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Brain disorders

The goal of personalized medicine will be achieved through the exponential growth of computing power. Epigenetics, pharmacogenomics, and machine learning are some of the approaches that are being driven by our ability to process massive amounts of data. Unfortunately, it may take another decade or two before we can offer our patients truly personalized medicine.

Until then, we still have to rely on clinical skills. In a study just published in the journal Pain, D. Bouhassira and his colleagues were able to predict the response of neuropathic pain to Botox injections. The prediction was based on a specific combination of symptoms and signs. They used the Neuropathic Pain Symptom Inventory (NPSI) in 628 patients to identify three distinct clusters of patients. The first group had a more severe pinpointed pain, the second one had more evoked pain, and the third had a higher score for deep pain.

The study included adult patients who had experienced pain for at least three months with a mean pain intensity three or greater on a 0 to 10 numerical rating scale. In more than 85% of the patients, neuropathic pain was due to a traumatic or surgical nerve injury. In the rest, it was due to postherpetic neuralgia (shingles).

The researchers used these three groupings to predicting treatment response through the analysis of their two previous controlled trials of Botox. They found significant effects of Botox compared to placebo in clusters 2 and 3, but not in cluster 1. They also developed and performed a preliminary validation of a web-based version of the NPSI and algorithm for the stratification of patients in both research and daily practice.

Botox is not yet approved by the FDA for the treatment of neuropathic pain. This means that insurance companies are unlikely to pay for it. Besides the pain of shingles, neuropathy, injured nerves (I’ve treated two patients with post-amputation pain), we use Botox “off label” to treat trigeminal neuralgia, cluster headaches, hemicrania continua, numular headaches, and other painful conditions. In one of my patients, even headache due to a large but benign brain tumor responded to Botox.

Botox helps such a wide variety of headaches and other painful conditions probably due to its proven effect on sensory nerve endings.

In treating migraine headaches with Botox, there were several attempts to find clinical predictors of response. More recent onset of chronic migraine and fewer days with migraine have been identified as predictors of a better response. . There have been also suggestions that eye pain was a good predictor of response to Botox. Patients with”exploding” (pressure from inside-out) headache may be less responsive than those with “imploding” (pressure from outside-in, or constricting pain) headache.

When studied in large groups, these features might have some predictive value. But it is not anywhere close to 100% or even 70%. Therefore, when dealing with an individual patient we would try Botox in patients with chronic migraines regardless of the presence or the absence of any of these symptoms.

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COVID-related lockdowns have saved many lives. We don’t yet fully appreciate, however, the other side of the ledger – the harms the lockdowns have caused. These include delays in diagnosing cancers, alcohol and drug abuse, depression, anxiety, deprivation of schooling and socialization in children, and worsening of pain and headaches. The latter not only because of lack of access to care but also due to the effect of loneliness.

Prior studies have shown that loneliness is consistently associated with pain. A study by British researchers published in the current issue of the journal Pain examined the question of whether loneliness worsens pain or pain leads to loneliness.

Drs. Anna Loeffler and Andrew Steptoe studied 4,906 men and women (mean age was 65) over a period of four years. They also looked at the role of inflammation in these people. Pain was defined by reports of being often troubled by pain at a moderate or severe intensity. Loneliness was measured using a standard scale. The researchers took into account age, sex, ethnicity, educational attainment, wealth as a marker of socioeconomic resources, marital status, physical activity, degree of mobility, and depressive symptoms.

They found that baseline loneliness was associated with pain four years later. Similarly, baseline pain independently predicted loneliness four years later. The likelihood of pain was increased when at the baseline loneliness was accompanied by an increase in an inflammation marker, C-reactive protein (CRP). On the other hand, inflammation did not predict future loneliness. Both pain and loneliness are distressing experiences that impact well-being and quality of life. The researchers concluded that the relationships between pain and loneliness are bidirectional.

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The headache of low cerebrospinal fluid (CSF) pressure can be very severe. Its main feature is that it gets worse on sitting or standing and improves upon lying down. Sometimes, this change is quick but occasionally the headache slowly gets worse as the day goes on and is mildest or absent upon awakening in the morning.

Low CSF pressure often results from the needle going in too far during an epidural steroid injection for low back pain or epidural anesthesia during delivery or surgery. This results in the spinal fluid leaking into the soft tissues of the back. The loss of fluid causes sagging of the brain which normally floats in a thin layer of CSF. Spinal fluid leaks usually seal on their own but sometimes require a “blood patch”– injecting the patient’s blood into the area of the leak. The injected blood clots and seals the leak.

If a CSF leak happens after a diagnostic spinal tap or an epidural procedure, it is better to have the blood patch sooner rather than later. I recommend doing it if the headache persists for more than a couple of days.

Rarely, a spinal fluid leak occurs spontaneously after straining or without an obvious trigger. This condition is called spontaneous intracranial hypotension (SIH). A review of scientific reports of SIH involving over 2,000 patients by a British physician Dr. Manjit Matharu and his colleagues provides a good description of this condition. Headache was present in 99% of patients. In 2% the headache did not change with the change of position and 1% had no headache but only other symptoms.

The five most common symptoms of SIH besides headaches, were nausea, neck pain or stiffness, tinnitus (ringing in the ears), dizziness, and hearing problems.

The diagnosis can be made by an MRI scan with an intravenous injection of gadolinium, which is a contrast dye. According to Dr. Matharu’s review, however, MRI was normal in 19% of patients. A spinal tap to measure the pressure can be a useful test, although it was normal in one-third of patients. This is explained by the fact that intracranial pressure often fluctuates. In some patients, a spinal tap can make headaches worse. Another test is an MRI of the spine to detect an accumulation of the leaking CSF. This test was helpful only in a little more than half of the patients. A more advanced test done when other tests are negative and a blood patch is ineffective is a digital subtraction myelogram. So even when SIH is suspected – and often it is not – it may be difficult to prove the diagnosis.

In 28% of patients, bed rest and hydration were sufficient to heal the leak. A single or repeated blood patch was effective in 64% of patients. When the site of the leak is not found, most specialists do a blind patch at the lumbar level. A larger volume of blood, 20-30 ml is more effective than smaller volumes. In a small proportion of patients, surgical repair of the leak is necessary and it is done by a neurosurgeon.

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Magnesium supplementation for the prevention of migraine headaches has been gaining wider acceptance. Dozens of studies, including several of our own, have shown that migraine sufferers often have a magnesium deficiency. Studies have also shown that taking an oral supplement or getting an intravenous infusion of magnesium, relieves migraines.

The causes of magnesium deficiency include genetic factors, poor absorption, stress, alcohol, and low dietary intake of foods rich in magnesium. A study just published in the journal Headache looked at the dietary intake of magnesium, including supplements, in those with migraines compared to people without migraines.

The study included 3626 participants, 20- to 50-years old. A quarter of these people suffered from migraines. People who consumed the recommended daily amount (RDA) of magnesium had a lower risk of migraine. This risk was the highest in those who were in the bottom quarter of magnesium consumption.

This was a correlational study, meaning that it does not prove that taking magnesium prevents migraines. However, common sense and our clinical experience, combined with all the previously published studies, strongly support taking magnesium to prevent migraines.

There are many other benefits of magnesium that I’ve written about in this blog – just enter “magnesium” into the search box and you will find a few dozen posts.

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Transient global amnesia (TGA) is a very frightening condition. Suddenly, you feel confused and disoriented. You don’t know where you are, what time it is, what you are supposed to be doing. You can’t remember what you were just told and keep asking, what time it is, where you are, what is going on. Fortunately, it is a benign condition and tends to last four to six hours.

A study published last year by the Mayo Clinic researchers analyzed records of over one thousand patients who experienced TGA. The majority (86%) had a single episode and 14% had more than one. The mean age was 65. History of migraines was present in 20% of people with a single episode and in 36% in those with multiple attacks. Family history of migraines was found in 19% and 31% respectively.

TGA is a benign disorder. MRI scan and EEG were abnormal only in a small number of patients. The authors speculate that a similar mechanism may be responsible for TGA and migraines. This may apply to those with a personal or family history of migraines, but the majority of patients did not have either. It is not clear why TGA tends to occur in older people and why a family history of TGA is uncommon.

A review of several prior studies that looked at the incidence of TGA in large groups of migraine patients was published last month. This meta-analysis showed that people who suffer from migraines are 2.5 times more likely to have an episode of TGA.

A study from Taiwan showed that patients with an attack of TGA are more likely to develop dementia, but mostly in those who were older and suffered from diabetes. People with a history of TGA are not at an increased risk of a stroke.

Despite the low yield, most people who experience a TGA undergo an MRI scan for a possible tumor or a stroke. An EEG, or brain wave test is done because some types of epileptic seizures can present with confusion.

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My new book, The End of Migraines: 150 Ways to Stop Your Pain, was just published by Amazon. It is also available on Google Play and Kobo.
I am very grateful to all my colleagues who took the time to read the book and to provide advance praise for it.
This is a self-published book. This allows me to update it regularly and to set a very affordable price – the e-book version is only $3.95 and the paperback is $14.95. The e-book version has the advantage of having many hyperlinks to original articles and other resources.
If you read it, please write a brief review on Amazon or Google and spread the word about it.

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The loss of the sense of smell is the second most common presenting symptom of COVID. It occurs in 65% of patients. Fatigue occurs in 68% and headache, in 43%. Severe loss of the sense of smell was still present in 11% of patients after one month and in 7% after two months.

A study published by French researchers in Neurology, reports on the likely cause of the loss of smell. They obtained MRI scans in 20 patients with COVID-related loss of smell. Nineteen out of 20 had complete occlusion of the olfactory clefts due to swelling. The clefts are two narrow vertical passages at the upper part of the nasal cavity. They are lined with the olfactory epithelium containing olfactory receptors. They found a correlation between the degree of olfactory impairment and the degree of occlusion of the olfactory cleft.

The logical conclusion is that treating the swelling could help improve the sense of smell and possibly reduce the chance of permanent impairment. In the discussion section of the paper, the authors state that most treatments for virus-induced inflammation do not work. However, the only reference they provide is a study of 34 patients who were given the equivalent of 10-15 mg of prednisone. The majority of published trials of oral steroids for chronic sinusitis used 30 to 60 mg. Sudden hearing loss and Bell’s palsy are very different conditions but are also thought to involve swelling and inflammation and are treated with a short course of prednisone, typically 60 mg a day.

One of the articles cited above was accompanied by an editorial that recommends using a steroid nasal spray. This sounds reasonable for milder cases, but if I were to completely lose my sense of smell, I would take at least 30 mg of prednisone.

Persistent loss of smell can be a devastating condition. According to Healthline, the loss of the sense of smell can lead to
1. an inability to taste food, which can lead to eating too much or too little
2. an inability to smell spoiled food, which can lead to food poisoning
3. increased danger in the event of a fire if you cannot smell smoke
4. losing the ability to recall smell-related memories
5. loss of intimacy due to the inability to smell perfume or pheromones
6. losing the ability to detect chemicals or other dangerous odors in your home
7. lack of empathy from family, friends, or doctors
8. inability to detect body odors
9. mood disorders such as depression
10. lack of interest in social situations, which might include being unable to enjoy the food at a social gathering

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Frequent use of marijuana has a negative effect on the developing brain. Researchers at Tulane and Dartmouth medical schools looked at the possible protective effect of marijuana in severe head injury. The results were recently published in an article, Preinjury Use of Marijuana and Outcomes in Trauma Patients.

They examined records of adults who presented to two large regional trauma centers between 2014 and 2018. They included patients who had detectable levels of delta-9-tetrahydrocannabinol (THC) in the blood. They excluded those who had other illicit drugs present.

Of the 4849 patients, 1373 (28.3%) had THC present in the blood. These patients tended to be younger, more likely to be males, and more likely to be injured by “penetrating mechanism” than those who did not have THC present. Patients with THC had a shorter hospital stay, shorter need for ventilation, and a shorter stay in the intensive care unit. The mortality rate was somewhat lower in the THC-positive group (4.3% versus 7.6%) but this difference did not reach statistical significance.

The mechanism could be related to the anti-inflammatory effects of marijuana mentioned in the previous post. Head trauma is known to trigger an immune response that leads to inflammation that in turn worsens brain damage. The researchers did not measure any inflammatory markers so this is just a speculation. It is also possible that the THC-positive group did better because it was significantly younger than the THC-negative group.

In another very large chart review study that looked at older trauma patients, intoxication with alcohol predicted better survival and shorter hospital stay. On the other hand, the presence of cocaine or marijuana worsened the prognosis.

In the US, trauma is the leading cause of death and disability in 18 to 44-year-olds. This is also the age group that is more likely to use marijuana. Consuming marijuana may increase the risk of trauma as suggested by the fact that THC-positive patients were more likely to have a “penetrating injury”. Despite the protective effect of marijuana, it is very likely that reducing its use will lead to fewer injuries and more lives saved.

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Having given Botox injections to thousands of patients, I know that some patients tolerate pain better if they curse during the procedure.

A British psychologist Richard Stephens seems to have made a career out of studying the effect of cursing on pain. His first paper Swearing as a response to pain, appeared in 2009 in NeuroReport. It showed that swearing improves pain tolerance in volunteers whose hand was submerged in icy water. His next paper, which I mentioned in a post in 2011, Swearing as a Response to Pain—Effect of Daily Swearing Frequency was published in The Journal of Pain.

In this study, Stephens looked at the effect of repeated daily swearing on experimental pain. The volunteers were again subjected to pain by submerging their hand into icy water. And they again showed that swearing reduces pain. However, people who tended to swear frequently throughout the day had less of a pain-relieving effect than those who did not.

His latest paper, Swearing as a Response to Pain: Assessing Hypoalgesic Effects of Novel “Swear” Words, was just published in the Frontiers in Psychology. The authors show that made-up “swear” words are not as effective as the good old four-letter f-word.

The conclusion of this 6,500-word research paper suggests that there is still a lot more swearing …er … I mean, studying to be done on this subject. Whether this is a good use of the British taxpayers’ money is another matter. Is the ultimate goal to save the British National Health Service money by replacing pain medications with scientifically validated swear words?

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Two patients treated at MD Anderson Cancer Center for brain tumors were given Botox injections for their tumor-related headaches. The report at the recent meeting of the American Headache Society describes two patients, one with a meningioma (“extensive meningiomatosis”) and the second one with metastatic breast cancer. The first patient completed 14 treatments with Botox over 4 years and the second, 9 treatments over 2 years. Both patients had sustained improvement in their headache intensity, duration, headache-free days, and quality of life. The recurrence of headaches often began 90 days after each treatment, which is the usual duration of the effect of Botox.

Botox is approved by the FDA for the preventive treatment of chronic migraine headaches, which are defined as headaches occurring on at least 15 days each month. However, most headache specialists I know use it for other types of headaches as well. Cluster headaches, hemicrania continua, post-traumatic headaches, numular headaches, trigeminal neuralgia have all been reported in the medical literature to respond to Botox. I’ve also successfully treated patients with these types of headaches, as well as a large number with episodic migraines (less than 15 headache days a month) and a few with chronic tension-type headaches.

Neuropathic pain also seems to respond to Botox and I’ve treated patients with post-herpetic neuralgia (shingles), stump pain after amputation, post-surgical scar pain, and other pain types.

It is not surprising that Botox could help headaches caused by a brain tumor. The brain itself is not pain-sensitive – neurosurgeons can cut it in an awake patient without causing any pain. Most of the pain originates in the brain covering called meninges which are innervated by the trigeminal nerve and which can be stretched and irritated by a tumor. The trigeminal nerve also provides sensation over the face and the anterior part of the head. Botox works by reducing pain signals sent from the trigeminal nerve endings to the brain.

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A large population-based 11-year long study just published by Norwegian researchers confirmed that an elevated level of an inflammatory marker C-reactive protein (CRP) is associated with an increased risk of developing chronic migraine.

Inflammation is a well-established part of the pathophysiology of migraine. Pro-inflammatory aspects of obesity are thought to underly the correlation between excessive weight and the frequency of migraines. While it is not clear how high CRP leads to chronification of migraines, there are several ways to lower this marker.

CRP is also a well-documented marker of risk for cardiovascular disease. Statins, such as atorvastatin (Lipitor) lower CRP levels independently of their lipid-lowering effect. Metformin is another drug that can lower CRP levels.

There are several ways to lower CRP without drugs including lifestyle changes such as regular exercise, a healthy diet, and moderate alcohol consumption.

A Japanese study of over 2,000 people showed that blood levels of vitamin C are inversely correlated with CRP levels. A review of 12 published studies of the effect of vitamin C on CRP showed that vitamin C lowers CRP levels.

A meta-analysis of 12 published studies showed that vitamin E (alpha-tocopherol or gamma-tocopherol) is another vitamin that lowers CRP levels.

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It is not surprising that when a doctor is tired or hurried he or she is more likely to make a mistake. A new study published in JAMA Network Open provides some hard data on doctor performance as it relates to the prescribing of opioid (narcotic) analgesics. Opioids are still overprescribed, especially for migraine headache patients.

The researchers at the University of Minnesota discovered that doctors were 33% more likely to prescribe an opioid pain medicine at the end of the workday than in the beginning. If the doctor was running an hour or more behind schedule her or she was 17% more likely to prescribe an opioid. Prescribing of nonsteroidal anti-inflammatory drugs and referral to physical therapy did not display similar patterns. This was a very large study which means that the results are likely to be reliable. The study looked at 5,603 primary care practitioners who were involved in 678,319 primary care encounters for a painful condition.

Prescribing an opioid seems like a quick fix for a problem that saves doctors time, but usually is not be the best treatment for the patient.

Nobel Prize winner Daniel Kahneman in his book, Thinking Fast and Slow suggests that there are additional and easily correctable factors that may be contributing to poor decision making. Here are some quotes from the book.

“The most surprising discovery made by Baumeister’s group shows, as he puts it, that the idea of mental energy is more than a mere metaphor. The nervous system consumes more glucose than most other parts of the body, and effortful mental activity appears to be especially expensive in the currency of glucose. When you are actively involved in difficult cognitive reasoning or engaged in a task that requires self-control, your blood glucose level drops.

The bold implication of this idea is that the effects of ego depletion could be undone by ingesting glucose, and Baumeister and his colleagues have confirmed this hypothesis in several experiments… Restoring the level of available sugar in the brain had prevented the deterioration of performance.

A disturbing demonstration of depletion effects in judgment was recently reported in the Proceedings of the National Academy of Sciences. The unwitting participants in the study were eight parole judges in Israel. They spend entire days reviewing applications for parole. The cases are presented in random order, and the judges spend little time on each one, an average of 6 minutes. (The default decision is denial of parole; only 35% of requests are approved. The exact time of each decision is recorded, and the times of the judges’ three food breaks—morning break, lunch, and afternoon break—during the day are recorded as well.) The authors of the study plotted the proportion of approved requests against the time since the last food break. The proportion spikes after each meal, when about 65% of requests are granted. During the two hours or so until the judges’ next feeding, the approval rate drops steadily, to about zero just before the meal. As you might expect, this is an unwelcome result and the authors carefully checked many alternative explanations. The best possible account of the data provides bad news: tired and hungry judges tend to fall back on the easier default position of denying requests for parole. Both fatigue and hunger probably play a role.”

So for best results you may want to try to see your doctor right after lunch and hope that he or she had time to eat lunch.

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