Sit Down Before Reading: A Memoir by Dave Bexfield
Days after I discovered I had Lyme disease and not multiple sclerosis, struggling to comprehend just how such an error could possibly have occurred, I had noticed the striking anomalies in the U.S. MS prevalence maps: the overwhelming tilt of cases being diagnosed in the far Northeast and upper Midwest, the heart of tick country. The more I observed, the more alarmed I became. Evidence of a lurking tickborne plague seeped into my reading, my social media, my MS communities. It was and remains unmissable.
“It started with tingling in hands shortly after I moved to New England from the Chicago area,” writes an MSer in a recent issue of Momentum, the National MS Society’s quarterly magazine. The issue featured letters to the editor from Pennsylvania, Pennsylvania again, Massachusetts, and Illinois, broken only by a lone letter from the Lone Star state. On my Facebook, Instagram, and Twitter feeds, daily pleading for help with unusual MS symptoms—crushing pain, odd cardiac issues, stubborn UTIs—symptoms dreadfully common in Lyme, turned overwhelming in their frequency. After fruitlessly trying to reach out a few times to offer assistance, I realized my folly. Like Dr. Marshall 30 years ago, I was powerless to help without convincing evidence at my back. Until then, I was a grasping-at-straws kook. Even among cherished members of ActiveMSers.org who would be inclined to believe me, what could I do? What?
Sure, I could inform Barbara from Minnesota that she has glaring warning signs of being misdiagnosed. But then in the same breath I’d have to tell her that the current tests for Lyme disease are inaccurate, few doctors would entertain her case without a positive test, and the treatment options for untreated Lyme—if she could get treated at all—are decidedly uncertain, costly, and not covered by insurance. That she is, to use an unoriginal opaque euphemism, fudged. Thanks so much, Dave.
If I was going to start un-misdiagnosing people, I needed to give them an exit ramp that didn’t resemble the closing scene from Thelma and Louise. I reasoned that if I had the brains to figure out the source of my health issues and the wherewithal to finger a potential million MS misdiagnoses worldwide, maybe I could also somehow tackle the woeful testing issue. So, I started sleuthing around my own case to see what else the neurologists had missed, what they had overlooked and dismissed. It was easy to pinpoint the subjective clinical whiffs—the swollen knee, the cardiac issues, the facial palsy—but uncovering objective laboratory clues proved more challenging. Based on most Lyme disease studies, my spinal fluid held the most promise. But what to look for?
I started by examining any numbers of mine that were skewed out of range, and aside from the documented presence of oligoclonal banding (zero is normal) there were two other notable outliers: albumin (serum) and nucleated cell count, both of which were high. Indeed, my nucleated cell count was bonkers high at 14, far outside the normal range of 0-5. Were those signs of Lyme disease?
A high albumin serum would normally just mean that you are a bit dehydrated, but not when it comes to markers for Lyme disease. The central nervous system (CNS) is protected by both the blood-brain barrier and the blood-cerebrospinal barrier. While the former gets the most attention, the blood CSF barrier is more accessible to foreign invaders. A 2017 research study out of Germany analyzing neurological manifestations of neuroborreliosis states that “the albumin CSF-serum concentration quotient (QAlb) is generally considered as the best indicator for a blood-CSF barrier dysfunction.”
Fig. 1: Cerebrospinal fluid system, 11 February 2014 (Blausen.com staff (2014). "Medical gallery of Blausen Medical 2014". WikiJournal of Medicine 1 (2). DOI:10.15347/wjm/2014.010. ISSN 2002-4436). Fig. 2: A schematic sketch of blood vessels in the brain; March 2009 (Armin Kubelbeck, Wikimedia Commons)
Stick with me, here, because what they discovered is critically revealing.
[I am interrupting this analysis as the ghost of SDBR future. While most of Sit Down Before Reading was written and published in real time, Chapter 36 was written over the course of months. As new revelations emerged, past interpretation of data changed with it. Instead of revising and hacking up this part to mesh with later findings, I’ve opted to leave this deep-dive exploration into the minutiae of diagnostic markers relatively unchanged for reasons that will be illuminated pages from now. The following analysis is still quite relevant, only in ways unexpected. And rest assured, future entries are not going to be so technically dense, thank heavens. I will now return you to our story.]
Seriously, stick with me, here, because what they discovered is critically revealing.
In that particular study, 87% of the 68 patients with confirmed neuroborreliosis had elevated levels of albumin (serum) and 98.5% of patients had an elevated nucleated cell count—all but one. Something expected in 100% of cases of Lyme, though, was curiously absent in some patients. “Importantly, 6% of patients did not show Borrelia specific antibodies in the blood.” Like me, this subset of patients definitely had Lyme … and they definitely had zero detectable antibodies to the disease. The lack of antibodies is supposedly definitive evidence that Lyme disease is absent. That is a categorically false assumption—research consistently shows that Lyme can be present even when antibodies are AWOL.
There was one more alarming finding of note: a whopping 90% of patients with neurological Lyme disease had oligoclonal banding in their CSF, which also happens to be the signature marker neurologists use when diagnosing MS. Researchers in the 2019 study “The Cerebrospinal Fluid in Multiple Sclerosis” made a specific point to acknowledge this bias, as the detection of these same bands is thought to be “highly sensitive and specific for MS,” but when “inflammatory diseases are particularly considered, the specificity of OCB for MS drops substantially from 94 to 61%.” The study’s authors caution that the predictive value of OCBs depends on other factors, “such as cell counts or albumin/protein concentrations. E.g., in neuroborreliosis, OCB are frequently encountered, in contrast to MS, however, total protein concentration and CSF cell counts are substantially higher.” My protein was elevated, my albumin was high, and my cell counts were off the charts, nearly triple the expected maximum. Alarm bells should have been clanging.
If only there was a study that looked at CSF markers in both MS and Lyme and compared the two, now that would be enlightening. If only? Nearly 20 years ago a 2005 Scandinavian study, Relevance of immunological variables in neuroborreliosis and multiple sclerosis, looked specifically at those same markers in the two diseases.
The results generally mirrored those from that later German study when it came to their Lyme disease findings: 89% of patients with Lyme neuroborreliosis tested positive for borrelia antibodies (a disturbing 11% lacked antibodies), 92.6% of patients had an elevated nucleated cell count, 81.5% had elevated albumin, and 74% had banding in their CSF. But when it came to the MS patients in that study, the data gets far, far more interesting.
While an expected 81.5% of MSers had oligoclonal banding—not wildly different from the 74% in the neurological Lyme arm—the percentage of people diagnosed with MS who had elevated albumin, nucleated cell count, and positive antibodies for Lyme disease will have neurologists worldwide scrambling to crosscheck their own patient records. “But, but, but,” neuros will protest, “we often see those elevated numbers in our MS patients—they are not exclusive to Lyme!”
Are you sure they aren’t exclusive? Sure, sure? For my estimate to be correct that approximately one third of people believed to have MS are in reality misdiagnosed and instead are afflicted with Lyme disease, there is a narrow Goldilocks window where those numbers have to fall. Twenty percent? Too low. Forty percent? Too high. From a kid who watched too many episodes of Family Feud after school: Survey says!!!
Elevated albumin: 31%. Elevated nucleated cell count: 33.3%. Positive for borrelia antibodies: 26.2%. One third, one third, and with strong evidence that antibodies to Lyme are notably absent in 6-11% of patients with confirmed Lyme disease (add this to that 26.2%), drumroll… one third.
Jackpot. Reliable science has to be consistent. And it’s consistent. It’s absolutely consistent. Other CSF research in MS has consistently produce similar findings—for example 32% of MSers in another study had elevated albumin (serum). And the rate is steady across all types of the disease—relapse remitting, secondary progressive, and primary progressive.
The evidence appears to be piling up. For people diagnosed with MS, elevated albumin (serum) and total nucleated cell count seem like highly suspicious markers for Lyme disease, with or without antibodies to borrelia (their presence just makes it even more likely). To quote a certain Jesse Pinkman from Albuquerque’s Breaking Bad, “Yeah, science!” But as painful as it may be to read, none of this should be a shock to the laboratory research hounds who have been investigating biomarkers in cases believed to be MS. Because they’ve already identified a number of suspect markers—for Lyme disease—without ever realizing it.
One biomarker recently presumed to be sensitive for multiple sclerosis is something known as the central vein sign, or CVS, on MRI. What is it exactly? I’ll let the researchers from a 2022 study explain.
The central vein sign (CVS) is a central linear hypointensity within lesions, visualized on susceptibility-sensitive MRI sequences (such as T2*-weighted scans) and corresponding to the small vein or venule around which the lesion formed. The CVS has been proposed as a radiologic biomarker and is seen with high frequency in MS lesions such that it can effectively differentiate MS from other etiologies associated with nonspecific white matter lesions.
If this hypothesis is correct, it certainly could help clear up uncertainty that routinely swirls around MS diagnoses by helping to eliminate imposters. “Imaging findings in MS partially overlap with MS mimics such as vascular (mostly small vessel disease–associated) signal abnormalities, migraine, neuromyelitis optica spectrum disorder (NMOSD), and systemic lupus erythematosus (SLE)–associated cerebral vasculitis.” But scientists have repeatedly been flummoxed by studies that show that while the CVS shows up in the majority of suspected MS cases, and is often reduced or absent in the mimics, the marker is not quite universal. It keeps running into a familiar wall like a misguided Roomba: the wall of one third. “Of the new lesions that were eligible for CVS analysis, 68% were CVS+, which is in line with the overall rates of cross-sectional baseline CVS+ percentage previously described in MS,” reported the study’s authors. Another study landed at 69.6%. Close, but that elusive Cuban cigar has been just out of reach.
Until, possibly, now. Those numbers again fall squarely into our one third misdiagnosed Goldilocks zone. If the cerebral spinal fluid results align with the central vein sign—if the CSF from the CNS meshes with the CVS from the MRI—we may have just hit on both the acronym and diagnostic MS Powerball. If the two markers consistently go hand-in-hand—elevated albumin serum and total nucleated cell count in the spinal fluid combined with lesions on MRI that lack a central vein sign—researchers might be able to correlate them with further identifiers, perhaps even in blood work. Being able to diagnose MS accurately from an inexpensive blood test instead of an invasive needle-in-the-spine lumbar puncture would be a game changer—and in a tangible, not in a Theranos 2.0, way.
Since time is of the essence, to accelerate this research and give struggling scientists a helpful boost to see over the misdiagnosis fence—beyond standing on tippy toes or jumping awkwardly in a white lab coat to steal a glance—I’d recommend leafing through past studies. I am confident it’s all right there, already discovered, dissected, and distilled.
Past Perfect
You could start with the latest research, like the oral presentation Robustness of Emergent MS Phenotypes Derived from Multiprotein Serum Biomarker Data given at the Consortium of Multiple Sclerosis Centers (CMSC) Annual Meeting 2023 in June. The award-winning talk discussed “emergent MS subtypes associated with specific protein signatures” to help identify unique subsets of patients by looking at blood protein levels. They are indeed unique, as elevated protein levels are a known biomarker in the disease. Future research should investigate whether any of these protein signatures match the elevated protein levels that are a known biomarker of Lyme... in which case they could be identifying the unique subset of MS-diagnosed patients who have Lyme.
But among markers attached to Lyme disease, there is one that is so omnipresent it’s like Jimmy Stuart at Christmastime: CXCL13. You know, the “B-cell chemokine produced mainly by mesenchymal lymphoid tissue organizer cells, follicular dendritic cells, and human T follicular helper cells.” I don’t have the foggiest clue what I just quoted, but it could have outsized importance. And why do I think that? Researchers have discovered that “CXCL13 was associated with disease exacerbations and unfavourable prognosis in RRMS.” Yet critically, “increased CXCL13 was not specific for MS since subjects with viral/bacterial infections exhibited even higher levels.”
I’m not so sure the “highness” in these CXCL13 levels is the distinguishing factor that MS researchers believe it to be. But it’s a rock-solid marker for Lyme disease, with over 96% of cases in one study revealing demonstrably elevated levels of the chemokine in the CSF (blood tests were unremarkable). “The study confirms the relevance of CXCL13 as a diagnostic biomarker of [neuroborreliosis].” In 2005 a German research group, meanwhile, looked at the B-cell chemokine and found elevated levels in all types of MS. Wanna guess what percentage was elevated? Even though the sample size was relatively small, let’s just say that, predictably, the bed wasn’t too hard or too soft, but just right, hovering around 30%.
Regretfully, as this perfect storm rages, that same German research group, despite seeing the direct influence of Lyme disease on CXCL13 in their own research, as Lyme disease patients were included for comparison, came to the sinking conclusion… that instead of a sign of a potential MS misdiagnosis, it should be chalked up as an a-ha marker of the autoimmune disease.
Our results confirm a recent report about elevation of CXCL13 in neuroborreliosis (Rupprecht et al., 2005). In addition, we show that a high CXCL13 level can also be observed in non-neuroborreliosis patients, in particular in those with a disturbed BBB [blood-brain barrier]. Our PCR analysis of a total of 14 multiple sclerosis lesions and the CSF examinations indicated that intracerebral CXCL13 production is a feature of acute inflammation in the CNS.
Over and over, researchers confirm and reconfirm: If you’ve been diagnosed with MS and have got elevated CXCL13 in your CSF, you best start shopping for a new set of wheels, as in a wheelchair. “Positive patients were on average 7.5-times more likely to develop disease activity” during one study’s follow-up period compared to patients with normal levels. Alas, they admit even their robust study has limitations, as “elevated intrathecal CXCL13 synthesis may occur in other neuroinflammatory diseases, e.g., Lyme neuroborreliosis.”
You don’t say.
The best part of these diagnostic-focused twists is that the presence of some of these potential diagnostic markers for Lyme can be checked in most supposed MS patients virtually right away. As in during a long weekend between rounds of golf. Many patients diagnosed with MS undergo a spinal tap during diagnosis, meaning neurologists can simply check their medical records to see which of them have elevated levels in their CSF for the above markers suggestive of Lyme disease (elevated albumin serum and total nucleated cell count). And then, if their MRIs were done on a more sensitive 3T or 7T machine, doctors can look for a lack of a central vein signal on image scans for additional confirmation, if that connection proves to be accurate.
Patient being positioned for MR study of the head and abdomen. Device pictured: Siemens MAGNETOM Aera (1.5 Tesla superconducting magnet). 9 Oct 2017 (Ptrump16, Wikimedia Commons)
If this all sounds clear and straightforward, well, theoretically it very well could be. Which means initially it’s going to be an unmitigated cluster. Upwards of 3 million people are living with a diagnosis of MS… and I am rather confidently suggesting that as many as 1 million of those are likely misdiagnosed and instead have Lyme disease, which is kind of a lot. If I’m right, essentially overnight, MS neurologists are going to discover a river of potentially misdiagnosed patients—a third of their patients, and up to half in highly endemic areas. Pharmaceutical companies are going to have to recalibrate, as demand for expensive MS drugs plunges and the need for antibiotics surges. Infectious disease doctors are going to be overwhelmed. Primary care physicians are going to be swamped with questions and will have few answers.
The silver lining to this looming fiasco is that Lyme disease, in many cases, is curable and its treatment is orders of magnitude less expensive than treatment for multiple sclerosis. But treatment is no salve if it falls short of expectations.
I have already completed a 50-day course of IV antibiotics combined with nearly a year and a half of spirochete-busting oral antibiotics—a motley crew of doxycycline, minocycline, and others—and to combat potential parasitic coinfections, Malarone (atovaquone and proguanil). There have been myriad gains, and the resounding improvements in the bladder and bowel arena have been life changing—skip the Depends! No, we don’t need to pull into the next rest stop! Sleeping through the night!—but after early promise, leg strength and creeping numbness have stubbornly persisted and gains have retreated. More disturbingly, less than two months after my IV antibiotic infusions were complete, even my troublesome swollen feet returned.
I had been so confident, hopeful, that the ceftriaxone was going to work that I had made a “before” video to contrast with my certain future progress. To date I haven’t made another video. But the odds that I will are such that it would be decidedly unwise to bet against me. Or anyone with a form of chronic Lyme disease left untreated for years.
The reason? Potential treatment options abound. Even better, many have already been extensively studied and trialed. There’s just a single, complicating wrinkle to the research. No one realizes these treatment options even exist for Lyme. And no one would have any clue as to where or how to look for such research. Until now, thanks to our next delightful twist.