About 10 years ago, Howard Burnett, a financial adviser with Morgan Stanley, noticed reddish patches on his cheeks and nose. At first he endured the facial redness and swollen bumps, but when they got worse in 2019, Burnett consulted a dermatologist, who diagnosed him with rosacea—an inflammatory skin condition common in middle-aged and older adults—and prescribed a compounded skin cream. Burnett uses the cream mornings and evenings, and the redness has decreased.
What Burnett didn't realize at the time was that the rosacea might be connected to the tremors he'd begun experiencing a few years before his skin problems started. His doctor initially diagnosed him with essential tremor. In 2021, when Burnett, who had moved from Columbus, OH, to Houston, visited a new doctor for an unrelated problem, he was told he should see a neurologist about his tremors. “The neurologist in Houston told me that I actually have Parkinson's disease,” says Burnett, now 77.
Recently, a new neurologist—Joseph Jankovic, MD, FAAN, director of the Parkinson's Disease Center and Movement Disorders Clinic at Baylor College of Medicine in Houston—told him that rosacea might have been an early warning sign that he was at higher risk for later developing Parkinson's.
“Most people with rosacea don't go on to develop Parkinson's, but it is one of several skin conditions associated with the disease that often predate the development of tremors and other symptoms by several years,” explains Dr. Jankovic. For example, a study in Movement Disorders published in 2020, involving 1.5 million veterans, found that skin disorders may manifest decades before a diagnosis.
Parkinson's disease is one of many neurologic disorders that can affect the skin. Others include certain vascular conditions that can cause stroke as well as tuberous sclerosis complex (TSC) and neurofibromatosis. The reason the central nervous system affects the skin is that when the human embryo is developing, the skin and nervous system arise from the same germ cell layer, known as the ectoderm, says Douglas R. Nordli Jr., MD, professor of pediatrics, chief of the section of pediatric neurology, and co-director of the comprehensive epilepsy center at the University of Chicago's Comer Children's Hospital. “My wife is a dermatologist, and we often joke that we are treating the same origins of disease, just different end points.”
Sometimes skin problems develop after diagnosis; in other cases, existing skin abnormalities are signs that help pinpoint the diagnosis of an unknown neurologic disorder. “For any neurologic condition, it is critical that a thorough physical examination include a careful examination of the skin,” says José Biller, MD, FAAN, professor and chair of the department of neurology at Loyola University Medical Center and Loyola University Chicago Stritch School of Medicine. “There are literally hundreds of neurologic disorders with manifestations in the skin or with skin-related side effects to their treatment.”
Birthmarks May Be a Hint
Two of them—TSC, which causes benign tumors to grow in several different regions of the body, including the skin, and neurofibromatosis type 1 (NF1), a genetic disorder that causes tumors to form on nerve tissue (some of which can become cancerous)—are complex and difficult to diagnose and can include cardiovascular complications, behavioral challenges, and seizures.
“A child who is being seen for suspicious birthmarks and then has a seizure may end up in a neurologist's office,” says Dr. Nordli. “In combination with seizures, hypopigmented lesions of the skin—spots where the skin is lighter, also called ‘ash leaf spots'—can be a sign of an underlying neurologic condition like TSC or NF1.”
Both disorders have other skin manifestations such as facial angiofibromas (small, firm, smooth, dome-shaped raised spots on the skin that are usually pink to red in color) and café au lait macules (painless, light- to dark-brown-pigmented birthmarks). Having one or two of these spots is common in the general population, but multiple café au lait spots can be a sign of one of these disorders. “Freckling in the armpit and groin regions is also common, as are neurofibromas—soft, raised, tan-colored areas on the head, trunk, and other parts of the body,” says Dr. Biller. “These signs may be confused with acne in a child or adolescent, so the diagnosis can be challenging and require a doctor with a lot of experience.”
Ryland Charronsmith was diagnosed with NF1 as an infant after his mother noticed freckling in his armpits, an area that was unlikely to have sun exposure. The doctors recommended genetic testing, which confirmed the diagnosis. “I genuinely feel I've been lucky overall,” says Charronsmith, who's now 37 and lives in north central Maine. “I know a lot of people who have had more tumors internally and on the skin than I've had.”
The tumors he does have can be itchy and bothersome. To ease the discomfort, Charronsmith applies lidocaine or another numbing cream, or a hot pack. “It helps calm down the area and get the blood circulating,” he says. When the skin tumors become too irritating, he has them removed by a dermatologist. “I have one right now that's going to be removed soon. It feels like an itchy bug bite, and it's just within my reach on my back, so I end up scratching and tearing it open regularly.”
Charronsmith's neurologist, Justin T. Jordan, MD, MPH, FAAN, director of the Family Center for Neurofibromatosis at Massachusetts General Hospital in Boston, monitors these dermal tumors closely for any changes that may indicate something more serious, such as skin cancer. A study in JAMA Dermatology in 2022 found an increased risk of skin cancers in people with NF1. In addition, NF1 is one of the most frequently mutated genes in melanoma. “My dad has a history of skin cancer as well, so I'm very careful about that,” Charronsmith says. “So far, I have not had any worrisome skin patches, but I keep in close touch with my doctors and give them as much information as I can.”
Another condition distinguished by skin changes is Sturge-Weber syndrome, a rare vascular disorder characterized by abnormal blood vessels in the brain, causing angiomas, which can form a port-wine birthmark on the face; they also can develop in the brain, causing seizures.
Not every birthmark is a warning sign, cautions Dr. Nordli. “Everyone has birthmarks of some kind, and the overwhelming majority are nothing to be worried about.” However, for those who do have neurologic issues such as seizures, it's worth mentioning any birthmarks or skin lesions to their neurologists. “A patient may have a serious neurologic disorder that is difficult to diagnose, but if on our physical exam we see a relevant skin finding, our diagnosis has suddenly been narrowed to a few conditions rather than hundreds.”
Skin Signs in Stroke
Examining the skin of someone who has had a stroke can provide clues to its cause, says Dr. Biller. “Skin abnormalities are often seen in stroke and can differ from one another depending on family history, age of the patient, stroke subtype, and stroke cause.”
For example, he says, when a younger stroke survivor has small red, brown, or purple spots on the skin, known as petechiae, that can be a sign that the cause was endocarditis, an infection of the inner surface of the heart that usually involves the valves.
If a person has lacelike purplish discoloration on the skin, known as livedo reticularis, the culprit may be antiphospholipid syndrome, an autoimmune disorder that causes abnormal blood clots to form and is a common source of stroke, especially in younger people.
In people who have red or purple spots on the skin, ulcers, or blisters that can become painful or itchy, the cause may be vasculitis or vasculopathy. “These inflammations of the blood vessels can be hereditary and can cause blood clots, swelling, and stroke,” says Dr. Biller.
In someone who has had a stroke, a reddish-purple, slightly raised rash between the belly button and the knees, known as an angiokeratoma, can point to Fabry disease, an inherited metabolic disorder that leads to a buildup of certain proteins in the body, causing damage to several organs, including the heart, lungs, kidneys, skin, brain, and stomach.
Clues in Parkinson's
Several skin abnormalities may precede the development of classic motor symptoms in Parkinson's disease by years. In addition to the rosacea that Howard Burnett experienced, these conditions can include seborrheic dermatitis, which affects oily areas of the body, such as parts of the face (sides of the nose, eyebrows, ears, eyelids) and chest, causing scaly patches, inflamed skin, and dandruff.
“Most people with seborrheic dermatitis never get Parkinson's, but if someone has this condition along with other known pre-Parkinson's symptoms, like constipation and sleep disturbances, it might suggest that he or she is at higher risk for developing the movement disorder in the near future,” says Nicki Niemann, MD, assistant professor of neurology at Barrow Neurological Institute and a neurologist at the Muhammad Ali Parkinson Center in Phoenix.
The most serious skin condition linked to Parkinson's disease is melanoma. “Many studies have demonstrated that patients with Parkinson's have a much higher risk of developing melanoma,” says Dr. Jankovic. “The reason for this is not fully understood. We know that melanin in the skin protects against skin cancer. People with Parkinson's have less melanin in the brain, in part because of the degeneration of neurons that produce dopamine, which contains melanin. It's possible that they also have decreased melanin in the skin.”
The relationship appears to run both ways: A study published by Mayo Clinic researchers in 2017 found that people with melanoma have four times the risk of developing Parkinson's. Neurologists who treat the condition generally recommend that their patients see a dermatologist for annual skin checkups.
For a time, there were concerns that levodopa, a medication used to treat Parkinson's, might be associated with an increased risk of melanoma. “Fortunately, however, several studies have recently shown that levodopa does not seem to be associated with an increased risk of developing melanoma, so those fears have been allayed,” says Dr. Niemann.
Another skin disorder that may be associated with Parkinson's and other neurologic diseases is bullous pemphigoid, an autoimmune blistering disease that mainly affects older people and typically starts with an itchy red rash. Many studies, including one published in the European Journal of Dermatology in 2017, have found a significant association between bullous pemphigoid and neurologic disorders, including dementia, Parkinson's disease, epilepsy/seizures, multiple sclerosis, and stroke. It appears to be a two-way street: People who have these neurologic conditions are more likely to develop bullous pemphigoid, and people who have bullous pemphigoid are at increased risk for these conditions. “In one study, 50.3 percent of patients had at least one neurologic disease prior to their diagnosis of bullous pemphigoid compared with 24.2 percent for controls,” says Dr. Jankovic. “When a patient has a known neurologic disorder and a new skin condition, bullous pemphigoid should be high on the list of suspects.”
Howard Burnett had no idea of the association between Parkinson's disease and skin conditions, including melanoma, until he met with Dr. Jankovic, but he had been seeing a dermatologist for an annual skin checkup for at least the past 10 years. “So far, everything looks good, with no signs of melanoma,” he says. “But now I know the things I should be looking out for.”
Managing Skin Conditions
Neurologists often work closely with dermatologists to treat skin abnormalities associated with neurologic disorders. Treatment depends on the condition and can be as simple as topical creams and special shampoos or as complex as cryosurgery and laser therapy.
Topical creams
“Treating seborrheic dermatitis associated with Parkinson's disease is relatively straightforward,” says Nicki Niemann, MD, assistant professor of neurology at Barrow Neurological Institute and a neurologist at the Muhammad Ali Parkinson Center in Phoenix. “We mainly use topical treatments such as antifungal creams. Tar-based shampoos also can help, as can avoiding the excessive use of drying soaps. In more stubborn cases we might use medications such as steroids.” Steroids, both topical and oral, are often used to treat bullous pemphigoid as well. The first topical treatment for angiofibromas in people with tuberous sclerosis complex (TSC) was approved in 2022.
Changing medication
In some cases, people with Parkinson's disease can develop a rash related to a dye used in a particular formulation of levodopa medication. The rash usually resolves within months after switching to a different formulation of the drug.
Surgery
The many surgical options for skin problems associated with TSC include vascular laser treatment for flat red spots to destroy the blood vessels with minimal risk of scarring, ablative laser treatment for raised angiofibromas, photodynamic therapy, surgical excision, dermabrasion, and cryosurgery. For people with neurofibromatosis, the skin growths known as cutaneous neurofibromas may grow and multiply with age, but they usually don't cause significant symptoms other than possible itching and tenderness. Some, however, grow particularly large or in inconvenient places that cause cosmetic concerns and other issues; when that happens, they can be surgically removed. Currently, no medication can reduce the size of most neurofibromas.
Skin as Biomarker
“The skin can be a window into the diagnosis of Parkinson's disease,” says Joseph Jankovic, MD, FAAN, director of the Parkinson's Disease Center and Movement Disorders Clinic at Baylor College of Medicine in Houston. A significant body of research is focused on developing skin-based biomarkers for diagnosing Parkinson's and differentiating it from other movement disorders, such as essential tremor, multiple system atrophy, and progressive supranuclear palsy (PSP).
“In Parkinson's there's an accumulation of a protein called alpha-synuclein in the brain,” Dr. Jankovic says. “Recent studies have shown that this protein also accumulates in the skin. We are now developing skin biopsies for the diagnosis of Parkinson's, which involve taking small skin samples from the neck, upper thigh, and lower leg. People with PSP may have symptoms that look initially like Parkinson's, but PSP is due to the accumulation of the tau protein, so they will not have the alpha-synuclein protein in their skin. Multiple system atrophy also involves alpha-synuclein accumulation, but the protein is more widely distributed in the skin. In Parkinson's, the protein typically accumulates only in the neck.”
Research published in Neurology and the Journal of Parkinson's Disease suggests that these biopsies are very accurate in distinguishing Parkinson's from other disorders, and Nicki Niemann, MD, assistant professor of neurology at Barrow Neurological Institute and a neurologist at the Muhammad Ali Parkinson Center in Phoenix, predicts they will soon be more widely available. “This is a very active area of research, and we believe it will significantly improve the accuracy of a Parkinson's diagnosis, which in turn will improve the quality of clinical trials of new treatments for the disease,” he says.
Parkinson's may not be the only neurodegenerative disease to have a skin biomarker. One such biomarker appears to be highly sensitive and specific for distinguishing patients with Alzheimer's disease from those with other forms of dementia. Details of the study were presented at the Alzheimer's Association International Conference in 2022 and later published in Scientific Reports.
