Dear Editor,

Parkinson’s disease (PD) and related movement disorders have been increasingly associated with skin diseases, but studies on skin disorders in atypical parkinsonian disorders, such as progressive supranuclear palsy (PSP) and multiple system atrophy (MSA), are scarce. To date, no reports have documented bullous pemphigoid (BP) in PSP patients. This study highlights four PSP patients with BP at a neurology center at Universiti Malaya Medical Centre, expanding the understanding of potential links between parkinsonian disorders and BP.

An 81-year-old woman of Indian (Sri Lankan) ancestry presented at the age of 76 years with a 2–3-year history of difficulty with left limb movements and frequent falls. Examination revealed an unsteady gait with a tendency to lean backward, dragging speech, slowing of up saccades, and neck rigidity greater than limb rigidity. A brain magnetic resonance imaging (MRI) revealed the “hummingbird” sign. She was diagnosed with probable PSP-Richardson syndrome (PSP-RS) per the Movement Disorders Society (MDS) PSP clinical diagnostic criteria. Despite medication treatment, her condition progressively worsened. She was wheelchair dependent, anarthric, severely rigid, and required softened food due to swallowing difficulties. She also exhibited supranuclear vertical gaze palsy, with intact horizontal gaze. Her medications included levodopa 300 mg three times a day (combined with benserazide and entacapone) and gabapentin for pain and insomnia.

Seven years after PSP onset, she developed tense blisters with serous discharge over her back, arms, buttocks, and thighs (Figure 1A-C). A diagnosis of BP was made by the dermatology team, and prednisolone, doxycycline, and topical clobetasol propionate 0.05% ointment were initiated, with significant clinical improvement. Autoantibody blood tests for BP using enzyme-linked immunosorbent assay technique, revealed the presence of anti-BP antigen 2 (anti-BP180) and anti-BP antigen 1 (anti-BP230) antibodies, confirming the diagnosis of BP.

A 71-year-old Chinese man with hypertension and dyslipidemia presented with a 1-year history of difficulty walking. Over time, the patient experienced frequent falls, and saccadic eye movements were noted to have slowed vertically and horizontally. A brain MRI revealed a clear “hummingbird” sign. He was diagnosed with probable PSP-RS per the MDS criteria. He progressively worsened, becoming bedbound and requiring tube feeding, with purposeless groaning. The neurological and genetic findings of this patient (with MAPTp.V565M and GBA1p. R89Q variants) have been previously described [1]. His medications included levodopa-benserazide, amantadine, zolpidem, quetiapine, and morphine.

At 7 years post-PSP onset, this patient developed multiple tense blisters on his armpits, arms, groins, posterior neck, and back (Figure 1D and E). A clinical diagnosis of BP was made by the dermatology team. Owing to his frail condition, a skin biopsy and autoantibody blood tests were not performed. He improved with topical clobetasol propionate 0.05% ointment, doxycycline, and prednisolone. However, a recurrence of blisters 2 months later necessitated a second course of prednisolone. Long-term management included doxycycline and intermittent low-dose oral prednisolone. The patient, aged 78 years, eventually succumbed to aspiration pneumonia from advanced PSP.

An 82-year-old Indian (Sri Lankan) man with heart disease, diabetes, and hypertension presented with a 5-year history of stiffness, tremor, and gait disorder. Neurological examination revealed facial masking, cogwheel rigidity, bradykinesia, and impaired vertical saccades. His gait was festinant with freezing. Brain MRI revealed the “hummingbird sign”. He was diagnosed with probable PSP with predominant progressive gait freezing. Despite treatment with methylphenidate, levodopa-benserazide, and amantadine, the patient became increasingly disabled.

Nine years after PSP onset, he developed itchy blisters on his wrists, forearms, and ears (Figure 1F and G). The dermatology team clinically diagnosed BP and successfully treated it with ciclosporin and subsequently mycophenolate mofetil.

A 63-year-old Chinese man was initially diagnosed with PD at age 57. He presented to us with gait freezing, festination, and frequent falls. Examination revealed stammering speech, slowed vertical saccades, and horizontal gaze-evoked nystagmus. Brain MRI revealed flattening of the upper midbrain border, leading to a revised diagnosis of probable PSP with predominant parkinsonism. He was on levodopa-benserazide. Three years into his neurological illness, he developed urticated papules and plaques consistent with BP (Figure 1H), which was confirmed via skin biopsy. He was successfully treated with oral prednisolone, which was later weaned off without recurrence. Later, he developed supranuclear vertical gaze palsy.

BP is an autoimmune blistering skin disease that primarily affects older adults. It is associated with significant morbidity and increased mortality rates due to its associations with dementia, infection, and sepsis. BP typically presents with intense itching and tense blisters on erythematous skin, and urticated lesions can also occur. BP has been linked to neurological conditions, including PD, dementia, and multiple sclerosis. A Malaysian case-control study previously reported that neurological diseases were more common among BP patients than among age- and sex-matched controls, with an adjusted odds ratio (OR) of 3.5 [2]. A meta-analysis revealed an association between the use of dopaminergic medications and BP, with a pooled OR of 2.03 [3]. However, this observation does not imply causation and should be interpreted with caution.

The pathogenesis of BP involves autoantibodies targeting components of hemidesmosomes, specifically BP230 and BP180, which cause subepidermal blister formation. The shared expression of BP180 and BPA230 in both skin and brain tissues may help explain the connection between BP and neurological diseases [4].

Several mechanisms have been proposed to explain the increased occurrence of BP in patients with neurological diseases. One hypothesis suggests that microtrauma, inflammation, or blood‒brain barrier disruption in neurodegenerative diseases may expose BP antigens to the immune system, triggering BP [5]. Additionally, human leukocyte antigen (HLA) alleles, particularly HLA-DQB1*03:01, have been implicated in BP, although to our knowledge, the relationship between HLA alleles and PSP remains unclear. Antigen-presenting cells expressing this allele have high affinity for BP180, initiating a BP180-specific T-helper cell response, secretion of immunoglobulin G autoantibodies, and eventual BP manifestation [4].

PSP is a type of 4-repeat (4R) neurodegenerative tauopathy. A recent study using postmortem skin samples from patients with PD and atypical parkinsonism disorders, including PSP, detected normal tau protein in all participants. However, 4R-tau seeding was identified in 6 out of 7 PSP patients, whereas none was found in 14 patients with PD, MSA, or corticobasal degeneration via 4R seeding amplification assays (SAAs) [6]. This finding is promising, as skin 4R-tau SAA could serve as a minimally invasive and reliable diagnostic tool for PSP.

While BP has been reported in synucleinopathies such as PD and, recently, in MSA [7], no cases of BP linked to PSP have been reported until now. Our four cases represent the first documented report of BP in PSP patients, constituting around 2%–3% of the 150 PSP cases managed at our center [1]. However, this estimate is likely conservative due to the absence of systematic dermatological evaluations. Milder BP cases could have been overlooked. This limitation highlights the need for systematic studies involving larger cohorts to better understand the association between PSP and BP and provide insights into managing this troublesome condition in older persons with neurological disorders.

Notes

Ethics Statement

This study was approved by the hospital’s human research ethics committee (Medical Research Ethics Committee number: 20241029-14362), and given its retrospective nature and non-identification of patients, the need for obtaining written consent from patients was waived.

Conflicts of Interest

The authors have no financial conflicts of interest.

Funding Statement

None

Acknowledgments

We would like to acknowledge Division of Dermatology and Division of Neurology for their support in the write up of this case series.

Author Contributions

Conceptualization: Shen-Yang Lim. Data curation: Shen-Yang Lim, Winn Hui Han. Investigation: Shen-Yang Lim, Winn Hui Han. Methodology: Shen-Yang Lim, Winn Hui Han. Project administration: Shen-Yang Lim, Winn Hui Han. Resources: Shen-Yang Lim, Winn Hui Han. Supervision: Shen-Yang Lim. Writing—original draft: Winn Hui Han. Writing—review & editing: Shen-Yang Lim, Zhenli Kwan, Shin Shen Yong.

Figure 1.

Clinical photographs of 4 patients with coexisting progressive supranuclear palsy and bullous pemphigoid. A-C: Erosions and tense blisters with hemorrhagic and serous blister fluid over the back and knee of patient 1. D, E: Small, tense blisters and erosions over the forearm and posterior neck of patient 2. F, G: Small, tense blisters over the forearm and dorsum of the hand of patient 3. H: Erosions over the knee and forearm healed with postinflammatory hypopigmentation and milia in patient 4.

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Figure & Data

References

Citations

Citations to this article as recorded by  

• Expert Commentary on “A Case Report of Palatal Tremor in Progressive Supranuclear Palsy”
  Shen-Yang Lim, Anthony E. Lang
  Parkinsonism & Related Disorders.2025; : 107873.     CrossRef

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