Neuro-Ophthalmology of Lewy Body Dementia

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Disease Entity

Lewy body dementia (LBD) is a neurodegenerative disorder associated with cognitive, neuropsychiatric, sleep, motor, and autonomic symptoms.[1] The disease is characterized by a neuronal accumulation of Lewy bodies, which are chiefly comprised of the protein 𝛼-synuclein. In addition to LBD, other primary neurodegenerative diseases characterized by an accumulation of 𝛼-synuclein include Alzheimer disease, Parkinson disease, and Multiple System Atrophy.[2]

Epidemiology

LBD affects approximately 1.4 million individuals in the United States of America.[2] Age is a risk factor for LBD, with the approximate age of onset occurring between age 70 and 85 years. Men develop LBD more frequently than women, as approximately 60% of LBD cases have been found to occur in men.[3]

Although most cases of LBD are not inherited, some genes that have been found to be associated with LBD include leucine-rich receptor kinase 2, apolipoprotein E (APOE), synuclein alpha (SNCA), and scavenger receptor class B member 2 (SCARB2), microtubule-associated protein tau, and glucocerebrosidase A genes.[2]

Pathophysiology

LBD is caused by an accumulation of Lewy bodies in neurons, primarily in the cytoplasm of neurons. Lewy bodies are aggregates of overexpressed 𝛼-synuclein, a protein oligomer thought to be involved in cell membrane remodeling at neuronal terminals. The accumulation of Lewy bodies results in mitochondrial fragmentation, ultimately resulting in neuronal death.[4] Lewy bodies initially deposit in the olfactory nerve, glossopharyngeal nerve, vagus nerve, and reticular system before spreading to the brainstem, limbic system, and neocortex.[5] Certain initial symptoms of LBD occur in the areas initially affected. Anosmia occurs due to deposition in the olfactory nerve, constipation occurs due to deposition in the vagus nerve, and rapid eye movement (REM) sleep behavior disorder occurs due to deposition in the reticular system.[2]

Diagnosis

A diagnosis of DLB is made based on clinical features and indicative biomarkers. The presence of dementia is essential to the diagnosis. The additional four core clinical features of DLB include fluctuating cognition, recurrent visual hallucinations, REM sleep behavior disorder, and parkinsonian features. Reduced dopamine transporter uptake in the basal ganglia on SPECT or PET, low uptake of iodine-MIBG myocardial scintigraphy, and REM sleep without atonia on polysomnography have been reported in DLB.

DLB is considered to be probable if two or more core clinical features are present, or if one core clinical feature and one indicative biomarker is present. DLB is considered to be possible if one core clinical feature is present, or if one or more indicative biomarkers are present.[6] The diagnosis of Parkinson’s disease dementia (PDD) differs from the diagnostic criteria of DLB, in that the patient must have an onset of motor symptoms of parkinsonism one year prior to the onset of dementia.[1]

History

Patients with LBD may report Parkinsonian symptoms including bradykinesia, limb rigidity, and tremor. Patients can present with cognitive impairments include fluctuating cognition, executive dysfunction, and attention deficits. Patients can also present with psychiatric symptoms, autonomic abnormalities, excessive daytime somnolence, and severe sensitivity to antipsychotic medication.[6] The characteristic ocular findings of LBD are visual hallucinations and some patients experience pareidolias. Pareidolias are visual illusions of meaningful objects that appear from ambiguous forms within visual scenes. Hallucinations occur in the absence of visual stimuli while pareidolias occur in the presence of sensory stimuli. Patient most commonly experience hallucinations and pareidolias of animals and people.[7] Visual hallucinations have been found to occur in approximately 70% of DLB patients and 50% of PDD patients.[8] The visual hallucinations in LBD have been shown to have an association with possible underlying retinal dysfunction, specifically of the photopic and scotopic inner retina.[9] It has also been found that patients can experience a significant change in pupil diameter prior to the occurrence of pareidolias.[7]

Patient may experience impairments in color vision and impairments in visual spatial processing including visual search and visual perception.[7] [10] [11] Dyschromatopsia has been reported in approximately 65-80% of patients with DLB.[10] [11] The presence of color vision impairment (CVI) in these patients has also been found to be associated with lower scores on the Montreal Cognitive Assessment (MoCA), a test that evaluates memory, visuospatial abilities, executive functions, attention, language, conceptual thinking, calculations, and orientation.[12]

Motor dysfunction in LBD also may result in ophthalmic symptoms. Patients can develop apraxia of eyelid opening which manifests as an inability to open the eyes voluntarily. Blepharospasm (episodic spasmodic closure of both eyelids) is another manifestation of LBD.[13] Patients may have decreased rate of blinking, which leads to the development of dry eye. LBD can also lead to worsening of a pre-existing phoria, a misalignment of the eyes when synchronization between the eyes is broken.

Physical Examination

Patients with LBD can present with Parkinsonian neurologic features including a shuffling gait, slowed turns, and reduced arm swing. Compared to Parkinson disease, LBD presents with bradykinesia and rigidity that is more symmetric and tremor that is more likely to be a symmetric postural tremor.[14]

On ocular exam, eyelid retraction can be observed. This finding has been reported in approximately 15% of patients with DLB.[15] Eyelid retraction occurs due to supranuclear motor impairment. The nuclei of the posterior commisure have specifically been found to be associated with eyelid retraction.[16] An accompanying sign that can be found with the eyelid retraction is activation of the frontal and superior portion of the orbicular muscle with frontal wrinkling.[15] Additional common exam findings include blepharospasm, apraxia of eyelid opening, decreased blink rate, and dry eye.

LBD can result in impairment in reflexive saccade execution for gap and overlap tasks, as well as complex saccade performance for prediction, decision, and antisaccade tasks.[17] [18] Patients with both DLB and PDD have an increased latency of reflexive and voluntary saccades, with increased latency corresponding with greater severity of disease.[18]

Patients with DLB have been reported to experience horizontal saccades, impaired saccade suppression, and impaired predictive saccades. They also have a reduced tendency in making express saccades in the gap task, in which a gaze-fixation target is removed immediately prior to the appearance of a saccade target. Cases of vertical supranuclear gaze palsy and vertical gaze palsy have also been reported but progressive supranuclear palsy (PSP) should be excluded in these patients. The patients have reduced velocity, reduced accuracy, and increased variability in horizontal saccades.[18] Although patients with LBD often have an upgaze palsy, this may occur in Parkinson disease and as an age-related physiologic finding in the general population. A downgaze palsy is more consistent with progressive supranuclear palsy (PSP). Patients with LBD can develop convergence insufficiency. On ophthalmic exam, patients will have an exotropia at near greater than distance with full ductions and versions.

Diagnostic Procedures/Investigations

Neuroimaging options for LBD include brain positron emission tomography (PET), single photon emission computed tomography (SPECT), and MRI. PET and SPECT can show occipital hypometabolism and reduced dopaminergic activity in the basal ganglia. MRI findings can include atrophy of the amygdala, striatum, substantia innominata, hypothalamus, and dorsal midbrain.[14] Patients with DLB with CVI have also been found to have lower volumetric percentiles in the right transverse/superior temporal gyri on volumetric brain MRI scans.[10]

Iodine-metaiodobenzyl guanidine (MIBG) myocardial scintigraphy, a measure of postganglionic cardiac innervation, shows reduced uptake in LBD. Electroencephalogram (EEG) findings can demonstrate prominent posterior slow-wave activity and periodic fluctuations in the pre-alpha-theta range. On polysomnography, REM sleep without atonia can be observed.[6]

On optical coherence tomography (OCT), patients with LBD are found to have thinning of the retinal nerve fiber layer (RNFL).[19] Thinning specifically occurs in the parafoveal ganglion cell inner plexiform complex (GCIPL) within the central 3 mm disc.[20] Thinning of the RNFL in LBD patients is associated with a greater decline in cognitive function, low contrast visual acuity, and visual cognition.[19] [20] [21] [22]

Differential diagnosis

There is frequently overlap between the presentations of LBD, Parkinson disease, and Alzheimer disease.[23] Additional differential diagnoses include medication effect, Creutzfeldt-Jakob disease, Multiple System Atrophy, progressive nuclear palsy, vascular dementia, and corticobasal degeneration.

Management

The management of LBD involves both nonpharmacologic and pharmacologic interventions. The nonpharmacologic interventions include exercise, cognitive training, and caregiver-oriented training. Exercise has been shown to lead to both motor and cognitive benefits. Pharmacologic management includes the use of cholinesterase inhibitors, primarily rivastigmine and donepezil. These medications are used to improve cognition and global function, as well as to reduce apathy, visual hallucinations, and delusions.[6]

If patients with LBD require glasses, they should receive single vision glasses instead of bifocal or trifocal glasses. Patients with LBD have an increased risk of falls due to their systemic motor symptoms, and the use of bifocal and trifocal lenses can further exacerbate their risk of falls.

Prognosis

LBD is a progressive disease with no cure.[2] After the time of diagnosis, DLB patients have a median survival of 4.7 years and PDD patients have a median survival of 3.8 years.[3]

Summary

Ophthalmologists should recognize the key clinical features of LBD and be aware that visual hallucinations or visual pareidolias may be presenting features of LBD. Convergence insufficiency, blepharospams, eyelid retraction, and apraxia of eyelid opening may also occur in LBD. Supranuclear upgaze palsy may occur in LBD but downgaze palsy should prompt consideration for PSP rather than LBD. Although patients may have nonspecific visual complaints (e.g., blurred vision, dry eye) and OCT findings of RNFL thinning, there are no diagnostic ocular findings for LBD. There is no cure for LBD but supportive therapy and referral to neurology are recommended.

References

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