From the Desk of Dr. Nev Zubcevik
A letter to our supporters from Dr. Nev Zubcevik, Chief Medical Officer, on a new clinical tool that will help doctors better understand & care for patients with neurological Lyme disease.

Dear community members and supporters,

As a physical medicine and rehabilitation physician, my primary focus is on identifying the root cause of my patients’ illnesses. Only by addressing the underlying cause can we effectively rehabilitate our patient’s injuries. Throughout my years of practice, I have witnessed the devastating impact of untreated or under-treated Lyme disease infection on patients’ nervous systems. This destructive effect severely impairs their cognitive abilities, physical functioning, and overall quality of life. Our team at Invisible International has developed a clinical guide to assist clinicians in the recognition of neurological Lyme disease symptoms and subsequent diagnostic, testing, and treatment strategies to help diagnose and treat patients faster. We are grateful to donors like you who help fuel our work to pave the way for making sure every physician is a Lyme+ knowledgeable physician. To partner with us in developing and disseminating our education to physicians, please consider a tax-deductible donation today.

Lyme patients are at an increased risk of suicide

My deepest concern as a physician is that Lyme patients are extremely vulnerable as a population. Research has shown that Lyme patients face a heightened risk of suicide, primarily because their neurological injury remains largely invisible, causing immense suffering (Fallon et al., 2021). Understanding the clear mechanism of injury caused by the Lyme bacterium is crucial in explaining this invisible damage. By raising awareness among physicians and healthcare professionals about this mechanism, we can approach these patients with a clearer path to diagnosis and treatment.

Our study shows damage to the nervous system

In 2019, our team at Harvard conducted research and published the study “Association of Small Fiber Neuropathy and Post Treatment Lyme Disease Syndrome,” where we investigated the potential link between small fiber neuropathy (SFN) and post-treatment Lyme disease syndrome (PTLDS). Our findings provided both a biomarker of injury and a testing protocol that other physicians can use to objectify their patients’ neurological injury caused by Lyme disease.

In the study, we explored ten participants with a history of PTLDS, and through skin biopsies, we discovered evidence of SFN in all cases. Specifically, nine participants displayed sensory SFN with abnormal epidermal nerve fiber density, and seven individuals exhibited severe SFN. We observed autonomic dysfunction in all PTLDS participants. Additionally, our study revealed reduced cerebral blood flow in all PTLDS patients, suggesting cerebral hypoperfusion.

Our findings suggest that SFN and related dysautonomia may serve as objective markers for PTLDS. The assessment of small fiber density and autonomic dysfunction using skin biopsies and reflex testing could be valuable in therapeutic trials and offer physicians a clearer understanding of PTLDS and its associated symptoms, including cognitive impairment and brain fog.

The mechanisms like direct cytotoxicity by the spirochete, neurotoxic mediators during host-pathogen interactions, and triggered autoimmune reactions are likely to be involved in the pathogenesis of this neuronal injury.

The mechanism of neuronal injury in Lyme is clear

The article “The Pathogenesis of Lyme Neuroborreliosis: From Infection to Inflammation” by Rupprecht et al. (2008) is a crucial source of information that sheds light on the intricate mechanism of neuronal injury in Lyme disease. Lyme neuroborreliosis, caused by the spirochete Borrelia burgdorferi, can lead to neurological manifestations, including painful meningoradiculitis and cranial or peripheral neuritis. Understanding the pathogenesis of this condition is essential for effective management and treatment.

The infection process begins with the spirochetes entering the tick’s salivary glands during feeding and subsequently invading the host’s skin, leading to a local infection called erythema migrans. During the second stage of Lyme disease, the spirochetes can spread to various organs, including the central nervous system (CNS), resulting in neurological complications.

The spirochetes employ various strategies to evade the host’s immune system. They downregulate immunogenic surface proteins, such as OspA and OspC, to minimize their recognition by immune cells. Additionally, they express complement-neutralizing proteins and induce anti-inflammatory cytokines to suppress the host’s immune response. These mechanisms enable the spirochetes to establish infection and persist in the host.

Once the spirochetes enter the CNS, they encounter local immune cells, leading to the production of proinflammatory cytokines and chemokines. The chemokine CXCL13 plays a pivotal role in attracting B-lymphocytes into the cerebrospinal fluid (CSF), resulting in the production of borrelia-specific antibodies. This immune response, however, can also contribute to the neuronal injury.

The neurological dysfunction observed in Lyme neuroborreliosis may result from multiple factors. The spirochetes can directly adhere to neural and glial cells, causing cytotoxicity and inflammation in the surrounding tissues. Furthermore, they induce the release of neurotoxic substances, such as nitric oxide and quinolonic acid, exacerbating the damage. Additionally, the immune response may lead to an autoimmune reaction, with antibodies targeting neural antigens due to molecular mimicry, further contributing to inflammation and demyelination.

The demyelination process is particularly significant as it can disrupt nerve function and result in various neurological symptoms. Damage to the myelin sheath, the protective covering of nerve fibers, can lead to muscle weakness, numbness, tingling, and coordination difficulties.

What we are doing and how you can help

The mechanisms discussed, including immune evasion, inflammation, and demyelination, contribute to the complex clinical picture of this condition. Understanding these processes is crucial for developing targeted therapies to mitigate nerve injury and promote recovery in patients with Lyme neuroborreliosis. We must do better to educate the medical system about this mechanism of injury. With this information, the stigma will disappear, and the patients will be listened to and treated properly. Insurance companies will follow this by covering treatments.

Education leads to meaningful and lasting change. And we are paving the way.

Just in the last 6 months, we have educated physicians via the Montecalvo Education Platform for Vector-Borne Illness to impact over 750,000 patient visits. Our virtual courses have been viewed over 14,000 times. This work is only possible with your support: we rely on gifts from donors like you to make sure no Lyme patient is left behind. Your donations help us expand programming, send our team to conferences, and help us develop educational guides. Please consider making your tax-deductible donation today.

From all of us here at Invisible,
With gratitude,

Nevena Zubcevik, DO
Chief Medical Officer
Invisible International

References:

1. Fallon BA, Madsen T, Erlangsen A, Benros ME. Lyme Borreliosis and Associations With Mental Disorders and Suicidal Behavior: A Nationwide Danish Cohort Study. Am J Psychiatry. 2021 Oct 1;178(10):921-931. doi: 10.1176/appi.ajp.2021.20091347. Epub 2021 Jul 28. PMID: 34315282.
2. Novak P, Felsenstein D, Mao C, Octavien NR, Zubcevik N. Association of small fiber neuropathy and post treatment Lyme disease syndrome. PLoS One. 2019 Feb 12;14(2):e0212222. doi: 10.1371/journal.pone.0212222. PMID: 30753241; PMCID: PMC6372188.
3. Rupprecht TA, Koedel U, Fingerle V, Pfister HW. The Pathogenesis of Lyme Neuroborreliosis: From Infection to Inflammation. Mol Med. 2008 Nov-Dec;14(11-12):205-12. doi: 10.2119/2007-00091.Rupprecht. PMID: 18787810; PMCID: PMC2270991.

Dear community,

As you all are aware, the treatment of patients suffering from tick-borne diseases can be quite complicated. However, a research article published in Antibiotics (June 2023) by Trouillas and Franck (1) offers an encouraging method for addressing the severe neurological symptoms associated with these diseases. They observed full recovery in seven out of ten patients with severe neurological Lyme disease, marked by paresis. Importantly, these patients stayed healthy even two years after recovery.

Patients in this study had been dealing with their illnesses for periods ranging from six months to seven years. None had been treated with antimicrobials. The researchers scrutinized several recognized, but under-researched, problems within the field.

Their findings contradicted the existing recommendation to treat neuroborreliosis with 21 days of a single drug, Ceftriaxone. Out of 16 treatment studies focused on patients with Neurologic Lyme, only 15 individuals could be diagnosed as having late-stage Lyme neuroborreliosis. Interestingly, studies employing long-term antibiotics showed better outcomes for patients (2,3,4).

A key aspect of their research was the consideration of patients suffering from multiple tick-borne diseases simultaneously, such as Borrelia, Babesia, Bartonella, and Anaplasma.

Patients were treated until their neurological symptoms disappeared. If symptoms recurred after a period of remission, treatment was resumed and continued until remission could again be achieved.

In line with this, the researchers treated patients for Lyme disease (Borreliosis) and other co-infections such as Babesiosis, Bartonellosis, and Anaplasmosis, if a patient’s symptoms and lab tests suggested the presence of these diseases. They used a combination of clinical judgment and lab testing to guide their treatment decisions. They also referred to studies suggesting the persistence of these infections, which justified the need for prolonged antimicrobial treatment.

Treatment continuation was decided based on the patient’s clinical response, emphasizing a patient-centric approach. The results were significant: seven out of ten patients regained their health, allowing them to resume societal and family roles, without previous discomfort. On average, treatment duration needed to achieve this was 25 months. This study represents a promising development in the management of severe tick-borne diseases, although more research is needed to validate and apply these findings more broadly.

 

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Help us fund the Tick Bytes Clinical Data Repository

Patients who suffer with tick-borne diseases need faster research results that translate to meaningful clinical interventions and better outcomes. A solution to this is Invisible’s Tick Bytes Clinical Data Repository. This is an initiative to organize clinical information from the ten best tick-borne disease physicians across the nation within a privacy-protected database, enabling researchers to analyze and publish best practices for treating patients.

With this precision medicine approach, more quality evidence will reach physicians, insurers, and the government, leading to better patient outcomes, insurance coverage, and a deeper understanding of tick-borne diseases.

Based on prior work by Dr. Nevena Zubcevik and Dr. Charlotte Mao at the Dean Center for Tick Borne Illness in Boston, it’s anticipated that it will take 12 months for database set-up, and 24 months for data collection, analysis, and publication. To move forward, all we need is funding from people like you. Please help us launch this important initiative.

References:

1. Trouillas P, Franck M. Complete Remission in Paralytic Late Tick-Borne Neurological Disease Comprising Mixed Involvement of Borrelia, Babesia, Anaplasma, and Bartonella: Use of Long-Term Treatments with Antibiotics and Antiparasitics in a Series of 10 Cases. Antibiotics (Basel). 2023 Jun 7;12(6):1021. doi: 10.3390/antibiotics12061021. PMID: 37370340; PMCID: PMC10294829.
2. Logigian EL, Kaplan RF, Steere AC. Successful treatment of Lyme encephalopathy with intravenous ceftriaxone. J Infect Dis. 1999 Aug;180(2):377-83. PMID: 10395852  DOI: 10.1086/314860
3. Oksi, J.; Kalimo, H.; Marttila, R.J.; MariamaÃàki, M.; Sonninen, P.; Nikoskelainen, J.; Villanen, M.K. Inflammatory brain changes in Lyme borreliosis. A report on three patients and review of literature. Brain 1996, 119 Pt 6, 2143-2154. https://doi.org/10.1093/brain/119.6.2143
4. Fallon, B.A.; Keilp, J.G.; Corbera, K.M.; Petkova, E.; Britton, C.B.; Dwyer, E.; Slavov, I.; Cheng, J.; Dobkin, J.; Nelson, D.R.; et al. A randomized, placebo-controlled trial of repeated IV antibiotic therapy for Lyme encephalopathy. Neurology 2008, 70, 992–1003. DOI: https://doi.org/10.1212/01.WNL.0000284604.61160.2d