Visual Hallucinations in Posterior Cortical Atrophy

Abstract

Objective

To compare clinical and imaging features of patients with posterior cortical atrophy (PCA) with and without well-formed visual hallucinations.

Setting

Tertiary care medical center

Methods

Fifty-nine patients fulfilling criteria for PCA were retrospectively identified, and divided into two groups based on the presence (N=13) and absence (N=46) of visual hallucinations. Both groups were then compared statistically for clinical differences, as well as with voxel-based morphometry (VBM) for imaging differences.

Results

In PCA patients with hallucinations, parkinsonism and rapid eye movement sleep behavior disorder occurred more frequently (p<0.0001), as did myoclonic jerks (p=0.0002). VBM analysis showed greater atrophy in a network of structures, including the primary visual cortex, lentiform nuclei, thalamus, basal forebrain and midbrain in the patients with hallucinations.

Conclusions

Hallucinations in patients with PCA are associated with parkinsonism, rapid eye movement sleep behavior disorder, and myoclonic jerks. The results from the VBM analysis suggest that hallucinations in PCA cannot be exclusively attributed to atrophy of the posterior association cortices and may involve a circuit of thalamocortical connections.

INTRODUCTION

Posterior cortical atrophy (PCA) is a clinical syndrome, characterized by visuospatial and visual perceptual impairment, visual agnosia and features of the Balint’s and Gerstmann syndrome^1–3. Case studies in PCA demonstrate atrophy of bilateral occipital, parietal, and posterior temporal lobes on MRI^{1, 2, 4}. Similarly, functional imaging studies in PCA reveal a pattern of decreased perfusion affecting these same regions⁵. Many pathological studies demonstrate that the predominant underlying histological features of PCA are the presence of neurofibrillary tangles (NFT) and senile plaques. However, the distribution of pathology differs from that of typical Alzheimer’s disease (AD), affecting predominantly the occipital and parietal lobes^{6, 7}.

While there are cardinal features of PCA, studies have described additional features not originally reported in PCA. One such feature is visual hallucinations which have been reported to occur in up to 25% of patients who meet criteria for PCA^3,8. It is not known however if patients who meet criteria for PCA but have hallucinations are different from those that meet criteria but do not have hallucinations. We therefore set out to compare clinical and imaging features of PCA patients with and without visual hallucinations.

METHOD

Subjects

The Mayo Clinic medical records database was used to identify all patients with a clinical diagnosis of PCA that had been evaluated between January 1^st 1995 and December 31^st 2005. Seventy patients were identified.

The medical records of each of these 70 patients were reviewed independently by one behavioral neurologist (KAJ) to ensure that they fulfilled the proposed diagnostic criteria for PCA^1–3. Inclusion criteria were as follows: 1) insidious onset of symptoms; 2) a chief complaint of at least two prominent symptoms referable to the occipital, parietal or posterior temporal lobes that have been liked to PCA; 3) no primary ocular disease accounting for the compliant after ophthalmologic evaluation by an ophthalmologist, 4) an evaluation by at least one behavioral neurologist, 5) progression of symptoms, and 6) MRI or CT head demonstrating a predominant posterior pattern of atrophy on visual inspection. The list of prominent symptoms linked to PCA included visuospatial deficit, visual perceptual deficit, visual agnosia, color agnosia, environmental disorientation, dressing apraxia, ideomotor apraxia, alexia, hemianopia, transcortical sensory aphasia, anomia, prosopagnosia, body schema distortion, or any feature suggestive of the Balint’s or Gerstmann syndromes^1–3.

Patients were excluded if there were any findings of a hemispheric infarct in the occipital, parietal or temporal lobes on head MRI or CT (reviewed by CRJ and JLW), that could have contributed to the presenting syndrome.

A total of 11 patients did not meet our inclusion and exclusion criteria. The remaining 59 patients were divided into two groups: those with visual hallucinations and those without. Visual hallucinations were defined as a false visual perception, not associated with real external stimuli and not associated with falling or awakening from sleep. A patient was placed into the group with hallucinations if the hallucinations were well-formed, recurrent, well-documented, non-fleeting, and spontaneous

Volumetric MRI

Voxel based morphometry was used to compare the pattern of grey matter atrophy in all patients with hallucinations (N=7) that had an available volumetric MRI, to a group of age and sex matched patients without hallucinations (N=7) and to normal controls (N= 38).

T1-weighted volumetric MRI were acquired at 1.5T (22x16.5cm FOV, 25° flip angle, 124 contiguous 1.6mm thick coronal slices). An optimized method of VBM was applied^{9, 10}, implemented using SPM2 (http://www.fil.ion.ucl.ac.uk/spm). In order to reduce any potential normalization bias across the disease groups’ customized templates and prior probability maps were created from all patients in the study. To create the customized template and priors all images were registered to the MNI template using a 12dof affine transformation and segmented into grey matter (GM), white matter (WM) and CSF using MNI priors. GM images were normalized to the MNI GM prior using a nonlinear discrete cosine transformation (DCT). The normalization parameters were applied to the original whole head and the images were segmented using the MNI priors. Average images were created of whole head, GM, WM and CSF, and smoothed using 8mm full-width at half-maximum (FWHM) smoothing kernel. All images were then registered to the customized whole brain template using a 12dof affine transformation and segmented using the customized priors. The GM images were normalized to the custom GM prior using a nonlinear DCT. The normalization parameters were then applied to the original whole head and the images were segmented once again using the customized priors. All images were modulated and smoothed with an 8mm FWHM smoothing kernel.

Two-sided t-tests were used to analyze the smoothed modulated images from the PCA group with hallucinations compared to controls, and from the PCA group without hallucinations compared to controls. In addition, two direct comparisons were performed between the two PCA groups, firstly to identify regions that showed greater loss in PCA with hallucinations than those without, and second to identify regions that showed greater loss in PCA without hallucinations than those with hallucinations.

Regions of grey matter loss identified by VBM were also visually rated: 0 = no loss, + = mild loss, ++ = moderate/severe loss (uncorrected p<0.001).

Statistics

Statistical analyses were performed utilizing the JMP computer software (JMP Software, version 5.1.2; SAS Institute Inc, Cary, NC) with statistical significance set at p < 0.05. Mann Whitney-U test was used to compare the mean ages of disease onset between the two different clinical groups. Gender ratios and the presence or absence of clinical signs were compared using a Chi-squared test. Fisher’s Exact Test was used in any comparison with small numbers (N < 6).

RESULTS

Clinical

The demographics and clinical features of all 59 patients are shown in table 1.

Table 1.

Comparison of patients with PCA with and without visual hallucinations

	PCA with hallucinations (n=13)	PCA without hallucinations (n=46)	Total PCA patients (n=59)
Gender: Male/Female	6:7	17:29	23:36
Median age at disease onset in years (range)	63 (49–86)	57 (40–74)	59 (40–86)
Right-handed	13 (100%)	45 (98%)	58 (98%)
Median number of years of education (range)	12 (12–17)	14 (8–20)	14 (8–20)
RBD present *	8 (62%)	0 (0%)	8 (14%)
Parkinsonism present *	10 (77%)	7 (15%)	17 (29%)
Myoclonic jerks present **	6 (46%)	1 (2%)	7 (12%)
Median difference in years between onset of hallucinations and onset of PCA (range)	4 (1–12)	N/A	N/A
Median difference in years between onset of RBD and onset of PCA	3 (1–7)	N/A	N/A
Median difference in years between onset of parkinsonism and onset of PCA	4(2–10)	3 (2–7)	N/A
Median difference in years between onset of myoclonic jerks and onset of PCA	2(1–11)	N/A	N/A

Significantly different

^*p<0.0001:

^**p=0.0002

N/A = not applicable

Twenty-two of the 59 patients have been previously reported³. Thirty-six patients (61%) were female, and 58 (98%) were right handed. All patients had been evaluated by at least one behavioral neurologist, and on average had been evaluated 2.6 times throughout their disease course. Fifteen patients had one evaluation, 39 patients had 2 to 5 yearly evaluations, and 5 patients more than 5 evaluations. All patients had typical early signs and symptoms of PCA and over time developed a number of additional features (Figure 1). Of the cardinal signs and symptoms of PCA assessed, five patients had 2–3 signs or symptoms, 16 patients had 4–5, 36 patients had 6–10, and two patients had more than 10 signs or symptoms present during their disease course. In addition to the typical features of PCA, cerebellar ataxia was noted to have occurred in 10% of the patients. Syncopal attacks were also described in three patients, and two patients were found to have temporal lobe epileptic spikes on electroencephalogram (EEG). Episodic memory loss was never the dominant presenting symptom in any of the 59 patients.

Figure 1.

Histogram shows the frequency of the typical signs and symptoms of PCA in our cohort (n=59), split by whether the symptoms occurred early or late in the disease course.

Thirteen patients with PCA had well formed visual hallucinations (Tables 1 and 2). These 13 patients did not differ from those without hallucinations in terms of gender, or age of disease onset, although there was a trend for them to be older (median 63 years vs. 56.5 years). The patients with PCA and hallucinations had a greater frequency of rapid eye movement sleep behavior disorder (RBD) (p<0.0001), parkinsonism (p<0.0001), and myoclonic jerks (p=0.0002). Rapid eye movement sleep behavior disorder was confirmed by a board-certified sleep specialist (BFB) and met the new diagnostic criteria B for RBD, defined as abnormal, wild flailing movements occurring during sleep, with sleep related injurious, potentially injurious, or disruptive by history¹¹.Parkinsonism was defined as the presence of two or more of the following: cogwheel rigidity, stooped posture, shuffling gait, bradykinetic alternating motor rates, facial masking, and resting tremor and was scored based on the modified Hoehn and Yahr Stage¹². Only spontaneous, well-documented parkinsonism was included. Postural tremor or drug induced parkinsonism were excluded. All 13 patients eventually met diagnostic criteria for probable DLB¹³, however none would have met criteria at baseline evaluation or within the first two years of follow-up. None of the other 46 patients without hallucinations would have fulfilled criteria.

Table 2.

RBD, parkinsonism and hallucinations in 13 patients with PCA and visual hallucinations

	Gender	Age at onset	RBD	Parkinsonism	Description of dominant recurrent visual hallucinations
Patient 1	M	74	−	+	Not described
Patient 2	M	60	+	−	Headless boy in passenger seat of truck
Patient 3	F	66	−	+	People inside the house
Patient 4	F	63	+	−	Women inside the house
Patient 5	M	55	−	+	Realtor inside the house. Persistent pink blob on hand
Patient 6	F	64	+	+	Children with guns
Patient 7	F	58	−	+	Very pretty woman inside the house
Patient 8	M	73	+	+	Man standing in the corner, animals
Patient 9	F	59	+	−	People, animals, trees and bugs
Patient 10**	F	86	+	+	Deceased relatives inside the bedroom
Patient 11*	M	63	+	+	Strange man with his wife
Patient 12	F	49	+	+	Bugs, spiders (would stomp on them)
Patient 13	M	63	−	+	Bugs, spiders, people looking inside the house

^*Positive mirror sign (would see a strange person, rather than oneself when looking into a mirror)

^**Positive Capgras’s syndrome

The onset of the hallucinations occurred on average four years after the onset of the typical symptoms of PCA, as did the onset of parkinsonism (four years), RBD (three years) and myoclonic jerks (two years), in the patients with hallucinations. The parkinsonism was always less than or equal to a modified Hoehn and Yahr stage of 1.5¹². There were seven PCA patients without hallucinations who 3 years after the onset of visual complaints developed parkinsonism, without any other features of DLB.

Volumetric MRI

The PCA patients with hallucinations showed bilateral grey matter atrophy involving the occipital, parietal and posterior temporal lobes compared to controls (uncorrected for multiple comparisons, p<0.001)(Figure 2). Regions that were particularly involved included the primary visual cortex, thalamus, hypothalamus, globus pallidus and putamen (the lentiform nucleus), head of the caudate nucleus, midbrain and the basal forebrain. The loss also extended forward to involve regions in the posterior frontal lobe and the medial temporal lobes. Small regions of loss were also identified in the posterior cingulate and cerebellum (uncorrected p<0.001).

Figure 2.

Patterns of grey matter loss identified in the PCA patients with, and without, hallucinations when compared to controls (uncorrected, p<0.001), overlaid on an MRI from a healthy control.

The PCA patients without hallucinations showed a similar pattern of global atrophy compared to controls, involving the occipital, parietal, posterior temporal lobes and posterior frontal gyri (uncorrected, p<0.001) (Figure 2). However, the regions of loss focused on the posterior cingulate and retrosplenial cortex, the temporal and parietal association cortices and the medial temporal lobe. The patterns of loss were bilateral but with a slight right-sided predominance. There was also mild involvement of the midbrain, primary visual cortex and the cerebellum (uncorrected, p<0.001).

Table 3 summarizes the patterns of loss observed in both groups when compared to controls, and indicates the severity of loss in each region based on a visual assessment of the VBM results (uncorrected, p<0.001). It demonstrates that the patients with hallucinations showed relatively more loss in the primary visual cortex, midbrain and basal ganglia regions than the patients without hallucinations, and conversely that the patients without hallucinations showed a greater loss in the posterior cingulate, temporal parietal association cortices and the right temporal lobe. A direct statistical comparison between the groups on VBM revealed that the patients with hallucinations had greater atrophy bilaterally in the thalamus, although greater on the left, and globus pallidus than the patients without hallucinations (uncorrected, p<0.005) (Figure 3). The only region found to be significantly more atrophied in the patients without hallucinations on direct comparison was a small region in the cingulate gyrus (uncorrected, p<0.005, not shown).

Table 3.

Differences in regional atrophy on VBM in PCA patients with and without hallucinations compared to controls.

Structure	PCA with hallucinations	PCA without hallucinations
Posterior frontal	+	+
Basal forebrain	+	0
Right medial temporal	+	++
Left medial temporal	+	+
Temporal/parietal association cortices	+	++
Posterior cingulate/retrosplenial cortex	+	++
Primary visual cortex	++	+
Thalamus/hypothalamus	++	0
Head of caudate	++	0
Globus pallidus/putamen	++	0
Midbrain	++	+
Cerebellum	+	+

Figure 3.

VBM demonstrates that the thalamus and bilateral globus pallidus show significantly greater atrophy in the PCA patients with hallucinations than the PCA group without hallucinations (uncorrected for multiple comparisons, p<0.005), overlaid on an MRI from a healthy control. L = left, R = right, A = anterior, P = posterior.

DISCUSSION

This was a large group study on patients with PCA that reveals clinical and imaging differences between those with and without visual hallucinations.

Each of the 59 patients with PCA in our study satisfied published criteria for the diagnosis of PCA ^1–3. In all cases, additional features of PCA also developed later in the disease course, sometimes with as many as 11 typical features being present. The most frequent presenting symptom was visual spatial/visual perceptual deficits and included features of the Balint’s syndrome, and visual disorientation, with presenting complaints such as “difficulty climbing stairs,” “difficulty finding the handle of a car” or “difficulty following the lines of text while reading.” Approximately 50% of our PCA patients did eventually complain of episodic memory loss, however in none was the memory loss the most prominent presenting feature, and in the majority the memory loss developed later in the disease course. In our series, women were over-represented. This higher frequency of women with PCA is similar to the higher frequency of women reported in studies on typical AD¹⁴ and is not necessarily surprising, since the most common pathology underlying PCA is NFT and senile plaques^{3, 15}.

Almost a quarter of our patients of PCA (N=13) were found to have visual hallucinations, similar to two other series of PCA^{3, 8}. The visual hallucinations were well formed, recurrent, spontaneous, non-fleeting, and in many cases were present for many years. The hallucinations were also very similar to the type of hallucinations encountered in patients with DLB and occurred at least one year after PCA symptom onset, as previously reported⁸. All patients with visual hallucinations met clinical research criteria for probable DLB¹³, although not at baseline evaluation, as all had coexisting RBD⁹ or spontaneous parkinsonism. None of the 46 patients without hallucinations met criteria for probable DLB. Surprisingly none of the 13 patients with hallucinations were ever diagnosed as DLB by the treating physicians, suggesting that it is not generally recognized that isolated and prominent visuospatial deficits, classic features of PCA, may later progress into a DLB-like phenotype. This should be of no surprise as many different pathologies underlie the PCA syndrome¹⁵. We therefore suggest that when patients meet criteria for PCA, but develop well formed visual hallucinations, a diagnosis of DLB be rendered given that DLB is a well recognized clinicopathological entity in which treatment approaches differ from those of ‘typical’ PCA and Alzheimer’s disease.

The findings of increased myoclonic jerks in the group of patients with hallucinations is interesting, however the cause for the association is unknown. We speculate that both phenomena may occur as a result of atrophy or damage to a common network of cortical and subcortical structures. While both groups of PCA patients showed a posterior pattern of atrophy on VBM, confirming previous reports in PCA^{1, 2} and correlating with the clinical features, there were some striking differences between the patients with and without hallucinations. The group of patients with hallucinations showed greater atrophy in a network of structures including the primary visual cortex, thalamus, hypothalamus, basal ganglia, midbrain and basal forebrain, than the patients without hallucinations. In contrast, the group of patients without hallucinations showed greater loss in the posterior cingulate (including the retrosplenial cortex), the temporal and parietal association cortices, and the medial temporal lobe than the patients with hallucinations. These findings suggest that visual hallucinations in PCA are not occurring as a result of atrophy of the posterior cortical association regions as the posterior association regions were more affected in the patients without hallucinations. Of the structures most affected in the PCA patients with hallucinations (thalamus, hypothalamus, basal ganglia, midbrain and primary visual cortex), the most likely regions accounting for the hallucinations would be the primary visual cortex, midbrain and thalamus¹⁶. However, atrophy of one of these regions is unlikely to be the sole cause. More likely would be destruction of a network of interconnecting anatomical structures, specifically thalamocortical and ascending midbrain pathways¹⁶.

Of the other structures that were most affected in those patients with hallucinations, atrophy of the midbrain and basal ganglia regions would explain why more than three quarters of the patients with hallucinations also had parkinsonism. Furthermore, the midbrain has been liked to RBD¹⁷.

The major strengths of this study were the large number of well defined cases. All patients in this study were initially assessed by a behavioral neurologist with expertise in neurodegenerative diseases. The average follow up time of our patients was more than two years, suggesting that the majority of our patients had at least two evaluations, with some patients even being followed for up to nine years. More than a third of the patients were also initially enrolled in our ADRC and ADPR, which are longitudinal studies with standardized clinical, imaging and genetic protocols.

The major limitations of our study were the relatively small number of patients with hallucinations that had a volumetric MRI available for the VBM analysis however, PCA is a relatively rare syndrome.

Multiple different pathologies can underlie the PCA syndrome. The late occurrence of hallucinations in patients who meet criteria for PCA suggest progressive damage to thalamocortical connections and should prompt the clinician to consider the diagnosis of DLB.