Young Hearts, Hidden Battles: A pediatric infectious disease physician’s perspective on Lyme disease and neuropsychiatric manifestations

Distinguished Speaker Series Transcript

 

“Everything about this disease is infinitely more complex and nuanced than is taught to physicians.”

– Charlotte Mao, MD MPH

Charlotte Mao: Thank you Dana for that amazing introduction and Brandi too. I want to thank Brandi for so generously opening up your beautiful home for this event and Bay Area Lyme Foundation for inviting me to speak tonight about my personal perspectives as a pediatric infectious disease physician about Lyme disease in children, particularly neuropsychiatric manifestations. 

When Brandi asked if I might give a talk for this Speaker Series, I suggested this topic because, first, I hope there might be something instructive in some of my personal musings on key lessons I’ve learned about Lyme disease in the course of caring for children with this contested disease. Second, I want to highlight neuropsychiatric manifestations because I feel they generally are the least recognized by physicians as being potential manifestations of Lyme disease. Yet, taking into account all levels of severity, they are, in my view, actually quite common—certainly not uncommon—and when severe, they are among the most devastating of Lyme manifestations to the lives of children and their families.

So, I’ll start with my origin story of how I got interested in Lyme disease after spending the first 20 or so years of my career focusing almost exclusively on pediatric HIV clinical care and clinical research at Boston Children’s Hospital. With the advances in HIV care with highly effective antiretroviral therapy and the level of acuity of HIV care decreasing, my clinical work shifted to also include seeing patients in the general ID or infectious disease referral clinic at Boston Children’s. It didn’t take long for me to find that Lyme disease was by far the single most common reason for referral for which I was seeing patients in this clinic. The volume of Lyme cases might not be surprising since Lyme disease is the most common vector-borne disease in the US. The latest estimate from the CDC is 476,000 new diagnoses per year. Also, as we all know, the Northeastern US is a highly Lyme endemic area, and finally, children aged five to nine years are the age group with the peak incidence of cases—presumably because they’re out playing in the grass and the woods and getting the most tick exposure.

“Lyme disease was by far the single most common reason for referral… I saw case after case of the confusing constellation of symptoms and signs with doctor after doctor not suspecting Lyme disease.”

– Charlotte Mao, MD, MPH

But still, I was surprised by the magnitude of patient referrals for this diagnosis compared to all others. What really surprised me, though was the cases I saw: case after case of a confusing constellation of symptoms and signs with doctor after doctor not suspecting Lyme disease, just as Dana and Brandi both described in their own stories, and I myself at that point likewise would not have suspected it. But it proved to be Lyme disease—more accurately, I should call it Lyme disease complex—and I’ll return to that point later. Sometimes, the diagnosis became apparent because a clear objective manifestation eventually developed like meningitis, Lyme meningitis confirmed by a spinal tap, or the child developed a Bell’s Palsy, or in other cases because Lyme testing was finally done and was definitively positive. Lo and behold, on searching the literature, I found report after report supporting the idea that these unusual symptoms my patients had were likely related to their Lyme disease. Thus began my education in Lyme disease or, as I call it, my down-the-rabbit-hole experience.

When I started seeing patients in this clinic, I had accepted what I read in traditional Lyme disease diagnostic and treatment guidelines, review articles, et cetera, as an accurate and full reflection of the existing evidence base in the medical and scientific literature. The impression I had from what I read was that Lyme disease was grossly over-diagnosed that many patients had unexplained nonspecific symptoms that were mistakenly attributed to Lyme disease, either self-diagnosed or by an alternative camp of physicians who had their own set of guidelines and held controversial even fringe views that were not supported by existing science. I’d read that chronic Lyme disease was a controversial diagnosis, and the impression I had was that there was no good evidence for Lyme persisting as an active infection after standard courses of therapy. 

The more patients I saw and the more I read in the primary scientific and medical literature, both clinical and basic science, the more I came to believe that the traditional paradigm of Lyme disease might be an elegant model for the diagnosis and management of the ‘typical’ patient as defined by that paradigm but grossly failed for the ‘atypical’ patient and—in fact—put blinders on physicians’ eyes leading to missed or late diagnoses for a very large number of Lyme patients.

“The more patients I saw and the more I read in the primary scientific and medical literature, the more I came to believe that the traditional paradigm of Lyme disease might be an elegant model for the diagnosis and management of the ‘typical’ patient as defined by that paradigm but grossly failed for the ‘atypical’ patient and—in fact—put blinders on physicians’ eyes leading to missed or late diagnoses for a very large number of Lyme patients.”

– Charlotte Mao, MD, MPH

While any single atypical manifestation might indeed be atypical or infrequent, the collective number of all atypical cases together, I suspected, had to be a sizable proportion of Lyme cases. The experience was an eye-opening and life-altering educational experience that led to my leaving Boston Children’s Hospital and eventually moving to the Pediatric Infectious Disease Division at Mass General to see patients at a multidisciplinary clinic for children and teens with complex Lyme disease at Spalding Rehab Hospital, the Dean Center for tick-borne illness, where my education continued.  So, what are some of the lessons I learned? 

Lesson One: Everything about this disease is infinitely more complex and nuanced than is taught to physicians.

Starting with the most fundamental information physicians need to know to be able to recognize and diagnose Lyme disease, what are the potential clinical manifestations of this disease, and how can they present? Some broad categories of manifestations are not described well or even at all in the standard paradigm, psychiatric symptoms being one such example. This despite a broad range of psychiatric symptoms being associated with Lyme disease in the medical literature, including anxiety, depression, personality changes, mania, bipolar disorder, panic attacks, OCD, violent outbursts, paranoia, hallucinations, schizophrenia, catatonia… they’ve all been described in the literature. In children and adolescents, common neuropsychiatric symptoms include difficulty with attention and concentration, behavioral and mood disturbances such as irritability, oppositional behavior, depression, and new onset anxiety disorders. 

In a US study of pediatric patients with neurologic Lyme disease, behavioral or mood disturbances were the second most commonly reported symptoms after headaches, occurring in 38% of their patients with Lyme neuroborreliosis. Yet commonly used medical references like the American Academy of Pediatrics Red Book, which is considered the Bible of infectious disease for pediatricians, has no mention of psychiatric manifestations in its chapter on Lyme disease, and the latest version of the most commonly used diagnostic and treatment guidelines for Lyme disease authored by representatives from three different medical societies, namely infectious disease physicians, neurologists, and rheumatologists specifically recommend against routine testing for Lyme disease in children presenting with developmental, behavioral or psychiatric disorders stating, I quote: “There are no data to support a causal relationship between tick-borne infections and childhood developmental delay or behavioral disorders such as attention deficit hyperactivity disorder, pediatric autoimmune and neuropsychiatric disorders associated with streptococcal infections [PANDAS], learning disabilities or psychiatric disorders.”

“Commonly used medical references like the American Academy of Pediatrics Red Book, which is considered the Bible of infectious disease for pediatricians, has no mention of psychiatric manifestations in its chapter on Lyme disease.”

– Charlotte Mao, MD, MPH

These guidelines fail to acknowledge any of the numerous published reports of psychiatric symptoms in children with Lyme disease, including a striking series of three papers describing psychiatric manifestations of Lyme disease in children that are the first such papers that I’m aware of by lead author Andrew Pachner, a young neurologist at Yale at the time. Included in his reports were five patients with neuropsychiatric symptoms, and one of them, the fifth patient, had such a notable case that Pachner and his colleagues reported it in even more detail a couple of years later in a separate case series. So clearly, these authors were struck by these cases, particularly the fifth patient whose case they reported in three separate publications over three to four years. There’s even an excellent 1991 lay article entitled Bicycle Boy* that describes this fifth patient’s case and the young male Yale neurologist’s diagnosis of it as being due to neurologic Lyme, which you could probably still find online.

I’m going to recount some details of these patients as it troubles me greatly that these psychiatric cases were described in the historical literature from more than 30 years ago, and some 500 have since been published on Lyme disease, on psychiatric manifestations of Lyme disease in adults and yet to this day, psychiatric symptoms remain so poorly acknowledged or recognized as manifestations of Lyme disease, especially in children. 

The five patients in the first two papers were all infected before the age of 10 and developed psychiatric diseases one to eight years later. All five presented with personality changes during childhood. Examples of their symptoms included irritability, wide mood swings, difficulties with concentration and interacting with peers, loss of friends, drop in school, grades, seizures, frank psychosis with auditory hallucinations, personality changes, and sleep disturbances. And in the fifth patient, a 12-year-old boy with an anorexia nervosa-like syndrome for many months that developed two months after treatment for Lyme arthritis, he became depressed, uncommunicative, and obsessively dieted and compulsively exercised on an exercise bike. Hence, his name was dubbed Bicycle Boy in that lay article. This led to a severe weight loss of 31 pounds and hospitalization in a psychiatric institute. 

“It troubles me greatly that these psychiatric cases were described in the historical literature from more than 30 years ago, and some 500 have since been published on Lyme disease, on psychiatric manifestations of Lyme disease in adults, and yet to this day, psychiatric symptoms remain so poorly acknowledged or recognized as manifestations of Lyme disease, especially in children.”

– Charlotte Mao, MD, MPH

Turns out that young Yale neurologist Pachner was moonlighting at the psychiatric Institute and, given the child’s history of Lyme arthritis, suspected he might have neurologic Lyme. Based on his history along with positive Lyme testing in the blood (although notably negative testing in the spinal fluid), he was treated with intravenous penicillin for 14 days and, within several weeks, was eating more, gaining weight, talking again, and had returned to school. In the Bicycle Boy lay article where Pachner is interviewed, it’s reported his behavior changed within days of initiation of therapy and Pachner describes watching those first changes as “like a fairytale”. Over the next several months, the boy’s behavior returned to normal, and at the time of the third paper, he remained asymptomatic for three years. 

 

Lesson Two: Complex Lyme disease, which refers to the idea of chronic persistent or chronic recurrent and often debilitating symptoms in these patients, is typically not just  a Borrelia burgdorferi infection, but rather what I call a ‘multiple hits’ model of disease that includes other co-infections.

These other infections don’t have to be acquired at the same time, for example, with a single tick bite, but rather can be acquired progressively over time and via other means, not necessarily tick transmission. In terms of neuropsychiatric manifestations, other co-infections that are high on the list to think about include Bartonella, Babesia, Chlamydia, and Mycoplasma pneumoniae. In some patients, potential hits can include non-infectious hits such as environmental toxic exposures. 

One that particularly comes to mind is mold and mold toxin, (also known as mycotoxin) exposure, which I don’t really have the time to talk about in detail today. I’ll just note that learning about the health impacts of mold and mycotoxin exposure came a bit later in my educational journey and it is not something that is taught to physicians in their medical training. I see it as an area of emerging science that I firmly believe may play a significant role in a subset of patients struggling with persistent symptoms, including neuropsychiatric ones related to Lyme disease and, in particular, I found in some of my patients with PANDAS/PANS, which is the next lesson I’m going to be coming to, that there seems to be a significant intersection between mold mycotoxin exposure and Lyme, Bartonella, and tick-borne disease-related symptoms in these patients. 

In terms of neuropsychiatric symptoms, the possibility of Lyme and Bartonella co-infections, in particular, is a distinct consideration. Borrelia and Bartonella infections share a lot of potential symptoms, especially neuropsychiatric and neurologic ones. Asymptomatic infections are common in both these infections as demonstrated in studies in healthy blood donors and other asymptomatic persons. They’re both organisms that have the capacity for what’s been called stealth pathogenesis as they have multiple mechanisms by which they can evade the immune system and lie silent for extended periods, alternating with periods of active infection causing immune-mediated disease and inflammation.

“Borrelia and Bartonella infections share a lot of potential symptoms, especially neuropsychiatric and neurologic ones. They’re both organisms that have the capacity for what’s been called stealth pathogenesis as they have multiple mechanisms by which they can evade the immune system and lie silent for extended periods alternating with periods of active infection causing immune-mediated disease and inflammation.”

– Charlotte Mao, MD, MPH

 

Lesson Three: It’s all in the history. Being able to make a clinical diagnosis of Lyme disease, which ultimately is what’s needed with Lyme disease, requires taking an extremely thorough and comprehensive medical history.

The physician needs to do a very detailed review of systems as patients commonly have symptoms that they don’t think to report that may increase suspicion of Lyme disease or co-infections. And I always say when obtaining a history, ask the child directly about symptoms. I found some children don’t verbalize complaints to their parents, and they will report symptoms only upon questioning. At visits, parents sometimes express that they’re hearing about these symptoms for the first time and report they think their child hides symptoms or doesn’t want to talk about them maybe because they don’t want to go to the doctor.

“At visits, parents sometimes express that they’re hearing about these symptoms for the first time and report they think their child hides symptoms or doesn’t want to talk about them maybe because they don’t want to go to the doctor.”

– Charlotte Mao, MD, MPH

As an example, I had a young child with multiple unexplained physical and emotional symptoms, joint pains, mood swings, totally out of character. She was tearful, irritable, upset, and whining much more than usual, episodes of anxiety followed by increased heart rate, but it was attributed maybe to some change in her environment. She had started a school that she didn’t particularly like. She had random intermittent physical complaints, fatigue, and urinary complaints, including pain with urination, uncharacteristic incontinence, new constipation, and sensitivity to lights and sounds. When questioned about numbness and tingling in her extremities, she admitted to having this intermittently. I find this is a symptom that children sometimes don’t report. Since peripheral neuropathy with numbness and tingling is a well-recognized neurologic manifestation of Lyme disease, even in the traditional paradigm, it sometimes can help bolster the case for Lyme disease to other clinicians who may be skeptical of the diagnosis or to insurance companies. And then regarding her symptoms of urinary voiding problems and new constipation, these are symptoms that have been described in the literature as being associated with Lyme disease, and the feeling is that they suggest involvement of the autonomic nervous system, so it’s autonomic dysfunction, and the autonomic nervous system is the part of the nervous system that either controls or plays a role in automatic bodily functions like heart rate, blood pressure, gastrointestinal motility or regulation of bladder voiding. And so again, examples of symptoms that are not discussed at all in the traditional paradigm, but when you hear clues like that when they’re new onset in a child, then you do want to think about autonomic dysfunction and the possibility of Lyme disease, or I also think that Bartonella could potentially cause this. 

 

Lesson Four: The association between PANDAS/PANS and Lyme and Bartonella is real and needs to be addressed.

For those who may not be familiar with PANDAS/PANS—or is everyone here familiar with it? Because then I could maybe skip through. I think everyone is! Okay, let’s go on. So, as you all know, the proposed mechanism is that the child, in response to an infection, forms antibodies to protein fragments of strep bacteria or one of these other organisms that have molecular mimicry, as we call it, with human host proteins in areas of the brain responsible for movement disorders or other neuropsychiatric symptoms. And strikingly to me, the clinical criteria of PANDAS/PANS overlap fully with potential neuropsychiatric or physical manifestations of Lyme disease or Bartonellosis or both, except for the emphasis on an abrupt, dramatic onset of symptoms. I know a number of clinicians who care for children with Lyme disease and Bartonellosis who have seen the same in their patients… that symptom onset is not the typical dramatic acute onset overnight that is considered a defining criterion of PANDAS/PANS, but rather, the onset is more subacute. The 12-year-old boy in Pachner’s three reports would meet the diagnostic criteria for PANS with his obsessive dieting, compulsive exercising, and depression, and provides an example of how some neuropsychiatric manifestations of complex Lyme disease can be viewed as an infection-induced immune-mediated encephalitis.

Particularly striking to me is the fact that urinary voiding issues or potential physical manifestation in PANDAS/PANS, as I mentioned before, as they can be seen in Lyme disease, and I suspect again from anecdotal experiences I mentioned, possibly also Bartonellosis. I have my own hypothesis that’s too technical to go into detail here, but which I think might potentially explain how, in PANDAS/PANS, so many different infectious and even non-infectious triggers might result in the same flavor of symptomatology and this constellation of neuropsychiatric and physical symptoms. The hypothesis involves activation of Bartonella, which is the ultimate stealth pathogen, as I mentioned, by multiple diverse triggers, including the infectious and non-infectious triggers commonly cited, inducing PANDAS/PANS. I’m happy to discuss that in more detail with anyone if they’re interested, but in the interest of time, I won’t do so here. So, let’s go quickly through the last few lessons.

 

Lesson Five: Standard approaches to Lyme testing and the interpretation criteria for those results are problematic and miss many infected persons, particularly patients with neurologic disease, as opposed to joint involvement in arthritis.

That, in fact was shown in the single study that forms the basis for the choice of those criteria, surprisingly. Patients with arthritis had—it was 96% or 98% of patients that were detected—whereas for neurologic patients, it was only 72%. So if you’re evaluating for Lyme as well as Bartonella testing, which, by the way, Bartonella serology testing at standard commercial labs is, in my view, exceedingly low sensitivity. You cannot just look at the labs, count up the number of bands, and assume — (I am referring here to the bands on the Western blot. I assume maybe some of you or a number of you are familiar with bands on Western blots) —and assume that you have ruled out Lyme disease. Also, you need to seriously consider using specialty labs that test for more than the ten select bands that are reported by Standard Labs. 

The topic is far too much to cover here, but if you’re interested in details with supporting references on what is problematic about these standard interpretation criteria for Lyme antibody testing, you might want to check out the Lyme disease section of a paper I recently co-authored with two psychiatrists, Bob Bransfield and Rosalie Greenberg entitled Microbes and Mental Illness Past, Present, and Future. 

So, some concluding thoughts. To parents who feel challenged trying to work with their child’s doctors to get them to consider workup for Lyme disease or co-infections or PANDAS/PANS, I say trust your instincts. You know your child best and are their best advocate. There is nothing like lived experience to make you an expert on a condition. Don’t feel shy to beg or demand testing, which is something I commonly heard from parents that they needed to do with their doctors. Keeping in mind, as I mentioned before, the limitations of testing. If you’re not getting anywhere, look for a clinician who will be your partner. There are lists of physicians and other clinicians who take a broader, more open-minded view of complex Lyme disease and evaluate and treat accordingly. 

I didn’t cover treatment at all in this talk, but suffice it to say that response to treatment is highly variable. The rapid response experienced by the 12-year-old boy with anorexia nervosa-like syndrome is one end of the bell curve in terms of duration of treatment and rapidity of a sustained response. Although treatment courses are sometimes far lengthier and require multimodal treatments, there are so many success stories where severely ill children have gotten their lives back. It takes a lot of trial and error, and it’s a grueling road at times. But yes, the hope is always there and lives have been transformed with the appropriate evaluation and treatment. 

“There are so many success stories where severely ill children have gotten their lives back. It takes a lot of trial and error, and it’s a grueling road at times. But hope is always there, and lives have been transformed with the appropriate evaluation and treatment.”

– Charlotte Mao, MD, MPH

I’ve also been pleasantly surprised and enormously impressed with many of my most severely affected patients who do not seem bitter over their experience, even when the medical system failed them over and over through their illness. I think children have incredible resilience, idealism, and hope, and I feel that often, even if they still have some physical symptoms, hopefully in a milder form, they’re happy to be back to living their normal lives. It’s the most gratifying thing to see them return to their friends and schooling, graduate from high school, et cetera, and many of them become old souls of sorts, truly wise beyond their years because of their experience. So what needs to happen? 

 

Lesson Six: We need a paradigm shift in the understanding of complex Lyme disease, but how do we get there?

Clearly, physician education is an enormous unmet need. Patient-focused research to advance the diagnosis and treatment of these very complex and misunderstood conditions. And that’s what I love about Bay Area Lyme. There is a scientific advisory board that helps with the grant-making process, but the great majority of the core team that is directly responsible for that grant-making process are former Lyme patients or lay people with a laser focus on what research is needed to best help patients. So, it’s a real honor to be associated with Bay Area Lyme. I’m now part of that science team, and I’m so grateful to all of you for coming tonight to hear Dr. Michal Tal and me speak. If anyone has any questions or wants to discuss some of the topics I raised more, I’d love to have lengthy conversations.

Thank you so much.

*Recovery from Lyme-Induced OCD: The Bicycle Boy. Washington, DC: The Washingtonian; (1991).