Leukemia (Blood Cancer)

 

With meningitis, mening- refers to the meninges which are three protective membranes that cover the brain and spinal cord, and -itis refers to inflammation, so meningitis is an inflammation of the meninges. More specifically, it refers to the inflammation of the two inner layers which are called the leptomeninges. The outer layer of the meninges is the dura mater, the middle layer is the arachnoid mater, and the inner layer is the pia mater. These last two, the arachnoid and pia maters, are the leptomeninges. Between the leptomeninges, there’s the subarachnoid space, which houses cerebrospinal fluid, or CSF.

CSF is a clear, watery liquid that is pumped around the spinal cord and brain, cushioning them from impact and bathing them in nutrients. In one microliter or cubic millimeter, there are normally a few white blood cells, up to 5. If we look at a bigger sample, like say a decilitre, then around 70% of those will be lymphocytes, 30% monocytes, and just a few polymorphonuclear cells -- PMNs -- like neutrophils. That same volume will contain some proteins, as well, about 15-50mg as well as some glucose, about 45-100mg, which is close to 2/3 of the glucose we’d find in the same volume of blood. The CSF is held under a little bit of pressure, below 200mm of H2O, which is just less than 15mm of mercury -- which is less than a fifth of the mean arterial pressure. Now at any given moment, there’s about 150ml of CSF in the body. This is constantly replenished, with around 500ml of new CSF produced every day, and the excess, or 500minus 150mL or 350mL is absorbed into the blood. But for any nutrients to enter and leave the CSF, and the brain itself for the matter, they have to go through the tightly regulated blood-brain barrier.

The blood-brain barrier is the special name given to the blood vessels in the brain. That’s because the endothelial cells in the blood vessels are so tightly bound to one another that they prevent leakage and only allow certain molecules to slip through them. Meningitis is the inflammations of the leptomeninges, which remember are the inner two membranes around the brain and spinal cord. It is not the inflammation of the brain itself, that’s encephalitis, but sometimes they can occur together and when that happens it’s called meningoencephalitis. So meningitis needs some kind of trigger for the inflammation and could be an autoimmune disease, where the body attacks itself, like lupus, or the body has an adverse reaction to some medication, which can happen with intra-thecal therapy when medication is injected directly into the CSF. But, by far, infection is the most common trigger for meningitis across all age groups, like with the Neisseria meningitides bacteria or herpes simplex virus for example.

Now there are two routes that infection takes to reach the CSF and lepto-meninges. The first way is direct spread, which is when a pathogen gets inside the skull or spinal column, and then penetrates the meninges, eventually ending up in the CSF. Sometimes the pathogen will have come through the overlying skin or up through the nose, but it’s more likely that there’s an anatomical defect to blame. For example, it could be a congenital defect like spina bifida, or an acquired one like a skull fracture, where there might be CSF leaking through the sinuses. The second way is hematogenous spread, which is when a pathogen enters the bloodstream and moves through the endothelial cells in the blood vessels making up the blood-brain barrier, and gets into the CSF. To do this, the pathogens typically have to bind to surface receptors on the endothelial cells in order to get across. Otherwise, they have to find areas of damage or more vulnerable spots like the choroid plexus. Once the pathogen finds a way into the CSF it can start multiplying. Soon enough, the handful of white blood cells surveilling the CSF identify the pathogen and release cytokines to recruit additional immune cells.

Over time, a microliter of CSF might go on to contain up to thousands of white blood cells, but any more than five usually defines meningitis. In most bacterial cases, there’ll be above 100 white blood cells per microliter, and more than 90% PMNs. In most viral cases, there’ll be 10 to 1000 white blood cells; over 50% lymphocytes, and fewer than 20% PMNs. In most fungal cases, there’ll be 10-500 white blood cells, with over 50% lymphocytes. In most cases of tuberculous meningitis, there’ll be 50-500 white blood cells with over 80% being lymphocytes. The additional immune cells attract more fluid to the area and start causing local destruction as they try to control the infection. As a result the CSF pressure typically rises above 200mm of H2O. The immune reaction also causes the glucose concentration in the CSF to fall; below 2/3^rd of the concentration in the blood, and makes the protein levels increase to over 50mg/dL. When it comes to the causes of meningitis, viruses and bacteria usually cause acute meningitis, whereas fungi usually cause chronic meningitis.

Now for bacteria, there are a lot of possibilities. In newborns, the most common causes are Group B streptococci, E Coli, and Listeria monocytogenes. In children and teens, the most common causes are Neisseria meningitidis and Streptococcus pneumoniae. In adults and the elderly, the most common causes are Streptococcus pneumoniae and Listeria monocytogenes. There are also tick-borne causes of meningitis like Borrelia burgdorferi bacteria - which is the cause of Lyme disease. As for viruses, the main culprits are enteroviruses, especially the coxsackie virus, and herpes simplex virus. HIV is usually contracted through body fluids and can also cause viral meningitis. Less common causes include mumps virus, varicella zoster virus, and lymphocytic choriomeningitis virus.

There are also fungi, like those from the Cryptococcus and Coccidioides genera, which mainly affect immune-compromised individuals. And then of course there’s tubercular meningitis is caused by the Mycobacterium tuberculosis bacteria, and finally parasitic causes of meningitis like P. falciparum which is the main cause of malaria. Now, the classic triad of meningitis symptoms as headaches, fevers, nuchal rigidity, or neck stiffness. It can also cause photophobia which is discomfort with bright lights, or phonophobia, which is discomfort with loud noises. Meningoencephalitis can cause an altered mental state or seizures. The diagnosis of meningitis starts with a physical exam. One maneuver is when a person lies flat on their back facing upwards, and one of their legs is raised with the knee flexed to a 90degree angle. Then, the leg is supported and slowly straightened at the knee. If this causes back pain, then it’s called the Kernig’s sign.

Another maneuver is when a person lies flat on their back facing upwards and has their neck supported and flexed. If this causes them to automatically flex their knees or hips, then it’s called the Brudzinski’s sign. If meningitis is suspected, a lumbar puncture can be done. This is when a needle goes through the lower lumbar vertebral levels of the spinal cord, between L3 and L4 for example. The needle penetrates into the subarachnoid space and a few milliliters of CSF are taken. The opening pressure can be measured, and the CSF can be analyzed for white blood cells, protein, and glucose. Polymerase chain reaction, or PCR, might be used to find Specific causes like HIV, enterovirus, HSV, or tuberculosis. If a particular infection seems like an obvious cause, then a test for that might be used, like the Western blot for Borrelia burgdorferi bacteria, or a thin blood smear for malaria.

The treatment of meningitis depends on the underlying cause. For bacterial meningitis, its common is to administer steroids and then antibiotics, to prevent massive injury to the leptomeninges from the inflammation caused by the antibiotics destroying the bacteria. In general, the treatment - antivirals, antibacterials, antifungals, or antiparasitic drugs are aimed at the specific cause of meningitis. Prevention with a vaccine is appropriate for some causes like Neisseria meningitidis, but also for mumps and for disseminated tuberculosis. Prophylactic antibiotics can also be administered, to avoid outbreaks of bacterial meningitis like in households where individuals haven’t been vaccinated against Neisseria meningitidis.

All right, as a quick recap... meningitis is an inflammation of the leptomeninges, the inner two membranes that surround and protect both the brain and spinal cord. It normally starts when a foreign substance, often times bacteria, makes its way inside the leptomeninges, either by direct contact or hematogenous spread through the blood-brain barrier. The immune system responds to the antigen by flooding the subarachnoid space with white blood cells, which, release chemokines - and create inflammation and this results in the classic triad of symptoms: headaches, fevers, and neck stiffness.  

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