[ed note: Doc Gumshoe is our favorite medical writer, and he usually pops in to explore a topic or answer questions readers have posed a couple times a month — he’s not a medical doctor and, as always, his opinions are his own.]
Let’s start this off with a hypothetical case, or rather, three hypothetical cases: three sisters – Maxine, Patty, and LaVerne – go for a lovely walk in the woods on a fine summer day. These young women are not dedicated hikers. They do not wear long pants tucked into their socks, they do not wear boots, they do not spray themselves with insect repellent. On the contrary, they wear nifty short shorts, sleeveless blouses, and cute open-toed sandals. They look like jazz babes, and they have a terrific time.
About a week later, Maxine starts to feel a bit strange. She’s unusually tired. She has chills and a headache. She’s surprised to find that she’s running a temperature – about 102°, in fact. She thinks she’s picked up some kind of a virus, and she figures that she’ll likely develop some other symptoms pretty soon.
After a couple of days, she feels worse – genuinely lousy – but no other symptoms have appeared. Her sisters urge her to get herself to the doctor, and she does so.
Her doctor looks her over, and in the course of the physical examination, he notices several round reddish rashes on her upper legs and lower back. They are over an inch wide and show no signs of a bite. There are small reddish areas in centers of the rashes, surrounded by a lighter area, and then darker slightly raised red ring at the edges, making the rashes look like bull’s eyes.
The doctor tells Maxine that she almost certainly has Lyme disease. She was bitten by a tick when she went for that nice walk in the woods, and the tick – Ixodes scapularis, also called a deer tick or a black-legged tick – infected her with a micro-organism, a spirochete called Borrelia burgdorferi. He explains that spirochetes are nasty little creatures, hard to eradicate, because they tend to travel far from the site where they enter the body and hide deep in the tissues where the antibiotics that are used to kill them don’t easily penetrate. A particularly dangerous spirochete is Treponema pallidum, the pathogen that causes syphilis, which – if not properly treated early on – can penetrate the tissues and cause dementia, cardiac damage, and liver damage many, many years after the initial infection. The Lyme pathogen is thought by some to have the same potential. That’s why early, aggressive treatment is crucial. A four week treatment with any of several oral antibiotics eliminates the Lyme pathogen most of the time.
The doctor does not do any further testing. Maxine’s symptoms and her bull’s-eye rashes are enough to diagnose Lyme disease, and, in any case, the blood tests for Lyme depend on the formation to antibodies to the pathogen, and antibodies wouldn’t yet have formed. There’s no reason to delay treatment pending confirmation by a blood test, and every reason to start treatment right away, to kill those evil little pathogens before they further conceal themselves.
Maxine’s bull’s-eye rashes – known as erythema migrans – are not the sites of the tick bite, by the way. The tick probably landed on Maxine’s leg as she brushed against a bush on her walk. Then it wandered over her body until it found a nice spot to dig in, which might have taken a full day or even longer. Then the tick buried itself in Maxine’s tender flesh, feasted on her blood, and dropped off when it had had enough. Maxine would likely have felt nothing when the tick bit her – tick bites don’t sting or itch. As her doctor explained, if Maxine had felt the tick bite, she would have likely brushed the tick away, and the tick would have gotten no free lunch. Ticks are not quick, like mosquitoes, which can get their blood meal in a few seconds before you swat them.
Maxine’s doctor prescribes a 28-day course of a common antibiotic, probably doxycycline (although a number of other oral antibiotics work just as well – he checks first to see whether Maxine has demonstrated any allergies or sensitivity to doxycycline). And he firmly tells her that she must complete the full 28-day course, even if she feels perfectly fine after a week or so.
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However, about a week later, Maxine develops another very distressing symptom. She feels numb on the left side of her face, and she has trouble fully closing her mouth on that side. In fact, she dribbles her food, and she’s afraid she’s had some kind of stroke.
She runs back to her doctor in a state of considerable concern. But her doctor reassures her: she has a touch of a temporary neurologic condition called Bell’s palsy. The emphasis here is on “temporary.” It will certainly pass in a few days, and she will be totally back to normal. Episodes of Bell’s palsy are quite common with Lyme disease, and Maxine should not worry.
Indeed, in a few days, the numbness in her face is gone, the bull’s eye rashes have disappeared, and Maxine is feeling like her old self again. The next time she’s invited to go for a walk in the woods, she will cover up and use insect repellant, resuming her more glamorous outfit when she’s on the boardwalk at Coney.
About a year later, Patty develops troubling pains in her knees. She racks her brain to try to remember anything she has done that would account for these pains, which seem to be a combination of soreness and stiffness. The pains are in both knees, and they seem to originate in the joint itself and to spread to the sides of the knees. They aren’t sharp pains, and they don’t really prevent her from doing anything she needs to do. But they slow her down, and, more than anything else, they are puzzling and disturbing. After all, she says to herself, I’ve just turned 40, and there’s no reason for me to be developing arthritis or anything like that.
So Patty goes to the doctor, and the doctor examines her and orders blood tests. The doctor explains that it’s possible, although unlikely, that Patty really is developing rheumatoid arthritis – women as young as their mid-30s sometimes develop rheumatoid arthritis – and it’s important to make sure Patty does not have this disease, because if she does, she needs to be treated quickly and aggressively to make sure the disease does not progress. There are also other possibilities that might need to be considered, including fibromyalgia, but the top priority is to rule out rheumatoid arthritis.
But at the same time, the doctor, remembering that Patty’s sister Maxine had Lyme disease the year before, decides to do a blood test for Lyme disease.
The rheumatoid arthritis tests all come back negative. But the test for Lyme antibodies – the enzyme-linked immunosorbent assay, or ELISA – came back positive. ELISA is a type of test, and ELISA tests can be used for a very wide variety of conditions, or even just for the presence of a large number of proteins. The advantage of ELISA tests is that they are relatively quick and inexpensive. However, they are far from definitive. There can be false positives, meaning that they appear to identify an antibody when in fact that specific antibody is not present, but the test reagents have responded to a different antibody. And there can be false negatives, meaning that the reagents have failed to respond to an antibody that may be present, but perhaps at insufficient levels.
However, a positive ELISA for Lyme disease at least requires further investigation, so Patty’s doctor orders the next level of test, a Western blot test. This is a more complex and more expensive test, and it evaluates several immunoglobulin types, typically about 10 immunoglobulin M (IgM) bands and 3 immunoglobulin G (IgG) bands. According to the Centers for Disease Control, a Western blot test for Lyme disease is considered positive if either 5 of the 10 IgG bands or 2 of the 3 IgM bands are positive. Western blot bands are distinguished by the size of proteins that migrate through a series of gels, as measured in kiloDaltons (a kiloDalton is 1000 Daltons, one Dalton being equivalent to the weight of one nuclear particle). Some particular Western blot bands are thought to be specific to Lyme disease, while others are not considered to be specific.
In any case, the point of this perhaps unnecessarily technical blather is to make it clear that the positive identification of Lyme disease is not simple. For most infectious diseases, identifying the pathogen is relatively straightforward. A tissue or blood sample is cultured, and colonies of the pathogen grow out in the culture and are usually fairly easily identified microscopically, frequently with the aid of stains. But Borrelia burgdorferi doesn’t grow in cultures, or at least not quickly enough to diagnose and treat the patient, so clinicians and the lab folks are stuck with trying to identify the antibodies that the wicked little pathogens elicit as they go around making mischief. And identification of Lyme antibodies is not always absolutely accurate; the best the lab is able to do is track correlations. For example, proteins in the 39 kiloDalton band are found in the serum of patients with established Lyme disease frequently enough so that proteins of this size are thought to be specific indicators of Lyme. The sensitivity and specificity of Western blot ranges is in the low to mid 90%s, which is good, but not perfect.
No surprise, Patty’s Western blot test comes back positive, and her doctor now has to recommend a course of treatment. Available options include oral, intramuscular, and intravenous antibiotics. The doctor and Patty talk it over, and the decision is to try a course of oral treatment first and see if it leads to improvement. There are a number of antibiotic candidates, with no single candidate having an edge over the others. Patty sticks with her antibiotic regimen for the recommended 28 days, and gradually begins to feel better.
And, about a year after Patty’s experience, LaVerne develops problems of her own. Only these problems are a good deal more complicated and troubling. Yes, she has pains in her joints. But she’s having other problems as well – headaches, problems with her memory, difficulty concentrating. She feels truly lousy and in a bad mood. And she’s definitely worried.
Her doctor, knowing about Maxine’s and Patty’s Lyme disease episodes, immediately suspects Lyme, even though, like Patty, LaVerne had none of the typical Lyme symptoms after that historic walk in the woods. But the doctor knows that many patients overlook the initial symptoms. The erythema migrans doesn’t always take on the bulls-eye appearance, and the other symptoms, even if the appeared at all, might have been so mild that LaVerne shrugged them off. So, of course, the doctor orders the standard Lyme disease tests, the ELISA and the Western blot.
But they both come back negative. Or rather, the ELISA comes back negative, and the Western blot doesn’t meet the Centers for Disease Control standards for diagnosis of Lyme disease. Only one of the bands was positive, and it was not considered specific for Lyme.
LaVerne’s doctor still thinks that Lyme disease is a possibility; however, other possible sources of LaVerne’s symptoms need to be investigated and either confirmed or ruled out. So the doctor recommends to LaVerne that she consult with two other physicians – a neurologist and a rheumatologist.
The appointment with the rheumatologist comes up first. After reviewing LaVerne’s symptoms and her medical history, the rheumatologist orders blood tests to rule out rheumatoid arthritis, because RA, although unlikely, could be a real threat to LaVerne’s long-term health. LaVerne has tenderness and stiffness in several joints, and also at several points in her body which are not joints. While joint pain is characteristic of RA, the other pains that LaVerne is experiencing are not typical RA symptoms, so the rheumatologist thinks it’s not likely that LaVerne will turn out to have RA. But LaVerne should not take the risk of ignoring the possibility, since untreated RA can lead to permanent joint damage in as little as a few months. Fortunately for LaVerne, the RA blood tests – erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), rheumatoid factor (RF), and antinuclear antibody (ANA) all come back negative.
This leaves the rheumatologist to explore the possibility that LaVerne is suffering from fibromyalgia. This condition is genuinely difficult to diagnose precisely, and treatment is by no means straightforward. The causes are uncertain, and there are some who question whether fibromyalgia is a bona fide disease entity and not just a cluster of unrelated symptoms. A theory about the cause of this condition or syndrome that has many adherents is that fibromyalgia is brought about by low levels of serotonin. This is supported by the observation that women typically have lower levels of serotonin than men, and also that women, by a large ratio, are more susceptible to fibromyalgia than men. This has led to the use of drugs that boost serotonin levels, such as antidepressants of the selective serotonin reuptake inhibitor (SSRI) class – e.g., Prozac – and, indeed, these drugs do relieve some of the fibromyalgia symptoms in many cases.
LaVerne demonstrated some of the typical fibromyalgia symptoms, and the rheumatologist, in consultation with LaVerne’s main physician, suggests that LaVerne at least try a course of an SSRI. LaVerne agrees to give it a shot.
After about a month on the SSRI, LaVerne’s general mood, not surprisingly, improves. But the tender and painful areas in her body have not improved, and she is taking large doses of over-the-counter pain medications – non-steroidal anti-inflammatory drugs, or NSAIDs – just to get through the day. Her doctor does not think that long-term chronic NSAID use is a good option for LaVerne, and urges her to keep her appointment with the neurologist.
The neurologist, as the rheumatologist had done, examines LaVerne and reviews her medical history. Once again, the question of Lyme disease comes up. In spite of negative ELISA and Western blot results, the neurologist thinks that Lyme is a possibility. The other leading possibilities have been, if not entirely eliminated, reduced to “highly unlikely” status, and there’s no evidence of trauma or repetitive stress that could lead to LaVerne’s symptoms.
The neurologist recommends one more test – a spinal tap. The sample is sent for analysis to two different academic laboratories, and one of them reports identification of antibodies to the Lyme pathogen.
At this point, the treatment decision is fairly straightforward. LaVerne should be treated with intravenous infusions of an antibiotic that has optimal penetration, such as a cephalosporin. After consulting both with LaVerne’s primary care physician and an infectious disease specialist, a four-week course of ceftriaxone is recommended, and LaVerne should be closely monitored for signs of relapse.
… but what if LaVerne’s Lyme tests had all been negative?
Maxine’s and Patty’s cases were relatively simple. Maxine had the usual definitive Lyme symptoms, and Patty’s tests came back positive. LaVerne’s doctors, in the face of symptoms that weren’t easily explainable, went to the next step and had her spinal fluid tested, and Lyme antibodies were detected. But what would have been a reasonable course if the spinal fluid tests had also been negative?
I’m not prepared to pronounce whether it’s a reasonable course or not, but there’s a contingent of clinicians out there that strongly hold the view that seronegative Lyme disease is a reality, and requires treatment. What is meant by “seronegative” is that no test, whether ELISA, Western blot, or spinal fluid analysis, reports the presence of Borrelia burgdorferi antibodies. An organization called the International Lyme Diseases and Associated Diseases Society (ILADS) issued guidelines in 2004 calling for antibiotic treatment of patients with a long list of symptoms associated with Lyme disease, regardless of whether their sera test positive for Lyme antibodies. Here is the list of symptoms, taken directly from their published guidelines:
Lyme Disease Symptoms:
- Low grade fevers, “hot flashes” or chills
- Night sweats
- Sore throat
- Swollen glands
- Stiff neck
- Migrating arthralgias, stiffness and frank arthritis
- Chest pain and palpitations
- Abdominal pain, nausea
- Sleep disturbance
- Poor concentration and memory loss
- Irritability and mood swings
- Back pain
- Blurred vision and eye pain
- Jaw pain
- Testicular/pelvic pain
- Cranial nerve disturbance (facial numbness, pain, tingling, palsy or optic neuritis)
The ILADS are suspicious of laboratory testing for Lyme disease. Here’s what they say about it:
Treatment decisions should not be based routinely or exclusively on laboratory findings. The two-tier diagnostic criteria, requiring both a positive enzyme-linked immunosorbent assay (ELISA) and western blot, lacks sensitivity and leaves a significant number of individuals with Lyme disease undiagnosed and untreated. These diagnostic criteria were intended to improve the specificity of tests to aid in identifying well-defined Lyme disease cases for research studies. Though arbitrarily chosen, these criteria have been used as rigid diagnostic benchmarks that have prevented individuals with Lyme disease from obtaining treatment. Diagnosis of Lyme disease by two-tier confirmation fails to detect up to 90% of cases and does not distinguish between acute, chronic, or resolved infection.
The Centers for Disease Control and Prevention (CDC) considers a western blot positive if at least 5 of 10 immunoglobulin G (IgG) bands or 2 of 3 immunoglobulin M (IgM) bands are positive. However, other definitions for western blot confirmation have been proposed to improve the test sensitivity. In fact, several studies showed that sensitivity and specificity for both the IgM and IgG western blot range from 92 to 96% when only two specific bands are positive.
And here’s what they would say about LaVerne if all her tests had come back negative:
Seronegative Lyme Disease
A patient who has tested seronegative may have a clinical presentation consistent with Lyme disease, especially if there is no evidence to indicate another illness.
Although many individuals do not have confirmatory serologic tests, surveillance studies show that these patients may have a similar risk of developing persistent, recurrent, and refractory Lyme disease compared with the seropositive population.
In other words, LaVerne’s likelihood of having Lyme disease is the same whether her lab tests were positive or negative? My warning antennae go up sharply!
What this come down to is a “diagnosis of exclusion.” If LaVerne does not have RA, and probably does not have fibromyalgia, and none of her doctors can come up with a clear diagnosis that explains her symptoms, then it’s Lyme disease by a process of elimination – especially when you look at that list of symptoms, many of which are quite commonplace.
What’s wrong with this? In my opinion, there are two problems. The first is a logical failing: it’s tempting to try to come up with a single diagnosis to explain a disparate array of symptoms. A few years ago I was having, at the same time, a persistently stiff neck and also upper GI pains. The stiff neck disappeared when I got a prescription for eyeglasses that let me look at my computer screen without tilting my head down to look over the top, and the upper GI pains were due to reflux. But they could both have been Lyme disease symptoms – and I did have Lyme disease, complete with bull’s eye rash, about 12 years ago!
The second, and a good deal more serious, is that a decision to treat so-called “seronegative Lyme disease” would likely lead to lengthy antibiotic treatment courses that might not be necessary and could produce definitely negative consequences. Such treatment would probably kill all or most of the beneficial micro-organisms in the GI tract, and lead to really troublesome opportunistic infections such as Clostridium difficile, which is nasty and difficult to deal with. And it could very well produce resistant strains of some of the bacteria that normally colonize our bodies, causing serious soft tissue and upper respiratory infections.
The ILADS are in outspoken disagreement with the Infectious Disease Society of America (IDSA), which is the professional organization to which most infectious disease specialists adhere. The IDSA, and the infectious disease community as a whole, casts doubt on the notion of seronegative Lyme disease; their view is that if the Lyme pathogen is present it would be bound to leave some traces. And the ILADS are also in disagreement with the Centers for Disease Control. It’s worth pointing out that neither the President of ILADS, Dr Daniel John Cameron, nor the members of the working group that prepared the Lyme disease guidelines, are board certified in infectious diseases. Moreover, their guidelines, which were initially listed by the National Guidelines Clearinghouse (NGC), are no longer listed.
All of this said, it’s certainly possible that some people have seronegative Lyme disease. There’s no doubt that the pathogen is exceedingly elusive, and the antibody tests are far from perfect. Nevertheless, I don’t think that it’s remotely reasonable to conclude that there’s anything like an even chance that a person with someof the symptoms on that long list, whose Lyme tests are all negative, actually has Lyme disease. My guess is that an experienced and wise physician would go slowly in a situation of that kind, perhaps suggesting topical analgesics for pain. It might be nerve-wracking for the patient, but I doubt whether such a physician would initiate aggressive antibiotic treatment without some indication as to what pathogen was the culprit.
However, the wise and experienced physician would do well to consider other possibilities, such as …
other possible tickborne illnesses
In LaVerne’s case, the positive spinal fluid test made further investigation unnecessary. One could say that she was lucky. Other patients may not be so lucky. The same species of deer ticks, Ixodes scapulari, that carry the Lyme pathogen, may also carry at the same time other pathogens.
The more common of these other pathogens is babesia, a parasite or piroplasm that infects erythrocytes (red blood cells). The initial symptoms are fairly similar to those of Lyme disease. The bulls-eye rashes don’t appear, but then, in many Lyme patients these don’t show up until well after the other symptoms appear. A potentially useful difference between babesiosis and Lyme is that, whereas in Lyme disease, patients tend to get over the first wave of symptoms as the little spirochetes migrate to other parts of the body, in babesiosis, patients tend to feel worse as the infection progresses. That’s because the parasite is actually destroying their erythrocytes. Erythrocytes are the cells that latch on to oxygen in the lungs and convey it to all the cells in the body, so as the babesia parasite destroys blood cells, the body is deprived of oxygen even though the lungs themselves are working just fine. The condition is called hemolytic anemia, and in some people it can be life-threatening. Treatment for babesiosis is usually double therapy – an anti-parasitic drug called atovaquone plus an antibiotic of the macrolide family, such as erythromycin.
These are similar tick-borne illnesses caused by different, but related, bacterial pathogens. Both attack types of white blood cells – monocytes or granulocytes – and the result can be severe damage to several organ systems. These illnesses are uncommon, so far – the emphasis is on so far! Erlichiosis is somewhat more common in the middle-Atlantic states and the south, whereas anaplasmosis is more common in the Northeast. The number of reported cases of these two illnesses is relatively small, but there is evidence that many more persons have been infected without developing symptoms. Treatment usually consists of relatively short courses of doxycycline.
The risk from these diseases is somewhat aggravated by their relative rarity. A health-care worker who has not had experience with them might tend to stop the diagnostic process once the more usual suspects had been eliminated. Difficult diagnoses can lead to delays in treatment, or to misdirected treatment. If the patient should happen to be infected with the babesia parasite, but the physician is convinced that Lyme is the default option, the initial treatment is apt to fail, and the patient may be put at considerable risk. The situation may call for patience on the part of the physician – and fortitude on the part of the patient!
A Lyme disease vaccine?
Currently, no Lyme disease vaccine is available – for humans, at least! (There’s one available for dogs, and it works prettty well.) A vaccine was developed by SmithKline-Beecham (now GlaxoSmithKline – GSK), but was taken off the market in 2002 because of lawsuits claiming that the vaccine caused Lyme disease. The vaccine was administered as a series of three injections, and it had a reported efficacy rate of 78%. There never was any evidence that the vaccine caused Lyme. Objections to it were based on the way it was licensed, which was interpreted as resulting in the vaccination of lots of people who would be highly unlikely ever to be exposed to the tick. This might have been a bit of overreach on the part of the developer, who obviously wanted to have the vaccine used as widely as possible.
In the light of that fiasco, pharma is treading lightly. Other vaccines are in clinical trials. We’ll have to wait and see how effective they turn out to be, and how they fare in an environment which has become (in some quarters at least) highly suspicious of vaccines. I’ll have more to say about vaccines in a future piece, but an effective Lyme vaccine would be a Good Thing.
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I look forward to seeing your comments and criticism of this, and will try to address them. I note a comment that I should not use the “Doc Gumshoe” nom de plume, since I am not a doctor and don’t pretend to be. But calling myself “Medical Writer Gumshoe” is a bit awkward, don’t you think? I hope you don’t mind if I stick with Doc Gumshoe. I think of myself as a guy to whom folks put the question, “What’s up, Doc?” My answers will be based on curiosity, skepticism, and, as always, applying myself.
— Michael Jorrin, (aka Doc Gumshoe)
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