Exploring the associations of herpes simplex virus infection and cognitive dysfunction in schizophrenia: Studies in India.

BACKGROUND: Cognitive dysfunctions being core features of schizophrenia (SZ), cause disability, increase burden and are refractory to treatment. Viral infections are not risk factors for SZ, but growing evidence indicates infection with some neurotropic viruses, particularly Herpes simplex virus type 1 (HSV -1) as a risk factor for cognitive dysfunction. STUDIES IN INDIA: Three research studies in India are described. In the first, participants were evaluated for HSV-1 infection and cognitive functions (cases 198 and controls 100). In the second, patients and normal nonpsychotic control individuals were examined at baseline and followed up over 1-3 years (cases 138 and controls 88). In the third, a randomized, double-blind placebo-controlled antipsychotic adjunctive trial was conducted to examine the effect of anti-viral drug valacyclovir over 16 weeks on cognitive functioning (valacyclovir 30; placebo 32, treatment for 16 weeks). RESULTS OF INDIAN STUDIES: Cross-sectional study: HSV-1 infection was associated with modest dysfunction, especially on attention (accuracy) and spatial processing (speed). LONGITUDINAL STUDY: HSV-1 seropositive participants had lower scores at baseline on 6/16 measures, regardless of SZ diagnoses. At follow-up, there was a significant decline in HSV-1-positive participants for abstraction and mental flexibility and emotion discrimination. RANDOMIZED CONTROLLED TRIAL: Significantly, greater improvement in accuracy index of emotion discrimination in the valacyclovir-treated versus placebo sample was found.
CONCLUSIONS: Indian studies are consistent with a causative role for HSV-1 in cognitive dysfunction regardless of SZ diagnosis; more rigorous studies of the causal hypothesis are needed, particularly larger randomized controlled trials.

COGNITIVE DYSFUNCTION IN SCHIZOPHRENIA

Since its first description as dementia praecox, it has been recognized that schizophrenia (SZ) is associated with cognitive dysfunction which may be a core feature of the illness,[1] occurring in all phases of the illness;[2] indeed, cognitive dysfunction may predate a diagnosis of SZ by several years.[34] Sufferers may be unaware of these deficits.[5] While deficits have been reported in almost all domains of cognition,[6] the domains most affected are memory, attention, working memory, problem-solving, processing speed, social cognition,[7] as well as impaired executive functioning.[8910] However, these deficits can stabilize.[11] Cognitive deficits are often a cause of functional impairment in SZ.[12]

There is a need for systematic research to discover factors that affect cognitive impairment in SZ participants because: (a) Cognitive deficits in SZ cause disability, impair the ability to carry out day-to-day tasks and adversely affect rehabilitation,[1213] cognitive deficits impose considerable burden on patients’ families,[14] and cognitive functions do not improve appreciably with currently available treatments.[1516]

WHAT CAUSES THESE DEFICITS?

There are no definitive etiologic factors, though genetic factors likely play a role. Neurotropic agents are being investigated as risk factors. Herpes viruses have been investigated because they can cause infection in the brain.[1718] These viruses can infect humans in early life, and reactivate throughout life.[19]

HERPES SIMPLEX VIRUS TYPE 1

Herpes simplex virus type 1 (HSV-1) is a double-stranded DNA virus. Infection occurs via mucocutaneous junctions, primarily through oral contact, sexual contact (increasingly common), or during childbirth.[20] From the infection site, the virus migrates to sensory ganglia where it remains latent for long periods of time-sometimes even the host's lifetime,[21] becoming active usually during periods of stress or immunosuppression[2122] The virus assumes a circular form and produces few if any untranslated viral transcripts during latency[2123] The latent virus remains for life in various parts of the nervous system such as the trigeminal ganglia, the cornea, and brain even after acute infection.[24] Following reactivation, the virions migrate along neural processes and infection flares up, typically in mucous membranes, producing cold sores.[21]

HSV-1 infections are common and in vulnerable individuals, can result in encephalitis, Mollaret's meningitis, neonatal herpes, and possibly Bell's palsy. Ocular herpes is one of the chief causes of blindness worldwide, with a global incidence of approximately 1.5 million cases per year, with an estimated 40,000 new cases of visual impairment or blindness annually.[25] During immuno-compromised periods, the recrudescence of the infection may occur. HSV infection has been associated with cognitive deficits of SZ,[2627] bipolar disorder,[282930] and Alzheimer's disease.[31] Higher antibody titers have been reported in recent-onset SZ[32] and specific subtypes of SZ as well.[28]

Infection can occur at any time-from intrauterine up to adulthood, and its prevalence is inversely related to socioeconomic status (SES). In Western countries, it increases with age up to 90%.[33] Once the active phase is over, HSV infection early in life may affect neurodevelopmental processes which may lead to later cognitive impairment and psychopathology.

Psychiatric symptoms after herpes encephalitis may persist for years.[3435] The most prominent cognitive deficits are in working memory, visual object recognition,[36] and anterograde amnesia.[36]

Herpes virus particles in blood or body are typically difficult to detect during the latent phase.[37] However, the indirect proof of infection can be obtained by estimating specific host-generated serum immunoglobulin G antibodies (which remain elevated for prolonged periods).

HERPES SIMPLEX VIRUS 1 AND SCHIZOPHRENIA

It should be noted that extensive studies between herpes virus exposure and SZ did not present proof of increased SZ risk as such,[38] though an early Indian study reported the significant prevalence of various viral infections in “psychiatric patients” including-cytomegalovirus (CMV), HSV-1, mumps, measles, and varicella-zoster virus.[39]

HERPES SIMPLEX VIRUS TYPE 1 AND COGNITIVE DYSFUNCTION IN NONPSYCHOTIC PERSONS

Cognitive impairment may occur among persons without a history of encephalitis due to HSV-1. A study of Finnish patients with vascular disease suggested cumulative effects of exposure to CMV, HSV-1, and HSV-2.[40] Another study of healthy controls reported an association between HSV-1 exposure and impairment in total scores on the Repeated Battery for the Assessment of Neuropsychological Status (RBANS).[41] The same group reported immediate verbal memory deficits among HSV-1 seropositive bipolar patients.[42] Using the memory deficits as a template, others studied the possibility of HSV-1 affecting Alzheimer's disease, but the results were inconsistent[4344] To our knowledge, two US studies did not detect significant associations between HSV-1 exposure and cognitive function[4546] Patients with bipolar disorder, another group with illness-related cognitive impairments also showed association.[41]

HERPES SIMPLEX VIRUS TYPE 1 AND COGNITIVE DYSFUNCTION IN PERSONS WITH SCHIZOPHRENIA

Dickerson et al. reported HSV-1 antibody status as an independent predictor of cognitive impairment, specifically of immediate memory (n = 229 outpatients with SZ), using RBANS.[47] Similar associations were reported independently.[27] Later, cognitive dysfunction accompanied by decreased dorsolateral prefrontal cortex volumes were reported among HSV-1 seropositive as compared to seronegative patients with SZ.[4748] Prefrontal gray matter volumes (decrease in gray matter in Brodmann areas 9-dorsolateral prefrontal cortex, and 32-anterior cingulate cortex) were significantly correlated with HSV1 serological status among SZ patients.[48]

MECHANISMS FOR THE ASSOCIATION BETWEEN HERPES SIMPLEX VIRUS TYPE 1 INFECTION AND COGNITIVE DYSFUNCTION

The impairment may be explained by several mechanisms, including direct cytopathic effects of reactivation, or secondary to neurotoxic effects of cytokines released during reactivation cycles,[2149] The timing for the damage is also uncertain, as it can extend from the perinatal period to adulthood. Cytokine imbalance, reported in some SZ patients may be attributable to HSV-1 seropositivity.[505152]

INDIAN HERPES SIMPLEX VIRUS TYPE 1 STUDIES

Our group has been conducting studies on HSV-1 infections among the Indian population since 2009. A series of projects were undertaken. Results are presented below.

Effect on cognitive functions among nonpsychotic controls and patients with early course of schizophrenia

We began with examining the type and extent of cognitive deterioration associated with HSV-1 exposure among patients with early course SZ or schizoaffective disorder.[53] We recruited nonpsychotic control individuals as well. We assessed eight cognitive domains (accuracy and speed) using the Penn Computerized Neurocognitive Battery (Penn CNB).[54] A total of 298 individuals (cases 198, controls 100) were recruited. Persons with a history of substance abuse, medical or neurological disorders (head injury, encephalitis, and epilepsy) and those unable to complete cognitive tests were excluded. Categorical HSV-1 status (positive, negative, or equivocal) was determined using venous blood sample based on antibodies to HSV-1 in the serum[55] from a commercial laboratory using commercial kits.

We found that the prevalence of HSV-1 exposure was similar among cases and controls. Thus, HSV-1 exposure did not influence the risk of SZ. Patients performed significantly worse on the Penn CNB than controls, regardless of HSV-1 serostatus. HSV-1-positive persons, controlling for age, performed less well on 6/15 CNB domains, for accuracy (abstraction and mental flexibility, attention, spatial memory, and spatial processing) and speed (spatial processing, emotional processing, and sensorimotor dexterity). Thus, HSV-1 exposure was associated with modest, specific localized effects, the largest effect sizes were for attention (accuracy) and spatial processing (speed). Dickerson et al. reported that the difference in cognitive functioning between HSV-1 positive and negative SZ patients could be attributed to immediate verbal memory and that the difference in the controls by HSV-1 status was in delayed memory.[56] We could not study the verbal memory domain in the Penn CNB as it was unavailable in the Hindi version. Thus, we did not find a significant association between exposure to HSV-1 and risk for SZ. On the other hand, significant cognitive dysfunction was detected with respect to several variables among HSV-1 exposed patients and controls, compared with unexposed persons.

Effect of herpes simplex virus exposure on longitudinal cognitive performance

We followed up patients with SZ and controls (recruited participants overlapped with the above project), over 1 or 3 years (ages 18–50 years).[57] We excluded those with neurological disorders, drug abuse or those who could not undergo cognitive assessment. After recruiting 412 participants with due informed consent (SZ n = 265 and controls n = 146), and excluding those with equivocal serological results, 138 persons with SZ and 88 individuals without psychosis were evaluated after at least 1 year. Persons with SZ performed less well on cognitive functions, as in the first study. Across the entire sample, HSV-1 seropositive participants, after controlling for SZ status, had lower scores at baseline on 6/16 measures: accuracy index of abstraction and mental flexibility (P = 0.001), face memory (P = 0.25), spatial memory (P = 0.0002), working memory (P = 0.028), spatial ability (P = 0.001), and emotion (P = 0.001). On speed index of spatial ability (P = 0.004) and sensorimotor (0.014) also, HSV-1 seropositive participants were significantly impaired at baseline. After follow-up of at least 1 year, there was a significant decline in HSV-1 positive participants on abstraction and mental flexibility (P = 0.004) and emotion (P = 0.008). In the entire sample, seropositive individuals at follow-up showed a significantly greater decline, especially in the emotion discrimination domain. Identifying emotions correctly is important for social functioning, and along with emotion perception forms an important part of social cognition.[545859]

Can antiviral treatment improve cognition in herpes simplex virus type 1 affected schizophrenia cases?

Given the scale of infection and its possible effect on cognition, a clinical trial of the antiviral agent is warranted. In a small randomized controlled adjunctive (to regular antipsychotics) trial (n = 24),[60] we administered the HSV-1 specific antiviral drug Valacyclovir for 18 weeks versus placebo. They reported significant improvement in verbal memory, working memory, and visual object learning.

We conducted a similar double-blind placebo-controlled randomized 20-week trial with Indian HSV-1 seropositive individuals with SZ.[57] We included early course SZ patients with <7 years of illness, aged 18–50 years, and on stable doses of antipsychotic drugs for ≥1 month at initiation, with a score of ≥4 on any item of the Positive and Negative Symptoms Scale.[61] Stratified random sampling based on age (older or younger than 30 years) and sex was used to place individuals into active group (valacyclovir) or placebo. Antipsychotic dose as far as possible was kept stable through the 20-week trial (valacyclovir 1.5 g by mouth, twice daily or placebo twice daily for 16 weeks, followed by review after 4 more weeks).

We used intention to treat analysis for a final total of 62 patients (valacyclovir 30; placebo 32), and mixed model repeated measures analytical method. A total of 56 participants completed the study (valacyclovir 25; placebo 31). Analyzing intent to treat sample or the completed sample, we found significantly greater improvement in the accuracy index of emotion discrimination in the valacyclovir-treated versus placebo sample (the same cognitive domain that worsened over time in the Indian sample). No serious or major adverse effects were noted. Thus, as in the follow-up sample, the treated sample showed effect on emotion discrimination as well.

DISCUSSION

None of our patients were medication free, and it is possible that antipsychotics may have influenced some of our results. Cycles of active infection alternating with latency periods may affect differing brain areas. If the initial infection had occurred in utero or very early in life, it may have caused subclinical damage which may manifest differentially subsequently. Infection outside the central nervous system with cytokine release which can cross the blood-brain barrier may disrupt cognitive functions,[6263] It is well known that infections are more common among those of lower SES. In all our studies, we controlled for SES as well.[64]

What are the implications of our studies? Today adequate cognitive functions are crucial for survival. As such any potentially remediable factor for improving cognition deserves to be investigated in detail. Impaired cognitive functioning has been associated with seropositivity for HSV-1 infection, in varied samples and study designs from different centers. Further studies are warranted to investigate possible etiologic links between persistent HSV-1 infection and cognitive dysfunction in otherwise healthy individuals.

CONCLUSIONS

Modifiable factors, such as HSV-1 infection need to be investigated from an etiologic and therapeutic perspective in persons with serious major mental illnesses such as SZ and even in otherwise healthy persons.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.