Photophobia, visual hallucinations, and REM sleep behavior disorder in progressive supranuclear palsy and corticobasal degeneration: A prospective study

1. Introduction 

Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are neurodegenerative disorders that display some overlapping clinical features. The core clinical features of PSP include vertical gaze palsy, axial more than appendicular rigidity, and early postural instability [1]. The core clinical features of CBD include asymmetric appendicular rigidity and cortical dysfunction including apraxia of limb [2]. The term corticobasal syndrome (CBS) has been applied to the clinical entity [2], while CBD refers to the pathologic entity.

When the cardinal features of these two diseases are present at disease onset, diagnosis may be relatively straightforward. However, clinical features of these two diseases often overlap and some of the cardinal features may not occur until later in the disease course. These atypical disease presentations can present a diagnostic dilemma, which may make it difficult for clinicians to predict disease progression. Therefore, additional clinical features that could distinguish PSP from CBD would be helpful in clinical practice. Photophobia has been described in PSP but not CBD to our knowledge [3]. Visual hallucinations and REM sleep behavior disorder (RBD) have not been emphasized in either PSP or CBD. We conducted a study to determine the frequency of photophobia, visual hallucinations, and RBD in these two disease populations.

3. Results 

Ten patients had PSP (Table 1), two with pathologic confirmation, and 11 patients had CBS (Table 2), one with pathologic confirmation. The median ages at disease onset in PSP and CBS were 66 (range 59–77) and 65 (range 49–91), respectively, with no significant difference between the two groups (p=0.4). No significant gender differences occurred between both groups. Based on clinical criteria for PSP [1], four patients were classified as possible, four as probable, and two were definite (i.e. pathologically confirmed). Photophobia occurred in all 10 (100%) PSP patients vs 2 (18%) CBS patients (p=0.0002). The mean time between when the patient first reported photophobia and disease onset was 3.1 years. Blepharospasm was noted in only one patient in this series. He was one of the two CBS patients with photophobia and was pathologically confirmed to have CBD. Visual hallucinations occurred in 1 (5%) PSP patient and RBD occurred in 1 (5%) CBS patient. The visual hallucinations occurred in a PSP patient taking Levodopa/Carbidopa. The patient reported seeing people mostly at night time. The hallucinations continued despite reduction of the Levodopa/Carbidoba and, unfortunately, the patient died before further dose reductions could be made. The CBS patient with RBD had symptoms consisting of talking and performing exercising movements usually during the first 1–2h of sleep.

Table 1. Characteristics of subjects diagnosed with progressive supranuclear palsy

		Sex (F/M)	Age of disease onset	Presence of photophobia	Presence of visual hallucinations	Presence of REM behavior sleep disorder	Main presenting features	Comments
	1	F	70	Yes	No	No	Vertical supranuclear gaze palsy, parkinsonism
	2	M	62	Yes	No	No	Vertical supranuclear gaze palsy, parkinsonism
	3	F	59	Yes	No	No	Reduced vertical gaze velocity, parkinsonism, incontinence
	4	M	76	Yes	Yes	N/A	Upgaze paresis, parkinsonism	Pathology confirmed
	5	M	69	Yes	No	No	Vertical supranuclear gaze palsy, parkinsonism
	6	F	74	Yes	No	No	Vertical supranuclear gaze palsy, parkinsonism, apraxia of speech
	7	F	62	Yes	No	No	Vertical supranuclear gaze palsy, parkinsonism	Pathology confirmed
	8	F	77	Yes	No	No	Vertical supranuclear gaze palsy, parkinsonism
	9	M	61	Yes	No	No	Vertical saccadic slowing, parkinsonism
	10	F	59	Yes	No	No	Vertical supranuclear gaze palsy, parkinsonism

Table 2. Characteristics of subjects diagnosed with corticobasal syndrome

		Sex	Age of disease onset	Presence of photophobia	Presence of visual hallucinations	Presence of REM behavior sleep disorder	Main presenting features	Comments
	1	F	65	No	No	No	Asymmetric apraxia, aphasia
	2	M	52	Yes	No	Yes	Parkinsonism, dysexecutive syndrome, personality change, vertical supranuclear gaze palsy	Pathology confirmed
	3	F	72	Yes	No	No	Asymmetric apraxia, parkinsonism, vertical supranuclear gaze palsy
	4	F	55	No	No	No	Asymmetric parkinsonism, alien arm phenomenon
	5	M	65	No	No	No	Asymmetric apraxia, agraphesthesia, parkinsonism, vertical supranuclear gaze palsy
	6	F	53	No	No	No	Asymmetric parkinsonism, alien arm phenomenon
	7	M	69	No	No	No	Asymmetric apraxia, parkinsonism,
	8	F	65	No	No	No	Asymmetric apraxia, agraphesthesia
	9	F	68	No	No	No	Asymmetric apraxia, parkinsonism, agraphesthesia
	10	F	81	No	No	No	Asymmetric parkinsonism, aphasia, alien leg phenomenon
	11	M	49	No	No	No	Asymmetric parkinsonism

4. Discussion 

The present study demonstrates a significant difference in the frequency of photophobia in patients with PSP compared to those with CBS. This result suggests that the presence of photophobia may help clinicians to better differentiate between PSP and CBS on a clinical basis, and may be a helpful feature in predicting underlying pathology.

The pathophysiology of photophobia is not entirely understood. Studies have pointed to the trigeminal nerve as one necessary component for photophobia. Rat studies have demonstrated trigeminal connections to the thalamus, superior colliculi, ventral part of the zona concerta, and anterior pretectal nucleus [4]. Other studies have suggested a role of the optic nerve and its connections with the pretectal nuclei. Indeed, it may be an interaction of these two pathways that produce photophobia [4]. The corresponding subcortical location of the trigeminal and optic nerve connections and typical subcortical location of PSP pathology, such as the superior colliculi, may explain the high incidence of photophobia found in our PSP population. The subcortical location of PSP pathology contrasts with the more cortical location of pathology found in CBD and may explain the relatively low frequency of photophobia found in patients with CBS in our study. In fact, both CBS patients with photophobia were two of only three CBS patients with vertical gaze palsy suggesting pathological involvement of brainstem nuclei in these two subjects. A more definitive explanation of the mechanism for why photophobia is more prevalent in PSP compared to CBS will require further research into the exact pathophysiology of photophobia.

Visual hallucinations and RBD were rare occurrences in each population making them unhelpful in clinical differentiation between PSP and CBS. The low occurrence of RBD is not surprising since this clinical phenomenon has been shown to be suggestive of underlying alpha-synuclein pathology, and both PSP and CBD are characterized by the deposition of the microtubule associated protein tau (MAPT) and not alpha-synuclein pathology [5]. One clinicopathologic study investigated the underlying neurodegenerative pathology in clinically or polysomnography confirmed cases of RBD in patients with dementia or parkinsonian symptoms. The pathologic diagnoses in this study of 15 autopsy confirmed cases were Lewy body disease (LBD) in 12 patients and multiple system atrophy (MSA) in 3 patients [5]; both LBD and MSA are characterized by alpha-synuclein pathology.

Litvan et al. showed that the presence of gait abnormality, bilateral bradykinesia, and moderate to severe vertical supranuclear gaze palsy help to distinguish PSP from CBS [6]. Their study was based on pathologically confirmed cases of these two diseases. Since our study is based on clinical and/or pathologic criteria, we cannot conclude that the presence of photophobia will definitely predict pathologic confirmation of PSP. However, 15% of our cases were pathologically confirmed and prior studies have shown that more than 75% of clinically diagnosed PSP patients have PSP pathology [7].

The results of our study suggest that patients suspected to have PSP or CBD should be questioned regarding the presence or absence of photophobia as part of routine questioning. As we continue to recruit more subjects, we expect to have significantly more power, as well as more autopsy confirmation, which is a current limitation, and we will be able to provide sensitivity and specificity statistics. In this study, we demonstrate for the first time that the presence of photophobia may be an additional useful clinical feature to differentiate PSP from CBD.

Conflict of interest 

The authors have no conflict of interest.