By Dirk Hoffman
Published December 18, 2023
A number of medical students are gaining valuable clinical research experience studying autonomic disorders under the direction of Svetlana Blitshteyn, MD, a clinical associate professor of neurology at the Jacobs School of Medicine and Biomedical Sciences.
The students see patients with Blitshteyn at the Dysautonomia Clinic in Amherst, which she founded in 2009.
Dysautonomia refers to a dysfunction of the autonomic nervous system (ANS) that generally involves disturbance or failure of the sympathetic or parasympathetic components of the ANS.
The ANS is the part of the nervous system that controls involuntary body functions such as heart rate, blood pressure, breathing, digestion, body and skin temperature, hormonal function, bladder function, sexual function and many other functions.
Third-year medical student Emily Fuster recently collaborated with Blitshteyn as first author on a case report of a rare occurrence where a clinic patient presented with symptoms of two different syndromes.
The resulting case report, “A Tale of Two Syndromes: Nontraumatic Frey’s Syndrome in a Woman With Sjögren’s Syndrome,” was published earlier this year in the journal Clinical Autonomic Research.
“In this report, we discuss both syndromes. Sjögren’s syndrome is a chronic autoimmune disorder in which the glands that make moisture in the eyes, mouth and other parts of the body are attacked by a person’s own immune system,” Fuster says. “As a result, symptoms often include dry eyes and dry mouth as well as fatigue, joint pain, dry skin, acid reflux, dry cough, and swelling of the glands around the face and neck.”
Sjögren’s syndrome can be difficult to diagnose, especially in those patients who present with various neurologic manifestations, negative Sjögren’s antibodies and minimal or absent symptoms of dry eyes and dry mouth.
Frey’s syndrome is considered a relatively rare neurologic condition for which the cause is poorly understood, although current theory suggests the disease is caused by damage to sympathetic and parasympathetic nerves near the parotid gland (a type of salivary gland located just below and in front of each ear).
Most cases of Frey’s syndrome occur as a result of head and neck surgery, trauma to the face diabetes or infection, Fuster explains.
Symptoms typically include excessive facial sweating and flushing after eating or thinking about food.
Blitshteyn says the patient, a 39-year-year old woman, was referred to her for a second opinion and possible diagnosis of an autonomic disorder.
The patient had an eight-month history of facial flushing following most meals, regardless of the type of food she had been eating. The episodes were occurring one to two times per day and would last for about five minutes, followed by milder flushing after the episodes.
The neurology consult resulted in the diagnosis of two disorders: one rare (Frey’s syndrome) and one common autoimmune disorder, Sjögren’s syndrome.
“I immediately thought, ‘what an interesting presentation,’ and upon my literature review, I did not see any cases of Frey’s syndrome described in association with Sjögren’s syndrome,” Blitshteyn says.
Knowing that Sjögren’s syndrome is associated with dysautonomia and small fiber neuropathy, Blitshteyn thought that it made sense for Frey’s syndrome, a rare neurologic and autonomic disorder, to occur in the context of Sjögren’s and was frankly surprised that it was never reported before in the literature.
Blitshteyn ultimately referred the patient back to the rheumatologist for treatment of Sjögren’s syndrome with immunomodulatory therapy because she felt treatment of the underlying cause of flushing may improve flushing and other symptoms that she had been experiencing.
“Interestingly, on her follow-up visit, she reported some relief with famotidine, an over-the-counter heartburn medication that blocks histamine receptors, which I often try in patients with flushing of any kind, not just related to allergies.”
“Histamine is one of the major mediators released by mast cells, usually in response to external triggers like food or smells, but histamine can also be released in response to activation of the sympathetic nervous system that ties into Frey’s syndrome or in response to the inflammatory process that’s involved in Sjögren’s syndrome,” Blitshteyn says.
Fuster says because inflammation of the salivary gland is commonly seen in patients with Sjögren’s syndrome, a diagnosis of co-occurring syndromes should be considered by clinicians in patients with gland swelling and facial flushing, especially when accompanied by other autoimmune markers and symptoms.
“Otherwise, other patients with ‘Sjögren’s-associated Frey’s syndrome’ may be undiagnosed or misdiagnosed when their flushing is attributed to other causes, which would lead to a different and possibly ineffective course of treatment,” she says.
Fourth-year medical students Anna Lange and Paige Guy have also been working with Blitshteyn — on a study of postural orthostatic tachycardia syndrome (POTS) and sexual dysfunction.
Lange presented the group’s preliminary findings at the Dysautonomia International Conference in Washington, D.C., in July and is currently working on a full-length paper for the study.
Guy, a co-author on the same study, presented a continuing medical education lecture on dysautonomia and hormones with Blitshteyn in November to a national multidisciplinary physician group interested in mast cell disorders.
Blitshteyn notes that POTS is one of the most common autonomic disorders and a type of dysautonomia that may develop after COVID-19 infection.
“The field of autonomic disorders is very much evolving because autonomic dysfunction often occurs as a manifestation of systemic disorders,” she says. “Dysautonomia is also one of the major pieces of the long COVID puzzle, and with the ongoing COVID-19 pandemic, long COVID is a major public health issue so studying autonomic dysfunction as part of long COVID is essential to identifying the pathophysiology and treatment for long COVID.”
Clinical research is an important part of patient care and medical education, according to Blitshteyn.
“There are many unanswered questions and opportunities for innovation and discoveries to improve diagnostic and therapeutic options for our patients,” she says.
Blitshteyn says she has always been interested in clinical research and completed a summer research program when she was a medical student at the Jacobs School and extra months of clinical research as a neurology resident at the Mayo Clinic.
“It’s why I pay it forward by being a research adviser and a mentor to medical students myself,” she says. ”Working with Emily, Paige and Anna has been wonderful and rewarding: they are very intelligent, motivated and hard-working students who are eager to learn new and complex topics and acquire new skills.”
The benefits of teaching medical students the basics of clinical research are enormous, according to Blitshteyn.
“The students learn how to investigate a multitude of unanswered clinical questions that we have in patient care, how to conduct clinical research studies to answer these questions and how to interpret the findings and put them in clinical context,” she says.
Fuster says Blitshteyn is “a wonderful and incredibly well-connected mentor — I recommend her to any student interested in studying neurology or learning more about the brain, nervous system and dysautonomia.”
“She is especially gifted at supporting research-minded medical students and connecting them to fruitful, publication-worthy projects. She also has great insights into what a career in neurology looks like currently, and the direction the field is headed,” she says. “I entered medical school with an interest in neurology, and Dr. Blitshteyn has done nothing but further solidify this interest by fostering inquisitive exploration.”
Over the last decade, Blitshteyn and her mentees have completed multiple innovative studies on topics such as pregnancy, autoimmunity, immunotherapy, dietary changes and sexual dysfunction in patients with POTS — topics that have never been investigated previously.
“I am always pushing the envelope when it comes to creativity, innovation and clinical research at Dysautonomia Clinic, and because of that, we are doing the type of research that has not been done before,” she says.
“The papers and abstracts that have been published as a result of our research studies advanced our understanding of POTS and helped other researchers to investigate these topics further,” Blitshteyn says.
“For many students, these research studies are their first experience presenting, writing and thinking as scientists, and that’s what we want our future physicians to be in order to advance and improve clinical medicine, neurology, autonomic disorders and patient care.”