Author: virtualmedstudent

Dr. Bror Rexed and His Laminae (The Rexed Laminae)

virtualmedstudent

The Rexed laminae are a system for organizing the neurons of the spinal cord (they were actually designed to torture medical students, I joke of course, sort of…). They are named after Dr. Bror Rexed who was a Swedish neuroscientist.

There are ten Rexed laminae and they follow a topographic organization, with the lower numbers being towards the back of the spinal cord (ie: posterior) and the higher numbers being towards the front of the spinal cord (ie: anterior).

The Rexed laminae are not strictly organized based on anatomical location, but are actually based on the types, and functions, of the neurons in each laminae. Let’s discuss each of the ten layers in more detail (let the fun begin!)…

Layer one contains neurons that receive pain and temperature information from the body and limbs via the axons coming from the dorsal root ganglia. The neurons in layer one then pass this information along to the brain via the spinothalamic tract on the opposite side of the cord.

Layer two, which is also known as the substantia gelatinosa, gets information from the spinothalamic tract as well as the dorsal columns. The spinothalamic tract relays information about painful stimuli and the dorsal columns relay information about non-painful stimuli.

Therefore, the neurons in layer two receive information about both painful and non-painful stimuli. These neurons then send information to Rexed laminae three and four. The neurons in these laminae then pass the sensory information to the brain where it is further interpreted. Interestingly, there are large amounts of opiate (ie: think morphine or heroin) responsive neurons in laminae two of the spinal cord.

The nucleus proprius, which constitutes layers three and four, receives information from the body about touch and proprioception (hence the name “proprius”). It then relays this information to numerous areas in the brainstem, brain, and other Rexed laminae for further processing.

Nobody knows exactly what the heck layer five does, but it receives information from a wide variety of sources including pain sensation from the bodies’ organs, as well as information about movement from the brain (via the corticospinal tracts) and brainstem (via the rubrospinal tracts).

The sixth layer can be divided into two sections: medial and lateral. The medial layer (ie: towards the middle of the spinal cord) gets input from muscle spindles. Muscle spindles (by way of type Ia fibers) tell the spinal cord how much a given muscle is being stretched. The neurons in the medial layer act as messengers for this information.

The lateral layer (ie: towards the periphery of the cord) gets information from the brain and brainstem via multiple descending tracts.

So what is the purpose of the sixth layer? The neurons in this layer send information to two places: the cerebellum (via the ventral spinocerebellar tracts) and motor neurons in the anterior horn of the spinal cord.

The cerebellum interprets the information and modulates movement and muscle tone accordingly. The direct communication between the neurons in Rexed laminae six and the motor neurons in the anterior horns are responsible for spinal reflexes.

Layer seven is most prominent between C8 and L2. This prominence is known as the dorsal nucleus of Clarke. The neurons in Clarke’s nucleus receive lower extremity position and sensory information and then pass that information to the cerebellum via the dorsal spinocerebellar tract.

Layer seven also receives and sends information from, and to, the bodies’ organs. The sympathetic and parasympathetic autonomic system have their pre-ganglionic neurons in Rexed laminae seven. These neurons are responsible for the fight or flight response (sympathetic) and rest and digest (parasympathetic) functions of the bodies’ organs.

Neurons in layer eight obtain information from the reticulospinal and vestibulospinal tracts. The reticulospinal tract is important in maintaing the tone of muscles that flex joints. The vestibulospinal system helps maintain the tone of muscles that are important in extending joints.

So what do the neurons in layer eight do? They take competing information from the reticulospinal and vestibulospinal tracts and help modulate movement and muscular tone. Pretty cool, huh?

Finally an easy layer! This layer contains the α, β, and γ motor neurons of the cord. Simply stated, these neurons send impulses to muscles leading to movement and its’ modulation. The more complex story is that motor neurons in layer nine are influenced by numerous inputs from other Rexed laminae, as well as by descending information coming from the brain.

The neurons in layer nine are topographically organized based on what type of muscle (flexor or extender) they control, as well as where in the body that muscle is located (axial or limb).

Neurons that are located towards the center of the cord control axial muscles and those located towards the periphery of the cord control the muscles of the limbs. In similar fashion, neurons that control muscles that extend joints are located towards the front of the layer (ie: anterior), and those that flex joints are located towards the back of layer nine (ie: posterior).

Like layer five, no one really knows what layer ten actually does. We do know that it is composed of neurons that surround the fluid filled central canal of the spinal cord like a donut. Hungry yet???

Overview

The Rexed laminae are layers of neurons within the spinal cord that perform specific functions. In general, neurons in the laminae towards the back of the cord (ie: laminaes one, two, three, four, and five) are predominately involved in interpreting and relaying sensory information from the body to the brain. On the other hand, neurons in the laminae towards the front of the cord (ie: laminaes seven, eight, and nine) are involved primarily in executing movement and controlling the functions of the bodies organs.

References and Resources

  • Kitahata L, Kosaka Y, Taub A, et al. Lamina-specific suppression of dorsal-horn unit activity by morphine sulfate. Anesthesiology, V41, issue 1, 1974.
  • Anamizu Y, Seichi A, Tsuzuki N, et al. Age-related changes in histogram pattern of anterior horn cells in human cervical spinal cord. Neuropathology. 2006 Dec;26(6):533-9.
  • Stephens B, Guiloff RJ, Navarrete R, et al. Widespread loss of neuronal populations in the spinal ventral horn in sporadic motor neuron disease. A morphometric study. J Neurol Sci. 2006 May 15;244(1-2):41-58.
  • Baehr M, Frotscher M. Duus’ Topical Diagnosis in Neurology: Anatomy, Physiology, Signs, Symptoms. Fourth Edition. Stuttgart: Thieme, 2005.
  • Neuroscience. Fourth Edition. Sinauer Associates, Inc., 2007.

The Dumbing Down of Medical Education: A Critical Look at Our History

virtualmedstudent

It is quite likely that this article will make me sound old and cynical, as in – “I walked uphill to school in the snow both ways and so should you…”, but my intention is not to be any of these things, but rather to bring to light some important issues in the work ethic of doctors, and perhaps more generally, in our society as a whole.

It seems that health care education, at both the medical school and resident level, needs to be tinkered with, again. But before I go any further, let me give you a little background information as to why I think this is the case…

Medical education in the United States took a huge step forward at the beginning of the 20th century. Under the leadership of medical greats like Sir William Osler and Harvey Cushing, the Johns Hopkins University became the sine-qua-non of medical education in the early 1900s.

Prior to this, the best medical schools in the world were mostly in Europe. In fact, many American physicians made medical “pilgrimages” to see surgeons and physicians diagnose and treat disease throughout the European continent (especially Britain and Germany). The European model of medical education was rigorous, well designed, and well executed.

It wasn’t until the Flexner Report came out in 1910 that the United States overtook Europe as the premiere training ground for future doctors. The Flexner report, written by Abraham Flexner, made important recommendations about how medical education should be structured in the United States.

From that report, medical school admission and curricula in the United States became more rigorous and standardized. Perhaps more importantly, it created generations of physicians and surgeons who were extremely well trained.

Several tweaks here and there created the medical system that the United States knew for most of the 20th century. All doctors went through a rigorous four years of medical school, followed by even more rigorous residency training. Medicine was a calling; if you weren’t up to the task you either quite, or weren’t allowed to finish.

Fast forward to the late 20th and early 21st century… New York State has passed a law – known as the Libby Zion Law – that restricts work hours on residents to less than 80 hours per week. Prior to this, residents were called “residents” because they “resided” in the hospital, frequently spending over a hundred hours a week taking care of patients.

The purpose of being a resident was to see and treat as many patients and diseases as possible. The more cases you saw, the better equipped you were to practice medicine confidently, independently, and most important capably.

In 2003, when the 80 hour work week became the “standard” in resident education across the country it forced physicians-in-training to work fewer hours than they normally would. Prior to this, medical students and residents took care of their patients from admission to discharge. The new restrictions forced doctors to “sign-out” medical coverage and decision making to the next “shift” of physicians coming on call. The paradigm for training a physician became less about the calling of medicine and more about shift work.

So what’s the big deal? At this point, it seems to make sense… If doctors are less tired they should make fewer errors, right? Wrong! Since the 2003 standards few studies have shown that patients do better under the new work hour restrictions. In fact, it is not uncommon for more errors and additional, and frequently un-needed, testing to occur while the “covering” physician is in charge of the patient’s care. This is because the doctors who receive “sign-out” usually do not know the patient as well as the admitting doctor.

I would contend (albeit a controversial stance) that the work hour restrictions are inadvertently creating a generation of shift workers who are comfortable “signing-out” their patients to the on call doctor. Whoaaa, pump the brakes! I know that I am using some pretty inflammatory language, and many of you will not agree, but…

This generation of medical students and residents have been forced (and the reason I say forced is that many medical trainees today would certainly survive the brutal training of the past) to be less invested in taking care of their patients. Instead, they are being trained to be more concerned about getting “out on time” so their training programs are not sanctioned.

As a result, medical education in the United States has become a fragmented time line of admitting some patients, treating different patients, and then discharging others. The traditional method of seeing a patient, working up their complaint, offering a treatment, seeing if it works or not, and then following them through their hospital course has become a thing of yesteryear (or perhaps yester-century). However, I feel strongly that the process of seeing, treating, and following “your” patients is vital to forming the clinical judgment necessary to create a great (and yes I use the term “great” deliberately) doctor.

Before I finish my rant I will leave you with an analogy… Doctors used to be the Navy Seals of the health care team. They were better trained and worked harder and longer than anyone else in health care. Their training allowed them to think outside the box and problem solve difficult cases.

Unfortunately, medical education for physicians in the United States is being “dumbed down”. We need to bring back the days of medicine as a calling, as a right of passage that not everyone is, nor should be, capable of completing. It is time to re-claim our rights to being the best and brightest, and to regain our status as the best medical training ground in the world. But we can only do that through hard work and perseverance, not by punching a time card.

References and Resources

(1) Brensilver JM, Smith L, Lyttle CS. Impact of the Libby Zion case on graduate medical education in internal medicine. Mt Sinai J Med. 1998 Sep;65(4):296-300.

(2) Jones AM, Jones KB. The 88-hour family: effects of the 80-hour work week on marriage and childbirth in a surgical residency. Iowa Orthop J. 2007;27:128-33.

(3) Kramer M. Sleep loss in resident physicians: the cause of medical errors? Front Neurol. 2010 Oct 20;1:128

(4) Irby D. Educating physicians for the future: Carnegie’s calls for reform. Med Teach. 2011;33(7):547-50.

(5) Desai SV, Feldman L, Brown L, et al. Effect of the 2011 vs 2003 Duty Hour Regulation-Compliant Models on Sleep Duration, Trainee Education, and Continuity of Patient Care Among Internal Medicine House Staff: A Randomized Trial. JAMA Intern Med. 2013 Mar 25:1-7.

The Basics of Myocardial Infarction (Heart Attack)

virtualmedstudent

Pathology

An acute coronary syndrome refers to any process where heart muscle receives less oxygen than it needs. It encompasses three separate, but overlapping pathologies: unstable angina, non-ST elevation myocardial infarction (NSTEMI), and ST elevation myocardial infarction (STEMI). Therefore, acute coronary syndrome represents a continuum of severity, which if severe enough, can lead to irreversible cardiac muscle death.

NSTEMI and STEMI are distinguished from unstable angina by the presence of heart muscle death. NSTEMI occurs when the inner most portion of the heart wall dies, and is generally due to a partially occlusive thrombus (blood clot) in one of the coronary arteries or their branches. An NSTEMI can, in some ways, be thought of as a "partial" heart attack.

On the other hand, STEMI occurs when a coronary blood vessel becomes fully blocked by thrombus. If untreated, the result is transmural (full wall) death of the heart muscle that the occluded vessel serves. A STEMI, in non-technical terms, can be thought of as a "full blown" heart attack.

Coronary thrombi (blood clots) form after rupture of an atherosclerotic plaque. The exposed plaque surface is highly thrombogenic, which means that blood clots form easily on it. The exposed surface causes platelet and coagulation cascade activation, which results in a thrombus that can occlude the entire vessel diameter resulting in decreased, or in the worst case scenario, no blood flow to the heart muscle. This is the basis of a "heart attack" or myocardial "infarction".

Signs, Symptoms, and Complications

Symptoms of acute coronary syndrome are consistent with anginal chest pain. If angina occurs at rest, or with less activity than it normally does, this is referred to as "unstable" angina, and signifies increased narrowing (ie: decreased diameter) of a coronary blood vessel.

Substernal “crushing” chest pain is the classic description of a heart attack (either NSTEMI or STEMI) and is usually accompanied by diaphoresis (ie: excessive sweating). In addition, nausea and vomiting can also occur. Pain from the chest can sometimes radiate into the arm (usually the left arm) or the jaw. Numbness and tingling in the arm and jaw are also common features. Shortness of breath is another symptom of heart attack, and is usually due to the acute back up of blood into the vessels of the lung, which leads to pulmonary edema.

Complications of infarction are due to mechanical changes in the heart. Damage of the electrical conduction system can lead to arrhythmias (abnormal heart rhythms), which are common in the first few days after an infarction.

If enough heart muscle is destroyed cardiogenic shock can occur. This happens when the heart is no longer able to pump enough blood to the rest of the body. Decreased blood flow to the other organs can lead to ischemia of these organs and multi-organ failure.

Myocardial infarction
and "heart attack"
refer to the same thing –
death of heart muscle.
Other complications are a result of the scarring process that occurs hours to days after the initial heart attack. Dead heart muscle is slowly replaced by scar tissue in a process called fibrosis. During the scarring process there are periods in which the scar and adjacent tissue is weaker than normal. This weakness can cause various complications such as rupture of the heart wall, interventricular septum rupture, or papillary muscle rupture. All of these complications occur roughly 5 to 10 days after the initial heart attack, and are due to structural instability in the newly formed fibrotic area(s). In addition, aneurysm (ie: a ballooning out of the heart) formation may occur several weeks after myocardial infarction.

Finally pericarditis, or inflammation of the sack that the heart sits in, can also occur. A condition known as Dressler’s syndrome is pericarditis that occurs after a heart attack. It usually occurs two weeks to several months after the infarction.

Long term complications of myocardial infarction include heart failure. Ultimately the damaged heart is unable to beat as well as it did in the past. This leads to the back up of blood and fluid in the lungs causing shortness of breath, amongst other symptoms.

Diagnosis

Diagnostic studies can confirm NSTEMI or STEMI. An electrocardiogram (ECG) is the gold standard. It will show ST segment depression in NSTEMI, and ST segment elevation in STEMI. Q-waves are also seen, but may represent previous infarction.

STEMI
Image (left) – An ECG of someone with a STEMI would look like the image to the left. Note how the ST segment is elevated relative to the baseline.

Blood tests can also show elevations in specific proteins released by the dying heart muscle. Cardiac troponin I is one of these markers, and is the most specific for heart muscle injury. It begins to rise 4 hours after the initial thrombus formation and stays elevated for 7-10 days. CK-MB (creatine kinase myocardial band) is another protein released by damaged heart tissue; it is useful in that it is cleared relatively quickly compared to troponin; this is useful in that it can aid in detection of early re-infarction.

Image (right) – An ECG of someone with an NSTEMI. Notice how the NSTEMI ECGST segment is depressed below baseline.

Treatment

The main goals of treatment are to restore blood flow, and to decrease the amount of work the heart is doing. Both of these measures help provide oxygen to the dying heart muscle. One of the main problems in myocardial infarction is that the heart is working harder than usual, and is doing so under decreased oxygen delivery (ie: decreased blood flow). This deadly combination increases the rate of heart muscle death. Therefore, treatment is designed to increase oxygen flow (ie: by restoring blood flow), or by decreasing the work of the heart, and therefore the amount of oxygen the heart needs to survive.

Treatment of any patient with suspected acute coronary syndrome should include pain control. For example, morphine controls the pain associated with heart attacks, and this indirectly lowers the heart rate. Lowering the heart rate decreases the amount of work the heart muscle is doing, and therefore decreases the amount of oxygen that must be delivered for muscle survival.

In addition, nitroglycerin is given because it decreases preload. Preload refers to the amount of blood inside the left ventricle just before contraction of the heart. A larger preload means that the heart must work harder because, in essence, it is pumping more blood per beat. Nitroglycerin dilates blood vessels (mostly veins) in the body and effectively decreases the amount of blood within the heart itself. Less blood to pump, equals less work the heart must do.

Oxygen therapy should also be started to help improve blood oxygen levels. This will ensure that any blood getting to the myocardium will have as much oxygen as possible.

There are several methods for restoring blood flow. The preferred method is through percutaneous coronary interventions (PCI). In this procedure a small catheter is inserted into blood vessels in the groin and threaded up towards the heart; once in the blood vessels of the heart the catheter can be used to mechanically remove any blockage. This is known as "angioplasty" or "thrombectomy". Percutaneous coronary intervention should occur in a reasonable amount of time. There is debate about the exact timing and depends on the type of acute coronary syndrome (ie: STEMI vs NSTEMI).

If the hospital does not have the capacity to do PCI then medications can be used to "break up" the blood clot/thrombus. All patients with suspected infarction should receive an aspirin. Aspirin works by inhibiting platelet plug formation. This helps slow the rate of thrombus formation. First line medications for restoring flow in myocardial infarction are intravenous unfractionated heparin or subcutaneous enoxaparin. Fibrinolytics like tissue plasminogen activator (tPa), reteplase, streptokinase, and urokinase are also sometimes used to try and restore blood flow.

Finally, revascularization operations (ie: coronary artery bypass grafting) may also be necessary depending on the level of disease in the other coronary vessels.

Overview

Acute coronary syndrome refers to a continuum of coronary blood vessel blockage. On the least extreme end is unstable angina; on the most extreme (ie: most dangerous) end is ST elevation myocardial infarction. Symptoms are usually crushing chest pain that radiates to the jaw and arm, but may also include nausea, vomiting, dizziness/fainting, and sweating. Diagnosis is based of ECG and blood tests for heart muscle damage. Treatment is aimed at increasing blood flow, and therefore oxygen delivery, to the heart muscle. This is done by decreasing the amount of work the heart is doing, increasing the amount of oxygen present in blood, and breaking up the blood clot via mechanical or medical means.

References and Resources

  • Husted SE, Nielsen HK. Unfractionated heparin and low molecular weight heparin for acute coronary syndromes–assessment of a Cochrane review. Ugeskr Laeger. 2010 Sep 13;172(37):2522-6.
  • Lepor NE, McCullough PA. Differential diagnosis and overlap of acute chest discomfort and dyspnea in the emergency department. Rev Cardiovasc Med. 2010;11 Suppl 2:S13-23.
    • >
  • Kumar V, Abbas AK, Fausto N. Robbins and Cotran Pathologic Basis of Disease. Seventh Edition. Philadelphia: Elsevier Saunders, 2004.
    • >
  • Lilly LS, et al. Pathophysiology of Heart Disease: A Collaborative Project of Medical Students and Faculty. Fourth Edition. Lippincott Williams and Wilkins, 2006.
  • Flynn JA. Oxford American Handbook of Clinical Medicine (Oxford American Handbooks of Medicine). First Edition. Oxford University Press, 2007.
  • Ferguson JJ, Califf RM, Antman EM, et al. Enoxaparin vs unfractionated heparin in high-risk patients with non-ST-segment elevation acute coronary syndromes managed with an intended early invasive strategy: primary results of the SYNERGY randomized trial. JAMA. 2004 Jul 7;292(1):45-54.

Parkinson’s Disease: Pathology of Movement

virtualmedstudent

Parkinson’s disease is caused by the death of neurons in a part of the brain known as the substantia nigra.

The substantia nigra is part of a system of connected neurons known collectively as the basal ganglia. This system is very important in the control of movement. The substantia nigra contains neurons that secrete a molecule known as dopamine. The loss of dopamine’s effect on the basal ganglia leads to the signs and symptoms of Parkinsonism.

Visible abnormalities are also seen in the neurons of patients with Parkinson’s disease. These abnormalities are called Lewy bodies. They are collections of abnormal protein (specifically, a protein known as α-synuclein) that clump together to form a redish-pink cytoplasmic inclusion in the substantia nigra neurons.

Lewy body
Interestingly, it is not known what causes most cases of Parkinson’s disease. However, there are some known causes, almost all of which involve insults to the substantia nigra.

For example, toxins such as carbon disulfide, manganese, and certain street drugs have been known to kill substantia nigra cells resulting in Parkinson’s.

Another toxin known as MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, trying saying that four times fast!), which was produced accidentally by drug chemists trying to make a synthetic opiod, is extremely toxic to substantia nigra cells. It caused irreversible Parkinson’s disease in those who were unfortunate enough to ingest it!

Finally, the genetics of Parkinson’s disease are not well known. There appears to be multiple genetic causes of the disease. One such genetic mutation involves the gene for α-synuclein, the main component of Lewy bodies. Other genetic mutations may also play a role in Parkinson’s, but they appear to contribute to only a small percentage of cases.

Diagnosis

Parkinson’s disease is a clinical diagnosis. This means that there are currently no special laboratory tests that can reliably detect the disease. Instead, the disorder is diagnosed based on the clinical symptoms discussed below. A true pathological diagnosis can only be made at autopsy by looking at the neurons of the substantia nigra under a microscope.

Signs and Symptoms

Parkinson’s disease has a number of symptoms that commonly begin in the 6th and 7th decade’s of life. Most of these are related to difficulties with movement. The classic description of Parkinson’s involves several signs and symptoms: resting tremor (4-7 Hz frequency), postural instability, bradykinesia (slow movements), rigidity (of the cog-wheeling type), and masked facies.

In addition, late in the disease course other symptoms can become apparent. Roughly 10 to 15% of patients develop dementia. This is believed to be due to the development of Lewy bodies in the cerebral cortex. The dementia of Parkinson’s disease is likely on a continuum with another form of dementia known as Lewy body dementia.

This YouTube video illustrates the common signs and symptoms seen in Parkinson’s disease:

Treatment

The mainstay of treatment for Parkinson’s disease is replacing or augmenting dopamine levels in the brain. A molecule known as levodopa (L-dopa), which is a precursor of dopamine is commonly used. The reason L-dopa is given instead of dopamine is because it crosses the blood brain barrier more readily.

Once inside the brain, L-dopa is converted to dopamine by neuronal enzymes. Sinemet® is a common formulation of L-dopa. It also contains a molecule known as carbidopa. Carbidopa inhibits the breakdown of L-dopa in the body so that more of it can reach the brain. L-dopa is most effective at improving tremor and bradykinesia.

Other medications are designed to mimic the actions of dopamine in the brain. These medications are known as dopamine agonists. They bind to dopamine receptors and cause the same types of cellular reactions that dopamine normally would. The two common dopamine agonists in use today are ropinirole and pramipexole.

Treating Parkinson’s –
(1) Levodopa/carbidopa
(2) MAO-B inhibitors
(3) COMT inhibitors
(4) Dopamine agonists
(5) Anticholinergics
(6) Glutamate antagonists
(7) Deep brain stimulation
Other medications used to treat Parkinson’s disease attempt to indirectly increase the amount of dopamine.

One category of medications that does this is known as MAO-B inhibitors. MAO, or monoamine oxidase, is an enzyme that normally breaks down monoamines like dopamine. Therefore, inhibitors of this enzyme decrease the break down of dopamine allowing it to remain in the brain longer. Selegiline and rasagiline are example of MAO-B inhibitors.

Another class of medications that perform a similar function to the MAOIs are the COMT inhibitors. COMT (catechol-O-methyl transferase) is an enzyme that breaks down dopamine. Entacapone is a COMT inhibitor that may increase the amount of dopamine in brain tissue.

Medications that interfere with another neurotransmitter known as acetylcholine are also sometimes used. These anticholinergic medications, namely benztropine (Cogentin) and trihexylphenidyl (Artane), are most useful for tremor reduction. Since acetylcholine is present in many parts of the body, the anticholinergics tend to have many side effects (the mnemonic "dry as a bone (dry mouth), mad as a hatter (delirium), blind as a bat (pupil dilation), and hot as a hare (fever)" is commonly used for symptoms pertaining to anticholinergic medications).

Finally, medications that antagonize the neurotransmitter glutamate are less commonly used. Amantadine is the name of one medication in this category. It helps mostly with decreasing, or smoothing out, fluctuations in movement.

If medical therapy fails to control symptoms then surgical interventions may be used. In the past a procedure known as pallidotomy was used. This involved making a tiny incision in part of the basal ganglia. This procedure has been replaced by deep brain stimulation (DBS). During DBS surgery small electrodes are implanted in certain areas of the basal ganglia.

Deep Brain Stimulation

Overview

Parkinson’s disease is characterized by postural instability, resting tremor, slow movements, and rigidity. It’s caused by loss of dopaminergic neurons in the substantia nigra of the brain. Why these neurons die is not entirely understood. Diagnosis is based on clinical signs and symptoms. Treatment is by replacing or augmenting dopamine in the brain.

Related Articles

References and Resources

The Indirect Basal Ganglia Pathway

virtualmedstudent

The basal ganglia represent a system of several discrete collections of neurons within the brain. These collections of neurons interact closely with the part of the cerebral cortex that initiates movement. The basal ganglia fine tune the starting and stopping of movements.

The term "basal ganglia" encompasses several separate, but interrelated neuron populations. The putamen, caudate, globus pallidus internus (GPi), globus pallidus externus (GPe), substantia nigra (SN), and subthalamic nucleus (STN) are all discrete neuron populations that, as a whole, compose the "basal ganglia". These named populations of neurons work together to achieve a common goal. The term "striatum" includes the caudate and putamen only, and the term "lentiform nuclei" includes the putamen and globus pallidus.

The basal ganglia modulate movement through a complex loop of both inhibitory and excitatory signals. When you decide to move, your frontal lobes send an excitatory signal via the neurotransmitter glutamate to the striatum (FYI: striatum = caudate and putamen).

In the indirect basal ganglia pathway the striatum then sends an inhibitory signal via the neurotransmitter GABA to the external segment of the globus pallidus. This is different from the direct pathway where the striatum sends a signal to the internal segment of the globus pallidus.

The external segment of the globus pallidus normally indirectly (more on this in the next few paragraphs) inhibits its internal counterpart. Thus, when the striatum inhibits the external segment, it is, in effect, releasing the internal segment from inhibition (that sure seems like a lot of double negatives!).

At this point, the internal segment of the globus pallidus is able to send its inhibitory signals to the thalamus, which causes thalamic neurons to stop sending excitatory signals to the motor cortex. The cortex is then unable to send an impulse down the spinal cord and, ta-da, the net result is a decrease in movement.

It would be easier to understand if the external segment of the globus pallidus “talked” directly to the internal segment, but that is not how it works. The message is relayed through another nucleus known as the subthalamic nucleus.

The subthalamic nucleus is usually inhibited by the external segment of the globus pallidus. Therefore, when the striatum inhibits the external globus pallidus, it causes the cells in the subthalamic nucleus to become more active (ie: the subthalamic nucleus is released from the inhibitory effects of the external globus pallidus).

The subthalamic nucleus, in turn, is able to send an excitatory signal to the neurons in the internal segment of the globus pallidus. The cells in GPi then become more active, which means that they suppress the activity of the thalamus more robustly. The thalamus is then unable to send its normal excitatory messages to the motor cortex. End result? Decreased movement!

 

Basal Ganglia Indirect Pathway Schematic

 

So how does dopamine act on the indirect pathway? Dopamine is secreted by the substantia nigra and binds to D2 receptors (these are different than the D1 receptors of the direct pathway) in the striatum. This causes striatal neurons to decrease their inhibitory message to the external segment of the globus pallidus. The external segment of the globus pallidus is then free to carry out its “normal” job and suppress the excitatory actions of the subthalamic nucleus on its internal counterpart. Less excitation going to the internal globus pallidus translates to less inhibition of the thalamus, and ultimately more excitation of the cortex!

Therefore, if you’ve managed to work through these complicated systems, you’ll realize that dopamine causes increased movement by activating the direct pathway and inhibiting the indirect pathway.

Overall, the indirect basal ganglia pathway has the exact opposite effect of the direct pathway. The indirect pathway serves as a negative modulator of movement and the direct pathway serves as a positive modulator of movement. Now that is some complicated sh**t!

Importance in Disease

Diseases of the basal ganglia cause unwanted movements, or a failure to initiate movement.

The classic basal ganglia disease is Parkinson’s disease, which has elements of both unwanted movement (resting tremor) and difficulty initiating movement (bradykinesia). Other diseases such as hemiballismus, in which the affected person violently flings an extremity, can occur when there is damage to the subthalamic nucleus.

Additionally, in Huntington’s disease the GABA and enkephalin projections from the caudate nucleus to the external globus pallidus are affected. This is believed to be responsible for many of the movement abnormalities seen in patients with this disease.

Overview

The indirect basal ganglia pathway fine tunes motor movements. It involves both excitatory and inhibitory signals through the striatum, globus pallidus, substantia nigra, thalamus, and motor cortex. Diseases such as Parkinson’s disease, hemiballismus, and Huntington’s disease may occur when there is damage to one of the components of the basal ganglia.

References and Resources

  • Baehr M, Frotscher M. Fourth Edition. Stuttgart: Thieme, 2005.
  • Bickley LS, Szilagyi PG. Bates’ Guide to Physical Examination and History Taking. Ninth Edition. New York: Lippincott Williams and Wilkins, 2007.
  • Nolte J. The Human Brain: An Introduction to its Functional Anatomy. Sixth Edition. Philadelphia: Mosby, 2008.
  • Purves D, Augustine GJ, Fitzpatrick D, et al. Neuroscience. Fourth Edition. Sinauer Associates, Inc., 2007.

    • Related Articles

The Direct Basal Ganglia Pathway

virtualmedstudent

The basal ganglia are a complex system of several discrete collections of neurons within the brain. These collections of neurons interact closely with the part of the cerebral cortex that initiates movement. As such, the basal ganglia are important in fine-tuning the starting and stopping of movements.

The term "basal ganglia" encompasses several separate, but interrelated neuron populations. The putamen, caudate, globus pallidus internus (GPi), globus pallidus externus (GPe), substantia nigra (SN), and subthalamic nucleus (STN) are all discrete neuron populations that, as a whole, compose the "basal ganglia". These named populations of neurons work together to achieve a common goal. The term "striatum" includes the caudate and putamen only, and the term "lentiform nuclei" includes the putamen and globus pallidus.

The basal ganglia modulate movement through a complex loop of inhibitory and excitatory signals. When you decide to move, your frontal lobes send an excitatory signal via the neurotransmitter glutamate to the striatum (ie: caudate and putamen).

The neurons in the striatum then send an inhibitory signal to the globus pallidus internus (GPi) and the substantia nigra pars reticulata (SNpr). As a result, GPi and SNpr are no longer able to inhibit the thalamus, which is their normal resting function.

The thalamus now finds itself disinhibited and is able to send a message back to the cerebral cortex saying it is ok to allow the desired movement to occur. The motor cortex then sends a message down the spinal cord causing the desired movement.

So where does the neurotransmitter dopamine enter the picture? Dopamine is secreted by a different part of the substantia nigra known as the pars compacta. These neurons secrete dopamine onto specific cells in the striatum. The dopamine interacts with the D1 (dopamine-1) receptors on these cells causing them to become more active (ie: dopamine has a stimulatory effect via the D1 receptor).

Basal Ganglia Direct Pathway

The overall effect is that dopamine activates the striatum (ie: caudate and putamen), which, as we discussed above, inhibits the internal segment of the globus pallidus. The GPi is then unable to inhibit the thalamus, which in turn allows the thalamus to stimulate the cortex. Huh??? Simply stated, dopamine causes an increased propensity towards movement. Dopamine has a similar role, but via a different mechanism in the indirect pathway, which is discussed in detail in another article.

Importance in Disease

When the basal ganglia malfunction it causes unwanted movements or a failure to initiate movements. The classic basal ganglia disease is Parkinson’s disease, which has elements of both unwanted movements (resting tremors) and difficulty initiating movement (bradykinesia). Other diseases such as hemiballismus, in which the affected person violently flings an extremity, can occur when there is damage to the subthalamic nucleus (the subthalamic nucleus is discussed in more detail on the indirect pathway article).

Overview

The direct basal ganglia pathway fine-tunes motor movements. It involves both excitatory and inhibitory signals through the striatum, globus pallidus, substantia nigra, thalamus, and motor cortex. Diseases such as Parkinson’s disease and hemiballismus may occur when there is damage to one of the components of the basal ganglia.

Related Articles

References and Resources

  • Baehr M, Frotscher M. Duus’ Topical Diagnosis in Neurology: Anatomy, Physiology, Signs, Symptoms. Fourth Edition. Stuttgart: Thieme, 2005.
  • Bickley LS, Szilagyi PG. Bate’s Guide to Physical Examination and History Taking. Ninth Edition. New York: Lippincott Williams and Wilkins, 2007.
  • Nolte J. The Human Brain: An Introduction to its Functional Anatomy. Sixth Edition. Philadelphia: Mosby, 2008.
  • Purves D, Augustine GJ, Fitzpatrick D, et al. Neuroscience. Fourth Edition. Sinauer Associates, Inc., 2007.

Ixodus, Burgdorferi, and Lyme Oh My!

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Borrelia burgdorferi is a gram negative spirochete bacterium. Its hosts are mice, deer, and humans. Spread from host to host is via a tick from the species Ixodes. Ixodes scapularis is the most common tick vector in the Northeastern United States, whereas Ixodes pacificus is the most common in the Western United States.

When an infected tick feeds from a human it can pass borrelia burgdorferi bacteria into the bloodstream. From there the bacterium is usually attacked by both the innate and adaptive immune systems. The innate immune system uses toll-like receptors on macrophages to bind to bacterial proteins. The adaptive immune response uses antibodies to bind to bacterial surface proteins, which results in complement activation and bacterial death.

Unfortunately, the immune response is often not enough to entirely eliminate this bacteria. This is because borrelia burgdorferi has the ability to evade the immune system by changing proteins on its cell surface.

Signs and Symptoms

Borrelia burgdorferi causes Lyme disease. Lyme disease manifests in different ways depending on which stage of the disease the patient enters. The first stage of the disease presents with a rash known as erythema chronicum migrans. This rash appears as a red ring around a clear central area (ie: it resembles a bull’s eye). During this stage of the disease many patients also have flu-like symptoms.

If left untreated the disease can progress to stage two. During this stage neurological, joint, and cardiac symptoms can occur. The bacterium can cause cardiac arrhythmias, especially heart block. Facial drooping can be caused by damage to the facial nerve (cranial nerve seven). Meningitis, which ranges in severity, can occur. Finally, a migrating intermittent arthritis can also be seen during this stage of the disease.

If the disease continues to remain untreated, stage three ensues! This stage happens approximately a year or more after the initial tick bite. It is characterized by chronic arthritis, which can cause severe joint damage. Encephalitis (inflammation of the brain tissue) and myelitis (inflammation of the spinal cord) can also occur.

Diagnosis

The diagnosis of Lyme disease is a two step process. A blood sample is taken from the patient and a test known as an ELISA is performed. ELISA stands for “enzyme linked immunosorbent assay”. This test detects antibodies made by the patient against borrelia burgdorferi antigens (ie: it’s surface proteins). If the ELISA is positive, then a second confirmatory test called a "western blot" is performed. This test further separates the different antibodies to borrelia. If both the ELISA and western blot are "positive" the likelihood of Lyme disease is high.

Treatment

Treatment for early stage disease is with an antibiotic known as doxycycline. Children and pregnant women are often treated with amoxicillin. Other medications used include cefuroxime; erythromycin is sometimes used in patients who are allergic to pencillin. Later stages of the disease may need intravenous antibiotics.

If patients do not respond to initial antibiotic treatment it is important to think of co-existent infections with other tick-borne illnesses. Ticks may carry not only borrelia burgdorferi, but also other pathologic entities so treatment may need to be further tailored.

Overview

Lyme disease is caused by the bacterium borrelia burgdorferi. It is transmitted by the Ixodes tick and is common in the northeastern United States. Symptoms include a bull’s eye rash known as erythema migrans. Neurological, joint, and cardiac symptoms can also occur. Treatment for early stage disease is with oral antibiotics, usually doxycycline, although amoxicillin is sometimes used. Intravenous antibiotics may be necessary for later stages.

References and Resources

When Brain Veins Go Bad: Cerebral Sinus Thrombosis

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In order to understand cerebral sinus thrombosis, we need a quick overview of blood vessel anatomy and the normal direction of blood flow in the body. In the most general terms, blood flows from the heart to large arteries (ie: aorta) then smaller arteries (branches off the aorta) then even smaller vessels called capillaries. It is at this point where the different body tissues extract nutrients and oxygen from the blood. The blood then drains into progressively larger veins until it empties back into the heart where it is re-oxygenated.

The largest veins of the brain are referred to as cerebral venous sinuses. They include the superior sagittal sinus, inferior sagittal sinus, a pair of transverse sinuses, a pair of sigmoid sinuses, straight sinus, cavernous sinus, a pair of superior petrosal sinuses, a pair of inferior petrosal sinuses, and the occipital sinus. The role of these sinuses is to collect all the “used” blood from the brain and deliver it back to the heart.

Like other veins in the body, the cerebral sinuses can form blood clots in them (the technical term for a blood clot is actually a "thrombosis", hence the name “sinus thrombosis”). When this happens a back up of blood in the brain occurs leading to increased pressure and sometimes hemorrhage within the brain tissue itself.

The exact cause of a dural venous thrombosis is not always clear. However, there are numerous risk factors associated with their development. They include inherited defects in proteins responsible for blood clot formation. These defects are collectively known as “thrombophilias”, which in Latin means “thrombus loving”. People with these inherited issues are more prone to forming blood clots.

In addition, patients with a kidney condition known as nephrotic syndrome are at increased risk. In this condition patients urinate out proteins responsible for keeping the blood clotting system at bay. The resulting imbalance can cause blood clots to form where they normally would not.

Infections such as mastoiditis and meningitis can cause inflammation of the sinuses, which can result in blood clot formation. Trauma to the head can also cause clot formation. In addition, that beautiful parasitic infection known as pregnancy (a joke of course!) also increases the risk of developing blood clots. Many commonly used birth control pills, especially those containing estrogen, can also increase a person’s risk.

Signs and Symptoms

Depending on the severity of the clot, everything from a mild headache (the most common presenting symptom) to death is possible. Patients with severe headaches may also have associated nausea and vomiting secondary to elevated intracranial pressures. Decreased mental status is also sometimes observed.

It is also important to remember that not all sinuses are created equal. For example, thrombosis in the superior sagittal sinus can present with leg weakness secondary to edema (ie: swelling) of the adjacent motor cortex.

If a clot forms in the cavernous sinus it may cause dysfunction of the third, fourth, fifth, and/or sixth cranial nerves. In addition, when blood pools in the brain behind the clot it can result in a type of stroke known as venous infarction.

Diagnosis

With todays modern imaging studies, MRI, and more specifically, MR venography has become a crucial diagnostic aid.

An example of an MR venogram is shown in the picture below. Other commonly used tests include traditional angiograms, in which radio-opaque dye is injected directly into the sinuses through catheters inserted in the groin. Finally, CT scans are also commonly obtained, especially to evaluate for possible co-existent hemorrhage into the brain.

MRV of Cerebral Sinus Thrombosis

Treatment

Treatment is usually with a blood thinning medication known as heparin. It is delivered through an IV and helps prevent further clot formation. If a venous stroke is present the use of blood thinning medications must be weighed against the possibility of causing bleeding into the stroked brain tissue. Aggressive hydration with normal saline is also often advocated.

Treating other underlying co-problems such as seizures and increased intracranial pressure is also an important part of managing patients with cerebral sinus thrombosis. Patients with substantial increases in intracranial pressure may require removal of the skull (craniectomy).

Overview

Cerebral sinus thrombosis is a abnormal blood clot in one of the large venous draining systems of the brain. They are uncommon and can present with everything from a mild headache to coma and death. Diagnosis is made most commonly with MRI. Treatment is based on preventing further clot formation with heparin and aggressive hydration.

References and Resources

  • Xu H, Chen K, Lin D, et al. Cerebral venous sinus thrombosis in adult nephrotic syndrome. Clin Nephrol. 2010 Aug;74(2):144-9. Review.
  • Dlamini N, Billinghurst L, Kirkham FJ. Cerebral venous sinus (sinovenous) thrombosis in children. Neurosurg Clin N Am. 2010 Jul;21(3):511-27.
  • Ju YE, Schwedt TJ. Abrupt-onset severe headaches. Semin Neurol. 2010 Apr;30(2):192-200. Epub 2010 Mar 29.
  • Kamal AK. Thrombolytic therapy in cerebral venous sinus thrombosis. J Pak Med Assoc. 2006 Nov;56(11):538-40.
  • Greenberg MS. Handbook of Neurosurgery. Sixth Edition. New York: Thieme, 2006.

The Letter Salad: Understanding Blood Types

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In order to understand the different blood types we have to understand two key words: antigen and antibody.

An antigen is any molecule (could be a protein, carbohydrate, piece of nucleic acid, etc.) that can become a target of the immune response. The immune system is our bodies’ natural defense against bad stuff. Antigens can be further broken down into two categories: self and non-self.

Non-self antigens are those molecules that are foreign to our body. For example, proteins created by bacteria or viruses would be examples of non-self antigens. Non-self antigens typically become the target of an immunological reaction because the body recognizes them as foreign and attempts to eliminate them.

Antigens are either
“self” or “non-self”.
Non-self antigens
are the target of
the immune response

Self antigens, on the other hand, are molecules that our body makes naturally. Self antigens include all the proteins that our genetic material codes for. Under normal circumstances they do not become the target of the immune response (except in certain autoimmune conditions.

Antigens, both self and non-self, are “displayed” by nearly every cell in the body on what are known as major histocompatibility complexes (MHCs). Immune cells interact with these MHCs to determine if the antigen attached to it is “self” or “non-self”. If it is non-self, an immune reaction begins; if it is self, the immune system remains quiescent.

Antibodies
bind antigens

The second term we must understand is antibody. Antibodies are proteins that our immune system makes. Their sole purpose is to bind to antigens and neutralize them.

Antibodies are formed against viruses, bacteria, parasites, etc. In addition, antibodies are the basis behind many vaccines. The vaccine is designed to induce antibody production against specific components of the threat (ie: virus or bacteria) it is trying to protect us against.

So how do antibodies and antigens relate to blood types? First, every person has specific antigens on their red blood cells. In other words, every person has self-antigens that stud the surface of the membranes of their red blood cells. The most commonly talked about are the “A” and “B” antigens.

Remember that antibodies bind antigens.
If a person has type “A” blood than their body naturally produces type “A” antigens. Since humans do not normally produce antibodies against their own self-antigens (this would be effectively attacking your own body), people with type “A” blood do not produce type “A” antibodies. However, they would produce type “B” antibodies. Alternatively, a person with type “AB” blood would have both “A” and “B” self-antigens on their red blood cells, and therefore would not produce antibodies to either one of these.

Type “O” blood lacks both “A” and “B” antigens. Therefore, people with type “O” blood produce antibodies against both “A” and “B” antigens. This is why giving someone with type “O” blood a transfusion of type “A”, “B”, or “AB” blood results in a transfusion reaction. In essence, the antibodies floating around in the blood of a type “O” patient attack the transfused blood; this leads to their destruction, which results in hemolysis (lysis of the blood cell). To review:

Blood Type Antigens Produced? Antibodies Produced?
O None Type A and B
A A Type B
B B Type A
AB AB None

Using the same logic, a patient with type "O" blood is a “universal” red blood cell donor. They can donate their red blood cells to any other human being because their cells do not contain any antigen (important caveat: this is not entirely true as there are other important antigens besides the "A" and "B" types). If they lack antigens on the surface of their red blood cells than the recipient of the blood cannot “attack” those cells. On the other hand, type "AB" individuals are universal recipients since they produce no antibodies; therefore they can receive "A", "B", "AB", or "O" blood.

Before transfusing blood it is important to do several tests to ensure that the appropriate blood is given. The first test is the "type and screen." In this test the patient’s ABO/Rh status is determined and an antibody screen is done. The second test is the "type and cross", in which the patient’s blood and donor blood are tested for compatibility.