Demyelinating disorders: Pathology review

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Case Study0:00–0:52

At the neurology department. A 23 year old male named Charles is brought in by his parents because of weakness in his feet that started two days ago and worsened over time.
During clinical examination, the deep tendon reflexes in his lower extremities are decreased but sensation is intact. Past medical history reveals a case of gastroenteritis about three weeks ago.
Next to Charles, there's a 26 year old female named Maria that came in because of an episode of blurring in her left eye and pain during eye movement.
She had a similar episode a few months ago that lasted about a week and resolved without any treatment. She also describes an episode where she felt an electric shock like sensation throughout her body after having a hot shower.
All right. So both of them have a demyelinating disorder.

Pathology0:52–2:16

This occurs when myelin, the protective sheath that surrounds the axons of neurons is destroyed. Now, myelin is produced by oligodendrocytes in the central nervous system or CNS, which includes the brain and spinal cord while in the peripheral nervous system or PNS, which includes all of the neurons that extend beyond the brain and the spinal cord it's produced by Schwann cells.
Myelin helps the neurons to quickly send electrical impulses. As a result.
The destruction of myelin or demyelination makes communication between neurons difficult, ultimately leading to all sorts of sensory motor and cognitive problems.
Ok. Now, demyelinating disorders can be classified into two groups.
The first one includes disorders that affect the myelin and the CNS such as multiple sclerosis, acute disseminated encephalomyelitis, progressive multifocal encephalopathy, and central pontine myelinolysis.
The second group includes diseases that affect the myelin and the Pian s like Guillain Barre syndrome and Charcot Marie tooth.
Now, other less high yield to myelinating disorders include crab disease, metachromic leukodystrophy and adrenoleukodystrophy.
All right. So, let's take a closer look at these different demyelinating disorders.

Multiple sclerosis2:16–8:45

Starting with the ones that affect the C NS, multiple sclerosis or MS is the most common demyelinating disorder and a very high yield topic for the exams.
It's an autoimmune disease which means that demyelination occurs because the immune cells like T cells, B cells and macrophages attack the myelin T cells get through the blood brain barrier and once inside the brain, they get activated by myelin.
Multiple sclerosis is a type for hypersensitivity reaction or cell mediated hypersensitivity reaction. This means that these myelin specific t cells release cytokines that dilate the blood vessels allowing more immune cells to get in as well as directly cause damage to oligodendrocytes.
The cytokines attract B cells which begin to make antibodies that mark the myelin next macrophages see those antibodies and attack the marked oligodendrocytes without oligodendrocytes, there's no myelin to cover the neurons leaving behind areas of scar tissue also called plaques.
Ok. Now, these immune attacks typically happen in bouts because regulatory T cells will come in and inhibit the inflammatory process.
Until the next time. This process happens early on.
In MS, the oligodendrocytes will heal and extend new myelin to cover the neurons, which is a process called remyelination.
But over time, the damage becomes irreversible with the loss of Exelon. Now, the exact cause of MS is unknown, but it is linked to both genetic and environmental factors.
Genetic factors include the female sex and genes encode a specific type of immune molecule called HLA Dr. Two.
Environmental factors include infections like Epstein barr virus and Vitamin D deficiency. Vitamin D deficiency can explain why the rate of MS is higher among people that live further from the equator where there's less sunlight.
Now, a very high yield concept is the symptoms and presentation of MS. There's a lot of these because they depend on the location of the plaques.
When they build up in the brainstem, it can affect nerve fibers to control the muscles of the mouth and throat, leading to problems with eating and talking and can lead to new things like a stutter.
Now, individuals with MS very often have vision problems. It's important to remember that plaques can form around the optic nerve causing optic neuritis that can lead to a decrease in visual acuity in the central field of vision and periorbital pain that is worsened by eye movement.
There's also an afferent pupillary defect on the affected side that causes a paradoxical dilation of pupil in response to light.
And that's referred to as Marcus Gunn pupil. There can also be diplopia or double vision due to internuclear ophthalmoplegia or in O which results from damage to the medial longitudinal fasciculus or M LF.
And the brainstem in o impairs abduction in the ipsilateral eye and causes nystagmus in the contralateral eye when it's abducting.
So if the right M LF was damaged, then when an individual looks left, the right eye won't abduct and the abducting left eye will have nystagmus.
And when you ask the individual to look cross eye, they can do it because convergence is unaffected, bilateral internuclear, ophthalmoplegia is highly suggestive of MS.
And that's a very specific clue. Plaques also form along the motor pathways in the spinal cord, which can lead to motor symptoms like muscle weakness, muscle spasms, tremors and ataxia.
In serious cases, this can lead to paralysis. In addition, plaques in the sensory pathways can cause symptoms like numbness and paresthesias which is often a tingling, feeling, painful, itching or burning sensation.
Plaques can also involve the autonomic nervous system leading to constipation, urinary incontinence and sexual dysfunction.
Finally, MS can also affect higher order activities of the brain causing poor concentration and critical thinking as well as depression and anxiety.
Now, two interesting features in MS that are difficult to pronounce are LMIT sign and uf's phenomenon. Lemme sign is an electric shock like sensation that radiates down the back with neck flexion.
Udf's phenomenon is a transient, worsening of MS related neurological symptoms when the body temperature increases like during exercise or a hot shower.
Now, individuals with MS can have more than one of these symptoms. One common trio of symptoms that you have to remember for the exams is called Charcot's neurologic triad, including dysarthria or unclear speech nystagmus, which is involuntary, rapid eye movements and an intention tremor.
Also another common but nonspecific symptom in MS is fatigue that tends to worsen with heat exposure and that's high yield for the test.
Ok. Now, MS can have different clinical patterns.
The most common and the most likely to appear on your exam is relapsing, remitting MS. This is characterized by clearly defined attacks, followed by full or partial recovery and in between the attacks, there is no progression of the symptoms.
An attack is an episode of focal neurological disturbance lasting longer than 24 hours with a preceding period of stability for at least 30 days.
Secondary progressive MS starts off as relapsing, remitting MS and over time, the symptoms and functional decline becomes continuous, primary progressive, MS doesn't have periods of stability at all and symptoms worsen continuously over time.
Ok. Now, next is acute disseminated encephalomyelitis also known as acute disseminated postinfectious encephalomyelitis.

Acute disseminated encephalomyelitis8:45–10:03

This disease is characterized by sudden inflammation and demyelination at multiple sites of the C NS, just like multiple sclerosis.
It is an autoimmune disorder and a type four hypersensitivity reaction that ultimately leads to destruction of the oligodendrocytes and demyelination.
The difference is that acute disseminated encephalomyelitis typically occurs as a single demyelination event that is thought to be triggered by an infection or a vaccine.
Whereas MS is a progressive disease with recurrent bouts of demyelination, also acute disseminated encephalomyelitis occurs more often in Children.
While MS is more common in young adults between the ages of 2040. And that's how yield for the exams.
Symptoms of acute disseminated encephalomyelitis have a sudden onset and progress rapidly. These depend on where the demyelination occurs and can cause visual problems, seizures weakness, irritability, confusion, drowsiness, and even coma.
Now onto another demyelinating disease of the C NS, progressive multifocal leukoencephalopathy or PML for the test. Remember that PML is caused by the John Cunningham virus or simply JC virus.

Progressive multifocal leukoencephalopathy10:03–11:57

JC virus is transmitted from person to person to the respiratory and gastrointestinal tract and then moves to the bloodstream and eventually enters kidney epithelial cells and starts replicating the immune cells can keep the virus in check by killing any cell that has replicating JC virus, but the virus is not eliminated and remains latent in the kidneys.
They can become active again. If the immune system gets weakened this is why a key clue to look for is the immune status of the individual and high risk populations include HIV positive people, an individual with leukemia or lymphoma or a patient taking immunosuppressive medications.
These can be monoclonal antibodies such as natalizumab, which is typically used to treat multiple sclerosis and riTUXimab, which is used to treat various cancers and autoimmune diseases.
All of these affect the lymphocytes which are critical in helping to keep JC virus under control. So, the JC virus can get into the blood and get through the blood brain barrier and into the brain within the brain.
JC virus begins to rapidly attack oligodendrocytes in multiple locations throughout the brain causing demyelination of axons.
Now PML primarily involves the parietal and occipital areas. So look for symptoms like changes in speech and loss of vision.
Other common symptoms include weakness, clumsiness due to lack of coordination, personality changes and dementia. The disease ultimately leads to death in about half of the cases.
And those who survive often have serious neurological disability. Next up is central pontine myelinolysis, which is the destruction of the myelin around the axons that are in the central part of the pons.

Central pontine myelinolysis11:57–14:50

The cause of destruction is rapid osmotic changes and the pons is a part of the brain that's particularly sensitive. So another name for central pontine myelinolysis is osmotic demyelination syndrome.
And it's a high yield topic for the exams. But first things first when brain cells are in an environment with a low sodium concentration called hyponatremia.
There's a lower osmolality outside the cell compared to inside the cell and water flows into the cells because the brain is restricted within the skull, there's no space to expand and the brain becomes compressed.
So the brain cells try to have fewer osmolyte or osmotically active substances in order to reduce the osmotic gradient, so that less water flows into the cell.
In the end, the cell will be in complete equilibrium with a hyponatremic extracellular space. Now, let's say that the hyponatremia is treated too quickly.
This time, the extracellular component has too much sodium and that creates an osmotic gradient that pulls water out of the cell.
The cells don't have enough time to allow osmolyte to enter and reestablish balance as a result, cells dehydrate and that causes massive structural damage.
Now, in general, when oligodendrocytes and neurons get damaged, reactive astrocytes come to the site and form scar tissue to fill the empty space.
A process called astrocytosis or gliosis. Since astrocytes are a subtype of glial cell, when there's enough damage to the pons, it can affect the function of the cranial nerve nuclei that are housed in the pons.
A great mnemonic for correcting hypo or hypernatremia too quickly is from high to low. Your brains will blow well from low to high, your pons will die.
Central pontine myelinolysis often leads to demyelination of the cortical bulbar tracts of cranial nerves 9, 10 and 11. This causes head and neck weakness, dysarthria and dysphagia or difficulty swallowing.
Since the nuclei of these nerves are not affected, it's referred to as pseudo bulbar, palsy, central pontine myelinolysis can also cause diplopia quadriplegia and a condition called locked in syndrome, which is where there's complete paralysis of most or all of the voluntary muscles in the body.
The person is fully conscious so its like they are locked inside their body. Ok.
Now let's switch gears and talk about demyelinating disorders of the PNS. Starting with guillain-barre syndrome for the test.

Guillain-Barré syndrome14:50–17:21

Remember that guillain-barre syndrome is associated with bacterial infections, especially with Campylobacter jejuni, but also mycoplasma pneumoniae viral infections like cytomegalovirus and Epsom barr virus vaccines.
But also stress. It's thought that these infectious agents have ganglioside like molecules on their surface that look similar to the ganglioside components of myelin.
This is called molecular mimicry. Anyways, the myelin particles get picked up by antigen presenting cells like dendritic cells which present it to the helper T cells.
These helper T cells produce cytokines which activate B cells and macrophages once activated the B cells make antibodies that mark the myelin and the macrophages use those antibody markers to bind to and strip the myelin off of the peripheral neurons.
The demyelination occurs in patches along the length of the axon and so under a microscope, segmental demyelination and endoneurial inflammation of the peripheral nerves can be seen the most common clinical variant is acute inflammatory demyelinating polyradiculopathy on the test.
They will describe a patient who had a respiratory or gastrointestinal infection. 2 to 4 weeks ago, they then developed rapidly progressive, symmetric ascending weakness in the distal lower extremities.
Rapidly progressive. In this context means the weakness usually develops within hours to days.
Symptoms are at their worst around four weeks later. Another important clue for the diagnosis is that there flaccid paralysis with decreased or absent deep tendon reflexes in the affected extremities, the paralysis may ascend to involve the diaphragm causing shortness of breath and potentially respiratory failure, which is an emergency.
The cranial nerves may also be affected especially bilateral facial nerve palsy. In addition, the weakness of the pharyngeal muscles cause difficulty swallowing and increases the risk of aspiration.
Autonomic dysfunction can cause fluctuations in BP, cardiac arrhythmias, diaphoresis or sweating and urinary retention. Importantly, sensory symptoms are rare.
Finally, we have Charcot Marie tooth disorder. This is actually a group of progressive hereditary motor and sensory neuropathies.

Charcot-Marie-Tooth disease17:21–18:48

Most are inherited in an autosomal dominant fashion. So there is usually a family history of the disorder.
They affect the peripheral nervous system and are characterized by defective protein production in the Schwann cells or the peripheral neurons axon.
The most common form of Charcot Marie tooth disease is CMT one CMT one is caused by mutations in the PMP 22 and M PZ genes which encode proteins that are part of the myelin sheath over time, Schwann cells try to replace myelin.
And as a result under a microscope, there's often an ion bulb formation which is when an axon is surrounded by new layers of myelin.
With underlying damaged layers of myelin. Individuals with Charcot Marie tooth typically have distal lower extremity weakness, which is similar to Guillain Barre syndrome.
The difference is there will also be sensory symptoms such as pain or numbness for motor symptoms, damage to the common perineal nerve can lead to foot drop.
While weakness of the intrinsic muscles of the foot can result in Pez Cavus, a high arching foot that doesn't flatten with weight bearing weakness of the back muscles can result in scoliosis.
All right. Now, let's move on to diagnosis in the exams.

Diagnosis18:48–23:11

Suspect multiple sclerosis in a young individual that has neurological symptoms disseminated in time and space, meaning that different locations in the CNS are affected at different times.
Also, MS should be suspected when neurological symptoms resolve partially or fully on their own. Now, for the test, remember that the diagnosis of MS requires an MRI MRI without the contrast gadolinium shows scattered hypo intense white matter lesions.
And when you add the contrast gadolinium, the acute lesions enhance while the older ones remain hypo intense. These plaques are often periventricular that is around the ventricles or juxtacortical that is near the cerebral cortex.
Also a relatively specific sign in MS are plaques around the corpus callosum that look like fingers on a sagittal MRI and are called Dawson's fingers.
A lumbar puncture can be done to look for increased myelin basic protein and oligoclonal bands in the CSF oligoclonal bands are discrete sets of antibodies found on gel, electrophoresis or cerebrospinal fluid IgG and can be an important clue for the diagnosis.
Another test is the evoked potential conduction velocity which shows slowing of the electrical events generated in the brain and spinal cord when a sensory organ is stimulated, for example, a visual evoked potential or V ep can be helpful, measuring the nervous system's response to a visual stimulus.
Ok. Now, a brain biopsy is not needed to confirm the diagnosis.
If it was performed, it would show the characteristic plaques in the gray matter with oligodendrocyte depletion, loss of myelin sheaths, infiltration by lymphocytes and lipid laden macrophages and astrocytosis.
In acute plaques, there's relative preservation of the axons. Whereas in chronic plaques, there's degeneration of the axons, acute disseminated encephalomyelitis is typically suspected when a child develops neurological symptoms after an infection or a vaccination.
The diagnosis is supported by an MRI which shows multiple lesions in the CNS similar to MS. Also a lumbar puncture shows oligoclonal bands in the CSF.
Finally, the evoked potential conduction velocity will show decreased nerve conduction velocity. Now, progressive multifocal leukoencephalopathy is usually suspected when an individual who recently became immunosuppressed, develops neurological symptoms.
The diagnosis can be confirmed by finding JC virus DNA in the cerebrospinal fluid as well as finding multiple white matter lesions on imaging techniques like a brain MRI.
In rare cases, a brain biopsy can be performed on a living person which will show the presence of JC virus within the oligodendrocytes.
Central pontine myelinolysis should be suspected in a patient that's being treated for hyponatremia. Too quickly.
Diagnosis can be confirmed with an MRI which will show damage to the white matter of the pons where the axons are located.
The diagnosis of Guillain Barre syndrome requires CSF analysis which classically shows albumin o cytological dissociation, which means there's an elevated CSF protein with a normal CSF white blood cell count.
Electrodiagnostic testing, which includes a nerve conduction study and electromyography can help differentiate if the disease is demyelinating or affecting the axon in acute inflammatory demyelinating polyradiculopathy, the conduction velocity is decreased.
Finally, serum antibodies can be sent to look for evidence of autoimmune inflammation from Guillain Barre Syndrome. Finally, for Charcot Marie tooth electrodiagnostic testing is usually done and the diagnosis is confirmed with genetic testing using gel electrophoresis or fluorescent in situ hybridization fish for short.
All right. Now, let's discuss treatment.

Treatment23:11–25:47

Treatment of MS starts with disease, modifying medications which reduce the attack rates of MS. They include interferon, beta glatiramer, acetate or natalizumab.
Next, symptomatic therapy includes muscle relaxants like baclofen, cyclobenzaprine or tiZANidine that can alleviate spasticity, neuropathic pain can be treated with anticonvulsants like carBAMazepine, gabapentin or pregabalin or antidepressants like desipramine and venlafaxine.
Now if there's a relapse, treatment depends on the severity of symptoms. Mild symptoms may not require treatment.
Whereas paralysis or visual loss would require treatment with high dose IV corticosteroids like methylprednisolone. If there's an inadequate response to corticosteroids, then plasma exchange or plasmapheresis can be done.
Treatment for acute disseminated encephalomyelitis includes corticosteroids and they should be given rapidly to reduce the inflammation.
Other treatments include intravenous immunoglobulin therapy to bind and neutralize the autoantibodies or cyclophosphamide, which is a cell cycle inhibitor.
Occasionally more severe cases may be treated with plasma exchange. The majority of individuals recover fully a few months after treatment but some have a residual disability.
Now, for PML, there is no treatment for JC virus but the disease can be slowed down by restoring the immune system so that it can control the virus.
For example, HIV infected people must start highly active antiretroviral therapy or heart. While for autoimmune diseases, it's helpful to stop immunosuppressive medications.
As for central pontine myelinolysis, there's no way to reverse existing damage but ongoing damage can be stopped by slowly correcting any electrolyte abnormalities.
Now, for the exams remember that Guillain Barre syndrome can cause respiratory failure which can be fatal. So close monitoring with serial measurements of vital capacity and respiratory support are critical.
Now, the syndrome can be treated with IV IG or plasma exchange. Uniquely.
Unlike many autoimmune diseases, corticosteroids are not effective in guillain-barre Syndrome. And finally, for Chott Marie tooth management focuses on physical therapy and rehabilitation.
All right. As a quick recap, the myelinating disorders are characterized by destruction of the myelin sheath that surrounds the axons of neurons.

Review25:47–26:27

They can either affect the central nervous system like multiple sclerosis, acute disseminated encephalomyelitis and central pontine myelinolysis or the peripheral nervous system like Guillain Barre syndrome and Charcot Marie tooth disease.
A diagnosis can be made on clinical presentation, imaging techniques like MRI and lab findings. The diagnosis can often be confirmed with more specific tests like electro diagnostic testing or genetic testing.
Ok. Back to the patients, Charles had bilateral rapid onset, lower extremity weakness with no sensory defects on physical exam.

Summary26:27–27:16

He had absence of deep tendon reflexes. All of this points to Guillain Barre syndrome, which is most likely triggered by the gastrointestinal infection.
He had a few weeks ago to confirm the diagnosis lumbar puncture to show albuminocytological dissociation and electrodiagnostic testing must be done.
All right. Now, Maria most likely has multiple sclerosis.
The episodes of blurry vision and pain with eye movement that resolve without treatment are characteristic of MS. Also the episode after the hot shower is ethos phenomenon, which is also typical of MS to confirm the diagnosis.
An MRI to show the sclerotic plaques must be ordered.