The World Health Organization estimated that in 2002 there were 161 million persons worldwide with visual impairment, with 37 million of them being blind (i.e., visual acuity less than 3/60; see Resnikoff et al.,). An estimated 1.4 million were blind children below the age of 15 years (Resnikoff et al.,). Other research suggests that these numbers are higher: 259 million persons with visual impairment worldwide, including 42 million blind persons (Dandona and Dandona,). According to the World Health Organization, schizophrenia affects about 24 million people worldwide2.
Despite these large numbers of prevalence for each one of the two conditions, it has been argued that patients with CB seem to be "immune" to schizophrenia, since numerous studies have failed to produce even one well-defined case (Sanders et al.,). The aim of this section is to present such cases. We suggest that two factors are necessary in order to delimit the origin of the protective effects: (a) age of blindness onset (congenital/early vs. late) and (b) origin of visual deficit (cortex vs. globe). The PaSZ hypothesis distinguishes between two factors as well: (a) age of blindness onset and (b) degree of visual capacity (i.e., blindness, impairment, normal vision, highly trained vision, etc.). The second factor is indeed relevant in the context of Landgraf and Osterheider, where the relative risk for schizophrenia is related to a continuum of visual capacity toward a "peak risk" (see also Landgraf et al.,; Silverstein et al.,). Both sets of factors enter into the relation between schizophrenia and blindness, but in the context of the present discussion the second factor of the PaSZ hypothesis is not so crucial, because we focus on the one edge of the continuum (i.e., blindness).
As the case-reports presented in this section show, only congenital/early cortical blindness:the type of blindness that occurs when bilateral lesions of the occipital cortex deprive the individual from vision (Cummings and Trimble,, p. 110):seems to confer protective effects. A factor to be taken into consideration is the lack of uniformity in defining age of onset of early blindness. In the context of our study, the distinction between congenital/early vs. late blindness is crucial; therefore, concurring with a long line of research, we take the age of onset of congenital blindness to be birth and the mean age of onset of early blindness to be <5-6 years of age (Arno et al.,; Kitada et al.,). Following the practice in previous studies (e.g., Silverstein et al.,), these two groups are merged and collectively referred to as CB.
The case-reports and their analysis examined in the present work are the result of extensive text-mining and database searching through PubMed, OMIM, String 9.1 as well as individual journal search for all results retrieved by searches of any combination of the terms "schizophrenia," "psychosis," "congenital/early/childhood/adolescent/late/peripheral/ocular/cortical/cerebral blindness." Our searches were not constrained by any time frame or language-/ethnic-group restrictions.
Table 1 shows case-reports for three out of four groups of blindness that arise when we combine the two factors: age of onset (CB vs. late blindness) and origin of the visual deficit (cortical vs. peripheral). Although we identified cases of CB and schizophrenia, they are all of the CPB type. Our research did not identify a single case of CCB and schizophrenia, although in one case presented in Table 2 (i.e., Stewart and Sardo,) the origin of the deficit is not reported.
In Table 2, the relevant case-reports are presented in further detail. Unless stated otherwise, all case-reports involve a diagnosis of schizophrenia.
Table 2 presents five cases of CPB and one case of EPB. Starting off from Stewart and Sardo, this is the only case of schizophrenia and CB brought up in Silverstein et al. and the validity of the schizophrenia diagnosis is questioned on the basis of absence of psychotic symptoms. However, it can be observed that the patient shows disorganized speech and grossly disorganized behavior. On this basis, diagnostic criterion A for schizophrenia of DSM-5 (American Psychiatric Association,) is met even in the absence of delusions or hallucinations5. Second, the patient does seem to show psychotic symptoms that meet DSM-5 diagnostic criteria for catatonia, as these are reviewed in Tandon et al. (: Table 1). More specifically, (i) echolalia, (ii) agitation, and (iii) phases of mutism are present in the patient's behavior. The origin of the visual deficit is not explicitly reported, but crucially there is evidence that blindness run in the family. Siblings of the patient are reported to be "afflicted with the same congenital blindness" (Stewart and Sardo,, p. 125). On this basis, we are inclined to assume this is a case of hereditary blindness that involves the globe (i.e., CPB).
The second case-report that is quite explicit on the existence of psychotic symptoms is given in Gobetz. Even if Silverstein et al. are right in questioning the schizophrenia diagnosis in Stewart and Sardo, our research has uncovered case-studies where both the psychotic features and the peripheral origin of CB are explicit; the case-report presented in Gobetz is one example. The cause of CB is optic atrophy. The patient was first hospitalized in the age of 15 and the medical reports make reference to psychotic features such as hallucinations and paranoid thinking. The extensive reference to the contents of her hallucinations leaves no doubt that this is indeed a case of comorbidity between CPB and schizophrenia, with psychotic features present.
Third, Kerschbaumer presents three cases of schizophrenia and CB. The cause of blindness is eye underdevelopment. Kerschbaumer does not offer the profile of the three congenitally blind patients in terms of psychosis. However, the comments offered in the Conclusion Section (point 9) of that medical report do not offer any reason for challenging the diagnosis of schizophrenia. More specifically, Kerschbaumer draws attention to the need to avoid the misdiagnosis of the catatonic type of schizophrenia as manic-depressive psychosis or the misdiagnosis of early schizophrenia with predominant somatic delusions as psychoneurosis with paranoid ideation. It seems that the diagnoses of schizophrenia have been made with the necessary caution so as to not misrepresent cases falling within the schizophrenia spectrum disorders as schizophrenia. On this basis, we do not have any reason to question the diagnosis of schizophrenia that is given in Kerschbaumer.
Last, Weiss et al. report a patient who at the age of 6 (upon going to school for the first time) was found to be "almost completely blind" (p. 259) and transferred to a special school. This case is less clear than the ones presented above for two reasons: first, the age of blindness onset is not birth, and second, the patient is almost blind, but not completely. Putting this case-report in the context of the PaSZ hypothesis, almost complete blindness should fall within the low-risk zone for developing schizophrenia identified in Landgraf and Osterheider (: Figure 1). With respect to the age factor, the absence of consensus across studies with respect to the age range that corresponds to "early blindness" makes it hard to unambiguously say whether 6 years of age classifies as early or late blindness. Depending on where one puts the limit on the age range, the patient in Weiss et al. may or may not count as early blind schizophrenic.
Overall, the conclusion to be drawn from these case-reports is that there are cases of comorbidity between congenital and early PB (i.e., CPB) and schizophrenia, but so far no such case has been discovered for congenital or early CB (i.e., CCB) and schizophrenia.
Usher syndrome is in part the ground on which Silverstein et al. comment on cases of congenital deafblindness by arguing that it is not clear at present why adding deafness to a case of congenital blindness lifts the protective effects against schizophrenia. As shown in Table 2, not all cases of CB and schizophrenia involve hearing loss. In light of this, deafness cannot be viewed as lifting the protective effect, since the latter appears lifted in cases that deafness is not reported. According to the US National Institute on Deafness and Communication Disorders, Usher syndrome is the most common condition affecting both vision, via retinitis pigmentosa, and hearing6. In the literature, one finds numerous reports on the relation between retinitis pigmentosa and schizophrenia (Shukla et al.,; McDonald et al.,). Recently, an association between usherin and psychotic symptoms has been established on the basis of a genetic analysis of two siblings with Usher syndrome and schizophrenia (Domanico et al.,).
Bardet-Biedl syndrome presents a similar picture. It has been referred to as Laurence-Moon-Bardet-Biedl, but Laurence-Moon and Bardet-Biedl are now recognized as separate entities, although not always (Moore et al.,). Blindness that is the result of childhood-onset retinitis pigmentosa and schizophrenia-like psychosis can co-exist in Bardet-Biedl syndrome (Weiss et al.,). The main symptoms of this syndrome are rod-cone dystrophy (atypical retinitis pigmentosa), postaxial polydactyly, mental retardation, hypogonadism, and renal dysfunction (Green et al.,; Beales et al.,). Language delays have been observed too (Chen et al.,; Aloulou et al.,). Case-reports indicate comorbidity between (Laurence-Moon-)Bardet-Biedl and schizotypal traits: Delusions of persecution have been reported (O'Mahony,), but also full-blown schizophrenia (Jain and Garg,).
Disrupted-in-Schizophrenia1 (DISC1) is one of the most frequently discussed susceptibility loci for schizophrenia. It could be described as the standard textbook example of a candidate gene for vulnerability in schizophrenia (e.g., Black and Andreasen,, p. 78). Numerous studies have found positive evidence of association between schizophrenia and genes encoding DISC1-interacting proteins across a variety of ethnic groups (Bradshaw and Porteous,). Crucially, DISC1 plays a "role in radial neuronal migration via anchoring dynein motor-related proteins to the centrosome, including NDEL1, BBS1 and BBS4, two of the proteins mutated in Bardet-Biedl syndrome" (Ishizuka et al.,, p. 92; see also Kamiya et al.,). In other words, the genetic basis of Bardet-Biedl suggests that this is a syndrome that may manifest comorbidity between schizophrenia and retinitis pigmentosa.
Our review of case-reports in different syndromes suggests that schizophrenia and, more generally, schizotypal features can be found in the CB population as long as the cause of blindness is found in the globe. The situation is less clear in cases of CCB; in the absence of case-reports that involve both CCB and schizophrenia, the PaSZ hypothesis (Landgraf and Osterheider,) can be maintained. Aiming to understand the genetic underpinnings of the patterns of comorbidity presented in this section, the next section elaborates on the genetic underpinnings of these patterns and the brain structures involved in the interplay between blindness and schizophrenia.