, is the initial drug of choice for patients with mild disease and no exacerbations. If the patient has more severe dyspnea, severe airflow obstruction, and lung hyperinflation.
  2. Combine a LAMA with a selective long-acting beta2-agonist (LABA) such as salmeterolformoterol, vilanterol) if the patient has more severe dyspnea, severe airflow obstruction, and lung hyperinflation, combining the two agents in a single inhaler to simplify treatment.
  3. Start therapy with a combination of a LABA and an inhaled glucocorticoid in patients with a history of asthma, wheezes, rhinitis, polyps, or allergies; a history of exacerbations; an elevated blood eosinophil count (>150 per cubic millimeter); or a combination of these findings.
  4. Monotherapy is not recommended because of evidence that use of an inhaled glucocorticoid (fluticasone propionate) alone is associated with an increased risk of death, as compared with the combination of fluticasone and salmeterol.
  5. For patients who have repeated exacerbations while receiving maximal inhaled therapy or who have side effects from inhaled glucocorticoids, oral macrolides are useful. Be careful if the QT is prolonged or if there are arrhythmias.
  6. Use a phosphodiesterase inhibitor roflumilast, which lowers exacerbation rates among patients with severe COPD.
  7. Trials of mepolizumab and benralizumab have shown marginal benefits in patients with COPD and exacerbations. Oral antioxidants are popular in Europe and the Far East but not in the rest of the world.

You must also be aware of surgical and bronchoscopic options for reducing lung volumes and treating acute exarcerbations of the disease and pulmonary rehabilitation maneuvers.

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.