Lewy body dementia (LBD) is a neurodegenerative disease characterized by the accumulation of Lewy bodies, composed of the protein alpha-synuclein, within neurons. LBD encompasses two clinical subtypes: dementia with Lewy bodies (DLB) and Parkinson’s disease dementia (PDD).
Approximately 1.4 million people in the United States are affected. Age of onset is around 70–85 years, and men account for about 60% of cases. Most LBD cases are not hereditary, but associations with LRRK2, APOE, SNCA, SCARB2, MAPT, and GBA genes have been reported.
The core clinical features of LBD are the following four.
It has been reported that over 70% of DLB cases are misdiagnosed at initial evaluation2). Neuro-ophthalmic findings play an important role in the diagnosis and management of LBD, but there are no specific diagnostic ophthalmic findings for LBD.
Both are diseases on the same spectrum characterized by the accumulation of Lewy bodies, but the diagnostic criteria differ. PDD requires that motor symptoms of parkinsonism have appeared at least one year before the onset of dementia. In DLB, dementia and motor symptoms occur almost simultaneously, or dementia precedes.
LBD presents with a variety of visual symptoms.
Visual hallucination is a phenomenon in which clearly formed images are seen in the absence of visual stimuli. In contrast, pareidolia is an illusion in which meaningful objects (e.g., a human face) are perceived from ambiguous visual stimuli (e.g., stains on a wall, wood grain). Both are characteristic of LBD but have different mechanisms of occurrence.
LBD presents a variety of findings in both eyelid abnormalities and ocular movement abnormalities.
Eyelid and Anterior Segment Findings
Eyelid retraction: Reported in about 15% of DLB cases. Caused by supranuclear movement disorder (lesion of the posterior commissure nucleus). Accompanied by forehead wrinkling due to activity of the frontalis and upper orbicularis oculi muscles.
Blepharospasm: Episodic spasmodic closure of both eyelids.
Apraxia of eyelid opening: Inability to voluntarily open the eyes.
Decreased blink rate: Causes dry eye.
Ocular motility findings
Saccadic abnormalities: Prolonged latency of reflexive and voluntary saccades (correlates with disease severity). Decreased horizontal saccade velocity, accuracy, and increased variability.
Upward gaze palsy: Relatively common in LBD. However, it can also occur in Parkinson’s disease and with aging.
Convergence insufficiency: Exotropia increases at near compared to distance.
Worsening of heterophoria: May worsen existing heterophoria.
Parkinsonian symptoms in LBD tend to be more symmetric in akinesia and rigidity compared to Parkinson’s disease, and tremor tends to be a symmetric postural tremor.
In DLB, impairments in saccade suppression, predictive saccades, and a decrease in express saccade tendency have also been reported. Cases of vertical supranuclear ophthalmoplegia have also been reported, but in such cases, progressive supranuclear palsy (PSP) must be excluded. Downward gaze palsy is more consistent with PSP than with LBD.
The cause of LBD is overexpression and aggregation of α-synuclein. α-synuclein is a protein oligomer involved in cell membrane remodeling at nerve terminals, and when it aggregates excessively, it forms Lewy bodies. Accumulation of Lewy bodies leads to mitochondrial fragmentation and ultimately neuronal death.
The propagation pattern of Lewy bodies is as follows:
Initial symptoms correspond to this deposition pattern. Olfactory nerve → loss of smell, vagus nerve → constipation, reticular formation → RBD are typical.
The main risk factors are as follows.
Approximately 75% of DLB patients experience psychiatric symptoms (including visual hallucinations and delusions)1). Visual hallucinations may involve underlying retinal dysfunction (inner retinal layer dysfunction in photopic and scotopic vision).
The diagnosis of DLB requires the presence of dementia, and is based on the following four core clinical features.
If there are two or more core features, or one core feature plus one or more indicative biomarkers, the diagnosis is probable DLB. If there is only one core feature, or only one or more indicative biomarkers, the diagnosis is possible DLB.
Three subtypes of prodromal DLB (MCI-onset, delirium-onset, and psychiatric symptom-onset) have been identified, which help in avoiding contraindicated medications and planning care through early diagnosis2).
| Differential Diagnosis | Key Points for Differentiation |
|---|---|
| Alzheimer disease | Visual hallucinations are rare. Hippocampal atrophy is prominent. |
| Parkinson disease | Motor symptoms precede dementia by more than 1 year. |
| Progressive supranuclear palsy (PSP) | Downward gaze palsy is consistent with PSP. |
| Multiple system atrophy (MSA) | Predominantly cerebellar symptoms and autonomic dysfunction |
| Vascular dementia | Stepwise cognitive decline |
In PSP, downward gaze palsy appears early, and upward and horizontal gaze are also impaired over time. Eventually, both eyes become fixed in an abducted position from midline. Blepharospasm, apraxia of eyelid opening, and lid retraction are also seen in PSP, so the presence or absence of downward gaze palsy is key to differentiation.
LBD is a progressive disease, and there is no curative treatment. Treatment focuses on symptom management.
LBD patients have a high risk of falls due to Parkinsonian symptoms (e.g., freezing of gait, postural instability). Bifocal or trifocal lenses alter the view of the feet and further increase fall risk, so single-vision glasses are recommended.
No antipsychotic is completely safe, but quetiapine and clozapine are considered relatively safer. Even non-antipsychotic drugs such as antiparkinsonian agents and gabapentinoids (e.g., mirogabalin, pregabalin) have been reported to induce psychotic symptoms at low doses 3), requiring caution with all medications.
LBD is progressive, with median survival after diagnosis of 4.7 years for DLB patients and 3.8 years for PDD patients.
α-Synuclein, the main component of Lewy bodies, is a protein oligomer involved in cell membrane remodeling at nerve terminals. Overexpressed α-synuclein aggregates to form insoluble Lewy bodies, leading to mitochondrial fragmentation and neuronal death.
In DLB, α-synuclein aggregates accumulate at high concentrations in presynaptic terminals. The number of cortical Lewy bodies is small relative to total neurons and does not directly correlate with the degree of cognitive impairment 3).
Visual hallucinations are considered a multifactorial phenomenon involving multiple mechanisms.
Oculomotor dysfunction in LBD occurs as a supranuclear motor disorder.
Pimavanserin is a selective serotonin 5-HT2A receptor inverse agonist and a novel second-generation antipsychotic that does not bind to dopamine receptors. It was approved by the FDA in 2016 for the treatment of psychosis in Parkinson’s disease dementia.
Rothenberg et al. (2023) administered pimavanserin to 4 DLB patients who were resistant to cholinesterase inhibitors or conventional antipsychotics. Three patients (75%) showed significant improvement in psychotic symptoms (reduction in hallucinations, delusions, distress, and agitation), and tolerability was good in all 4 patients. No worsening of motor symptoms was observed1).
Tholanikunnel et al. (2023) reported clinical cases of three subtypes of prodromal DLB (MCI-onset type, delirium-onset type, and psychiatric symptom-onset type). The research diagnostic criteria for MCI-LB (published in 2020) use four core features (cognitive fluctuations, visual hallucinations, RBD, and parkinsonism) and three indicative biomarkers (DAT scan, MIBG myocardial scintigraphy, and PSG) in addition to mild cognitive impairment. Early diagnosis is said to lead to avoidance of contraindicated antipsychotics and advance care planning2).
Kanemoto et al. (2025) reported cases of DLB patients who developed hallucinations, delusions, and irritability with low doses of gabapentinoids (mirogabalin 15 mg/day, pregabalin 25 mg/day), which resolved upon discontinuation. Because α-synuclein aggregates accumulate in presynaptic terminals in DLB, hypersensitivity to gabapentinoids acting on presynaptic terminals may have occurred3).
