Researchers say almost half of people with Monkeypox infection also report mental health problems

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New review of evidence finds monkeypox can lead to neurological complications.

The review, published in eClinicalMedicine, found that monkeypox can be linked to neurological complications such as encephalitis (brain inflammation), confusion or seizures in some patients. It provides the first comprehensive overview of the prevalence of neurological and psychiatric symptoms of monkeypox.

Across the studies with relevant evidence, 2-3% of monkeypox patients had severe complications such as seizure or encephalitis, although those studies mainly involved hospitalised patients from previous years. The researchers say there is not yet enough evidence to estimate neurological complication prevalence in the current monkeypox outbreak.

In some studies at least half of patients experienced at least one of myalgia (muscle aches), fatigue, headache, anxiety or depression, however the quality of the evidence was limited.

The team, led by researchers at the Institute of Psychiatry, Psychology & Neuroscience (IoPPN), South London and Maudsley NHS Foundation Trust and UCL, conducted a systematic review and meta-analysis of all studies reporting neurological or psychiatric symptoms of monkeypox that had been reported up until May 2022, before the outbreak spread globally.

“Monkeypox has traditionally been considered a skin disease with respiratory complications. Our work shows that there are rare but severe neurological consequences that clinicians need to be aware of,” said Dr Tom Pollak, NIHR Clinical Lecturer at King’s IoPPN, Honorary Consultant Neuropsychiatrist at South London and Maudsley NHS Foundation Trust, and joint senior author on the study.

Dr Tim Nicholson, Reader at King’s IoPPN and co-author on the study, said: “At present there is little data on how long these neurological and psychiatric symptoms persist for in monkeypox. Given that we now know that such symptoms can persist for months and even years after SARS-CoV-2 infections in Long COVID it is critical that clinicians and researchers monitor for and learn how to prevent or treat longer term consequences of other infections such as monkeypox.”

Monkeypox primarily causes skin lesions and fever, and can be fatal, however substantially fewer than one in 1,000 confirmed cases have resulted in death in the current outbreak, according to the World Health Organization (WHO).

While it has been endemic in parts of Central and West Africa for decades, with sporadic outbreaks elsewhere, 2022 has been the first time the virus has spread globally, attracting increased attention to an infectious disease that was previously relatively neglected.

Although the related smallpox virus is commonly associated with neurological symptoms, little work has been done to date to explore the neurological and psychiatric features of monkeypox.

The review incorporated 19 studies with a total of 1,512 participants (1,031 of whom had a confirmed infection) in the US, Nigeria, Democratic Republic of Congo, Republic of Congo, and the UK.

By pooling data from across a sub-set of studies with relevant evidence, the researchers estimated that 2.7% of monkeypox patients experienced at least one seizure, 2.4% experienced confusion and 2.0% had encephalitis, a serious condition of brain inflammation that can lead to long-term disability.

However, there was very limited evidence for the prevalence of such symptoms. The researchers say that further study is needed to determine the prevalence of symptoms and how monkeypox can impact the brain.

The researchers note that monkeypox may cause higher rates of mental ill health than other illnesses due to the presence of lesions as well as stigma linked to how transmission is typically from close physical or sexual contact.

The studies reviewed did not have enough long-term follow-up with patients to know whether any of the symptoms last substantially longer than the acute phase of the illness. The researchers also caution that most cases in this review were hospitalised patients, and so the studied symptoms might not be as common in people with more mild cases.

Dr Tom Pollak said: “While more research is needed, our work shows that symptoms such as anxiety and low mood may be common in people who have monkeypox. The reasons for this are not yet clear, but it is important that we do not allow stigmatisation of this disease to make matters worse.”

Joint senior author, Dr Jonathan Rogers (UCL and South London and Maudsley NHS Foundation Trust), said: “We found that severe neurological complications such as encephalitis and seizures, while rare, have been seen in enough monkeypox cases to warrant concern, so our study highlights a need for further investigation.

“There is also evidence that mood disorders such as depression and anxiety are relatively common for people with monkeypox.”


Detection of MPXV at a glance

Poxviruses have a large linear double-stranded DNA that encodes all enzymes to replicate and assembly, but they use the host cell’s ribosomes to conduct translation process in the cytoplasm of infected cells. Morphologically in MPXV, the virions are ovoid or brick-shaped that are covered by a lipoprotein outer membrane about 200 by 250 nm in size in electron micrograph examinations [26, 27]. MPXV is resistant to heat and cold as heating until 40 °C had no strong effect on its infectivity [28], while some chemical agents, such as chloroform, methanol, formaldehyde, and phenol significantly inactivate its pathogenesis [13, 28].

Host infection is mediated through the interaction of viral proteins to host glycosaminoglycans that subsequently initiate the cellular endocytosis process and virus entry. In most poxviruses infection, two types of morphologically different virions, such as intracellular mature virus and extracellular-enveloped virus spread infectious into the host [26]. MPXV transmits from animals to human and human to human. Animal to human transmission (zoonotic transmission) mainly takes place in direct contact with body fluids, touch, bite and scratch of infected live/dead animals [29, 30], just like what happened in the initiation of MPX endemic in Central and Western Africa in 1970. The second form of transmission is human to human which maybe the route responsible for raising the cases of MPXV worldwide.

The main human-to-human transmission routes are close contact with a MPX positive or symptomatic person, especially in health workers, sexual partners, and household members. Furthermore, respiratory droplets, contaminated materials, mouth ulcers and lesions as well as other mucosal secretions are considered transmission routes for human-to-human spread [31,32,33,34].

MPXV is diagnosed using a set of genetic, phenotypic, immunologic, and electron microscopic methods [26]. For example, a real-time polymerase chain reaction (RT-PCR) test is used to detect the MPX-specific DNA in the skin biopsy specimens [35]. Moreover, immunohistochemistry is applied to reveal the virus antigens in specific tissues and enzyme-linked immunosorbent assay (ELISA) is utilized to detect IgG and IgM antibodies against MPXV in the blood samples.

In some cases, electron microscopy may be used to identify poxvirus virions in tissue specimens [36]. It should be noted that MPXV can be identified if the characteristic skin lesions are present and there is a history of exposure with suspected cases of MPXV [37]. Despite the precise detection of MPXV, the invasiveness and complications of MPXV on the second organs, such as CNS are crucial for basic scientists and clinicians.

The CNS infection of MPXV not only can cause long-lasting brain injury but also can induce other neurological manifestations as we reported for SARS-CoV-2. Therefore, presenting current evidence of the neuroinvasive property of MPXV can inform us to focus on this aspect of the virus and make a better decision on clinical management. In the next outlines, we present evidence of neurological manifestations and neuroinvasive properties of MPXV.

Neurological manifestations of MPXV

The preliminary data showed a wide range of neurological manifestations from less serious and nonspecific symptoms including headache, myalgia and fatigue to more severe complications like seizure and encephalitis. The symptoms varied broadly, but the most prevalent were headache, myalgia, fatigue, photophobia, pain and fewer cases of encephalitis and seizure (Table 1).

Data for psychiatric symptoms (i.e., depression, anxiety, and suicide) were not included in the current study. Here are brief reviews of published reports on neurological manifestations after MPXV. For example, a severe case of MPXV, who suffered from headache, and myalgia was reported in The United States of America (USA). She was the third reported child there who exposed to an infected prairie dog before admission [38]. In addition, headache, fatigue and myalgia were frequent neurological symptoms in seven other confirmed MPXV patients in the Western hemisphere [9].

A family cluster with MPXV was also reported in the Midwestern USA that had been exposed with prairie dogs. Of three family members infected, two showed mild skin rash only and one presented with severe encephalitis which required hospitalization. The two milder forms had been previously vaccinated with smallpox vaccine. A wide range of neurological manifestations including headache, fatigue, myalgia, confusion and seizure were seen in the severe case.

Neurological examination revealed decreased level of consciousness, pupillary dilatation, optic disc edema, loss of corneal reflexes and reduced deep tendon reflexes. Additionally, magnetic resonance imaging (MRI) confirmed hyperintensity in thalamus, brainstem and right posterior parietal cortex consistent with mixed cytotoxic and vasogenic brain edema. Pleocytosis was also detected in the analysis of the cerebrospinal fluid (CSF) [7].

In another study, seizure and confusion accompanied other neurological manifestations such as headache and myalgia in the USA [6]. Furthermore, a variety of neurological complications such as headache, myalgia, pain and photophobia were reported in MPXV confirmed cases in the Bayelsa State of Nigeria in a cross-sectional study [39]. Taken together all previous reports we can conclude that currently, the development of CNS and peripheral nervous system complications in MPX patients has not been well established, but there are at least scattered case reports of patients with neurological features and those with severe complications, in particular, require emergent treatments. It is thus imperative to start treatment as quickly as possible while the pathogen spread is mitigated at the population level. To this point, we highlighted available evidence of the neuroinvasive potential of MPXV from experimental data.

Neuroinvasive propensity of MPXV

The neurotropic feature of MPXV on human subjects has not been fully understood, while data from animal studies (i.e., on rodents) have revealed that MPXV can cross the blood–brain barrier (BBB) and showed neuroinvasive capacity as summarized in Table 2. Intranasal and intraperitoneal administration of MPXV strain of 2003 is a well-established disease and caused animal death in ground squirrels after about 1 week.

Necropsy findings indicated high titers of MPXV, using the number of plaque-forming units (PFU) per millimeter of homogenized tissue, in the brain tissues of animals [52]. Furthermore, during the 2003 outbreak, results of MPXV-specific PCR assay of four MPXV suspected rodents (i.e., a prairie dog, a hamster, and two gerbils) showed that the virus penetrated into the brain tissue [53]. Similar findings were reported in rope squirrel, pouched rat, dormice, and again prairie dogs in which MPXV DNA was detected in the brain tissues [10].

As can be seen from Table 2, MPXV can reach the brain parenchyma in animal models; however, considerably more work will need to be done to detect the neuroinvasive and neurotropism of MPXV in human subjects. It is also important to figure out the transmission routes of MPXV to the CNS. Currently, the exact transmission routes of MPXV are not clearly defined; however, previous studies on animal subjects have suggested two probable different routes: (i) olfactory epithelium route and (ii) infected monocytes/macrophages transmission way (Fig. 2).

Figure 2 – Probable transmission routes for entry of MPXV into the brain tissue. MPXV can reach the brain tissue through two probable routes, such as olfactory epithelium and infected monocytes/macrophages. After intranasal inoculation, the virus rapidly is replicated in the nasal septum and mucosa and detected in the brain parenchyma. Data also showed that infected monocytes in circulation may cross the blood–brain barrier (BBB) and reach the brain tissue. MPXV can rapidly replicate into the macrophages and release from these cells into the brain. MPXV Monkeypox virus

For instance, the accumulation of MPXV was significantly increased in the nasal septum mucosa and brain tissue after intranasal inoculation of Congo Basin MPXV strain in ground squirrels [59]. Furthermore, intranasal inoculation of MPXV showed that the virus had more replication in the intranasal and brain areas of animals assessed by bioluminescence imaging [60]. Coupled with, the main organs for viral load were the brain, nasal septum, and nasal mucosa after intranasal inoculation of MPXV in mice.

These findings represented that the nasal cavity and olfactory epithelium may act as a major route for transmission of MPXV into the brain parenchyma (Fig. 2). MPXV may gain access to the CNS by infecting circulating leukocytes, e.g., monocytes/macrophages as a second route (Fig. 2). As an example, specific antigens of MPXV-Zaire 79 were identified in circulatory monocytes of macaques after intravenous injection of the virus [62].

Additionally, subcutaneously injection of MPXV in cynomolgus monkeys strongly increased viral particles in the alveolar and mediastinal lymph node macrophages detected by electron microscopy, indicating a high replication process in these cells [63, 64]. Also, the viral particles have been obviously detected after intranasal inoculation of MPXV in activated alveolar macrophages of ground squirrels, mice, and prairie dogs as shown by electron microscopy images [16, 59, 61]. It should be mentioned that the current data suggest the possible neuroinvasive potential of MPXV; however, more broadly, research is also needed to determine the exact invasion routes.

reference link : https://link.springer.com/article/10.1007/s00415-022-11339-w


Original Research: Open access.
Neurological and psychiatric presentations associated with human monkeypox virus infection: A systematic review and meta-analysis” by Thomas A Pollak et al. eClinicalMedicine

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