STIFF PERSON SYNDROME: A misleadingly flippant name for a serious disease

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Posted by Jennifer Ding, MSIV Drexel University College of Medicine

What is Stiff Person Syndrome (SPS)?

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Exaggerated lumbar lordosis in SPS

Stiff Person Syndrome (yes, the official moniker) is a very rare autoimmune disease of the nervous system that affects maybe 1 in 1,000,000 people worldwide. Most patients experience fluctuating, involuntary muscle rigidity in the trunk and limbs, an exaggerated lumbar curve, and a heightened sensitivity to their environment.

Loud or unexpected noise, touch and emotional distress can actually set off muscle spasms or even falls in those afflicted.

Attacks of spasms are usually unpredictable, last for minutes and tend to recur over hours. These spasms can be so intense that they actually can cause.

The rigidity seen in SPS is characterized by a stiffness (hence the name) that begins over several months along the spine and spreads to the legs. In the lucky few, the fluctuating rigidity becomes fixed leading to difficulty walking, bending, and frequent falling.

Who gets SPS?

Moersch and Woltman first described SPS in 1956 based on 14 cases that were observed over 32 years. It was initially called “stiff man syndrome” before the disease was found in females and children as well.

Today, we see that SPS affects twice as many women as men and is frequently associated with other autoimmune diseases, such as Diabetes Mellitus Type 1, thyroiditis and vitiligo. Age of onset varies between 30 to 60 with it occurring most frequently in people in their 40s.

What causes SPS?

Now for the science behind SPS: like any autoimmune disease, the problem is thought to lie with antibodies that attack the body’s own cells or enzymes. Patients with SPS have antibodies against glutamic acid decarboxylase (GAD), an enzyme, that produces gamma-aminobutyric acid (GABA), a chief inhibitory neurotransmitter (a chemical) that plays a crucial role in regulating our central nervous systems. GABA is also directly involved in regulating muscle tone.
Mechanism

The exact details of the way GAD antibodies cause SPS remain unknown. Many people with GAD antibodies don’t develop SPS. But most patients with SPS have a high level of GAD antibodies in their blood as well as antibodies that inhibit GABA-receptor-associated-protein (GABARAP). Therefore, scientists hypothesize that the root cause of the muscle rigidity and spasms seen in SPS lie in a GABA impairment.

Think of it this way: muscles work in pairs. When one contracts, the other relaxes, and vice versa. GABA is key in regulating this relaxation and without it, both muscles end up contracting. When both muscles contract, they lose the ability to work together, leading to a stalemate, or stiffness that we see in patients with SPS.

How is SDS diagnosed?

The level of GAD antibodies can be measured in the blood and cerebrospinal fluid (CSF). As aforementioned, the mere presence of GAD antibodies in the blood does not directly correlate with a diagnosis of SPS. Instead, the higher the level of GAD antibodies in the blood, the more likely SPS is the diagnosis.

Electromyography (EMG) can also be used to demonstrate involuntary neuronal firing in muscles.

How is SPS treated?

While there is no cure for SPS to date, there are treatment options that are aimed at symptom relief. Benzodiazepines, such as Valium (diazapam) or Ativan (lorazepam), that act similarly to GABA are the primary treatment for symptom relief. These drugs have muscle relaxant and anticonvulsant effects. Baclofen, another type of GABA-agonist that is dispensed from an implanted pump, can be used as a muscle relaxant. Neurontin (gabapentin) is a seizure medication that has also been used for symptom relief. However, SPS tends to worsen over time, leading to patients requiring increased dosages of drugs.

Intravenous immunoglobulin (IVIG) that target the antibodies themselves are also used in patients with advanced disease. IVIG has been shown to decrease stiffness and the heightened startle reflex. Steroids, rituximab, and plasma exchange have also been used to target the immune system in SPS patients, but the benefit of these treatments remains unclear.

Additional reading material

Click here for more information on SPS, the most up-to-date research on the neurological disease, and social networking for those interested, afflicted, or who have family members who are afflicted.

Click here for an article about a patient with SPS.


News segment about a young dancer with SPS.

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Another Gamma Knife Facial Pain Success Story

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Click here to find out more about gamma knife radiosurgery at Monmouth Neuroscience Institute.

New Advances on Pain Control: The Best Thing Since Sliced Bread?

Posted by Saeed Tarabichi, MSIV, Drexel University College of Medicine

Even before we learned how to use paper, mankind has delegated high priority towards learning to control one of the most instinctive of natural feelings: pain. As early as 5000 BC, there are clay tablets of the Sumerians regarding the cultivation of opium as a “joy plant.”

The point I’m trying to make is that people don’t like pain. A LOT. So much, that for as long as mankind has been in civilization these past 7000 years, we have constantly tried to eliminate it from our lives. Yet even after all these amazing technological advances we have made, it’s amazing to think that we have not yet solved the problem of unnecessary pain from our lives.

At this point, you might be thinking to yourself, “What are you talking about? What about all the powerful stuff we give people in the hospital like morphine, fentanyl, oxycontin? We even have things that can take the pain away from certain areas like lidocaine!” True, there are many options for pain that we can employ today, but these options are largely used to treat two of the three cardinal types of pain that humankind can experience: Somatic (the type of pain you get from cutting yourself) and Visceral pain (organ pain- think stomach ache). The third type of pain, neuropathic (damaged nerve pain), is one that we have not fully understood, and one that we have not fully learned how to deal with.

A recent research breakthrough might suggest otherwise. A group of researchers from France have found a very interesting new potential agent to help us treat this elusive neuropathic pain. This new agent was so interesting, that it intrigued the people over at Nature magazine to publish their article about it. So what is it that has all these people excited for the next potential cure to pain?

I bet you didn’t see where that was going (unless you already scrolled through this article, you cheater, you). That is a black mamba snake. The article published in Nature magazine is titled: Black mamba venom peptides target acid-sensing ion channels to abolish pain.

Black Mamba? Isn’t that the snake from Kill Bill 2?

Now you’re probably thinking to yourself, “Well isn’t that something?” Indeed, good reader, it is something. Something extremely dangerous, enough to “kill a man in 20 minutes,” can be used in a scientifically controlled environment for the good of mankind. If the promising stuff from this article holds true, we may have found our BOTOX equivalent for pain!

So now that I’ve beefed this article up enough, I think it’s time for me to get down to the nitty gritty details on what exactly the study was:

In order to understand the paper, there are a few concepts that need to be explained first. I’ll start with the physiological basis for how neuropathic pain works. There are these sensors within our peripheral and central nervous system embedded in the walls of these nerves called Acid Sensing Ion Channels (from here on known as ASIC). They are meant to sense the acidic changes outside of the neuron, which indicates local tissue damage has been done. Once these sensors are activated, they tell your body that there is pain in a particular area.

In the past, we have known there are specific types of agents that can be used to mess with these receptors. It was actually first noted that the Texas coral snake had a toxin that activated these receptors in order to cause pain. Amiloride, in high enough doses, has been shown to block this receptor as well. Now it has been shown that the snake venom from the black mamba contains a particular type of protein that interacts with this receptor in order to shut it off in a reversible fashion.

This protein is a 3 finger protein, that interacts perfectly with the ASIC receptor to shut it off in a reversible fashion.

The new class of protein that has been discovered from the black mamba snake venom has been cleverly named “mambalgins.” Try saying that 5 times in a row.

In both rats and humans, this research study has demonstrated that the use of this mamba venom blocks only the sensory ASIC receptors. They bind to the channel when it is in its “off” mode in order to decrease the sensitivity of the receptor to protons. The end result is that the receptor does not work when it’s supposed to, and signals can never begin to generate, stopping pain at the very source.

These complicated graphs show that when you increase the concentration of the mamba toxin, you decrease the total voltage seen in a specific neuron, indicating the neuron is no longer firing.

This graph compares the effect of the mamba toxin with morphine. They measure pain here within live mice by tail and paw flick latency. What this means, is the amount of time that elapses before there is a flick of the stated body part has been immersed in 46 degree C water.

What’s most amazing about this new finding is that “The central analgesic effect of mambalgin-1 shows reduced tolerance compared with morphine, no respiratory depression and involves the ASIC2a subunit.” On the graph below, you can see another comparision of the mamba toxin with morphine to the left. On the right, you can see the effect of each of the substances on respiratory effort.

Finally, they have shown that these ASIC receptors are also found in the distant extremities. They demonstrate that injection of the paw with the mamba toxin also effects paw latency indicating that not only are ASIC receptors located centrally, but are also implicated in nociception.

So what does this all mean? Have we finally found the cure to pain? I wouldn’t go so far as to say that. While the initial data from this study looks promising, there is still a very long way to go before we can apply this study into human treatment. We need to figure out the toxic effects it can exert on the human body. We need to find the optimal dosing and best way to deliver this drug to eliminate pain. We need additional studies to further investigate the potency of the toxin with regards to pain.

While much work remains to be accomplished, this article provides us with a promising starting point. In the not too distant future, we may see it applied towards people with chronic neuropathic pain in order to drastically improve their quality of life. There may be other uses in addition to pain for the black mamba toxin.

At the end of the day, I could see this new innovation used in intrathecal pumps to deliver very small doses of the toxin for people who have chronic neuropathic pain as a result of nerve injury, similar who how baclofen is used for spasticity. It will be interesting to see what other developments come from this protein.

To close this blog post out, I leave you with a video that will hopefully allow us to look at the most negative of situations and turn it around to something positive, just like these pioneering researchers did!

Comparing treatment options for trigeminal neuralgia

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First line of treatment for patients with trigeminal neuralgia TGN should always be medical, usually the anticonvulsant carbamazepine (Tegretol®), which provides at least partial pain relief for 80% to 90% of patients.  Common side effects include dizziness, drowsiness, forgetfulness, unsteady gait, and nausea. However, carbamazepine and other drugs prescribed do not always remain effective over time, requiring higher and higher doses or a greater number of medications taken concurrently, causing many patients to experience side effects serious enough to warrant discontinuation.

A study from the 1980s followed 143 TGN patients treated with carbamazepine (CBZ) over a 16-year period.  The drug was effective initially with few mild side effects in 99 patients (69%). Of these, 19 developed resistance between 2 months and 10 years after commencing treatment, and required alternative measures. Of the remaining 80 (56%), the drug was effective in 49 for 1-4 years and in 31 for 5-16 years. Thirty-six patients (25%) failed to respond to CBZ initially and required alternative measures, as did 8 (6%) who were intolerant of the drug.

Surgical treatment of TGN is reserved for people who still experience debilitating pain despite best medical management. Surgical options include gamma knife “radiosurgery” (GKS) and the more invasive microvascular decompresion (MVD).

Another study from 2008 compared outcomes for 80 consecutive TGN patients treated surgically with either MVD (36 patients) or GKS (44 patients) over 4-8 years:

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TGN KMG

In sum, MVD was more likely than GKS to achieve and maintain pain-free status in TGN,but  both procedures provided similar early patient satisfaction rates.  MVD is therefore preferred for younger healthy patients, while GKS is preferred for older patients with co-morbidies or contraindications, but neither should be considered unless medical therapy has already been tried and failed.

Post-operative peripheral neuropathy

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Post provided by Kevin Turezyn, Drexel University College of Medicine Class of 2013:

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While the overall risks of undergoing a procedure involving general anesthesia have decreased dramatically over the last 25 years, there is one phenomenon that still puzzles both anesthesiologists and surgeons: post-operative peripheral neuropathies.

Why a patient undergoing an appendectomy would wake up with weakness in their arm is still in large part a mystery. Luckily most patients recover fully, but a small subset suffer from permanent damage.

While relatively infrequent, peripheral nerve injury after anesthesia is one of the largest sources of professional liability for anesthesiologists. Estimates of its frequency range from .03% to .11% of patients who undergo anesthesia.

Interestingly, despite numerous attempts to decrease its incidence, anesthesiologists have had little success.

While the exact cause is unknown, many believe that it relates to patient positioning. There are several points in the body where nerves run very close to the surface leaving them vulnerable to injury. For example, the most commonly injured nerve is the Ulnar nerve of the arm. When this nerve goes through the elbow, it is very close to the surface where it has little body tissue for protection. People commonly hit this nerve in daily life, giving them a painful sensation called hitting your “funny bone”. Other commonly injured nerves include the radial nerve (compression in the spiral groove against the humerus), brachial plexus from traction on the arm, sciatic nerve in the buttock and peroneal nerve against the fibula head.

The American Society of Anesthesiologists has published guidelines for prevention of perioperative peripheral neuropathies. The guidelines focus on pre-operative assessment for patients who are at higher risk ( diabetics, alcoholics, patients with peripheral vascular disease) as well as proper positioning of the extremities and adequate padding.

Click here for the full guidelines.

positioning

When peripheral nerve injury does occur, it frequently resolves on its own, although this can take take several months. During this time, there is little that can done to speed recovery. Physical therapy is often recommended to prevent muscle contractures and atrophy during this time period.

If a patient feels that they suffered a nerve injury during surgery, it is important that they be evaluated right away by a trained neurologist. Testing such as an electromyogram (EMG) can be done to determine the location of the injury and prognosis for recovery.

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Feeling sunburnt in winter? It could be small fiber neuropathy.

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Nerves are composed of bundles of individual fibers (axons)

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Nerve fibers (axons) come in a variety of shapes and sizes.  Some are wrapped in insulation (myelinated) others are bare (unmyelinated).

Human nerve

You can see from the figure (above) that small unmyelinated fibers make up the majority of human sensory nerves.  These small unmyelinated fibers convey pain and temperature sensitivity.

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Small fiber neuropathy

Some diseases, particularly diabetes, preferentially affect these small unmyelinated fibers, leaving the other fibers relatively unaffected, resulting in small fiber neuropathy.

Symptoms of small fiber neuropathy are usually a mixture of numbness (sensory loss) and neuropathic pain.

The pain can be superficial and burning, deep aching, pins-and-needles, electrical shocks, or knife-like stabbing.  Innocuous contact (such as with clothing or bedclothes) can become painful like a sunburn.

Small fiber symptoms often worsen at night (when there are fewer distractions) and in the cold.

The symptoms usually begin in the feet, often first affecting the toes and/or soles.  As the condition worsens, the symptoms usually spread proximally up on to the legs and ultimately on to the hands, leading to a “glove and stocking” pattern.

Peripheral Neuropathy, Length Dependent

In most neuropathies, the ends of longest nerves are affected first (left), leading to a glove and stocking distribution of pain and numbness (right).

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Autonomic dysfunction from small fiber neuropathy can cause burning redness in the feet (“erythromelagia”):

erythromelagia

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Also, loss of innervation to the sweat glands can cause decreased sweating peripherally (where the neuropathy is worse), and lead to increased sweating on the head and trunk:

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Sweat test showing decreased sweating in t extremities (yellow) and increased sweating on the head and trunk (purple).

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A Diagnostic Challenge!

It is the large myelinated fibers which sub-serve strength and deep tendon reflexes.  Furthermore, it it these same large myelinated fibers which are tested during a conventional nerve conduction study.

So the physical signs and electrophysiologic findings we typically rely on to diagnose neuropathy may be absent in small fiber neuropathy.

The most widely available diagnostic test is the punch skin biopsy to quantify epidermal innervation.

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Skin biopsies, showing normal epidermal innervation (left) and epidermal denervation in small fiber neuropathy (right).

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Managing Small Fiber Neuropathy

So, you know you have sunburn from small fiber neuropathy, now what?

The most important first step is to look for an underlying (treatable) cause, particularly occult diabetes, with blood work that includes a glucose tolerance test.  In the case of diabetes, monitoring and controlling the blood glucose, is the most important next step.

Otherwise, treatment is usually limited to symptomatic measures, using drugs like gabapentin, pregabalin and/or duloxetine.