Glioblastoma or Glioblastoma Multiforme (GBM)

Glioblastoma is most malignant and most frequent primary brain tumor. Glioblastoma Multiforme ( GBM) is also called WHO grade IV astrocytoma and it is the most malignant of the astrocytomas.
Incidence
 It accounts for 12-15% of all intracranial neoplasms and 60-75% of all astrocytic tumors.
Age 
It may manifest at any age, but preferentially affects adults, with a peak incidence at between 45 and 75 years of age. About 1% of patients are younger than 20 years old. primary GBM is more common in older adults between 60-75 years.
Secondary GBMs which constitute about 5% of all GBMs , usually occur about a decade or two decade earlier.
 Location
Cerebral hemispheres are the most common site in adults. Glioblastoma occurs most often in the subcortical white matter and deep periventricular white matter of the cerebral hemispheres. Most affectected sites are temporal, parietal frontal and occipital lobes. Combined fronto-temporal location is particularly typical.
Tumor infiltration often extends into the adjacent cortex and through the corpus callosum into the contralateral cerebral hemisphere. Glioblastoma is notorious for its rapid invasion of neighbouring brain structures. A very common feature is extension of the tumor through the corpus callosum into the contralateral hemisphere, creating the image of a bilateral, symmentrical lesion ( Butterfly glioma).
Glioblastoma of the basal ganglia and thalamus is not uncommon, especially in children. Glioblastoma of the brain stem( malignant brain stem glioma)is infrequent and often affects children.
20% of GBM are multifocal and of which 2-5% are synchronous.
Types of Glioblastoma and clinical features
Two forms of GBM are currently recognized: Primary ("de novo") GBM and secondary glioblastoma. Primary glioblastoma constitute majority, about more than 90%, , which arise de novo.
Secondary glioblastoma arise from a previously pre-existing lower grade glioma. While the two types share similar histology, they differ genetically. Neurofibromatosis type 1 ( NF1), Li Fraumeni and Turcot syndrome demonstrate an enhanced propensity to develop GBM.
The clinical history of the disease is usually short ( less than 3 months in more than 50% of cases). Unless the neoplasm has developed from a lower grade astrocytoma ( secondary glioblastoma).
Symptoms and signs of raised intracranial pressure ( headache, vomiting, papilledema) are common. Seizures , focal neurological deficits  are common. Sometimes patients may present with sudden stroke like features due to acute intratumoral hemorrhage ( in about 2% patients).
Histopathology
Glioblastoma on gross appearance look like Reddish-gray " rind of tumor, with necrotic core with marked peritumoral edema. It shows increased vascularity, and intra-tumoral hemorrhage.
The histopathological features include nuclear atypia, cellular pleomorphism, mitotic activity, vascular thrombosis, microvascular proliferation, and necrosis.
As the term glioblastoma " multiforme " suggests , the histopathology is extremely variable.  The varied tumor cells include: pleomorphic fibrillary astrocytes, gemistocytes, bipolar bland appearing but mitotically active small cells ( including " microglia")and large bizzare multinucleated giant cells. While some lesions show a high degree of cellular and nuclear polymorphism with numerous multinucleated giant cells, others are highly cellular, but rather monotonous.
GBMs generally have a high proliferation index (MIB-1), usually exceeding 10%.
Immunohistochemistry shows GFAP and olig 2 positivity. IDH-1 is very helpful in distingushing secondary GBM (positive) from primary GBM ( negative).
Radiology of Glioblastoma
At least 90 -95% of GBM demonstrate a thick, irregular, enhancing "rind" of tumor surrounding a necrotic core.
CT scan of brain: Most GBMs demonstrate a hypodense central mass surrounded by an iso-to moderately hyperdense rim on non-enhanced CT scan. Hemorrhage is common but calcification are rare. marked mass effect and significant hypodense peritumoral edema are typical ancillary findings.
Contrast Enhanced Computerized Tomography (CECT) of Brain reveals strong but heterogenous irregular rim enhancement. In highly vascular GBMs prominant vessels are seen as linear enhancing foci adjacent to the mass.
MRI of Brain: T1W1 image shows poorly marginated mass with mixed signal intensity . Subacute hemorrhage is common. T2/FLAIR image shows heterogenous intensity with extensive vasogenic edema. Necrosis, cysts, hemorrhage at various stages of evolution are seen. Fluid-debris level is seen in some cases.
Contrast Enhanced magnetic Resonance Imaging ( CE MRI) of brain shows strong but irregular contrast enhancement with central non-enhancing core.
DWI MR : most GBMs do not restrict on diffusion weighted imaging.
DTI may show increased fractional anisotropy and disrupted white matter tracts from tumor invasion.
MR spectroscopy (MRS) may show elevated choline peak and decreased NAA.
On imaging the differential diagnosis of GBM is usually Metastasis and Abscess. Metastasis is usually multiple and occur at gray-white matter junction and non-infiltrating. Intracranial abscess is usually thinner with more regular rim which usually restrict on DWI.

Treatment of Glioblastoma
Neurosurgery and Radiation Oncology intervention: Craniotomy and tumor decpmpression. The cytoreductive surgery followed by chemo and radiotherapy.

Sources:
1. WHO classification of Tumours of the central nervous system Edited by David N.Louis, Hiroko Ohgaki, Otmar D. Wiestler , Webster K.Cavene
2. Handbook of Neurosurgery by Mark S. Greenberg

Decompressive Craniectomy(DC), Decompressive Hemicraniectomy, Cranioplasty and Duraplasty

Decompressive craniectomy and decompressive hemicraniectomy are the similar termnologies which are used interchangeably to describe a wide frontotemporoparietal craniotomy on one side of the cranium to reduce the intranial pressure.
This procedure is commonly done in cases of traumatic brain injury and middle cerebral artery ( MCA) infarcts. About 10-15% patients with MCA infarct suffer from progressive clinical detrioration due to increased brain swelling, raised intracranial pressure (ICP) and subsequent herniation. Such space cupying infarct is commonly referred to as malignant MCA infarct. Edema associated with these infarcts is usually observed between the second and fifth day after the index event. Malignant MCA infarct is associated with poor prognosis.Its fatality rate is about 80% and most survivors are left with severe diability. Medical management of malignant MCA infarction is generally ineffective and requires a surgical intervention in the form of decompressive craniectomy for its relief. Surgical decompression reduces the risk of death or disability. An observation study conducted at AIIMS, Delhi had reported that patients who were operated within 48 hours from onset of smptoms and who were less than 60 years old showed better clinical improvement following decompressive craniectomy.
All patients with life threatening malignant MCA infarction indicated to undergo (DH) on the basis of clinical assessment basedon National Institute of Health Stroke Scale [ NIHSS], Glasgow oma scale (GCS) and neuroimaging.

Criteria for Surgery in cases of malignant MCA infarct are:
                        *NIHSS score more than 16
                         * GCS score less than 13
                         * Decrease in level of consciousness
                          * Clinical signs of herniation
                          *Presence of radiological evidence

A large Fronto temoporo pariental free bone craniotomy of about 12 centimeter to 15 centimeter is elevated with lax duraplasty. The free bone is placed in the subcutaneous fat pocket in the right iliac region of lower abdomen inferolateral to the umbilicus. When patient improves the cranioplasty is done with the same preserved bone.
DH in large MCA stroke patients leads to markedly improved survival and better functional outcome ( motor and language) and recovery in motor and ahasia recovery is progressive and sustained after 1 year.[1]
Decompressive craniectomy was originally decribed by Cushing. It is used in cases of refractomy intracranial hypertension where convenional therapies have failed. The technique involves removal of a large bone flap and opening the dura. The dura may be left open as it is or a graft may be used to enlarge the volume of the dural compartment. Once the period of intracranial hyertension has settled and patinet has improved, cranioplasty is done with the preserved free boen cranial flap. Study conducted at AIIMS by Sinha et al has reported that DC can ameliorate the secondary damage due raied ICP in cases of traumatic brain injury (TBI).

References
1. Long term outcome of decompressive hemicraniectomyin patients with malignat MCA infarcts: A prospective observational study. VK Rai et al , AIIMS, Delhi in Neurology India, 2014
2. Decompressive craniectomy in traumatic brain injury : a single center, multivariate analysis of 1,236 patients at a tertiary care hospital in India. Sumit Sinha et al, Neurology India
3. Ramamurthy and Tandons' Manual of Neurosurgery

Non-contrast CT scan of head of the patient after 6 months of Middle cerebral infarction showing a large area of the infarct with large craniectomy defect. Now patients' CT scan does not suggest any midline shift so patient may undergo cranioplasty.

Craniotomy bone flap is preseved in the subcutaneous fat in the right iliac fossa region in abdomen.

           

ANTIBIOTICS

Antibiotics are the medicines which are used to treat infections. Infections may be due to bacteria, fungi or virsuses. Almost everyone suffers from infection someimes in his life time.

Being infected is a bad feeling and everybody dislikes it. Sometimes, these infections are so dreaded that it is better to get immunity against such bad infections. So, vaccines are used to present such bad infections, Commonly used vaccines are BCG ( to prevent Tuberculosis), DPT ( to prevent Diphtheria, Pertusis and Tetanus), Anti Hepatitis B Surface antigen Vaccine ( to prevent infection against hepatitis B), Polio vaccine, etc.

But, all infections are not so dangerous, like common cold, sore throat, and small furuncle or small reddish pimple. Such infections usually subside by themselves due to the immunity of our own body. This immunity is mainly provided by white blood cells (WBCs) and lymphocytes present in our body. These act like Policemen patrolling our internal security. These security personnel detect and kill the foreign microbials or microorgaisms like bacteria.

Sometimes, infecions may overwhelming and required to be treated with antibiotics. Like common cold not subsiding and persisting for longer duration with superadded bacterial infection or sinusitis. Or, sore throat associated with yellowish sputum with cough and fever. So, we need to take antibiotics to treat such infections.

Infections may be superficial or deep, local or systemic. The infection depends upon virulence or the microorganism, resistance of the person, and living conditions. Like persons with diabetes with uncontrolled blood sugar level and patients on long term steroids have low resistance or immunity against the infecive microrgansms. Person living in crowded places with other people infected with communicable diseases are prone to acquire infections of the airborne diseases like tuberculosis, influenza, etc.

Skin infections are commonly caused by Staphylococcus aureus and Streptococcus. Invention  of Penicillins in 1928 by Scottish researcher, Alexander Flemming, made a great difference to the outcome of patients with infecions.

Sir Alexander Fleming

Sir Alexander Fleming was a Scottish physician, microbiologist, and pharmacologist. His best-known discoveries are the enzyme lysozyme in 1923 and the world's first antibiotic substance benzylpenicillin from the mould Penicillium notatum in 1928. The simple discovery and use of the antibiotic agent has saved millions of lives, and earned Fleming – together with Howard Florey and Ernst Chain, who devised methods for the large-scale isolation and production of penicillin – the 1945 Nobel Prize in Physiology/Medicine.

Penicillin was effective against fatal infections caused by bacteria. But, over time, these bacteria outsmarted the drug and developed resistance to these drugs. But, consistent efforts by the physicians, microbiologists, pharmacologists, biotechnologists and other inventors led to the development of many anti-microbial drugs which are commonly known as antibiotics.

So, commonly uses antibiotics are penicillins, cephalosporins, tetracyclines, macrolides, quinolones, anti-viral drugs, anti-fungal drugs, etc.

Common bacteria are described as Gram positive or Gram- negative. Gram positive bacteria are stained positively by Gram stain. 

Some bacteria produce exotoxins and some produce endotoxins. 

Tbe bacteria which produce exotoxins are Cornyebacterium diphtheriae, Clostridium tetani, C.botulinum, C.perfringens, Bacillus anthracis, Staphylococcus aureus, Streptococcus pogens ( all are examples of Gram positive bacteria).

Gram negative bugs which produce exotoxins are E.coli, Vibrio cholerae, and Bordetella pertusis. 

Endotoxin is a polysaccharide and is found in the cell wall of Gram-negative bacteria. 

Some bacteria do not stain well with Gram-stain, like Treponema, Rickettsia, Mycoplasma, Legionella pneuophila, Mycobacteria and Chlamydia.

For treponemes-darkfield microscopy and fluorescent antibody staining is used. 

Mycobacteria are acid-fast bacilli. Legionella is stained with silver stain.

Gram positive bacteria are broadly classified in 2 groups; Cocci and Bacilli.

Gram positive cocci are classified into two; catalase positive clusters ( Staphylococcus) and catalase negative chains ( Streptococcus). 

Catalase postive staphylococci are further classified into two groups as Coagulase positive ( S.aureus) and coagulase negative [ Staphylococcus epidermidis ( Novobiocin sensitive) and Staphylococcus saprophyticus ( Novobiocin resistant ].

Gram postive and catalase negative chains of cocci are Strptococcus. On the basis of hemolysis Streptococci are divided into 3 categories: Green ( partial ) hemolysis; Sterptococcus pneumoniae, Clear hemolysis Streptococcus pyogens ( group A Bacitracin sensitive), S.agalactiae ( group B, Bacitracin resistant) and 3rd category of streptococci with no hemolysis examples are Enterococcus ( E.fecalis) and Peptostreptococcus( anaerobe).

Exapmple of Gram positive bacilli ( rods) are: Clostridium ( anaerobe), Cornyebacterium, Listeria and Bacillus.

Gram negative bacteria which appear pink are broadly classified into three groups : Cocci, C0ccoid rods and rods. 

Gram negative cocci are Neisseria mningitidis and N.gonorrhoeae. These two are differentiated on the basis of Maltose fermenter chacteristic. N. menigitidis is Malose fermenter and N. gonorrhoeae is Maltose noferenter.

The examples of cgram negative coccoid rods are Hemophlus influenzae, Pasteurella, Brucella and Bordetella pertusis.

Gram negative rods are further subdivided into two subtypes based Lactose fermenter characteristic. Lactose fermenter gram negative rods are Klebsiella, E,coli and Enterobacter which are Fast fermenter and Citrobacter, and Serratia Slow fermenters.

Lactose nonfermenter gram negative rods are subdivided into two groups, based on oxidase property. Oxidase positive are Pseudomonas and oxidase negative are Shigella, Salmonella and Proteus.

Penicillin C is for intravenous use and Penicillin V is for oral use. 

Penicillin binds penicillin-binding proreins , blocks transpeptidase cross-linking of cell wall and activates autolytic enzymes. It is bactericidal for gram positive cocci and rods, gram negative cocci and spirochetes.

Methicillin, nafcillin have narrow spectrum and used against penicillase resistant Staphyloccus aureus.

Ampicillin, Amoxicillin have wider spectrum, penicillanse sensitive, also combined with clavulanic acid ( penicillanase inhibitor) to enhance spectrum. Amoxicillin has greater oral bioavailability than ampicillin. These two extended-spectrum penicillin and are useful against certain gram positive bacteria and gram negative rods ( Hemophilus influenzae, E.coli, Listeria monocytogens, Proteus mirabilis, Salmonella and enterococci). 

Carbenicillin, Piperacillin and Ticarcillin are extended spectrum penicillin and useful against Pseudomonas  and gram negative rods , susceptible to penicillanase, used with clavulanic acid.

Cephalosporins are beta lactam drugs. It inhibits cell wall synthesis 

Imipenem

      Imipenem is a broad spectrum, beta lactamase-resistant carbapenem. It is always administered with cilastatin which is inhibitor of renal dihydropeptidase 1 to decrease inactivation in renal tubules. Ii is used against gram positive cocci, gram negative rods and anaerobes. It is drug of hoice against Enterobacter. Its toxicity includes GI distress, skin rash, and CNS oxicity ( seizures).

Vancomycin

Aminoglycosides

Tetracyclines 

Macrolides

Chloramphenicol

Clindamycin

Sulfonamides

Trimethoprim

Fluroquinolones

Metronidazole

References: 

Wikpedia

Alexander Fleming (1881–1955): Discoverer of penicillin, Siang Yong Tan, Yvonne Tatsumura

Singapore Med J. 2015 Jul; 56(7): 366–367. doi: 10.11622/smedj.2015105