Neuropsychiatric manifestations of monkeypox: A clinically oriented comprehensive review

Abstract Monkeypox (MPX) has emerged as a threatening outbreak in recent months. The understanding of disease pathogenesis and its systemic involvement has evolved with time. Both the virus and its vaccine, like other members of the Orthopoxvirus family, were always expected to have neuropsychiatric consequences. Several neurological complications have been reported with MPX and its vaccines that include but not limited to headaches, myalgia, encephalitis, and coma. Psychiatric complications like anxiety and depression have also been reported; however, we lack evidence to present a direct causality. We conducted a literature review to compile recent evidence on neuropsychiatric manifestations and underline the importance of evolving aspects and complications of MPX. We advocate for better reporting of cases and adverse events, to enhance our understanding of the disease, aiding physicians to make more informed decisions, thus facilitating timely diagnosis and treatment.

in 1970 in the Democratic Republic of Congo (DRC) (Breman et al., 1980). In 2003, the first outbreak of MPX outside Africa was reported from the United States and was attributed to infected pet prairie dogs that were kept in contact with Gambian pouched rats from Ghana (WHO, 2022b). The communicable disease can spread and present in disparate ways. MPV can be transmitted through direct or indirect contact with infected skin lesions, body fluids, or respiratory droplets of animals or humans. Furthermore, transplacental transmission and sexual transmission have also been reported (Grant et al., 2020). During the 2022 outbreak, the first reported case of MPX in nonendemic regions was a traveler returning to the United Kingdom from Nigeria on 7th May. Other cases were reported independently during a similar time frame. This was followed by a rapid uptick in cases, suggesting human-to-human transmission. Epidemiological data suggested a substantially higher risk in men, particularly gay, bisexual, and other men who have sex with men (GBMSM) (Global.health, 2022;GOV.UK, 2022;WHO, 2022d. The incubation period mostly ranges from 7 to 14 days with the lesions starting from the oropharynx and then spreading throughout the body . Symptoms include the characteristic lymphadenopathy and mild smallpox-like disease with fever, muscle aches, headache, lethargy, and back pain. The infection can broadly be divided into two phases: (1) the initial invasion phase (0−5 days marked by symptoms of fever, headache, lymphadenopathy, backache, myalgia, and asthenia) and (2) the eruptive phase marked by the classical rash. The rash is mainly concentrated on the face and extremities often extending to oral mucous membranes, genitalia, conjunctivae, and the cornea. It evolves sequentially from macules to papules, vesicles, pustules, and crusts that dry up and fall off. The symptoms can be potent in immunocompromised populations (WHO, 2022a). In cases of sexual transmission, anogenital lesions are predominant with sometimes no systemic symptoms. The rash starts as local pseudo-pustules that develop into generalized heterogeneous lesions (Català et al., 2022). Traditional cases of MPX prior to the 2022 outbreak presented with a febrile prodrome prior to the onset of the rash, whereas more recent cases have shown a complete absence of the febrile symptoms or fever following the appearance of the rash (WHO, 2022d; Thornhill et al., 2022). A study conducted in 2017 in the Democratic Republic of Congo showed that hunters, farmers, and people living in lower quality housing were more susceptible to the virus, indicating that direct, prolonged contact with afflicted animals may be the main mode of transmission (Quiner et al., 2017). More recent evidence suggests that sexual transmission through local inoculation is the main mode of transmission in nonendemic areas, highlighting a shift from animal-to-human to human-to-human transmission (Bunge et al., 2022). A gathering in the Canary Islands of around 80,000 attendants for the Maspalomas gay pride festival was suggested to be the probable cause of increased transmission of MPX in the area due to high contact rates Zumla et al., 2022). Several clinics in the United Kingdom reported that more than 90% of presenting cases affected people who identified as GBMSM, with a predominance of anogenital lesions. Around a quarter of the patients had a concomitant STI or were suffering from HIV (Girometti et al., 2022;Patel et al., 2022 (de Vries, 1960), Guillain-Barré syndrome (GBS) (Kisch, 1958), acute cranial neuropathies (MILLER, 1953), poliomyelitis-like syndrome, bell's palsy, and transverse myelitis (Sejvar, 2005). In the United States, 2.5 per million people have experienced neurologic problems, with postvaccinal encephalomyelitis (PVEM) being the most prevalent.
PVEM presents as stupor, coma, seizure, and paraparesis, especially in older children and adults. Around 16% of cases have reported longterm neurologic effects, while mortality rates amount to 1.5 per million per vaccination recipient (Abrahams & Kaufman, 2004). Similar neuropsychiatric complications have been reported for MPX as well (Jezek et al., 1987;Sejvar et al., 2004). The most common is "encephalitis" presenting with the expected constitutional symptoms (Shafaati & Zandi, 2022). It is unknown whether this encephalitis is caused by a direct spread or an autoimmune mechanism (Pastula et al., 2022).
In absence of a specific MPX vaccine, the use of smallpox vaccination for limiting the spread of MPX has been widely advocated but the known neurological complications of smallpox vaccines cannot be ignored, especially with the limited data. However, recent studies support that the addition of vaccines carries a very low risk of producing or exacerbating neurologic complications (Abrahams & Kaufman, 2004).
The neuropsychiatric manifestations of viral diseases have always been a feared yet ignored aspect. The literature is still evolving on MPX and its various systemic manifestations, but we must learn from our previous experiences and be better prepared for future outbreaks. The current review is an attempt to comprehensively compile the evidence on manifestations and suggest preventive and management strategies to help create awareness and reduce morbidity.

NEUROLOGICAL SYMPTOMS IN MPX PATIENTS
MPX like other viral illnesses has also presented with some neurological manifestations (Table 1), with the most common symptom being headache. These are seen in more than half of the MPX-infected patients. Sepsis, blindness (Shafaati & Zandi, 2022), seizures, photophobia (Sepehrinezhad et al., 2022), and encephalitis have also been reported. Though uncommon, encephalitis and seizures are significant neurological complications of MPX, with a prevalence of about 3% (Badenoch et al., 2022). Some of the recently reported cases have even presented with MPX-associated serious neurological symptoms. Two cases of MPX encephalitis were reported in young girls necessitating intubation and mechanical ventilation. The first patient, a 3-year-old TA B L E 1 Compilation of reports of neuro-psychiatric manifestations of MPX Serial no.
Treatment varied between symptomatic management and hospitalization.
All 11 of them recovered. Bolanda et al., 2005 19 Mary G. Headache (1) Fatigue (1) NA NA NA Reynolds et al., 2013 girl, died on the second day of her hospitalization, and no cerebrospinal fluid (CSF) confirmation of MPX disease was possible. While the other girl, a 6-year-old who recovered after 14 days in the intensive care unit, had Orthopoxvirus-reactive IgM in her CSF (Sepehrinezhad et al., 2022).
Encephalitis in MPX presents with pharyngitis, fever, headache, adenopathy, and a vesiculopapular rash that spreads rapidly throughout the body. MRI depicts diffuse edema, meningeal amplification, and signal hyperintensity in the thalamus and parietal cortex. This often presents with a slow wave activity on electroencephalogram.
The findings indicate the probability of mixed cytotoxic and vasogenic brain edema (Sepehrinezhad et al., 2022). CSF examination in the reported cases has revealed polymorphonuclear dominant pleocytosis with typical glucose and protein levels (Shafaati & Zandi, 2022

NEUROTROPISM AND NEUROINVASIVE NATURE OF THE MPX VIRUS
The evidence on the neurotropic effects of MPX is still growing, but our understanding of other Pox viruses and the recently reported literature on MPX support the idea (Chowdhury et al., 2022). MPX being detected in brain tissues of animals suggests a neuroinvasive propensity of the virus with its potential to cross the blood-brain barrier (Sepehrinezhad et al., 2022). The virus was found in the brain tissue of four rodent suspects in the form of MPXV DNA during the 2003 outbreak (Kulesh et al., 2004).
Reports from various parts of the world have indicated the neuroinvasive property of MPX. Cases from the midwestern United States have shown symptoms of headache, myalgia, and encephalitis with these patients developing MPX due to Prairie dog exposure (Sejvar et al., 2004). In Spain, two fatal neuroinvasive instances involving MPXV encephalitis were recently recorded. Two cases of MPXV with encephalitis appearing within 5-9 days were reported in the United States that hinted at either neuroinvasion or a parainfectious autoimmune mechanism. Both the reported findings are indicative of ADEM (Pastula et al., 2022).
Furthermore, animal investigations have revealed two pathways for MPX transport to the CNS. One of these is through the olfactory epithelium. This was thought to be related to the remarkable buildup of MPXV in the nasal septum and brain tissue following intranasal inoculation of Congo Basin MPXV stain in ground squirrels (Sergeev et al., 2017). Bioluminescence imaging also demonstrated fast viral replication in intranasal and cerebral tissues (Earl et al., 2015). Even in mice, the brain, nasal septum, and nasal mucosa have been shown to have a high viral load. The second route of infection to the CNS is thought to be blood-borne transmission through infected monocytes/macrophages (Figure 1). This hypothesis is substantiated by the discovery of distinct MPXV-Zaire 79 antigens in circulating monocytes after intravenous injection of the virus in macaques (Song et al., 2013).
There are also reports that support an increased replication of these viruses in mediastinal and alveolar lymph nodes (Zaucha et al., 2001).
Luciferase imaging to detect neurotropism in the virus could be useful in future research (Cook & Griffin, 2003).

PSYCHIATRIC SYMPTOMS IN MPX PATIENTS
MPX has been associated with some psychiatric manifestations as well. Anxiety and depression have been reported as the most commonly associated psychiatric manifestations. In Nigeria, around 25% of patients hospitalized for MPX were diagnosed with anxiety and depression . Three out of seven admitted patients with MPX in the United Kingdom had a low mood, as reported in a case series (Adler et al., 2022). In the Nigerian study, 11 patients out of 40 were reported to have anxiety and depression and required psychological counseling . One patient died by suicide due to the fear of the stigma associated with the illness and the route of transmission, though prior psychiatric history could not be established .
A catena of causes could be responsible for the said picture including but not limited to patient isolation, pain, skin lesions, and stigma.
In both studies reporting psychiatric complications, the patients were isolated for infection control, which could have contributed to the low mood. Pain could also be one of the potential contributors. In the study from the United Kingdom, one out of three patients with low mood had severe pain along with deep tissue abscesses, and another had an ulcerated inguinal lesion (Adler et al., 2022). The MPX rash is known to be initially painful but later becomes itchy as it crusts (CDC, 2022). In one study with participants who were predominantly men who had sex with men, 36% of patients had rectal pain and around 10% required hospitalization for pain management or penile edema (Patel et al., 2022). Furthermore, MPX has been seen to be associated with rashes over large areas of the body, including the face, trunk, limbs, and genitals.
Four patients in the Nigerian study feared potential permanent facial scarring due to the rashes . Facial scarring has been linked to long-term affective disorders such as depression, especially if the causative incident was traumatic in nature (Rogers et al., 2020).
Fear of discrimination and stigmatization among patients and healthcare workers was a prominent feature. In the Nigerian study, three patients initially refused to be admitted to the isolation ward, fearing stigmatization in their community .
In a U.K. study, a patient's landlord tried to evict them during their hospital stay, causing significant distress (Adler et al., 2022). impacts of the disease are not just restricted to the patients but also to their families and society (Sethi et al., 2022).
Instead of being a specific consequence of MPX, psychiatric complications might be the result of the events surrounding such a diagnosis, including isolation, stigmatization, physical pain, and disfigurement.
Nevertheless, they should be kept in mind while treating a patient with MPX.

DIFFERENTIAL DIAGNOSIS OF THE NEUROLOGIC AND PSYCHIATRIC MANIFESTATIONS OF MPX
Smallpox, belonging to the same genus of Orthopoxvirus, shares most of its clinical features and complications with MPX. Smallpox can present with fever, lethargy, headache, and delirium, even before the onset of rashes. Encephalopathy is common and acute perivenular demyelination was observed among those who died from smallpox (Cleri et al., 2003;Pickfordmarsden, 1934). It can present with delirium, hallucinations, and severe headaches. Eye complications leading to blindness have also been reported (Cleri et al., 2003). Interestingly, the smallpox vaccine has also been shown to cause certain neurological complica-  (Geddes, 2006).
Another infectious disease with overlapping features of MPX is Varicella Zoster. Fever, postinfectious encephalitis, meningitis, convulsions, and stroke are some of the neurological manifestations of varicella (Table 2). Key differentiating features include post-herpetic neuralgia and the less common acute cerebellar ataxia (Bozzola et al., 2012). The oral and genital lesions observed in MPX are similar to herpes simplex virus infections. Oral lesions are a prominent feature of herpes simplex virus type 1 (HSV-1) infection (Arduino & Porter, 2007). Genital lesions can be caused by both HSV-1 and HSV-2, though HSV-2 infection is more likely to recur (Xu et al., 2006). They start as vesicles, progressively transforming into vesicopustules, erosions, and ulcers (Corey, 1983).
HSV can enter the brain through the olfactory and trigeminal nerves to cause neurological complications (Steiner & Benninger, 2018). Encephalitis, typically involving the temporal lobe, is one of the dreaded complications of HSV-1 (Whitley, 2006). Aseptic meningitis is more common with HSV-2 (Kupila et al., 2006). Some unique psychiatric manifestations help differentiate it from other possible diagnoses. Hypomania may be observed initially due to inflammation of the limbic system or inferomedial temporal lobe (Fisher, 1996).
Klüver-Bucy syndrome is a rare manifestation of HSV encephalitis characterized by hypersexuality and a loss of normal anger and fear TA B L E 2 Comparison of neurological symptoms among Monkeypox, Smallpox, Varicella, and HSV  Murakami, 1996).
Encephalitis is a common feature among all the differentials. Unique neurological manifestations of MPX are yet to be described. Hence, comparing the characteristic skin lesions and the community prevalence of viral diseases might be of greater help in narrowing the differentials.

NEUROLOGICAL COMPLICATIONS OF MPX VACCINES
Neurological complications are known to be associated with some vaccines including smallpox, mumps, measles, and rubella vaccine. With various poxviral vaccines repurposed to be used for MPX prevention, the risk of vaccine-induced neurological complications cannot be ignored. Neurological complications have been widely reported with the smallpox vaccine (Guarner et al., 2022). ACAM2000 vaccine is approved for smallpox immunization and has been approved for use against MPX under an Expanded Access Investigational New Drug (EA-IND) protocol (Abrahams & Kaufman, 2004). JYNNEOS, on the other hand, is the only vaccine on the market that has been approved by the FDA to protect against MPX (Guarner et al., 2022). Neurological complications have been reported for both vaccines, especially ACAM2000. Patients with immunosuppression, human immunodeficiency virus infection, eczema, or pregnancy should not receive preexposure vaccination. Individuals who are more liable for complications should be identified and precautions should be taken to keep them from coming into contact with those who have active vaccination lesions (Cleri et al., 2003).
Vaccinia strains can differ in their neurovirulence, for instance, when comparing Dryvax ® to ACAM1000, six young adult monkeys were inoculated with Dryvax ® or ACAM1000, and 50% of the monkeys who received Dryvax ® developed neurological complications, while non among the monkeys that received ACAM1000 develop any neurological complications. The neurological illness observed in the Dryvax ® group included severe meningitis (Monath et al., 2004). While ACAM2000 has been linked to new-onset seizures, the third-generation smallpox vaccination, MVA, is considered to be a more attenuated vaccine and a safer option than previous generations (WHO, 2018).
The most dreaded neurological complication of these vaccines is ADEM (Huynh et al., 2008;Sejvar, 2005). Vaccination with smallpox vaccines has been linked to several neurological problems, the most concerning being PVEM. Postvaccinal encephalopathy is more prevalent in children under the age of two (Booss & Davis, 2003).
After 1-2 days, initial symptoms include fever, dizziness, and tiredness. Some people have high fevers together with neurological symptoms such as limb paralysis, urine retention, and seizures (Booss & Davis, 2003). PVEM mostly occurs after vaccination for the first time rather than after revaccination, while the incidence varies from 2 to 1219 cases following primary vaccination per million. PVEM can occur at all ages, although most primary vaccination against smallpox occurs at an age below 2 years; therefore, the incidence of PVEM is higher among this age group (Booss & Davis, 2003;Henderson & Moss, 1999).
According to a study conducted by James J. Sejvar et al., the incidence of neurological adverse events following smallpox vaccination was 214 cases, with headache as the most frequent symptom followed by nonserious limb paresthesia, meningitis, encephalitis, Bell's palsy, seizures, and Guillain-Barré syndrome (Sejvar, 2005).
Neurological manifestations of LC16 vaccines were assessed in a research project in which rabbits were administered the attenuated and unattenuated Lister strains; researchers found that rabbits injected with unattenuated Lister strain suffered from encephalitis, while no cases of encephalitis were observed among attenuated Lister strains (Kenner et al., 2006). However, current vaccination experience suggests that it has a very low risk of neurologic complications and does not cause exacerbations of chronic neurologic illnesses (Abrahams & Kaufman, 2004;Guarner et al., 2022). The overall prevalence of these vaccine-induced neurological complications is very low and the benefit of these vaccines largely outweighs the associated risk, but an understanding of these possible complications is integral to patient management, especially in the scenario of a widespread outbreak. and headlines used in news outlets and social media were major contributors to psychological disturbances and were shown to increase the trauma, rather than help to overcome it (Sethi et al., 2022). The MPX outbreak threatens a similar rise in homophobia, stigmatizing an already vulnerable community, through targeted headlines and media language (Bragazzi et al., 2022). It should be emphasized that direct contact with infectious scabs, body fluids, and sores is the main mode of transmission of the virus (CDC, 2022b). Sensitivity should be exercised by health organizations and news outlets while reporting on demographic data.

CONCLUSION
The

FUTURE PERSPECTIVES AND RECOMMENDATIONS
Medical professionals must be familiar with the neurological complications of MPX and the vaccines allowing early diagnosis and treatment.
Future studies are warranted to explore the neurological complications of MPX and the vaccines and contribute more data to understand their prevalence, impact, and prognosis. Policymakers should raise awareness of the problem and encourage stakeholders to collaborate on a solution.