Overlap Between Ophthalmology And Psychiatry – A Narrative Review Focused on Congenital and Inherited Conditions

Abstract

A number of congenital and inherited diseases present with both ocular and psychiatric features. The genetic inheritance and phenotypic variants play a key role in disease severity. Early recognition of the signs and symptoms of those disorders is critical to earlier intervention and improved prognosis. Typically, the associations between these two medical subspecialties of ophthalmology and psychiatry are poorly understood by most practitioners so we hope to provide a narrative review to improve the identification and management of these disorders. We conducted a comprehensive review of the literature detailing the diseases with ophthalmic and psychiatric overlap that were more widely represented in the literature. Herein, we describe the clinical features, pathophysiology, molecular biology, diagnostic tests, and the most recent approaches for the treatment of these diseases. Recent studies have combined technologies for ocular and brain imaging such as optical coherence tomography (OCT) and functional imaging with genetic testing to identify the genetic basis for eye-brain connections. Additional work is needed to further explore these potential biomarkers. Overall, accurate, efficient, widely distributed and non-invasive tests that can help with early recognition of these diseases will improve the management of these patients using a multidisciplinary approach.

1. Introduction

Ophthalmic and psychiatric diseases are associated with increased morbidity, resulting in considerable economic and social burden (Liu et al., 2020). A number of congenital, inherited or acquired disorders present with both ophthalmic and/or psychiatric features. There are also several psychiatric medications that can adversely impact various anatomical parts of the eye via diverse mechanisms (overdose, hypersensitivity, intolerance, or idiosyncratic) (Rajsekar et al., 1999). Thus, it is important for both ophthalmologists and psychiatrists to recognize early clinical features and co-morbidities that would facilitate diagnosis and treatment of the underlying issue.

Both the retina and the brain are derived from the anterior neural tube, sharing similar structural and functional features (London et al., 2013). Studies have shown that vision and visual processing are altered in psychotic disorders and that an association between ophthalmic and psychiatric diseases may exist but remains to be elucidated (Bannai et al., 2022; Gandu et al., 2021; Miller, 2006). For example, eye movement alterations have been identified in individuals with schizophrenia and in their siblings, rendering it an endophenotype of schizophrenia. This also suggests that genetic factors contribute towards a greater risk for visual disturbances (Kikuchi et al., 2018). In a study by Lencer et al, genome-wide association studies were used to evaluate three eye movement phenotypes in psychosis patients and found an association with the LMO7 gene, which has been related to retinal deficits (Lencer et al., 2017). In a recent cross-organ imaging genetics study, the authors identified a genetic basis for eye-brain connections, suggesting that retinal imaging can be used to elucidate the genetic risk factors of brain disorders (Zhao et al., 2023).

Advances in brain and retinal imaging have allowed for the careful and non-invasive investigation of these structures. For instance, lower retinal thickness, peripapillary ganglion cell layer, and retinal nerve fiber layer thickness have been reported in patients with schizophrenia and bipolar disorder (Lizano et al., 2020). Moreover, thinning in the primary visual cortex has been described using functional imaging in psychosis when compared to healthy controls (Adhan et al., 2020; Reavis et al., 2017; Türközer et al., 2022). However, despite the growing number of studies examining the eye in psychiatric disorders, much less has been concisely reviewed as it relates to genetic risk factors that may contribute to both ophthalmologic and psychiatric disorders. It is also important to acknowledge the challenge in disentangling mood and anxiety disorders related to visual impairment with or without dysmorphic features from behavioral and mental health disorders that are directly related to the underlying pathophysiological process of the disorder (Lundeen et al., 2022).

In light of the above, the aim of this narrative review is to provide an overview of the congenital and inherited diseases that present with ophthalmic and psychiatric features. This review focuses on the clinical and diagnostic characteristics of these disorders, while also highlighting the importance of a multidisciplinary approach for the management of these patients. The disorders are described by their physical, ophthalmologic, psychiatric, and molecular manifestations, which is followed up by current practice guidelines for the management of these disorders.

2. Methods

A comprehensive search was performed in PubMed between October 2021 and July 2022 by KD and VD using the following keywords in various combinations: psychiatry and behavioral symptoms and eye (7,737) or ocular diseases (509) and eye diseases (3,922). Abstracts were screened by KD and VD, and any discrepancies were discussed and deliberated on by PL and JBM. After screening the abstracts, KD and VD read the articles for study inclusion. For conciseness, conditions with ophthalmic and psychiatric overlap were included if there was a substantial literature identified and prevalence of the mental health conditions were reported. Only relevant articles reported in English were reviewed.

3. Results

1). Craniofacial Disorders

Noonan syndrome (NS)

NS is an autosomal dominant multisystem disorder with variable expression characterized by facial dysmorphism (large head, triangular face shape), neck webbing, developmental delay, short stature, failure to thrive, lymphatic anomalies (hygroma, lymphedema), bleeding diathesis, congenital heart defects (atrial or ventricular septal defects, pulmonary valvular stenosis, hypertrophic cardiomyopathy), cryptorchidism, musculoskeletal or renal abnormalities (rotational errors, hydronephrosis), neurological (Chiari malformation type 1, hydrocephalus, seizures), ocular abnormalities, and psychiatric disorders. Due to the great variability in its expression, the true NS prevalence is difficult to determine. Prevalence is believed to be 1 in 1,000–2,500 live births for the severe phenotype and 1 in 100 live births for mild cases (Bhambhani and Muenke, 2014). NS results from heterozygous mutation in the PRPN11 (protein tyrosine phosphatase, non-receptor type 11) gene which plays a role in the RAS-MAPK (mitogen-activated protein kinase) pathway to regulate cell proliferation, differentiation, migration, apoptosis and adhesion (RASopathy). Mutations in other RAS-MAPK pathway genes (SOS, RAF1, RIT1, KRAS, BRAF, LZTR1, NRAS) have been associated with NS (Ogata and Yoshida, 2005; van Trier et al., 2016). However, in about 20–30% of cases a genetic mutation is never identified (Carcavilla et al., 2020). NS diagnosis is largely a clinical diagnosis, but in mild cases molecular genetic testing (RASopathy panel) can assist in confirming NS. MRI should be considered in NS given the potential presence of Chiari malformation type 1, syringomyelia, and hydrocephalus (Carcavilla et al., 2020). Early diagnosis is vital as individualized and multitargeted treatment can reduce morbidity and mortality (Table 1).

Table 1:

Clinical presentation, pathophysiology, diagnostic assessment and management of diseases with ophthalmologic and psychiatric features

	Pathophysiology	Ophthalmologic features	Psychiatric features	Other clinical features	Diagnostic	MRI	Management
Craniofacial disorders
Noonan syndrome	AD/heterozygous mutation in PRPN11 gene role in the RAS-MAPL pathway/mutations in other genes of the pathway (SOS, RAF1, RIT1, KRAS, BRAF, LZTR1, NRAS)	Hypertelorism, epicanthal folds, ptosis, refractive errors, keratoconus, strabismus, nystagmuss, amblyopia, ataract, posterior embryotoxon, prominent corneal nerves, optic nerve head abnormalities(hypoplasia, coloboma, excavationn)	Attention deficit and hyperactivity disorder (ADHD), anxiety syndrome, specific/social phobias, depression	Facial dysmorphism, developmental delay, learning difficulties, short stature, congenital heart defects, genitourinaryab normalities, neurologic disorders, musculoskeletal (scoliosis, lordosis, hypotonia, pectus carinatum, pectus excavatum, cubitus valgus), blood disorders (bleeding diathesis, platelet function defects, low platelet count, factors VIII, XI and XII deficiency), neoplasias (gliomas, leukemia, neuroblastoma, rhabdomyosarcoma)	Molecular testing, ophthalmic examination, Neuropsychological evaluation	Intraventricular hemorrhage, cerebral parenchymal hemorrhage, cerebellar hemorrhage, punctate white matter lesions, corpus callosum hypoplasia, enlargement of the extracerebral space	Management guidelines divided by systems (ex. Physical therapy, speech therapy)
Trisomy 21 or Down Syndrome	supernumerary chromosome 21, resulting from partial (rare) or complete trisomy	strabismus, refractive error and amblyopia, nystagmus, accommodation deficits, nasolacrimal duct obstruction, keratoconus, optic nerve pathology, glaucoma, ocular neoplasm, and retinal pathology	mood disorders, anxiety disorders, obsessive-compulsive disorder, schizophrenia, psychosis, pseudobulbar affect, personality disorder, dementia, Alzheimer’s disease, conduct disorders, tic disorders, or impulse control disorder	Facial dysmorphism, obstructive sleep apnea, respiratory infections, thyroid disease, hematological disorders, immune dysfunction, gastrointestinal structural defects, male infertility, obesity, small statue, short fingers, hypotonia, atlantoaxial instability, and congenital heart defects	Prenatal genetic screening, molecular testing, ophthalmic examination, Neuropsychological evaluation	Smaller gray and white matter in cortical and cerebellar regions, as well as enlargement in subcortical, parietyal and temporal regions	Treatment depends on organ system involvement which may include medication, surgical, and behavioral management.
Retinal Disorders
Retinitis pigmentosa and Usher syndrome	AD, AR, X-linked, Y-linked/RL BP1, RP1, RHO, RDS, PRPF8, PRPF3, ABCA4, RPE65 Usher syndrome: Type 1:MYO7A (USH1B), USH1C, CDH23, PCDH15 (USH1F), SANS (USH1G), CIB2 Type2: USH2A, ADGRV1 (VLGR1) WHRN (DFNB31) Type 3: USH3A (CLRN1), HARS	night blindness, peripheral vision loss, photopsias, macularedema or macularcysts, bonespiculepigment deposits, vessel attenuation, retinal atrophy and waxy optic nerve pallor	Schizophrenia, schizophrenia-like psychosis, antisocial personality, paranoia, hypochondriasis, depression, hysteria, hypomania, delusion, hallucinations (visual, auditory), bipolar affective disorder, conduct disorder, autism, ADHD	Hearing loss, headache, vestibular dysfunction	Molecular testing, ophthalmic examination, ERG Neuropsychological evaluation	Cerebral and cerebellar atrophy, hypoplasia of corpus callosum, forth ventricle dilatation on MRI and CT of the brain	No treatment, dietary modification, vitamin supplementation, behavioral therapy, psychotropic medications
Susac syndrome	Self-limited syndrome of unknown etiology, autoimmune origin?	Branch retinal artery occlusion	Cognitive impairment, apathy, dissociation, psychosis, bipolar disorder and personality changes	Encephalopathy, sensorineural hearingloss	Neurological and ophthalmological exam, hearing exam, imaging of the brain (MRI) and eye (fluorescein angiogram, SD-OCT)	Supratentorial white matter lesions mainly in the corpus callosum on T2-wetghted MRI of the brain (characteristic “snowball ” sign from the microinfar cts), parenchymal and leptomeningeal involvement (enhancement) presented with augmented signal intensity on T2 and FLAIR images	Early treatment with immunosuppressive medications, induction treatment with pulse methylprednisolone combined with iv cyclophosphamide or rituximab
Norrie disease	XR/Norrie disease gene (NDP) on the Xp11.3 and encodes norrin protein, role in vascular development in retina and vascular maintenance in inner ear, is involved in cellular activities (cell division, adhesion and migration)	Congenital severe sight impairment, cataracts, nystagmus, microphthalmia, persistent hyperplastic primary vitreous, hyaloid vessels, retinal detachment, hemorrhages, leukocoria, atrophic irides	Cognitive impairment, behavioral disorders, depression	Sensori neural hearing loss	Clinical diagnosis, genetic testing		Based on the specific symptoms (e.g., Early vitrectomy +/− lensectomy for retinal detachme nts, Cochlear implants and hearing aid augmentation for hearing loss)
Other Disorders
Cerebrotendinous xanthomatosis (CTX)	rare autosomal recessive lipid storage disease caused by CYP27A1 gene mutations	Cataracts, xanthomas, palpebral xanthelas mas, proptosis, oculomotor changes, volitional saccades, optic nerveatrophy, myelinated optic nerve fibers, retinal vessel sclerosis, retina accumulation of cholesterol-like deposits, and intravitreal floating cholesterol crystals	dementia, seizures, dystonia and atypical parkinsonism, peripheral neuropathy, hallucinations, depression, agitation, aggression, insomnia, suicidal thoughts and attempts	infantile-onset diarrhea, childhood onset of cataract, tendon xanthomas and adult-onset progressive neurologic impairment	5 alpha-cholestanol and cholesteroal in plasma, alcohols are elevated in both serum and urine	Brain hyperintensities, decrease gray and white matter volume, decrease NAA, SPECT imaging demonstrating dopaminergic and mitochondrial dysfunction.	symptomatic treatment, replacement therapy with bile acids, surgery, chenodeoxycholic acid (750 mg/day) combined with HMG-CoA reductase inhibitors.
Kearns-Sayre syndrome	AR/AD/maternal, de novo deletions, alterations in mitochondrial or nuclear DNA or in both (heteroplasmy) leading to disruption of oxidative phosphorylation	Bilateral ptosis, diplopia, pigmentary retinopathy, retinoschisis, cornealedema	Psychosis, depression and chronic post-traumatic stress disorder	Pearson’s syndrome (sideroblastic anemia, exocrine pancreas dysfunction, diabetes mellitus), hearing loss, skeletal muscle weakness, endocrine disorders such as hypoparathyroidism, diabetes mellitus, hyperaldosteronism, gonadal failure, growth hormone deficiency, thyroid disease, neurological abnormalities-CSF protein > 1mg/ml, dementia and cerebellar ataxia	MRI, cardiac function screening, histologically-presence of ragged red fibers visualized on Gomori trichrome stain skeletal muscle biopsies, Multi-gene testing	Progressive hyperintense lesions on brainstem and white matter (cerebral and cerebellar) on T2-weighted MRI of the brain and higher signal has been detected on the same regions with FLAIR sequences	Coenzyme Q10 supplementation, functional reconstruction, levator advancement procedure and frontalis suspension forptosis
Wolfram syndrome	Orphan AR/WFS1 gene on chromosome 4pencodes transmembrane protein wolframin involved in the calcium homeostasis of endoplasmic reticulum, WFS2 is caused by mutation in the CISD2 a transmembrane protein located in endoplasmic reticulum, regulates calcium homeostasis through “mitochondria-associated ER membranes” (MAMs)	Optic nerve atrophy, dyschrom atopsia, increased cup to disc ratio, optic discpallor, cataracts, strabismus, nystagmus, glaucoma, pigmentary maculopathy (“perimacular granularity”), afferent pupillary defects, retinal nerve fiber layer thinning on OCT, visual field defects, microspherophakia	Psychosis, depression, aggression (physical, verbal), suicide, bipolar disorders, mania, schizophrenia	Neurodegeneration, central diabetes insipidus (DI), juvenile onset diabetes mellitus (DM), deafness, urinary tract disorders	Clinical diagnosis, genetic testing	Progressive optic and brain atrophy (cerebral, cerebellar, brainstem)	No effective treatment, antidepressants, antipsychotics or combination for psychiatric symptoms
Batten disease	AR/mutation in CLN3 gene located on the short arm of chromosome 16 at position 12.1 coding for the lysosomal and endosomal protein battenin	Optic nerve atrophy, pigmentary retinopathy, vascular attenuation, bull’s eye maculopathy, cataract, glaucoma, rotary nystagmus and eccentric viewing (“overlooking”)	Anxiety, restlessness, irritability, aggression, depression, mood impairment, inappropriate laughter, personality abnormalities and hallucinations (visual)	Epilepsy (myoclonic), generalized tonic-clonic and or partial seizures, progressive motor dysfunction	Clinical presentation, ophthalmic examination, neurologic evaluation MRI, genetic and biochemical assays, electroretinogram, neuropsychological test battery	Progressive cerebellar and cerebral atrophy on high-resolution T1-weighted MRI, enlarged lateral ventricles in NCL 1, 2 and 10, hypointense thalamic nuclei in NCL 2, 3, 5 and 7, hyperintense periventricular areas in NCL 1, 4, 5, 8, 13	Individualized symptomatic and palliative treatment, valproate, levetiracetam, lamotrigine, clonazepam and topiramate for epilepsy, citalopram and rispe ridone for behavioral symptoms
Lowe syndrome	XR, Lowe gene (OCRL), located on the Xq25–26 chromosome and encoding the inositol polyphosphate 5-phosphatase OCRL-1	Congenital cataract, glaucoma, corneal scarring and keloids	Obsessive-compulsive behavior, irritability, aggressiveness, self-abusive behavior, complex repetitive purposeless movements such as hand-flapping and violent tantrums	Intellectual impairment, proximal renal tubular dysfunction, postnatal growth retardation, muscle hypotonia, areflexia, joint swelling	Gene-targeted testing such as single- or multi-gene panel and comprehensive genomic testing, Prenatal diagnosis is based on measuring the activity in chorionic villi or amniotic fluid of PtdIns P2 5-phosphatase, Ophthalmologic exam, MRI	Ventriculomegaly and hyperintense periventricular and white matter lesions on T2-weighted images	Early removal of the lenses and post operative use of glasses, surgery or medications for glaucoma, neuroleptics, antidepressants, stimulants, benzodiazepines as well as clomipramine, paroxetine and risperidone are partially effective in managing the behavioral problems

Ocular abnormalities include hypertelorism (widely set eyes, 68%), epicanthal folds (skin fold of upper eyelid, 84%), ptosis (56%), refractive errors (40%–52%), keratoconus (thinning and outward corneal bulging), strabismus (misalignment of eyes, 40%), nystagmus (8%), amblyopia (32%), cataract, posterior embryotoxon (corneal abnormality) (32%), prominent corneal nerves (72%) and optic nerve head abnormalities such as hypoplasia (4%), coloboma or excavation (20%) (Ascaso et al., 1993; Bhambhani and Muenke, 2014; van Trier et al., 2016).

Psychiatric disorders were investigated in 27 children and adolescents aged 6–18 years old (mean=10.4) with mean intellectual quotient (IQ) of 94 and confirmed NS on molecular testing (PTPN11, SOS1, SHOC2 mutations) (Perrino et al., 2018). Overall, the rate of attention deficit and hyperactivity disorder (ADHD) was 22% and 48% for sub-syndromal ADHD (Perrino et al., 2018). Generalized anxiety was present in 7.4% and sub-syndromal anxiety in 29.6%. Specific and social phobias were reported in 37% of patients (Perrino et al., 2018). NS patients also present with internalizing and externalizing behavioral problems in patients with alexithymic tendencies (Roelofs et al., 2020). In adults, depression and anxiety occur in almost 50% of cases (Smpokou et al., 2012). Language development is often delayed in children and manifests as articulation difficulties in three-quarters of cases attributable to hearing deficits (15–40%) (Wingbermuehle et al., 2009). It is postulated that changes in hippocampal GABAergic transmission secondary to RAS-MAPK pathway dysregulation, prefrontal cortex, and striatum circuit dysfunction could explain these manifestations in NS (Perrino et al., 2018).

Management guidelines include but are not limited to growth hormone replacement, as well as cardiovascular and genitourinary surgeries to optimize outcomes. Due to the high incidence of ocular abnormalities, detailed ophthalmic examination should be conducted early in the diagnosis of NS (Bhambhani and Muenke, 2014). Psychiatric screening and neuropsychological evaluation should also be included early and regularly assessed as prompt interventions, such as educational and social support can lead to quality-of-life improvements (Roelofs et al., 2020; Wingbermuehle et al., 2009).

Trisomy 21 / Down Syndrome (DS)

DS is one of the most common genetic diseases in the world. Clinical findings vary by individual and may include flat nasal bridge, small low set ears, epicanthic folds, small mouth, up-slanting palpebral fissures, macroglossia, fissured tongue, narrow high arched palate, obstructive sleep apnea, respiratory infections, thyroid disease, hematological disorders, immune dysfunction, gastrointestinal structural defects, male infertility, obesity, small statue, short fingers, hypotonia, atlantoaxial instability, and congenital heart defects (Antonarakis et al., 2020). Craniofacial radiographic findings may show brachycephaly, calvarium thinning, defective ossification or delay closure of the sutures, absent or poorly developed air sinuses, decreased intra-orbital distance and small rudimentary nasal bones (Al-Shawaf and Al-Faleh, 2011). The estimated incidence of DS is ~1 in 1,000 live births worldwide (Chen et al., 2022). DS is caused by trisomy 21, which is the presence of a supernumerary chromosome 21, and this can be the result of partial (rare) or complete trisomy (Antonarakis et al., 2020). There are two prevailing hypotheses for the phenotypic expression of DS and they include a gene-dosage effect which increases expression and developmental instability which may have nonspecific global disturbances on gene expression (Pritchard and Kola, 1999; Shapiro et al., 1983). Prenatal screening and testing are available for early diagnosis, but screening and individualized plans related to social care, medical management, and neurodevelopment trajectories can help to reduce the morbidity and mortality related to DS (Table 1).

DS also has a range of ocular manifestations from the front to the back of the eye, which include strabismus (2–5%), refractive error and amblyopia (22–36%), nystagmus (up to 30%), accommodation deficits (55%), nasolacrimal duct obstruction (22%), keratoconus (8–71%), optic nerve pathology (3%), glaucoma (rare), ocular neoplasm (rare), and retinal pathology (28%) (Haseeb et al., 2022).

On brain MRI, individuals with DS show smaller overall volumes in both cerebral gray and white matter, smaller cerebellar volume, and larger subcortical and parietal gray matter as well as temporal white matter volume (Pinter et al., 2001).

There is an increased prevalence of behavioral and psychiatric disorders in DS compared with the general population. In a recent prevalence study in the United States, researchers found that individuals with DS had greater odds of experiencing mood disorders (OR: 3.4), anxiety disorders (OR: 1.1), obsessive-compulsive disorder (OR: 20), schizophrenia (OR: 1.9), psychosis (OR: 3.9), pseudobulbar affect (OR: 50), personality disorder (OR: 2.6), dementia (OR: 17.1), Alzheimer’s disease (OR: 66.9), conduct disorders (OR: 2), tic disorders (OR: 1.7), or impulse control disorder (OR: 23) (Rivelli et al., 2022). Additionally, the diagnostic clarity of mental health issues in DS is complicated by the presence of intellectual disability, communication difficulties and atypical symptoms. Lastly, psychological stressors such as transitions in accommodation, school or care arrangements, and bereavement can significantly impact behavior.

Management guidelines for DS focus on a variety of health problems that can impact morbidity, mortality, and quality of life. Thus, screening at regularly intervals is key and there are consensus screening guidelines for children with DS (Bull and the Committee on Genetics, 2011), but not yet for adults (Jensen and Bulova, 2014). Care is normally provided by a number of different clinicians with greater specialty being found for adults with DS compared to children (Antonarakis et al., 2020). Mental health treatment should be based on standard clinical guidelines, and individuals with DS generally demonstrate a positive response to behavioral, psychopharmacologic, and psychological interventions.

2). Retinal Disorders

Retinitis pigmentosa (RP)

RP is the most commonly inherited retinal disease (~35 genes or loci identified), which is characterized by progressive rod and cone degeneration leading to vision loss and visual field reduction with >75% of people affected by the 4^th decade of life (Hartong et al., 2006). It is categorized into non-syndromic (NSRP) or syndromic RP (SRP), with the latter involving neurosensory or neurodevelopmental disorders. NSRP incidence is 1:4,000–5,000 with carriers having 1:1,000 incidence (Hartong et al., 2006). RP can be inherited in an autosomal dominant, autosomal recessive or X-linked pattern, with Y-linked patterns also observed or mitochondrial (Hamel, 2006; Zeviani and Carelli, 2021; Zhao et al., 1995). Early onset RP is typically observed with Usher syndrome, Refsum disease, Bassen-Kornzweig syndrome, Bardet-Biedl syndrome or autosomal recessive mutations (Bassen and Kornzweig, 1950; Claridge et al., 1992; Pierrottet et al., 2014)(Table 1).

Usher syndrome (US), which includes RP, is the most common cause of severe sight and hearing impairment with a prevalence of approximately 4–17:100,000 people. US is characterized by varying degrees of sensorineural hearing loss and developmental delays (Brodie et al., 2021). Three subtypes of US have been described: type 1 has profound bilateral hearing loss, late onset RP and vestibular areflexia, type 2 has moderate to severe hearing loss, severe progression of RP without vestibular dysfunction, and type 3 has various levels of ocular progression, vestibular and hearing manifestations (Brodie et al., 2021).

Severity of ocular symptoms is variable and depends on the pattern of inheritance and age. RP typically presents with night blindness, peripheral vision loss and tunnel vision at advanced stages. Posterior subcapsular cataracts are also common while photopsias, headaches, macular edema or macular cysts have also been reported (Testa et al., 2014). On fundus examination bone spicule pigment deposits, vessel attenuation, retinal atrophy and waxy optic nerve pallor are observed. Electroretinography (ERG) findings vary by stage of the disease and can range from decreased or absent a- and b-wave amplitudes. Implicit time can be either normal at early stages or significantly prolonged at late stages (Gränse et al., 2004).

On brain MRI, CT or PET, US has been associated with cerebral and cerebellar atrophy, hypoplasia of corpus callosum, forth ventricle dilatation and other CNS lesions (Koizumi et al., 1988). In 1996, Tamayo et al, observed that 60% of US patients demonstrated cerebellar abnormalities on MRI such as atrophy of the cerebellar vermis and prominent cerebellar sulci (Tamayo et al., 1996). Schaefer et al also found a significant decrease in intracranial volume of the brain and cerebellum supporting the notion for global brain involvement (Schaefer et al., 1998).

Several reports have focused on psychiatric disorders associated with RP or US, but the exact prevalence is yet unknown (Hallgren, 1959). In a large Iranian study of RP, eight different psychiatric disorders were identified in a cohort of 417 patients. Of those, 39.3% had obsessive compulsive disorder, 38.1% schizophrenia, 37.6% antisocial personality, 36.7% paranoia, 35.3% hypochondriasis, 31.2% depression, 26.9% hysteria, and 23.7% hypomania (Adhami-Moghadam and Iran-Pour, 2014). Furthermore, a significant association was reported between hypomania and marital status, hypochondriasis and educational level, income and smoking and schizophrenia and onset of the disease (Adhami-Moghadam and Iran-Pour, 2014). Moschos et al demonstrated that RP patients were more likely to report depressive symptoms when assessed with the Patient Health Questionnaire-9, which was associated with visual loss and older age (Moschos et al., 2016).

Additionally, schizophrenia is considered to be the most common psychiatric disorder in RP/US (Adhami-Moghadam and Iran-Pour, 2014; Domanico et al., 2015). Delusions, hallucinations (visual or auditory), suicidal thoughts and paranoia have been reported (Domanico et al., 2015). Moreover, bipolar disorder, depression, conduct disorder, autism, attention deficit hyperactivity disorder and anxiety can co-occur in these patients suggesting pleiotropic linkage (Praharaj et al., 2012; Rao et al., 2010; Wu and Chiu, 2006).

While there is no cure for RP, treatments are available for managing aspects of the disorder. It has been suggested that vitamin supplementation or dietary modifications can be beneficial in cases of associated nutritional deficiencies such as in Refsum disease, a peroxisomal disorder which leads to accumulation of the phytanic acid (branched chain fatty acid) and Bassen-Kornzweig (abetalipoproteinemia) syndrome, which is characterized by fat malabsorption (Grant and Berson, 2001). Additionally, promising new treatments are under investigation and include gene therapy, transplantation of fetal retinal cells or stem cells, and implanted electrical devices. Psychiatric counseling in these patients is of key importance and proper medical or behavioral therapies should be considered.

Susac syndrome (SS)

SS is a rare vasculopathy first described by Susac in 1979 and is characterized by a triad of encephalopathy, branch retinal artery occlusion, and sensorineural hearing loss (Susac et al., 1979). It has been noted that this disease affects women more than men (3:1) usually between the age of 20 to 40 years. The natural history of the disease has not been fully elucidated. Some individuals only experience one episode in their lifetime while others have a more chronic and relapsing course with long-term symptoms, including cognitive decline, gait disturbance and hearing loss. It is a self-limited syndrome of unclear etiology but presumably of autoimmune origin. The diagnosis of this disease is challenging as the triad of symptoms may not manifest on initial presentation. In fact, Dorr et al. reviewed 304 cases and demonstrated that 13% of patients with SS presented with a triad of symptoms (Dörr et al., 2013). Thus, the diagnosis is based on clinical exam and should include neurological and ophthalmological examination (Table 1).

Branch retinal artery occlusions are common ocular manifestations in SS and patients usually complain of “dark spots” in their eye field. Occlusions are confirmed by fluorescein angiogram during acute phases of the illness. Furthermore, optical coherence tomography findings include patchy thinning extending from the retinal nerve fiber layer to the outer plexiform layer (Ringelstein et al., 2015).

Cognitive impairment (48%), apathy (12%), dissociation, psychosis (10%), bipolar disorder and personality changes (15%) are the most common neuropsychiatric manifestations seen in patients affected by Susac syndrome (Barrio et al., 2017; Pérez-Lombardo et al., 2019; Roessler-Górecka et al., 2017; Staelens et al., 2016).

During acute phases of the disease, supratentorial white matter lesions mainly in the corpus callosum are demonstrated on brain T2 MRI with a characteristic “snowball” sign from microinfarcts. Basal ganglia and thalamus are involved in up to 70% of cases. In general, the scans of these patients reveal a distinctive pattern of lesions often with parenchymal and leptomeningeal involvement (Susac et al., 2003). On hearing evaluation, audiograms demonstrate bilateral low to middle frequency sensorineural hearing loss.

Due to the rarity of the disease and the lack of clinical trials, empirical and individualized treatment is recommended (Vodopivec and Prasad, 2016). Early treatment with immunosuppressive medications is offered to these patients and studies have shown that this strategy can significantly decrease relapses. Induction with methylprednisolone plus cyclophosphamide or rituximab (CD20 biologic drug) can be tried in patients in the acute phase of the disease. Remission can be achieved with glucocorticoids plus immunoglobulins, mycophenolate mofetil, methotrexate, azathioprine, cyclophosphamide, or rituximab (Vodopivec and Prasad, 2016).

Norrie disease (NDP)

NDP is an X-linked recessive disorder characterized by congenital severe sight impairment, sensorineural hearing loss and neuropsychiatric abnormalities. It was named after Gordan Norrie who first described this disease in 1927 (Norrie, 1927).. The gene, Norrie disease pseudoglioma, is localized on Xp11.3 and encodes the norrin protein. Norrin binds to the frizzled-4 receptor and regulates molecular processes that play a significant role in the vascular development in the retina and vascular maintenance in inner ear (Rehm et al., 2002; Richter et al., 1998). In addition, norrin acts as a ligand for Wnt signaling pathway activation and is involved in several cellular activities such as cell division, adhesion and migration (Warden et al., 2007). Currently there are more than 116 pathogenic sequence alterations which result in genotypic heterogeneity and diverse phenotypical groups (Smith et al., 2012). NDP belongs to the spectrum of NDP-related retinopathies which includes persistent hyperplastic primary vitreous (Aponte et al., 2009; Payabvash et al., 2015), X-linked familial exudative vitreoretinopathy (Chen et al., 1993), retinopathy of prematurity (Haider et al., 2001), and Coats disease (Black et al., 1999). There are more than 400 reported cases of NDP worldwide, however, the exact prevalence and incidence is unknown. Since this is a X linked disease there is complete penetrance in males. Nevertheless, the disease has also been described in female carriers (Sims et al., 1997) (Table 1).

NDP is a clinically diagnosed disease that is supported by genetic testing. Fibrous and vascular changes presenting as grey-yellow fibrovascular masses and peripheral avascular retina with pigmentary changes, are typically seen at birth or early infancy (Drenser et al., 2007). Findings can overlap with other NDP-related retinopathies such as cataracts, nystagmus, microphthalmia, persistent hyperplastic primary vitreous, hyaloid vessels, retinal detachment, hemorrhages, leukocoria, and atrophic irides (Collins et al., 1992; Jia et al., 2017).

Based on the largest known study on extraocular clinical manifestations of NDP (n=56), 28% of the patients with NDP had cognitive impairment and more than 45% present with a wide range of behavioral disorders such as autism spectrum disorder or pervasive developmental disorder (Smith et al., 2012). In patients who present without cognitive impairment, depression is common and related to the hearing loss. In addition, up to 75% of patients can live and work independently.

Progressive sensorineural hearing loss is another characteristic feature of NDP that can present between the ages of 5 to 48 years (Halpin et al., 2005; Smith et al., 2012). Moreover, peripheral vascular disease consisting of varicose veins, leg ulcers and erectile dysfunction has been described (Michaelides et al., 2004; Rehm et al., 1997).

In general, management of NDP is directed based on the specific symptoms. Early vitrectomy with or without lensectomy can be beneficial for patients who present with retinal detachments (Walsh et al., 2010). Chow et al 2010, showed that laser photocoagulation at birth can prevent severe sight impairment in amniocentesis confirmed NDP cases (Chow et al., 2010). Cochlear implants and hearing aid augmentation might be considered in cases with hearing loss (Jacques et al., 2017; Nishio et al., 2017). Close observation and regular follow-up with ophthalmologists, audiologists, psychologists and psychiatrists can further assist in early identification and management of new symptoms (Smith et al., 2012).

3). Other Disorders

Cerebrotendinous xanthomatosis (CTX)

CTX is a rare autosomal recessive lipid storage disease caused by CYP27A1 gene mutations, which code for the mitochondrial enzyme sterol 27-hydroxylase. Deficiency of this enzyme results in accumulation of 5-alpha-cholestanol and/or cholesterol, and decreased bile acid synthesis (Nie et al., 2014). Prevalence is ~3–5:100,000 worldwide (Moghadasian et al., 2002) and is more common in Moroccan Jewish populations (Leitersdorf et al., 1993). Despite a lack of clinical diagnostic criteria, CTX should be suspected in people presenting with infantile-onset diarrhea, childhood onset of cataract, tendon xanthomas (localized lipid deposits) and adult-onset progressive neurologic impairment (Table 1).

Cataract formation is found in ~75% of patients in their first decade of life and typically precedes neurologic manifestations and xanthomas. These appear as irregular cortical opacities, anterior polar or dense subcapsular posterior cataracts, and may require surgery (Cruysberg et al., 1995). Other ocular findings include palpebral xanthelasmas (Philippart and Van Bogaert, 1969), proptosis (Morgan et al., 1989), oculomotor changes, volitional saccades (Rosini et al., 2015), optic nerve atrophy (Pilo de la Fuente et al., 2008), myelinated optic nerve fibers, retinal vessel sclerosis, retina accumulation of cholesterol-like deposits, and intravitreal floating cholesterol crystals (Rosini et al., 2015).

Neurologic findings include dementia, seizures (Matsumuro et al., 1990), extrapyramidal manifestations such as dystonia and atypical parkinsonism (Grandas et al., 2002), and peripheral neuropathy (Argov et al., 1986). Neuropsychiatric symptoms are seen in ~13% of CTX patients and may include hallucinations, depression, agitation, aggression, insomnia, suicidal thoughts and attempts (Fraidakis, 2013).

Blood based biomarkers include elevations of 5 alpha-cholestanol in plasma or tissue (DeBarber et al., 2014). Plasma cholesterol concentration can be either normal or low. Additionally, bile alcohols are elevated in both serum and urine. On brain MRI, hyperintensities can be detected in cerebellar and periventricular white matter with bilateral and symmetrical involvement of the dentate nuclei. Overall gray and white matter volume is decreased. Other imaging modalities supporting the diagnosis of CXT include magnetic resonance spectroscopy (MRS), where decreased N-acetylaspartate (NAA) and increased lactate and lipid peaks are detected (Mignarri et al., 2017). Regional cerebral blood flow changes are found in multiple brain regions (Caroppo et al., 2013). Chen et. al., found a correlation between ⁹⁹mTc-sestamibi thigh SPECT/CT imaging with mitochondrial status of a CXT patient (Chen et al., 2014). Schotsmans et. al., found alteration in ¹²³I-FP-CIT brain imaging in a CXT patient presenting with asymmetric parkinsonism suggestive of decreased presynaptic dopaminergic function of putamen and caudate nucleus which was correlated with the bradykinesia (Schotsmans et al., 2012). Yu et. al., using whole body CT revealed multiple metabolically abnormal areas in the quadriceps and Achilles tendons along with hypometabolic areas in the cerebellum, frontal and temporal lobes which correlated with patient’s cognitive and behavioral symptoms (Yu et al., 2016).

Early diagnosis is key for timely treatment and treatment plans consist of symptomatic treatment, replacement therapy with bile acids for reducing levels of plasma cholestanol (exogenous inhibition of bile acid production) and surgery. Long-term treatment with chenodeoxycholic acid (750 mg/day) can lead to significant improvement of neurological manifestations and an improved prognosis (Nie et al., 2014), especially when combined with 3-hydroxy-3-methyl glutaryl-CoA (HMG-CoA) reductase inhibitors which inhibit the conversion of HMG-CoA to mevalonate, a rate-limiting step in cholesterol biosynthesis (Verrips et al., 1999).

Kearns-Sayre ptosis or Kearns-Sayre syndrome (KSS)

KSS is an orphan multisystem genetic disorder first described by Kearns and Sayre in 1958, where they presented two patients with chronic progressive external ophthalmoplegia, pigmentary retinopathy and complete heart block (Kearns and Sayre, 1958). KSS is associated with alterations in mitochondrial or nuclear DNA or both (heteroplasmy), which lead to disruption of oxidative phosphorylation pathways. This syndrome can also have a maternal, autosomal recessive or autosomal dominant pattern of inheritance (Nemet et al., 1982). Overall, de novo deletions are most commonly detected. KSS typically affects young people (<20 years of age) without a sex-specific predilection (Table 1).

Ocular manifestations include bilateral ptosis, diplopia, pigmentary retinopathy which can vary from subtle pigmentary changes to extensive pigment atrophy (Khambatta et al., 2014), retinoschisis (Chertkof et al., 2020) and corneal edema (Kim et al., 2016; Ohkoshi et al., 1989). There is only one KSS confirmed case in literature where the retina appeared normal (Rajakannan et al., 2000).

Similar to other mitochondrial diseases, KSS can present with psychiatric disorders including bipolar disorder, cognitive impairment, psychosis and psychosomatic disorders (Anglin et al., 2012). For example, Norby et. al. described a case of a young female who was initially diagnosed with a psychosomatic illness due to hypersensitivity to light, increased fatigue and vertigo presenting in early childhood, which was later identified as KSS (Nørby et al., 1994). Additionally, depression and post-traumatic stress disorder can also be seen in these patients.

KSS is also associated with a wide range of systemic manifestations including Pearson’s syndrome (sideroblastic anemia, exocrine pancreas dysfunction, and diabetes mellitus) (Poulton et al., 1995), hearing loss and skeletal muscle weakness. Endocrine disorders such as hypoparathyroidism (Horwitz and Roessmann, 1978), diabetes mellitus (Bachynski et al., 1986), hyperaldosteronism, gonadal failure, growth hormone deficiency, thyroid disease (Harvey and Barnett, 1992), as well as neurological abnormalities such as CSF protein >1mg/ml, dementia and cerebellar ataxia (Bosbach et al., 2003) have been also reported.

Clinical presentation varies and depends on the degree of mitochondrial dysfunction. KSS diagnosis can be made in a person experiencing progressive ophthalmoplegia and pigmentary retinopathy before the age of 20 and any of the abovementioned disorders (Berenberg et al., 1977). Several diagnostic procedures can aid and support the diagnosis. For example, progressive hyperintense lesions in the brainstem and white matter (cerebral and cerebellar) have been reported on T2-weighted MRI of the brain with a higher FLAIR signal detected in these same regions (Nakagawa et al., 1994). It has been suggested that all patients with either a confirmed diagnosis of KSS or suspicion of KSS should be screened for cardiac dysfunction. The diagnosis can be also supported histologically by the presence of ragged red fibers which can be visualized on Gomori trichrome stain of skeletal muscle biopsies which are characteristic of mitochondrial diseases. Multi-gene testing should be considered in every case where KSS is suspected in order to identify deletions (Moraes et al., 1989).

Management includes supplementation with coenzyme Q10 which can improve ocular motility, corneal edema and cardiac conduction abnormalities (Kim et al., 2016). Additionally, improvements in oxidative stress markers have been demonstrated when coenzyme Q10 was used in combination with creatine monohydrate and alpha-lipoid acid (Tarnopolsky, 2008). Ptosis is managed by functional reconstruction with levator advancement and frontalis suspension procedures having been performed with mixed results (Papageorgiou et al., 2008; Weitgasser et al., 2015). However, ptosis often recurs and additional surgeries may be required. From a psychiatric perspective, since many psychotropic medications have side effects, as these interfere with mitochondrial function, minimizing the number and the doses or avoiding them if possible, is highly recommended. Prognostically, patients with KSS may maintain relatively good visual acuity which depends on the degree of retinal involvement. Cardiac dysfunction and endocrine disorders usually account for the morbidity and mortality related with KSS.

Wolfram syndrome (WS)

WS is an orphan autosomal recessive disorder characterized by neurodegeneration, central diabetes insipidus (DI), juvenile onset diabetes mellitus (DM), optic nerve atrophy (OA), deafness (acronym DIDMOAD) and urinary tract disorders (Urano, 2016). The first cases were described by Wolfram and Wagener in 1938 and in 1995 the clinical features of a larger cohort were presented by Barrett e.t al. (Barrett et al., 1995). Two genetic forms of WS are known; the more common Wolfram syndrome 1 (WFS1) and WFS2. WFS1 gene is found on chromosome 4p and encodes the transmembrane protein wolframin, which is involved in calcium homeostasis for the endoplasmic reticulum (Fonseca et al., 2005). Mutations in the WFS1 gene result in reduced function or loss of function of wolframin leading to cell apoptosis. WFS2 is caused by mutation in the CISD2 gene, a transmembrane protein located on endoplasmic reticulum, and regulates calcium homeostasis through mitochondria-associated ER membranes (MAMs) (Delprat et al., 2018). Mutation in WFS2 results in abnormal mitochondrial function and high stress in the ER secondary to the accumulation of unfolded proteins leading to irreversible damage and apoptosis (Pallotta et al., 2019). WS occurs in 1:160,000–770,000 live births with a carrier frequency of 1 in 354 people (Barrett et al., 1995; Cano et al., 2007) (Table 1).

WS is clinically diagnosed with diabetes mellitus being the first sign at ~6 years of age (Pallotta et al., 2019). Genetic testing is needed to confirm WS diagnosis. WS affected patients can also present with endocrine disorders, such as hypogonadism, and neurological manifestations, such as autonomic and peripheral neuropathy, headaches, taste and smell disorders, apnea and seizures (Urano, 2016).

Optic nerve atrophy is one of the main criteria used for the diagnosis of WS and it usually presents at ~11 years of age (Pallotta et al., 2019). Affected patients present with subnormal visual acuity (89%), dyschromatopsia (94%), increased cup to disc ratio (33%), and optic disc pallor (94%) (Hoekel et al., 2014). Other ophthalmic manifestations include cataracts (22%), strabismus (39%), nystagmus (39%), glaucoma and pigmentary maculopathy (perimacular granularity). In addition, afferent pupillary defects (61%), retinal nerve fiber layer thinning (100%), visual field defects (100%) and microspherophakia are also seen (Chacón-Camacho et al., 2013; Hoekel et al., 2014; Zmyslowska et al., 2019). On brain MRI, progressive optic nerve atrophy and brain atrophy (cerebral, cerebellar, brainstem) are typically demonstrated (Chaussenot et al., 2011).

A wide range of cognitive and psychiatric disorders have been reported. Up to 60% of affected (homozygous) WS patients can present with episodes of psychosis, depression, aggression and in up to 25% of individuals hospitalization may be required due to the severity of the underlying psychiatric illness (Swift et al., 1990). Moreover, heterozygous carriers are also at increased risk of developing a psychiatric disorder such as depression (Swift et al., 1998). For example, Swift et. al. demonstrated that blood relatives of WS families have an increased probability of carrying the mutated gene, but also have an increased likelihood of hospitalizations due to mental illnesses such as major depression (Swift and Swift, 2005; Swift et al., 1991). Sequeira et. al. also suggested that either carriers or patients with the WFS1 mutant gene have increased impulsivity scores, depression and suicidal behavior compared to controls (Sequeira et al., 2003). A case report of bipolar disorder type 1 has been reported in a 17-year-old girl with WS and a history of hypothyroidism and physical abuse (Xavier et al., 2016). Additionally, though rare, there are case reports where mania and schizophrenia were also diagnosed (Chatterjee et al., 2017; Gowda et al., 2018).

Early diagnosis and treatment are imperative. However, there is no effective treatment, but drug repurposing and gene therapy treatments are a promising future therapeutic avenue (Pallotta et al., 2019). The median age of death is approximately 35 years with a bimodal distribution at age 25 and 45. Respiratory failure, neurological manifestations and complications due to urinary tract atony are the main causes of death in the majority of cases (Kinsley et al., 1995). Patients who present with psychiatric disorders should be offered the appropriate and tailored treatment such as antidepressants, antipsychotics or combination of those in order to control the symptoms.

Batten disease or neuronal ceroid lipofuscinoses (NCL)

NCL is a family of primarily autosomal recessive neurodegenerative pediatric disorders. Batten disease is a progressive and invariably fatal disease with most affected people dying before the age of 30. NCL is caused by a mutation in the CLN3 gene, which is located on the short arm of chromosome 16 at position 12.1 and codes for the lysosomal and endosomal protein battenin (Lerner, 1995). It is characterized by progressive visual and cognitive disturbances, seizures and motor deterioration. In addition, psychiatric manifestations have been also reported (Zeman and Dyken, 1969). The incidence of NCL ranges from 0.02–4.8:100,000 worldwide (Elleder et al., 1997; Mitchison et al., 1995). There are currently 14 forms of NCLs classified into infantile, late-infantile, juvenile and adult forms (Ostergaard, 2016) (Table 1).

The diagnosis of NCL is based on clinical, ophthalmic, neurologic and brain imaging evaluation while genetic and biochemical assays are confirmatory of the diagnosis. In more than 80% of cases, visual impairment is the first symptom. Behavioral disturbances, epilepsy (myoclonic), generalized tonic-clonic or partial seizures, or progressive motor dysfunction develop during the course of the disease (Augustine et al., 2015). Generally, females are diagnosed later in life than males (Cialone et al., 2012; Nielsen and Østergaard, 2013). Moreover, cardiac involvement (Reske-Nielsen et al., 1981) and hormonal changes (hyperandrogenism in girls, early menarche) (Aberg et al., 2002) have also been described.

Common ophthalmic manifestations in NCL include optic nerve atrophy, pigmentary retinopathy, vascular attenuation and bull’s eye maculopathy (Collins et al., 2006). Cataract, glaucoma, rotary nystagmus and eccentric viewing (overlooking) are other ocular features that have been reported (Nielsen et al., 2015; Ostergaard, 2016).

Psychiatric disturbances include anxiety, restlessness, irritability, aggression, depression, mood impairment, inappropriate laughter, personality abnormalities and visual hallucinations (Bäckman et al., 2005, 2001; Johnson et al., 2019). These symptoms usually precede motor impairment and are not influenced by genotype (Adams et al., 2007). Sleep disturbances such as nocturnal awakenings and nightmares have also been reported and they negatively impact the quality of life of these patients (Santavuori et al., 1993).

On brain MRI, progressive cerebellar and cerebral atrophy can be detected. The occipital cortex is usually the first region affected, followed by frontal and parietal deficits in advanced cases. Each of the 14 NCLs have different MRI findings such as enlarged lateral ventricles in NCL 1, 2 and 10, hypointense thalamic nuclei in NCL 2, 3, 5 and 7, and hyperintense periventricular areas in NCL 1, 4, 5, 8, 13 (Jadav et al., 2014).

On electroretinogram, reduced rod-response and cone-response amplitude is evident in early stages of the disease, while during advanced stages there is an absence of rod-mediated activity and a reduction of cone activity (Quagliato et al., 2017).

A neuropsychological battery has also been developed in an effort to assess cognitive functioning during the first 5 years of NCL diagnosis. Lamminranta et. al. demonstrated this test can offer valuable information on the progress of NCL (Lamminranta et al., 2001).

The rarity of this disease, in conjunction with the short therapeutic window, makes management extremely challenging. Since there is no curative treatment, individualized symptomatic and palliative treatment options are offered to all patients. The proposed medical management in patients presenting with epilepsy include valproate, levetiracetam, lamotrigine, clonazepam, and topiramate, while behavioral symptoms are managed with citalopram or risperidone (Ostergaard, 2016). Gene therapies have shown promising results in preclinical and clinical trials (phase I/II) (de los Reyes et al., 2020). Specifically, along with the good safety profile, stabilization of motor and language decline was demonstrated when early intervention was offered in these patients (de los Reyes et al., 2020).

Lowe syndrome or Oculocerebrorenal syndrome (LS)

LS is a rare X-linked recessive disorder first described by Lowe in 1952 and consists of a triad of congenital cataracts, intellectual impairment, and proximal renal tubular dysfunction (Lowe et al., 1952). It can also cause glaucoma, postnatal growth retardation, muscle hypotonia, areflexia, joint swelling, and low molecular weight proteinuria. The estimated prevalence of Lowe Syndrome is 1:500,000. LS primarily affects males and in rare cases female carriers of the disease (Loi, 2006). The oculocerebrorenal syndrome (OCRL) gene is located on Xq25–26 and encodes for inositol polyphosphate 5-phosphatase (OCRL-1) (Bökenkamp and Ludwig, 2016) (Table 1).

Ophthalmologic manifestations of LS include cataract, glaucoma, corneal scarring and keloids. Signs present at birth with congenital dense cataracts in both eyes (Loi, 2006; Tripathi et al., 1986). In infancy, glaucoma can present with buphthalmos in approximately 50% of the patients with LS while corneal scarring and conjunctival keloids develop in around 25% of patients in early childhood resulting in progressive visual loss (Loi, 2006). Visual impairment can be the result of strabismus and retinal dystrophy (Ma et al., 2020).

Psychiatric manifestations include obsessive-compulsive behavior, irritability, aggressiveness, self-injury, complex stereotyped movements such as hand-flapping, and violent tantrums with more than 80% of patients presenting with these symptoms (Bökenkamp and Ludwig, 2016; Kenworthy and Charnas, 1995). In a case-control study, scores on maladaptive behavior were significantly higher in LS compared to controls explaining 41% of the variance (Kenworthy and Charnas, 1995).

LS can be suspected in a patient with congenital cataract, intellectual impairment, proximal renal tubular dysfunction, hypotonia and delayed development. Gene-targeted testing such as single- or multi-gene panels and comprehensive genomic testing which include exome and genome sequencing can help to establish the diagnosis of this syndrome (Lewis et al., 2001). Prenatal diagnosis is based on measuring the activity in chorionic villi or amniotic fluid for phosphatidylinositol (4,5)-bisphosphate-5-phosphatase (Tripathi et al., 1986). Increased levels of alpha-fetoprotein in maternal serum and amniotic fluid and the presence of fetal cataract in ultrasonography can help during prenatal screening (Daskalakis et al., 2010; Miller et al., 1994; Suchy et al., 1998). Ophthalmologic exam is the mainstay for diagnosis of cataract and glaucoma. Brain MRI findings include ventriculomegaly and hyperintense periventricular and white matter lesions on T2 MRI which are stable in size and location without any significant clinical meaning (Bökenkamp and Ludwig, 2016; Loi, 2006).

The patient’s quality of life is correlated with the degree of mental and/or renal impairment. Renal disease, hypotonia or respiratory illness are the most common cases of death in children and adults (Loi, 2006). Early removal of the lenses and postoperative use of glasses may improve vision. Use of contact lenses or implantation of artificial lenses are contraindicated as they can increase the risk for corneal keloids and infantile glaucoma respectively. Glaucoma can be managed surgically or with medications that decrease the intraocular pressure. Behavioral modification and medications such as neuroleptics, antidepressants, stimulants, benzodiazepines as well as clomipramine, paroxetine and risperidone are partially effective in managing behavioral issues (Bökenkamp and Ludwig, 2016; Lewis et al., 2001).

Visual function in psychiatric disorders

A number of ophthalmic manifestations have been detected in several psychiatric disorders some of which are attributed to the disease itself and others may arise secondary to the treatment offered. More specifically, in schizophrenia patients, deficits in visual acuity and in visual information processing have been demonstrated with contrast sensitivity being affected in luminance and chromatic conditions when compared to healthy individuals (Cadenhead et al., 2013). In the study by O’Bryan et. al., generalized deficits in moving, but not static, contrast sensitivity test was seen in patients with bipolar disorder, and this deficit was correlated with mania or depression symptoms (O’Bryan et al., 2014). Studies have identified an association between retinovascular and psychiatric disorders, with glaucoma showing the strongest association with schizophrenia, bipolar disorder, and major depressive disorder; whereas agerelated macular degeneration and dry eye syndrome were associated with major depressive disorder (Liu et al., 2020).

Retinal findings in psychiatric disorders

Advances in retinal imaging technology have allowed for better understanding of structural and functional alterations in the eyes of people with psychiatric conditions (Almonte et al., 2020). Thinner retinal nerve fiber layer (RNFL) thickness has been observed in patients with bipolar disorder (euthymic or not) compared to healthy controls irrespective of antipsychotic use. Moreover, it has been shown in some studies that RNFL thickness is negatively correlated with the duration of illness. Delayed cone b-wave latency, diminished rod b-wave amplitude and delayed latency have also been found on ERG (Almonte et al., 2020; Maziade et al., 2018). In major depressive disorder, OCT findings are inconsistent, with some studies supporting significant decrease in ganglion cell layer, inner plexiform layer and RNFL thickness in recurrent cases compared to healthy controls. However, in other studies differences were observed only upon comparison within major depression groups (Almonte et al., 2020). Prolonged cone b-waves and reduced rod/cone a-waves have been described on ERG in these patients which are thought to be medication-independent alterations (Hébert et al., 2017). Similarly, OCT findings in schizophrenia are incongruous. Several studies have demonstrated macular thinning mostly in the superior quadrants in patients with schizophrenia when compared to age-matched controls. There are a growing number of studies demonstrating retinal vascular deficits in schizophrenia and bipolar disorder (Bannai et al., 2022; Li et al., 2022). However, in some studies there were no significant differences (Almonte et al., 2020). ERG of patients with schizophrenia had significant reductions in a- and b-wave amplitudes (Youssef et al., 2019). This rapidly growing field of psychiatry ophthalmology has many open questions remaining, including the utility of retinal imaging in the assessment, prognostication, and treatment of psychiatric disorders. One example includes work from our group demonstrating that visual dysfunction and structural/functional alterations at the level of the eye and brain can be used to design targeted therapies using non-invasive brain stimulation that could have symptomatic benefit in psychotic disorders (Raymond et al., 2023).

Disentangling mental health disorders from visual impairments

Severe visual impairment secondary to ocular injuries and other ocular diseases such as age-related macular degeneration, glaucoma and diabetic retinopathy have been associated with greater risk for developing psychological distress. Anxiety and depression are the most common mental health problems encountered by these patients (Akuffo et al., 2021; Munaw and Tegegn, 2022). Furthermore, an increased risk of suicide has been reported which is either linked to the direct (emotional reaction to visual loss) or indirect (e.g., comorbidities, social isolation) effect of visual loss (Demmin and Silverstein, 2020). Whilst ophthalmologists can play a significant role in the emotional adaptation to visual loss, psychological support should be timely offered.

The current review has several limitations. For example, there are many more congential and inherited ocular disorders that present with mental health issues, but those could not be reviewed here due to limited literature being available at this time. Another limitation, is that some of the studies included in this review consisted of small samples sizes given the rarity of some of these ocular disorders.

4. Conclusion

Herein, we reviewed the clinical presentation, molecular biology, pathophysiology, diagnostic assessment and management of congenital and inherited disorders which have both ophthalmologic and psychiatric features. Genetic studies have revealed that genetic variation can be relevant to higher cortical areas also related to visual processing, including a recent cross-organ eye-brain imaging and genetic study which identified a genetic basis for eye-brain connections (Zhao et al., 2023). Recent studies using new technologies have identified retinal changes in patients with psychotic disorders but additional studies are warranted to explore the association that likely exists between ocular and psychiatric disorders. Additionally, future studies can expand our understanding of the underlying pathophysiology as well as the likelihood to develop useful biomarkers and implement integrative health care practices.

Highlights.

• Overlap between ophthalmic and psychiatric features has been described in a number of congenital and inherited disorders.

• Recent studies using new technologies for ocular and brain imaging have identified novel potential links between the eye and the brain.

• Prompt recognition of clinical features and co-morbidities by ophthalmologists and psychiatrists could facilitate diagnosis and treatment of the underlying issue and significantly improve prognosis.

• Future studies can expand our understanding of the underlying pathophysiology and contribute to the development of useful biomarkers.

Abbreviations:

ADHD

attention deficit hyperactivity disorder

DTI

Diffusion Tensor Imaging

ERG

electroretinogram

FLAIR

Fluid-attenuated inversion recovery

MRI

Magnetic Resonance Imaging

MRS

Magnetic Resonance Spectroscopy

NCL

Neuronal Ceroid Lipofuscinosis

SD-OCT

Spectral-Domain Optical Coherence Tomography

SPECT/CT

Single-Photon Emission Computed Tomography/ Computed Tomography

VBM

Voxel-Based Morphometry