Diabetic Peripheral Neuropathy

Scenario 1
Diabetes can progress and worsen, with nerve involvement in the limbs and digits. Without normal innervation to the digits, the feet and toes feel tingling sensation. The toes can feel when touched, rubbed or squeezed, but they are abnormal.

Scenario 2
In the Malay context, there is avoidance by mothers in the post-partum period (dalam tempoh pantang), not to walkabout and to remain in bed as much as possible. This is to avoid having mothers accidentally kicked the door frame, especially the raised door frame on the floor (bendul). Accidentally kicking the door frame (or the door itself) can cause serious injury to the toes involved. The mother does not feel the tingling sensation immediately, but much later, and for a long period, until the toes are put right by proper massage and stretching techniques. Ignoring the problem will cause the mother to experience extreme pain while walking for long periods. What can be done to alleviate such problem?

Is there hope
Can nerves in the foot be put right once there is tingling sensation? It depends on what happened and the level of severity. If the toes look normal colour and the nails are growing fine, there is some hope. Occasional massage is good to maintain and encourage blood flow. But will the nerves regenerate?

What can be done?

1. Massage the toes to reduce pain sensation. Some LMS will help. Menthol relieves pain (minyak angin). Tea tree oil is quite useful as it has menthol and the oil is good for massage.
2. Stretch Use the hands and flex the toes up towards the body, hold and then release. Repeat a few times. Then flex the toes towards the floor to see if they feel better.
3. Wiggle the toes while watching TV.
4. Massage the thigh by pulling action, pull them up towards the body. This is correct the nerve and blood vessels to the toes. 
5. Massage the affected foot before sleep. Use some oil to massage the thigh inward and upward towards the body. Raise the affected foot when sleeping. This will relieve pain in the thigh and affected foot. The thigh and foot will correct itself in about 2 days if done correctly. 

Pain and tingling sensation will return once in a while. Constant massage of the foot will help to keep the pain away and keep the foot alive. Blood vessels can regenerate and form new ones. The toes will maintain normal colour if there is blood flow. Nerves are difficult to regenerate but there is hope that they will generate given the right environment. Something to ponder upon.

External links
http://www.endocrinologyadvisor.com/an-overview-of-diabetic-peripheral-neuropathy/slideshow/3770/

Beta-Thalassemia Major

DISCOVERY OF HEMOGLOBIN

1. Hemoglobin was discovered by Hünefeld in 1840.
2. Hemoglobin (Hb) is an iron-containing oxygen-transport metalloprotein in the red blood cells (rbc's) of all vertebrates (with the exception of the fish family Channichthyidae) as well as the tissues of some invertebrates.
3. Hemoglobin has the formula C2952H4664O832N812S8Fe4. 
4. Each hemoglobin molecule has 4 iron (Fe) atoms.
5. The role of hemoglobin in the blood was elucidated by French physiologist Claude Bernard.
6. Hemoglobin carries oxygen in the blood from the respiratory organs (lungs or gills) to the rest of the body (ie. the tissues). 
7. Hemoglobin is red because it contains heme, which is a bright cherry red molecule.
8. Hemoglobin is a bright cherry red molecule which can undergo oxygenation and deoxygenation reactions.
9. Hemoglobin's reversible oxygenation was described a few years later (1851-1859) by Felix Hoppe-Seyler.
10. Presence of oxygenated hemoglobin gives blood a bright red colour and the smell of fresh blood as present in hospital corridors.
11. Presence of deoxygenated hemoglobin gives blood a dark red-brown colour and this blood stinks of dead bodies (corpses) if left to stand at room temperature.
12. Cells and tissues require oxygen for aerobic glycolysis. Complete biological oxidation produces energy (ATP), carbon dioxide (CO2) and water (H2O).
13. Hemoglobin + CO2 = carbaminohemoglobin. Carbaminohemoglobin carries carbon dioxide
14. Hemoglobin is also found outside red blood cells and their progenitor lines. 
15. Other cells that contain hemoglobin include the A9 dopaminergic neurons in the substantia nigra, macrophages, alveolar cells, and mesangial cells in the kidney. In these tissues, hemoglobin has a non-oxygen-carrying function as an antioxidant and a regulator of iron metabolism.
16. In 1959, Max Perutz determined the molecular structure of hemoglobin by X-ray crystallography.

HEMOGLOBIN GENES AND HEME & HEMOGLOBIN SYNTHESES

Hemoglobin forms in the developing rbc (reticulocytes) in the bone marrow (BM).

Steps in heme & hemoglobin synthesis:

1. Glycine + succinyl-CoA = delta-aminolevulinic acid (d-ALA)
2. d-ALA exits into cytoplasm
3. d-ALA is reacted upon by enzymes
4. forms protoporphyrin
5. protoporphyrin re-enters mitochondria
6. Iron (Fe) is added to protoporphyrin
7. forms heme
8. Globin is made at ribosomes of rbc's and involves 2 chromosomes. Alpha globin chains are made by Chromosome 16. Beta globin chains are made by Chromosome 11.
9. Heme + Globin = Hemoglobin
10. Lead (Pb) is an inhibitor of heme and hemoglobin synthesis

HEMOGLOBIN STRUCTURE AND FUNCTION

1. Hemoglobin helps to carry oxygen to body tissues.
2. Hemoglobin helps to carry carbon dioxide for disposal by the lungs.
3. Rbc's contain hemoglobin.
4. The level of hemglobin in blood varies for males and females.
5. Males perform more physical activities and have higher hemoglobin levels in blood.
6. Females perform less physical activities and have lower hemoglobin levels in blood.
7. Hemoglobin has a quaternary structure characteristic of many multi-subunit globular proteins.
8. There are 4 types of globin chains: alpha (a), beta (b), delta (d) and gamma (g)
9. Hemoglobin consists of 4 subunits: 2 alpha globins + 2 beta/delta/gamma globins
10. Fetal hemoglobin is Hb F.
11. Adult hemoglobins are Hb A1 and Hb A2
12. Hb A1 = a2 b2 (alpha2 beta2)
13. Hb A2 = a2 d2 (alpha2 delta2)
14. Hb F = a2 g2 (alpha2 gamma2)
15. Hemoglobin can be saturated with oxygen molecules (oxyhemoglobin), or desaturated with oxygen molecules (deoxyhemoglobin).

POSTNATAL GENETICS:
(1) GLOBIN CHAINS IN HEMOGLOBINS
(2) HEMOGLOBIN VARIANTS

1. A globin chain is a polypeptide.
2. The amino acid sequence of a globin chain is determined by DNA sequences called genes.
3. There are 4 globin chains: alpha (a), beta (b), delta (d) and gamma (g)
4. Different globin chains are synthesized at different times during fetal development and till adult stage.
5. There is more than one hemoglobin gene.
6. The main form of hemoglobin present in adult man is hemoglobin A (HbA).
7. In humans, hemoglobin A is coded for by the genes, HBA1, HBA2, and HBB.
8. Hemoglobin contains 2 alpha globin chains and 2 beta, 2 delta or 2 gamma globin chains
9. Thus, many configurations of globin chains are possible:
10. Hb A1 = a2 b2 (alpha2 beta2) (heterotetramer, α2β2)
11. Hb A2 = a2 d2 (alpha2 delta2)
12. Hb F = a2 g2 (alpha2 gamma2) (HbF, α2γ2)
13. Fetal hemoglobin is Hb F.
14. Adult hemoglobins are Hb A1 and Hb A2
15. Normal hemoglobin types found in adults are; 

• Hemoglobin A (Hb A), which is 95-98% of hemoglobin found in adults, 
• Hemoglobin A2 (Hb A2), which is 2-3% of hemoglobin found in adults, and 
• Hemoglobin F (Hb F), which is found in adults up to 2.5%. It  is the primary hemoglobin that is produced by the fetus during pregnancy.

     16. In the embryo:

• Hb Gower 1 (ζ₂ε₂)
• Hb Gower 2 (α₂ε₂)
• Hemoglobin Portland I (ζ₂γ₂)
• Hemoglobin Portland II (ζ₂β₂).

     17. In the fetus: Hemoglobin F (α₂γ₂) 

      18. After birth:

• Hemoglobin A (α₂β₂) – The most common with a normal amount over 95%.
• Hemoglobin A2 (α₂δ₂) – δ chain synthesis begins late in the third trimester and, in adults, it has a normal range of 1.5–3.5%.
• Hemoglobin F (α₂γ₂) – In adults Hemoglobin F is restricted to a limited population of red cells called F-cells. However, the level of Hb F can be elevated in persons with sickle-cell disease and beta-thalassemia.

    19. Variant forms that cause disease:

• Hemoglobin D-Punjab – (α₂β^D₂) – A variant form of hemoglobin.
• Hemoglobin H (β₄) – A variant form of hemoglobin, formed by a tetramer of β chains, which may be present in variants of α thalassemia.
• Hemoglobin Barts (γ₄) – A variant form of hemoglobin, formed by a tetramer of γ chains, which may be present in variants of α thalassemia.
• Hemoglobin S (α₂β^S₂) – A variant form of hemoglobin found in people with sickle cell disease. There is a variation in the β-chain gene, causing a change in the properties of hemoglobin, which results in sickling of red blood cells.
• Hemoglobin C (α₂β^C₂) – Another variant due to a variation in the β-chain gene. This variant causes a mild chronic hemolytic anemia.
• Hemoglobin E (α₂β^E₂) – Another variant due to a variation in the β-chain gene. This variant causes a mild chronic hemolytic anemia.
• Hemoglobin AS – A heterozygous form causing sickle cell trait (SCT) with one adult gene and one sickle cell disease gene
• Hemoglobin SC disease – A compound heterozygous form with one sickle gene and another encoding Hemoglobin C. Hemoglobin Hopkins-2 - A variant form of hemoglobin that is sometimes viewed in combination with Hemoglobin S to produce sickle cell disease.

      20. List of known hemoglobin variants

• Hb Kansas
• Hb S
• Hb C
• Hb E
• Hb D-Punjab
• Hb O-Arab
• Hb G-Philadelphia
• Hb Hasharon
• Hb Lepore
• Hb M
• Hb F
• Hb Hope
• Hb Pisa
• Hb J
• Hb N-Baltimore

HEMOGLOBIN F (Hb F)

1. Fetal hemoglobin (HbF, α2γ2) is found in the developing fetus, and binds oxygen with greater affinity than adult hemoglobin A.
2. Hemoglobin F (Hb F) is the primary hemoglobin that is produced by the fetus during pregnancy.
3. The levels can be normal to increased in beta thalassemia. 
4. Hemoglobin F frequently increases in individuals with sickle cell anemia and sickle cell-beta thalassemia. 
5. Individuals with sickle cell and increase of Hb F have a milder case of the disease. 
6. There are situations where the Hb F is increased. This rare condition is called Hereditary Persistence of Fetal Hemoglobin (HPFH).
7. HPFH is a group of disorders where the Hemoglobin F is increased without signs or clinical features of thalassemia. 
8. Some different ethnic groups have different mutations that cause HPFH. 
9. Hb F can also be increase by acquired conditions that involve the red blood cells. 
10. Elevated Hemoglobin F levels are also associated with Leukemia and myeloproliferative disorders.

HEMOGLOBIN H

1. Hemoglobin H (Hb H) increases the affinity for oxygen. 
2. Hb H holds onto the oxygen instead of releasing it into tissue and cells. 
3. Hb H usually occurs in some alpha thalassemia and is composed of four beta globin (protein) chains (beta tetramer, β4). 
4. This variant is usually produced in response to a severe shortage of alpha chains, and usually cause beta chains to function abnormally.

HEMOGLOBINOPATHY VS THALASSEMIA

1. Hemoglobinopathy is a hereditary condition involving an abnormality in the structure of hemoglobin.
2. Mutations in the genes for the hemoglobin protein in a species result in hemoglobin variants. Many of these mutant forms of hemoglobin cause no disease. Some of these mutant forms of hemoglobin, however, cause a group of hereditary diseases termed the hemoglobinopathies. The best known hemoglobinopathy is sickle-cell disease (SCD).
3. Hemoglobin variants are a part of the normal embryonic and fetal development. They may also be pathologic mutant forms of hemoglobin in a population, caused by variations in genetics. Some well-known hemoglobin variants, such as sickle-cell anemia (SCA), are responsible for diseases and are considered hemoglobinopathies. Other variants cause no detectable pathology, and are thus considered non-pathological variants.
4. Thalassemia is a reduced or no production of a or b globin chain. The a and b globin chains have normal structures.

HEMOGLOBIN CONTENT OF ERYTHROCYTES

1. Hemoglobin carries oxygen to tissues.
2. Hemoglobin carries carbon dioxide back to the lungs for expulsion (expiration).
3. Hemoglobin is not synthesized (made) in red blood cells (erythrocytes).
4. Hemoglobin synthesis occurs in nucleated reticulocytes.
5. Hemoglobin synthesis is regulated (controlled).
6. Erythrocytes have a half-life of 120 days (ie they survive approximately 120 days before they are cleared from the blood circulation).
7. When old erythrocytes are removed and broken down, hemoglobin in them too is broken down (degraded).
8. New hemoglobin will need to be synthesized to replace that lost.
9. If hemoglobin synthesis is slowed (or lags behind), there will be either insufficient hemoglobin, lack of hemoglobin or defective hemoglobin in the erythrocytes.

THALASSEMIAS

1. Thalassemias are a group of genetic blood disorders 
2. Thalassemias are inherited blood disorders
3. Thalassemia patients make normal globin chains, but at reduced rates
4. These blood disorders have defective production of hemoglobin
5. The thalassemias are autosomal recessive disorders which result in reduced production of one or more of the subunits of hemoglobin
6. There are 2 forms of thalassemia: alpha- and beta-thalassemia
7. There are two forms of beta-thalassemia: thalassemia minor and thalassemia major (also called Cooley's anemia)

ALPHA-THALASSEMIA

1. Reduced production of alpha globin chains
2. Results from gene deletion
3. Alpha-thalassemias have reduced production of alpha-globin chains to make new hemoglobin
4. The resulting hemoglobin molecule has either 1 or no alpha-globin chain; 
5. The resulting hemoglobin configuration can be b2 or ab2, which are defective hemoglobins.
6. Hemoglobin with b2 configuration occurs in alpha-thalassemia major.
7. Hemoglobin with ab2 configuration occurs in alpha-thalassemia minor.

ALPHA THALASSEMIA GENE DELETION

1. The alpha globin gene is present on Chromosome 16.
2. Alpha thalassemia results from gene deletion.
3. ONE alpha globin gene deletion is asymptomatic.
4. TWO alpha globin gene deletions, can be either from the same chromosome (cis deletion) or from different chromosomes (trans deletion)
5. Cis deletion is worse than trans deletion. 
6. Inheritance of cis deletion from both parents by the offspring is dangerous as it results in severe alpha thalassemia (no alpha globin chain).
7. THREE alpha gene deletions results in Hb H, with b2 dimer and b4 tetramer.
8. FOUR alpha gene deletions results in Hb Bart's, with g4 tetramer.

TREATMENT OF ALPHA THALASSEMIA

1. alpha carrier and Hb H don't need treatment as they are fine.

BETA THALASSEMIA

1. Reduced or no production of beta globin chains
2. It is genetically determined
3. The beta globin gene is located on a chromosome 11 (ie an autosome, not a sex chromosome, not X or Y)
4. Two copies are derived in the child, one from the father, and one from the mother
5. Each chromosome has an allele for beta globin
6. Each allele codes for beta globin chain, one from the father, one from the mother
7. Beta thalassemia also occurs as a result of gene mutation 

BETA THALASSEMIA GENE MUTATIONS

1. There are 2 types of beta globin gene mutations: B+ and B0
2. In B+ gene mutation, the gene is capable of producing beta globin chain even though at reduced rate; there is some production of beta globin chain
3. In B0 mutation, the gene is incapable of producing beta globin chain; there is no production of beta globin chain
4. Possible genetic combinations are thus: B+B+, B+B0, B0B+, and B0B0
5.         B+B+ = produce beta globin chain .... beta thalassemia major
6.         B+B0 or B0B+  = produce beta globin chain ... beta thalassemia minor
7.         B0B0 = do not produce beta globin chain .... beta thalassemia major

BETA-THALASSEMIA MAJOR & MINOR

1. Beta-thalassemias are of 2 types - thalassemia major and thalassemia minor
2. Thalassemia major is also called Cooley's anemia
3. Production of beta-globin chain of hemoglobin is reduced or none
4. The resulting hemoglobin molecule has either a2 or a2b, which are hemoglobins with reduced beta globin or no beta globin
5. Hemoglobin with a2 configuration occurs in beta-thalassemia major.
6. Hemoglobin with a2b configuration occurs in beta-thalassemia minor.
7. Beta thalassemia minor is a2BB+ with mild anemia and increased Rbc count
8. Beta thalassemia major is a2B+B+ or a2B0B0 with severe anemia and increased Rbc count
9. In B0B0, there is no beta globin production; there will be excess alpha globin chains
10. When there is no beta globin production, and there is excess alpha globins, 4 alpha globin chains combine to form an alpha globin tetramer, which in turn forms ineffective hemoglobin. This results in ineffective erythropoiesis.

THE BONE MARROW

1. When rbc count is low, the bone marrow compensates by producing more rbc's.
2. Rbc's with alpha globin tetramers (a4) are abnormal and are destroyed while still in the bone marrow.
3. Any rbc's with alpha globin tetramers (a4) that escaped from the bone marrow and are released into the circulation, are trapped by the endothelial system (eg  spleen) and are destroyed, thus removing them from the systemic circulation ... leading to anaemia.
4. Any rbc's containing alpha4 tetramer will be destroyed ... leading to anaemia.
5. When the body senses a rapid reduction in rbc count, it tries to make more rbc's in the bone marrow.
6. The bone marrow will become hyperactive in order to make rbc's.
7. The bone marrow is now hyperactive ... trying to make a lot of new rbc's even though beta globin synthesis is reduced.
8. When the bone marrow is active and increasing its mass (expanding), it compresses the cortex, thus thinning the cortex.
9. The thick cortex gives bone strength. Once the cortex is thinner, bone strength is reduced and the bones are weakened, and can possibly lead to pathological fracture. This can happen in thalassemia patients. The body will try to produce rbc's using all the bone marrow in the body.
10. Normally after birth, erythropoiesis is limited to a few bones - bone marrow of the central bones - of the skull, ribs, vertebra and a few long bones, ribs. However, in beta thalasemia with anemia, almost all bones with bone marrow will try to make rbc's.
11. As a result, when the bone marrow cavity expands rapidly to produce more rbc's in the skull and the cortex thins, the skull marrow will crack, giving a hair-on-end or crew cut appearance. Expansion of the bone marrow of the face will give a chipmunk appearance. These are findings in thalassemia patients.

VIRAL INFECTIONS IN THALASSEMIA PATIENTS

1. Parvovirus P19 infection halts rbc production for 1-2 weeks in normal healthy persons, as we have a large reserve of rbc's.
2. However, in beta thalassemia major patients, Parvovirus P19 infection is dangerous. They hardly have any rbc reserve and need all the rbc's in the bone marrow.

GEOGRAPHIC ORIGIN OF THE THALASSEMIAS

1. The Indians are classified as Caucasanoids. They are Aryans of Italian and Greek origins. Thus, they inherit beta-thalassemia from their Mediterranean ancestors.
2. The Malays of Indian heritage also inherit beta-thalassemia from their Indian Mediterranean ancestors. Beta-thalassemia is common among this Malay population in Malaysia.

THALASSEMIA COMMON CLINICAL FEATURES

1. Anaemia
2. Manifestation of increased hemopoiesis in face and skull
3. Extramedullary hemopoiesis in liver and spleen results in nucleated rbc's
4. Hepatosplenomegaly

BETA-THALASSEMIA MAJOR SYMPTOMS

1. fatigue, weakness, or shortness of breath
2. a pale appearance (pallor) or a yellow color to the skin (jaundice)
3. irritability
4. deformities of the facial bones
5. slow growth (retarded growth, short for stature)
6. a swollen abdomen
7. dark urine

INVESTIGATIONS OF THALASSEMIA

1. Microscopy
2. Skull radiography
3. Hemoglobin

MICROSCOPY OF ERYTHROCYTES IN THALASSEMIA

1. The microscope is the best way to examine erythrocyte appearances.
2. Erythrocytes with insufficient or deficient hemoglobin will not look normal when examined under the microscope.
3. Microscopic findings are diagnostic.
4. Pale erythrocytes point to anemia.
5. "Mexican hats" or target cells (or targets) point to thalassemia.
6. Small erythrocytes (microcytic) point to iron deficiency - microcytic anemia.
7. Big pale erythrocytes (macrocytic) point to vitamin B deficiency - macrocytic anemia.
8. Spiky erythrocytes (echinocytes) have spike-like projections on their surfaces.
9. Spindle-shaped erythrocytes
10. Sickle-shaped erythrocytes occur in sickle cell anemia (SCA)
11. Extramedullary hemopoiesis (occurs in liver and spleen) will lead to nucleated rbc's.
12. Liver and spleen are not equipped to make rbs'c. So these organs will make immature nucleated rbc's which are seen in the circulation.
13. Microcytic hypochromic anaemia
14. Normal rbc's are round biconcave discs, with 2/3 red due to hemoglobin and 1/3 pale due to less hemogloin
15. Target cells are seen thalassemia. Target cells lack tensile strength and rbc biconcavity has blebs (outgrowths) and are filled with hemoglobin. The rbc's now look like target cells, like bull's eye

TREATMENT OF BETA THALASSEMIA

1. Blood transfusion. Blood transfusion bags contain iron (Fe); 1 bag = 250 mg iron. When we transfuse patients at 4 weeks interval, we also supply them with extra iron (blood > rbc > Hb > rbc's are degraded in 120 days and free iron is released). Iron has no specific way for excretion. So iron is deposited in tissues, leading to hemosiderosis or hemochromatosis. So, iron overload results. A lot of problems thus result.
2. Iron chelation therapy

External links

Hemoglobin
https://en.wikipedia.org/wiki/Hemoglobin
https://youtu.be/M4cKGWP12w4

HBB
https://en.wikipedia.org/wiki/HBB

Hemoglobin variants
https://en.wikipedia.org/wiki/Hemoglobin_variants

Hemoglobinopathies
https://youtu.be/89feCoBXRGE

Thalassemia

https://www.medicinenet.com/beta_thalassemia/article.htm
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2943116/pdf/JBB2010-706872.pdf
http://www.tandfonline.com/doi/full/10.1080/00313020600922538?scroll=top&needAccess=true

Theodora Lam and Brenda S.A. Yeoh. 2004. Negotiating ‘home’ and ‘national identity’: Chinese-Malaysian transmigrants in Singapore
http://onlinelibrary.wiley.com/doi/10.1111/j.1467-8373.2004.00235.x/full

Videos - Thalassemia

https://youtu.be/39tW_o3SqDM
https://youtu.be/uowfqUc4ems
https://youtu.be/M4cKGWP12w4

Malaysia Statistics 2017

MALAYSIA

Geographic coordinates: 3 10 N, 101 42 E

Time difference: UTC+8 (13 hours ahead of Washington, DC)

National anthem: Negaraku (My Country/My Nation)

Population: 31,381,992 (July 2017 est.)

Ethnic groups:

• Malay 50.1%
• Chinese 22.6%
• Indigenous 11.8%
• Indian 6.7%
• Other 0.7%
• Non-citizens 8.2% (2010 est.)

East Malaysia indegenous languages: Iban and Kadazan most widely spoken

0-14 years: 27.83% (male 4,493,084/female 4,238,991)

Literacy (defined as age 15 and over can read and write):
total population: 94.6%
male: 96.2%
female: 93.2% (2015 est.)

School life expectancy (primary to tertiary education):
total: 13 years
male: 12 years
female: 13 years (2015)

Population below poverty line: 3.8% (2009 est.)
lowest 10%: 1.8%
highest 10%: 34.7%

Distribution of family income (Gini index):
49.2% (1997); 46.2% (2009)

The proverbial case where the richest 20% have 80% of all income (see Pareto principle) would lead to an income Gini coefficient of at least 60%.
An often cited case that 1% of all the world's population owns 50% of all wealth, means a wealth Gini coefficient of at least 49%. - Wikipedia

Electricity access:
population without electricity: 100,000
electrification (total population): 99.5%
electrification (urban areas): 99.8%
electrification (rural areas): 98.7% (2013)

Telephones (mobile cellular): 43,912,600

Internet users (total): 24,384,952
% of population: 78.8% (July 2016 est.) ... Internet penetration 78.8%

Airports: 114

Source:

CIA > World Factbook > Malaysia
https://www.cia.gov/library/publications/the-world-factbook/geos/my.html

Gini
https://en.wikipedia.org/wiki/Gini_coefficient

Malay Women
Khalidah Khalid Ali.  The Role of Malay Women in the Malaysian Workforce and its Impact on the Consciousness of Ethics and Integrity. Global Business and Management Research: An International Journal, Vol. 6, No. 4 (2014). https://www.gbmr.ioksp.com/pdf/vol.%206%20no.%204/v6n4-9.pdf

Tuberculous meningitis

KEYWORDS
Mycobacterium tuberculosis; antitubercular agents; case management; public health.


A. DISEASE BACKGROUND & PRESENTATION

===================

I. TUBERCULOSIS (TB)

====================

TB: Tuberculosis
BCG: Bacille Calmette-Guerrin
MDR-TB: Multidrug-resistant TB
XDR-TB: Extensively drug-resistant TB
DOT: Directly Observed Therapy

Tuberculosis (TB) is an ancient disease that is still present in many parts of the world today. It is endemic in 33 third world countries and absent in first world nations.

BCG, or bacille Calmette-Guerin, is a vaccine for tuberculosis. Many foreign-born persons have been BCG-vaccinated. BCG is used in many countries with a high prevalence of TB to prevent childhood tuberculous meningitis and miliary disease.

Malaysians must take the BCG vaccination when they first report for primary school at age 7 years. However, BCG does not provide full protection against TB. When BCG-vaccinated adults work in the hospital environment later on in life, some do acquire TB from their workplaces.

Some countries such the USA and Australia do not provide BCG vaccination as part of childhood immunization unless requested. Families who travel with unborns, newborns, babies, and young children from TB-rife countries travelling to first world nations may be safe at their destination. However, families with unborns, newborns, babies and young children from first world nations travelling to third world countries may possibly expose their family members to TB.

Today, we have an added health problem of TB coming from 3 populations - travellers and globe trotters, domestic helpers or maids, and foreign labourers. People ill with TB can infect up to 10-15 other people through close contact over the course of a year. TB is spread by airborne particles (which are moist droplets) via coughs, sneezing, speaking, singing, screaming and yelling. TB is spread through air and not by contact (touching) with the infected person.

Even though Malaysia has a good health monitoring system, TB seems to make a comeback. It was MDR-TB then, and now XDR-TB that we have to worry about now.

TYPES OF TB

There 2 types of TB, one of which is not easily detected because it is latent, and the other is obvious as it is active.

• Latent TB - the bacteria remain in the body in an inactive state. There are no symptoms visible. The carrier (person) seems normal. This type of TB is not contagious. However, the TB microorganism can become active, and thus become infectious.
• Active TB - the bacteria cause visible symptoms. This type of TB is infectious and can be transmitted to others.

SYMPTOMS OF TB

TB may be mild for many months before it progresses and cause more severe manifestations. Symptoms of TB include:

• Chills
• Fatigue
• Fever
• Loss of weight (LOW, weight loss)
• Loss of appetite (LOA)
• Night sweats

TB usually occurs in the lungs. TB of the lungs is called pulmonary TB (PTB). If TB is in the lungs (pulmonary), symptoms may include:

• Coughing for longer than 3 weeks
• Hemoptysis (coughing up blood)
• Chest pain

EXTRA-PULMONARY TB (EPTB)

Tuberculosis can involve virtually any organ or tissue in the body. TB can occur at sites outside the lungs, and thus is referred to as extra-pulmonary TB. These sites can be bones, brain, liver, kidneys, and heart.

• Bone - TB infecting the bones can lead to spinal pain and joint destruction
• Brain - TB infecting the brain can cause meningitis, which manifests as tonic clonic seizures
• Liver and kidneys - TB infecting the liver and kidneys can impair their waste filtration functions and lead to blood in the urine (refer Urine FEME)
• Heart - TB infecting the heart (tuberculous pericarditis) can impair the heart's ability to pump blood, resulting in a condition called cardiac tamponade that can be fatal (end-points are cardiac tamponade, mortality and constrictive pericarditis). 

CHEMOTHERAPY FOR EXTRAPULMONARY TB

Chemotherapy for extrapulmonary tuberculosis is initiated with INH, RIF, PZA, and EMB in an initial 2-month phase. After 2 months of 4-drug therapy, for extrapulmonary tuberculosis known or
presumed to be caused by susceptible strains, PZA and EMB may be discontinued, and INH and RIF continued during a continuation phase. Increasing evidence, including randomized controlled trials (RCTs), suggests that 6–9 month INH and RIF-containing regimens are effective for the majority of extrapulmonary sites of disease. The exception is tuberculous meningitis where the optimal duration of therapy has not been established through randomized controlled trials, but most experts and society
guidelines prescribe 12 months of treatment associated with prolonged wound discharge and scarring. Of note, the majority of lymphatic cases of mycobacterial disease in US children are caused by non tuberculous mycobacteria.

TREATMENT OF TB

Antituberculosis drugs are taken for 6 months, and there are associated risks. Non compliance (non adherence) with such a long-term antituberculosis course gives rise to MDR-TB. Follow DOT guidelines to ensure TB patients comply with taking the 6-month course of antituberculosis drugs.

The intensive phase of TB treatment consists of 4 drugs (INH, RIF, PZA, EMB):

• Ethambutol (EMB)
• Isoniazid (INH)
• Pyrazinamide (PZA)
• Rifampin (RIF)

First-line drugs

1. Isoniazid
2. Rifampin
3. Rifabutin
4. Rifapentine
5. Pyrazinamide
6. Ethambutol

Second-line drugs

1. Cycloserine
2. Ethionamide
3. Streptomycin
4. Amikacin/kanamycin
5. Capreomycin
6. Para-amino salicylic acid
7. Levofloxacin
8. Moxifloxacin

==========================

II. TUBERCULOUS MENINGITIS

==========================

BRAIN ANATOMY

The brain is protected by 3 layers of membrane, collectively known as meninges. The 3 membranes are the dura mater, arachnoid, and pia mater. They enclose the brain and spinal cord. Cerebrospinal fluid (CSF) fills the spaces between the membranes and cushions the brain.

MENINGITIS VS ENCEPHALITIS

Infection of the meninges by Mycobacterium tuberculosis can cause fever and seizures. Infected patients are immediately warded in the ICU and are closely monitored till they recover, if at all. Recovery is often a long process (1-2 years). Some patients may be able to recover fully, while others can only partially recover, and others die.

CHEMOTHERAPY FOR TUBERCULOUS MENINGITIS

Chemotherapy for tuberculous meningitis is initiated with INH, RIF, PZA, and EMB in an initial 2-month phase. After 2 months of 4-drug therapy, for meningitis known or presumed to be caused by susceptible strains, PZA and EMB may be discontinued, and INH and RIF continued for an additional 7–10 months, although the optimal duration of chemotherapy is not defined. Based on expert opinion, repeated lumbar punctures should be considered to monitor changes in cerebrospinal fluid cell count, glucose, and protein, especially early in the course of therapy.

In children with tuberculous meningitis, the American Academy of Pediatrics (AAP) lists an initial 4-drug regimen composed of INH, RIF, PZA, and ethionamide, if possible, or an aminoglycoside,
followed by 7–10 months of INH and RIF as the preferred regimen. There are no data from controlled trials to guide the selection of EMB vs an injectable or ethionamide as the fourth drug for tuberculosis meningitis. Most societies and experts recommend the use of either an injectable or EMB. For adults, based on expert opinion, our guideline committee prefers using EMB as the fourth drug in the regimen for tuberculous meningitis.

ADJUNCTIVE CORTICOSTEROID THERAPY

The role of adjunctive corticosteroid therapy in the treatment of tuberculous meningitis has been reported by numerous studies and an updated systematic review found a mortality benefit from the use of adjuvant corticosteroids. Therefore, we recommend adjunctive corticosteroid therapy with dexamethasone or prednisolone tapered over 6–8 weeks for patients with tuberculous meningitis.

===========

III. EPILEPSY

===========

A&E: Accident & Emergency Department

Synonyms:
 Seizure(s)
 Epileptic seizure(s)
 Fit(s)
 Electric ictus
 Malay terms - tarik; nyetok; guling; rasuk; gila babi

Epilepsy may develop as a result of a brain injury, tumour, stroke, prior infection or birth defect (genetic origin).

TB infecting the brain meninges and causing meningitis is common nowadays. Patients have a characteristic fall pattern and wriggle on the floor as if struck by a lightning bolt. Some have a slight saliva output while some have a foamy mouth. The seizure may last 5 minutes or longer - and for which it becomes a medical emergency, and the patient needs to be rushed to A&E at the nearest hospital.

WHAT IS EPILEPSY?
WHAT ARE THE SYMPTOMS?

Epilepsy is a group of neurological diseases characterized by recurrent seizures.

HOW DOES SEIZURE MANIFEST?

Depending on which part of the brain is affected, a seizure may manifest as follows:

Loss of awareness
Unusual behaviours
Unusual sensations
Uncontrollable movements
Loss of consciousness

TYPES OF SEIZURES and PART OF BRAIN AFFECTED

If the abnormal electrical surge happens within a limited area of the brain, it causes PARTIAL or FOCAL seizures.
If the entire brain is involved, GENERALIZED seizures will result.

Partial seizures subdivide further to:
- Simple partial
- Complex partial

Generalized seizures subdivide further to:
- Absence seizures
- Tonic seizures 
- Atonic seizures or drop attacks
- Clonic seizures
- Myoclonic seizures

MOST COMMON SEIZURE

The most common and also most dramatic are tonic-clonic seizures, also known as convulsive seizures, which are combinations of muscle stiffening and jerking. This type is what most people relate to when they think of a seizure. It also involves sudden loss of consciousness and sometimes loss of bladder control. A tonic-clonic seizure that lasts longer than 5 minutes requires immediate medical treatment.

GENERALIZED SEIZURES OF GENETIC ORIGIN

Generalized seizures that start in childhood are likely to involve genetic factors. Epilepsy due to a single gene mutation is rare. More often, an interaction of multiple genes and environmental factors is responsible. Hundreds genes have been implicated. Examples include genes encoding for GABA receptors – major components of the inhibitory circuit, and ion channels. Many genetic disorders that cause brain abnormalities or metabolic conditions have epilepsy as a primary symptom. The cause of epilepsy is unknown in about half of cases.

CAUSES OF EPILEPSY

Epilepsy may develop as a result of the following:

1. Brain injury (trauma or fall)
2. Tumour
3. Stroke
4. Previous infection 
5. Birth defect 

Babies with too much warm clothing on may suffer from seizures.
Seizures in children are caused by birth traumas, infections, congenital abnormalies, and high fevers.
Seizures in adults are caused by head injuries, infections, alcohol, stimulant drugs, side effects of medications.
Seizures in the elderly are caused by brain tumours and strokes.
Chemical causes of seizure are low blood sugar, low blood oxygen, low blood sodium, and low blood calcium.

PATHOPHYSIOLOGY OF SEIZURES

HOW DO SEIZURES HAPPEN?
WHY DO THEY HAPPEN?
PATHOPHYSIOLOGY (MECHANISM) OF EPILEPSY

NORMAL BRAIN ACTIVITY

The brain is a complex network of billions of neurons. Neurons can be excitatory or inhibitory. Excitatory neurons stimulate others to fire action potentials and transmit electrical messages, while inhibitory neurons SUPPRESS this process, preventing EXCESSIVE firing. A balance between excitation and inhibition is essential for normal brain functions.

BRAIN ACTIVITY IN EPILEPSY

Seizures happen as a result of a sudden surge in the brain’s electrical activities. In epilepsy, there is an UP-regulation of excitation and/or DOWN-regulation of inhibition, causing lots of neurons to fire SYNCHRONOUSLY at the same time.

DIAGNOSIS OF TYPE OF SEIZURE

Diagnosis is based on:

(i) Observation of symptoms
(ii) Medical history
(iii) An electroencephalogram (EEG) - to look for abnormal brain waves.
(iv) Genetic testing maybe helpful when genetic factors are suspected.

TREATMENT

There is no cure for epilepsy, but various treatments are available to control seizures.

TRADITIONAL CURE

The traditional cure used by the Malay community is freshly crushed onion. The patients lies down on a cooling pandanus mat. One big Bombay onion is coarsely pounded to yield coarsely ground juicy onion paste which is applied directly to the forehead and left to dry. A small wet towel maybe placed to avoid onion paste falling onto the eyes. The onion paste is removed when semi- or partially dry. A fresh onion paste can be re-applied if necessary, but normally one application is sufficient to cure seizure completely. This traditional method seems to work well in children whose eyeballs roll up and only the sclerae can be seen. It seems to work with children up to age 4 years, and does not recurr for 55+ years. No drugs are required when treated in this traditional manner.

TREATMENT OF EPILEPSY

The hospital provides 2 modes of treatment - dietary and drug therapies. Both are useful to control seizures. These will halt seizures and kill off M. tuberculosis.

(1) DRUG THERAPY

Medication successfully controls seizures for about 70% of cases. Many anti-epileptic drugs are available which target sodium channels, GABA receptors, and other components involved in neuronal transmission. Different medicines help with different types of seizures. Patients may need to try several drugs to find the most suitable regime for their cases.

Anticonvulsants: Phenytoin, lamotrigine

(2) DIET THERAPY

Dietary therapy: ketogenic diet has been shown to reduce or prevent seizures in many children whose seizures could not be controlled with medication. Ketogenic diet is a special high-fat, low-carbohydrate diet that must be prescribed and followed strictly. With this diet, the body uses fat as the major source of energy instead of carbohydrates. The reason why this helps control epilepsy is unclear.

Ketogenic diet reduces seizures.
Ketogenic diet is high-fat and low-carb.
When living on ketogenic diet, the body derives its energy from fat and not carbohydrates..
Ketone bodies are preferred substrates for brain energy; it utilizes ketone bodies more efficiently than glucose.
Ketone bodies are acidic as well as a cleansing agent that may cleanse the brain of unncessary firing.
The brain has a more calming effect when on ketogenic diet as occurs in strict fasting (eg Ramadan fasting).

(3) NERVE STIMULATION

Nerve stimulation therapies such as vagus nerve stimulation in which a device placed under the skin is programmed to stimulate the vagus nerve at a certain rate. The device acts as a pacemaker for the brain. The underlying mechanism is poorly understood but it has been shown to reduce seizures significantly.

(4) SURGERY

Finally, a surgery may be performed to remove part of the brain that causes seizure. This is usually done when tests show that seizures are originated from a small area that does not have any vital function.

====================
B. PATHOPHYSIOLOGY

• Coughing 3 weeks or longer, sometimes with mucus or blood - PTB
• Chills, fever & night sweats - bacterial infection
• LOW, LOA & fatigue - bacterial infection
• Tonic clonic seizures - meningitis

====================
C. DIFFERENTIAL DIAGNOSIS

Differential Diagnoses of TB:

1. Actinomycosis
2. Aspergillosis
3. Bronchiectasis
4. Constrictive Pericarditis
5. Fungal Pneumonia
6. Histoplasmosis
7. Lung Abscess
8. Nocardiosis
9. Non-Small Cell Lung Cancer
10. Pott Disease

Tuberculosis (TB) can masquerade as other infectious and disease processes, eg, congenital TB can mimic congenital syphilis or cytomegalovirus (CMV) infection.

Conditions with a presentation that may resemble pulmonary TB (PTB) (1-11) and can be included in the differential diagnosis of extrapulmonary TB include the following (1-22):

1. Blastomycosis
2. Tularemia
3. Actinomycosis
4. Mycobacterium avium-intracellulare infection
5. M chelonae infection
6. M fortuitum infection
7. M gordonae infection
8. M kansasii infection
9. M marinum infection
10. M xenopi infection
11. Squamous cell carcinoma
12. Hidradenitis suppurativa
13. Eosinophilic granuloma
14. Endemic syphilis
15. Erythema induratum (nodular vasculitis)
16. Erythema nodosum
17. Leishmaniasis
18. Leprosy
19. Cat scratch disease
20. Syphilis
21. Syringoma
22. Rheumatoid arthritis

Dermatologic differential diagnosis

Diagnosis of skin infection with M tuberculosis involves the following:

1. Differentiate primary-inoculation TB from ulceroglandular complexes and mycobacterioses
2. Differentiate TB verrucosa cutis from diseases such as North American blastomycosis, chromoblastomycosis, iododerma and bromoderma, chronic vegetative pyoderma, verruca vulgaris, verrucous carcinoma, verrucous atypical mycobacterial infection, and verrucous lupus vulgaris
3. Differentiate miliary TB of the skin (which appears as small, noncharacteristic, erythematous, papular or purpuric lesions) from drug reactions
4. Differentiate scrofuloderma from suppurative lymphadenitis with sinus-tract formation, such as blastomycosis or coccidioidomycosis
5. Differentiate TB cutis orificialis from glossitis, apotheosis, and deep fungal infections
6. Differentiate lupus vulgaris from lupoid rosacea, deep fungal or atypical mycobacterial infection, chronic granulomatous disease, granulomatous rosacea, and Wegener granulomatosis
7. Differentiate erythema induratum from nodular panniculitides (eg, Weber-Christian disease) and nodular vasculitides (eg, syphilitic gumma, nodular pernio)
8. Differentiate papulonecrotic tuberculid from other papulonecrotic entities, such as leukocytoclastic vasculitis, lymphomatoid papulosis, papular eczema, and prurigo simplex with neurotic excoriation
9. Differentiate lichen scrofulosorum from keratosis spinulosa, lichenoid sarcoid, and lichenoid secondary syphilis

=================
D. INVESTIGATIONS

TB is diagnosed by skin tests, blood tests, x-rays, and other tests.

1. Radiology - Chest radiograph; Brain and spine imaging - Imaging techniques: X-ray, CT-scan, MRI. Monitoring brain activity pattern: EEG. An EEG may also help in differentiating between partial and generalized seizures. EEG and MRI/CT-scan are tools to monitor the brain in unconscious patients.
2. Chemical Pathology - CSF Biochemistry - CSF protein (increased due to active infection), CSF glucose (reduced due to active infection); Renal function tests (RFT)
3. Microbiology - Tuberculin skin test; sputum test; Gram stain (Gram-); Ziehl-Neelsen stain for AFB; C&S - susceptibility and dose; Molecular techniques - DOT immunobinding assay for TB Ab
4. Hematology - Coagulation profile
5. Pathology - Autopsy: if brain death occurs
6. Genome - Genetic studies: Causes of lowered immunity - HIV/AIDS, coinfection (PCR)
7. Community Medicine - social and community studies; carrier status of family members
8. Ophthalmology - Visual acuity and red-green color perception testing

(1) RADIOLOGY

Imaging techniques are X-ray, CT-scan, and MRI.

1. Chest radiograph
2. Brain and spine imaging  

(2) MEDICINE, ANAESTHESIOLOGY & ANATOMY

SPINAL TAP

A spinal tap is performed to obtain CSF. The spinal tap is of 3 types, each puncture giving different characteristics for the CSF harvested. Lumbar puncture is the usual one performed to obtain CSF. There are risks associated with spinal tap.

1. Lumbar puncture
2. Cisternal puncture
3. Ventricular puncture

At HUSM, the CSF is collected into a sterile 20-ml vial with a yellow screw cap and sent for CSF Biochemistry.

(3) CHEMICAL PATHOLOGY

In the Chemical Pathology laboratory, a CSF specimen may show up as often as once every 2 days (ie about 10 CSF specimens per month). These samples can come from both pediatric as well as adults patients.

CSF and serum are analysed for various analytes. For CSF Biochemistry, there are 2 major analytes that are measured - ie CSF protein and CSF glucose. These tests are done on an automated chemistry analyser. CSF protein is elevated in tuberculous meningitis while CSF glucose is reduced.

Serum samples are obtained from blood specimens and are analysed for Renal Function Tests (RFT) and Liver Function Tests (LFT). All these chemistries are categorised as STAT and their analyses are performed ASAP. They are performed on automated chemistry analysers and the turnaround time (TAT) for these tests are less than an hour.

Patients with TB who are receiving pyrazinamide (PZA) should undergo baseline and periodic serum uric acid assessments.

1. CSF >> For CSF Biochemistry >> CSF protein & CSF glucose. Other analytes are included as required.
2. BLOOD >> SERUM >> Renal Function Tests (RFT) are performed to detect kidney involvement if any. RFT includes Sodium, Potassium, Chloride, and Creatinine.
3. BLOOD >> SERUM >> Liver Function Tests (LFT). LFT is performed to detect liver involvement, if any. LFT includes AST, ALT, Bilirubin, and ALP. Other causes of abnormal LFT should be excluded, if any (see HIV).*
4. BLOOD >> SERUM >> Uric acid.

(4) MICROBIOLOGY

PPD: purified protein derivative
IGRA: interferon-gamma release assay
DNA: deoxyribonucleic acid
rRNA: ribosomal RNA
PCR: polymerase chain reaction
PCR-RFLP: polymerase chain reaction-restriction fragment length polymorphism
NAAT: Nucleic Acid Amplification Tests
MODS: Microscopic-observation drug susceptibility (MODS) assay
TLA: thin-layer agar (TLA) assay

For Microbiology tests, CSF, sputum and bacterial isolates are tested when available. Sputum is the main specimen for PTB. Sputum is used for Culture and TB Drug Susceptibility Testing. However, in extra-PTB, and when there is no sputum, and other means of testing are tried.

Since conventional Microbiology techniques are time-consuming (3 weeks to 1 month), more recent/newer test methodologies are constantly being developed. These deploy molecular techniques (eg PCR, PCR-RFLP) and use either DNA or rRNA of the mycobacterium as samples. Some of these new/recent tests which have been developed are NAAT, MODS and TLA assays. These assays are less time-consuming and turnaround time (TAT) for results are shorter (about 2 weeks).

For CSF Microbiology, detection of the mycobacterium is done by the Microbiology lab and involves the following tests:

1. Skin on left forearm >> Mantoux tuberculin skin test using PPD. For detecting latent TB and previous exposure to TB or BCG. Noticeable bump (induration) larger than 5 mm/10 mm/ 15 mm diameter are positive Mantoux. The diameter is marked with a ballpoint pen as 2 black dots and the distance between the 2 dots is measured in mm.

An itchy red bump measuring 15mm indicates a positive Mantoux test.
The ballpoint pen outline is the size of a 50 sen coin.

1. Blood >> Serum >> An in vitro blood test based on IGRA with antigens specific for M tuberculosis can also be used to screen for latent TB infection and offers certain advantages over tuberculin skin testing. 
2. Sputum >> Mycobacterial culture and sensitivity (C&S) is done to plate out and isolate M. tuberculosis. MTB is isolated and identified. Its susceptibility to INH, RIF, PZA, EMB is determined.
3. Sputum >> An automated molecular test that uses sputum samples for the detection of M tuberculosis and resistance to rifampin has been developed.
4. Sputum >> Gram stain: Gram negative (Gram- pink rods)
5. Sputum >> Culture for acid-fast bacilli (AFB) and smear microscopy. M. tuberculosis is spread on a microscope slide and stained with Ziehl-Neelsen stain. M. tuberculosis are Gram- rods which appear as bright pink bullets under the microscope.
6. Sputum >> TB Drug susceptibility testing.  DNA sequencing analysis (PCR-RFLP) is a rapid and useful method for detecting drug-resistant TB.
7. Bacterial isolate >> Nucleic Acid Amplification Tests (NAAT): DNA probes specific for mycobacterial rRNA identify species of clinically significant isolates after recovery. In tissue, PCR amplification techniques can be used to detect M tuberculosis-specific DNA sequences and thus, small numbers of mycobacteria in clinical specimens.
8. Sputum >> TB Drug susceptibility testing >> Microscopic-observation drug susceptibility (MODS) and thin-layer agar (TLA) assays are inexpensive, rapid alternatives to conventional and molecular methods of TB drug susceptibility testing.
9. Blood >> Serum >> Hepatitis B and C screen

*Culture-Negative Pulmonary Tuberculosis in Adults
Failure to isolate M. tuberculosis from appropriately collected sputum specimens in persons who, because of clinical or radiographic findings, are suspected of having pulmonary tuberculosis (PTB) does not exclude a diagnosis of active tuberculosis. Some causes of failure to isolate organisms include low bacillary populations, inadequate sputum specimens, temporal variations in the number of expelled bacilli, overgrowth of cultures with other microorganisms, and errors in specimen processing


(5) IMMUNOLOGY

IRIS: immune reconstitution inflammatory syndrome
ART: antiretroviral therapy

HIV serology testing

*HIV/AIDS

1. Patients with HIV infection and tuberculosis are at increased risk of developing paradoxical worsening of symptoms, signs, or clinical manifestations of tuberculosis after beginning antituberculosis and antiretroviral treatments. 
2. These reactions presumably develop as a consequence of reconstitution of immune responsiveness brought about by ART, and are designated as the immune reconstitution inflammatory syndrome (IRIS). 
3. Tuberculosis IRIS has been noted to be more common in participants with earlier ART initiation and CD4+ cell counts less than 50 cells per microlitre.
4. Signs of IRIS may include high fevers, worsening respiratory symptoms, increase in size and inflammation of involved lymph nodes, new lymphadenopathy, expanding central nervous system lesions, worsening of pulmonary parenchymal infiltrations, new or increasing pleural effusions, and development of intra-abdominal or retroperitoneal abscesses .

(6) HEMATOLOGY

Anticoagulants: Warfarin

Monitoring blood coagulation is necessary.

1. Prothrombin time (PTT) 
2. Platelet count
3. Complete blood cell (CBC) count

*(7) PATHOLOGY & PHARMACOLOGY

1. Viral hepatitis (hepatitis A, B, and C in all patients; Epstein-Barr virus, cytomegalovirus, and herpes simplex in immunosuppressed patients)
2. Biliary tract disease
3. Other hepatotoxic drugs (eg, acetaminophen, acetaminophen-containing multiagent preparations, lipid-lowering agents, other drugs)
4. Select herbal and dietary supplements

(8) SOCIAL/COMMUNITY MEDICINE and PSYCHOLOGY

1. Weight
2. Vision assessment 
3. Diabetes screen
4. Alcohol
5. HIV/AIDS

Psychotropic drugs

1. Nortriptyline
2. Haloperidol, quetiapine
3. Benzodiazepines (eg diazepam, triazolam), zolpiderm, buspirone

(9) OPHTHALMOLOGY

Patients with TB who are receiving long-term ethambutol (EMB) therapy should undergo baseline and periodic visual acuity and red-green color perception testing. The latter can be performed with a standard test, such as the Ishihara test for color blindness.

========
E. DIAGNOSIS

A positive TB skin test or TB blood test only tells that a person has been infected with TB bacteria. It does not tell whether the person has latent TB infection (LTBI) or has progressed to TB disease. Other tests, such as a chest x-ray (CXR) and a sample of sputum, are needed to see whether the person has TB disease.

Tuberculous meningitis  (TBM)

==========
F. TREATMENT AND MANAGEMENT

Refer to sections above on Treatment for TB and Treatment for Seizures.

1. Isolation of TB patients (wards and ICU) are necessary to avoid further transmission
2. In patients with tuberculous meningitis, dexamethasone added to routine 4-drug therapy reduces complications.
3. DOT is necessary to ensure patients take their medications for 6 or 9 months
4. Monitoring the desired and adverse effects of the drugs is necessary

Monitoring

Patients diagnosed with active TB should undergo sputum analysis for Mycobacterium tuberculosis weekly until sputum conversion is documented. Monitoring for toxicity includes baseline and periodic liver enzymes (AST, ALT, ALP), complete blood cell (CBC) count, and serum creatinine.

========
G. MERCI

Medical (M)
An epileptic patient needs help when unconscioous or sub-conscious or when falling.
Falling and hitting the head may cause further injury to the H&N region.

Empathy (E)
An epileptic patient needs comforting, help and care during a seizure and post-seizure.

Rights and Respect (R)
Epileptic patients have the same rights and must be respected just like you and me.

Communication (C)
Talking to the patient pre- and post-seizure must be gentle and soothing so as not to create depression (blues) and more harm.
There are instances when epileptic patient must not drive. Seeing to patient compliance is very important.

Insight (I)
Timing and recording the characteristics of each seizure are important.
The duration between seizures is important to know.
Keeping a close watch on epileptic patient is important.
Seeing to that epileptic patient takes his/her medicine is important.

-------------

External links:

TB
https://www.medicalnewstoday.com/articles/8856.php
https://medlineplus.gov/tuberculosis.html

Epilepsy
https://youtu.be/L0XqL2I35n8

Epilepsy (animation)
https://youtu.be/e_Eb32Eq_fw

Causes of epilepsy
https://youtu.be/6NcqQkKjqTI

Epiletic seizure
https://youtu.be/MRZY2a2jnuw

Tonic-clonic (grand mal) seizure
https://youtu.be/c6vKvKuhHXI

Tonic-clonic seizure
https://youtu.be/FBEj9H42fa4

Pharmacology of Epilepsy
https://youtu.be/GMyCWup1Xqo

Antiepileptics
https://youtu.be/c-Cf1xkKofg

TB Workup
http://emedicine.medscape.com/

TB Differential Diagnosis
http://emedicine.medscape.com/article/230802-differential

TB Diagnosis
https://www.cdc.gov/tb/publications/factsheets/testing/diagnosis.htm

CSF Analysis
http://emedicine.medscape.com/article/2093316-overview

CSF Meningitis
http://www.globalrph.com/cerebrospinal_fluid.htm

NAAT
http://emedicine.medscape.com/

Drug susceptibility testing
http://emedicine.medscape.com/

BCG
https://www.cdc.gov/tb/publications/factsheets/prevention/BCG.htm

AFB
https://labtestsonline.org/understanding/analytes/afb-culture/tab/test
http://emedicine.medscape.com/

Neuropathology
http://neuropathology-web.org/chapter14/chapter14CSF.html

CXR
https://www.nhlbi.nih.gov/health/health-topics/topics/cxray
http://emedicine.medscape.com/

TB Treatment
http://emedicine.medscape.com/article/230802-treatment

TB Drugs
http://emedicine.medscape.com/article/230802-medication

MERCI
https://www.healthline.com/health/csf-total-protein#overview1

DOT
http://www.health.state.mn.us/divs/idepc/diseases/tb/lph/dot.html

TB Elimination
https://www.cdc.gov/tb/publications/factsheets/testing/diagnosis.pdf