Monkeypox encephalitis with transverse myelitis in a female patient

Abstract

The 2022 monkeypox outbreak has affected 110 countries worldwide, outside of classic endemic areas (ie, west Africa and central Africa). On July 23, 2022, the outbreak was classified by WHO as a public health emergency of international concern. Clinical presentation varies from mild to life-changing symptoms; neurological complications are relatively uncommon and there are few therapeutic interventions for monkeypox disease. In this Grand Round, we present a case of monkeypox with encephalitis complicated by transverse myelitis in a previously healthy woman aged 35 years who made an almost complete recovery from her neurological symptoms after treatment with tecovirimat, cidofovir, steroids, and plasma exchange. We describe neurological complications associated with orthopoxvirus infections and laboratory diagnosis, the radiological features in this case, and discuss treatment options.

Introduction

The increase in the number of people with monkeypox outside of classic endemic regions (ie, west Africa and central Africa) was first noted to WHO by the UK Health Security Agency (UKHSA) on May 7, 2022.¹ Infections were noted in all WHO regions, with 88% of laboratory-confirmed cases being reported from the European region in the first 2 months of the outbreak.² Previously, only a small number of cases of monkeypox had been observed outside of Africa.³

Monkeypox infections were first recognised in humans in the 1970s.⁴ Monkeypox is a zoonotic disease originally described in primates; to date the definitive animal reservoir (ie, the animal species that can host the virus without major evidence of disease so that virus transmission is possible) remains unknown. The disease is caused by an orthopox DNA virus. Currently, whole-genome sequencing data divide monkeypox species into clade 1 (previously known as the central African or Congo Basin clade), responsible for endemic infections in central Africa, and clade 2 (previously known as the west African clade), responsible for endemic infections in west Africa. The 2022 outbreak of monkeypox has spread extensively in areas outside of endemic countries due to subclade 2b,⁵ and has been shown to disproportionally affect gay and bisexual men who have sex with men.⁶ Monkeypox virus infection has an incubation period of 3–21 days and is characterised by a prodrome of fever, myalgia, and lethargy, then a characteristic maculopapular rash; it is often a self-limiting illness.⁶ However, it has been associated with severe disease, and before the 2022 outbreak had a 3–6% mortality rate.²

Clinicians worldwide should be familiar with both the common presentation of genital, skin, and pharyngeal lesions⁶ and the rarer, life-threatening complications of monkeypox, such as encephalitis.

Neurological complications have previously been documented in relation to many viral infections of epidemic potential, including SARS-CoV-2,⁷ MERS-CoV, Zika virus,⁸ Ebola virus, smallpox, and monkeypox.⁹ Encephalopathy, seizures, stroke, and Guillain-Barré syndrome are all recognised as substantial but rare complications which increase both morbidity and mortality.⁹ Three documented cases of encephalitis during the 2022 monkeypox outbreak have been fatal.¹⁰

In this Grand Round, we discuss the case of a female patient with monkeypox infection exacerbated by both encephalitis and transverse myelitis. We highlight the diagnostic tests that were done, the radiological features that were seen, and our rationale for the treatment options chosen.

Case report

A White woman aged 35 years and born in the UK developed abdominal pain and groin swelling, and the next day developed painful vesicular vulval lesions. She reported unprotected sex with a regular male partner 5 days before these symptoms. Her only medical history was mild gastro-oesophageal reflux, and she had no history of underlying immune deficiency. She had not been vaccinated against orthopoxviruses.

On the fourth day of her symptoms, she presented to her local emergency department complaining of a headache. She was assessed the next day in her local sexual health clinic, where review was advised. Monkeypox was considered as a possible diagnosis; swabs of the lesions were tested for herpes simplex virus (HSV) and varicella zoster virus (VZV), but both were negative. A monkeypox virus PCR was positive on the genital lesion swab (table ). Her blood-borne virus screen was negative for HIV, hepatitis B, and hepatitis C. She also tested negative for syphilis. Later that day, she was informed by her partner that he had a confirmed monkeypox infection. Due to severe genital pain and problems with passing urine, she was admitted to the local Infectious Disease Unit on the sixth day of her illness. She was noted to have monkeypox lesions at varying stages of evolution on her limbs, hands, and torso. She had extensive, painful lesions on the vulvovaginal area, with local oedema and groin lymphadenopathy. She was managed conservatively with analgesia and oral antibiotics for secondary vulval cellulitis. In addition to her genital and skin swabs, her throat swab was also positive for monkeypox virus on admission.

Table.

Diagnostic investigations on various days of illness

			Day 4	Day 9	Day 17	Day 20	Day 25
Cerebrospinal fluid
	White cell count, cells per μL (lymphocyte %)		..	16*	..	92 (100%)	..
	Red blood cells, cells per μL		..	<1	..	<1	..
	Protein, g/L		..	0·4	..	0·8	..
	Glucose		..	..	..	..
		Cerebrospinal fluid, mmol/L	..	3·4	..	3·1	..
		Plasma glucose, mmol/L	..	4·7	..	5·5	..
	Orthopoxvirus PCR (Ct value)		..	Positive (36·8)	..	Negative	..
	Monkeypox virus PCR (Ct value)		..	Positive (34·0)	..	..	..
	HSV, VZV, and enterovirus PCR		..	Negative	..	Negative	..
	Cytomegalovirus PCR		..	..	..	Negative	..
Lesions
	Orthopoxvirus PCR (Ct value)		Positive (18·7)	..	..	..	..
	Monkeypox virus (Ct value)		Positive (16·3)	..	..	..	..
Throat swab
	Orthopoxvirus PCR (Ct value)		..	..	Positive (30·4)	..	Negative
Urine
	Orthopoxvirus PCR (Ct value)		..	..	..	..	Negative

Ct=cycle threshold. HSV=herpes simplex virus. VZV=varicella zoster virus.

^*Differential white cell count not done.

On the ninth day of symptoms, she continued to have fever (≥38·1°C) and became drowsy (ie, Glasgow coma scale [GCS] score of 14), needing encouragement to have any food or fluids. She continued to have severe genital pain despite escalating analgesia, with new monkeypox lesions developing on her limbs. After urgent discussion with members of the national monkeypox multidisciplinary team, oral tecovirimat (600 mg) twice per day was started. On the tenth day, she became drowsier and more confused (GCS score of 11) than she had previously been. Encephalitis was suspected, and so a CT scan of the head and a lumbar puncture were done. The lumbar puncture revealed a mild leukocytosis of 16 white blood cells per μL with normal protein and glucose levels (table). Aciclovir and ceftriaxone treatment were started pending further results.

Bacterial culture and PCR tests on cerebrospinal fluid samples for HSV, VZV, and enterovirus were negative. Subsequently, an initial orthopoxvirus PCR done by the UKHSA High Containment Microbiology Laboratory was positive with a cycle threshold (Ct) value of 36·8. Confirmatory testing was then performed on two extracts from the cerebrospinal fluid sample with a monkeypox-virus-specific PCR assay; both were positive with Ct values of 34·0 and 36·0. An MRI head scan (figure 1 ) showed multifocal areas of atypical cortical, thalamic, cerebral, and cerebellar white matter T2 hyperintensities. The distribution of the signal change and cortical thickening was radiologically suggestive of encephalitis. Aciclovir was discontinued and tecovirimat was administered via a nasogastric tube (the intravenous formulation was not available in Europe at the time) until the patient was alert enough to swallow. Antibiotics were continued to treat possible secondary skin infection.

Figure 1.

Initial MRI scan

(A–B) Axial proton density images showing a supratentorial white matter atypicality (arrow, A) and cortical swelling (dotted arrow, A). Swelling of both thalami was noted (arrows, B). (C–D) T2-weighted images showed further hyperintensities within the supratentorial white matter (arrow, C), middle cerebellar peduncle (arrow, D), and brainstem (dotted arrow, D).

After 10 days of treatment, the patient remained confused, although her GCS score had steadily improved from 8 to 14. She then developed painless urinary retention, and on the next day (day 19 of illness) was noted to have decreased power (power 2 of 5 on a scale) in both legs throughout all muscle groups. After 24 h, this weakness developed into flaccid paralysis of both lower limbs with areflexia and absent sensation to all modalities up to the level of the tenth thoracic vertebrae. Upper limb neurology, including reflexes, was normal.

A repeat MRI head scan on day 20 of illness revealed diffuse T2 and Fluid Attenuated Inversion Recovery (FLAIR) hyperintensities in the cerebral periventricular white matter bilaterally, indicative of diffuse encephalitis (figure 2 ). A whole-spine MRI showed multiple central and peripheral intramedullary high T2 signal lesions of varying lengths, with regions of enhancement and associated enhancement of the cauda equina nerve roots (figure 3 ). The appearances of the whole-spine MRI were considered likely to represent extensive myelitis, with features of cauda equina enhancement. A repeat lumbar puncture showed ongoing lymphocytosis, a mild elevation in protein levels, and negative viral (including orthopoxvirus) PCRs (table).

Figure 2.

Encephalitis changes on MRI of the head

(A–E) Axial 3D-FLAIR images showing atypical hyperintensity within the posterior limb of the left internal capsule (arrow, A), bilateral thalami (B), splenium of the corpus callosum (arrow, C), middle cerebellar peduncle (arrow, D), and left side of the medulla (arrow, E). (F–G) Axial T2 sequence highlighting extensive cortical swelling (arrows, F) and resulting early uncal herniation with brainstem mass effect (arrow, G). (H–K) DWI (H, J) and ADC maps (I, K) show patchy, low ADC signal, suggesting reduced diffusivity within the cerebral cortex (arrows, H–I) and the left brachium pontis lesion (arrows, J–K). ADC=apparent diffusion coefficient. DWI=diffusion-weighted imaging. FLAIR=Fluid Attenuated Inversion Recovery.

Figure 3.

Transverse myelitis on MRI of the spine

(A–B) Sagittal short-tau inversion recovery sequence showing extensive transverse myelitis of the spinal cord with long segments of T2 hyperintensity and cord swelling in the cervicothoracic (arrow, A) and lumbar (arrow, B) cord. (C–D) Pre-contrast and post-contrast sagittal T1 sequences showing avid enhancement of the cauda equina nerve roots. (E–F) Axial T2 through the upper and mid cervical spine showing signal hyperintensity involving central grey and peripheral white matter (arrows). (G–H) Post-contrast axial T1 imaging through the upper and mid cervical spine showing patchy enhancement within the cervical spine (arrows). (I–J) Axial, post-contrast T1 imaging through the cauda equina nerve roots showing enhancement of the cauda equina nerve roots.

After discussion with the national monkeypox multidisciplinary team and the national encephalitis multidisciplinary team, the neurological complications of longitudinally extensive transverse myelitis (LETM) were considered to be secondary to a post-infectious, immune-mediated event. The patient had no history of CNS demyelination or optic neuritis. Because of the presence of ongoing skin lesions and the risks associated with immunosuppression in the context of ongoing infection, she was treated with methylprednisolone on day 22 of illness and a single dose of cidofovir on day 24 of illness. Her cognitive function improved during the next 5 days; mini-Addenbrooke's Cognitive Examination score was 17 of 30 initially on day 22 of illness, improving to 21 of 30 on day 26 of illness. The power in her lower limbs started to recover to power 2 of 5 in both legs, with sensation to light touch returning. The course of tecovirimat was extended to 19 days, at which point treatment was discontinued due to abdominal pain (day 28 of illness). After further discussion with the neurology team, the patient was switched to high-dose prednisolone (60 mg once per day), and a 14-day course of plasmapheresis was started on day 35 of illness.

After seven plasma exchanges as part of the plasmapheresis, a reducing dose of prednisolone, and an extended period of rehabilitation, the patient was able to walk independently after her discharge from hospital. She remains healthy and had recovered from almost all her neurological deficits 3 months after her initial infection.

Neurological complications of epidemic viral infections

To our knowledge, this is the first reported case of PCR-confirmed monkeypox encephalitis complicated by post-infectious LETM in a woman. On Sept 23, 2022, two cases of monkeypox-associated encephalitis were reported in healthy gay and bisexual men who have sex with men.¹¹ Encephalitis has been reported as part of the current outbreak and remains a serious and sometimes fatal complication.2, 12 Two cases of encephalitis in patients with confirmed monkeypox virus from skin lesions and a report of three cases in suspected monkeypox exist in the literature; these cases have predominantly been in children.¹² Altered mental state (eg, confusion and central nervous deficits) was a recognised feature of smallpox with encephalomyelitis documented after both variola virus (ie, smallpox) and vaccinia virus (ie, post-smallpox vaccination).9, 10, 13, 14, 15 Histological findings in people who have died of smallpox and had neurological complications showed acute perivenular demyelination.¹⁴ Encephalitis from smallpox occurred in approximately 1 in 500 patients with variola major and 1 in 2000 patients with variola minor presenting at 6–10 days of illness.9, 14

Post-infectious isolated transverse myelitis is around 27% of post-infectious CNS neurological syndromes, as observed in a previous prospective cohort study.¹⁶ 44% of patients with post-infectious isolated transverse myelitis did not have detectable aquaporin-4 antibodies. Most cases were responsive to steroids. Predictors of poor outcomes in post-infectious transverse myelitis are increased spinal cord involvement, increased disability at onset, and sphincter involvement.16, 17 A small number of cases of both transverse myelitis and acute disseminated encephalomyelitis have been reported after smallpox vaccination; however, post-infectious isolated transverse myelitis after active monkeypox infection is a newly described occurrence.18, 19

Laboratory diagnostics

Due to the advances in molecular testing, there is increased diagnostic ability to identify the underlying pathogen of monkeypox, as well to monitor treatment. All monkeypox patients are recommended to have swabs from throat and skin lesions sent for molecular testing.²⁰ If there are concerns of CNS involvement, then cerebrospinal fluid testing could be informative. A previous case of imported monkeypox, acquired from close contact with prairie dogs, had detectable IgM for orthopoxvirus in cerebrospinal fluid.²¹ The patient in this Grand Round had two lumbar punctures that showed an evolving lymphocytosis and raised protein levels. The initial sample was positive for monkeypox virus by PCR (table). Therefore, we hypothesise that this is the first reported case in the current outbreak of monkeypox to show the presence of monkeypox virus in cerebrospinal fluid with encephalitis, suggesting that there is direct viral invasion of the cerebrospinal fluid. The second lumbar puncture was negative for monkeypox virus, suggesting that LETM might be secondary to post-infectious autoimmunity rather than direct viral invasion.

Other common infectious pathogens known to cause encephalitis should also be considered and tested for in the cerebrospinal fluid, if clinically relevant. These pathogens include HSV-1; HSV-2; VZV; cytomegalovirus; Epstein-Barr virus; West Nile virus; Borrelia burgdorferi (ie, lyme disease); syphilis; and cultures for bacterial, mycobacterial, and fungal pathogens.²²

The analysis of cerebrospinal fluid can provide insight into the causes of neurological symptoms. Infectious causes are usually associated with increased opening pressures, increased leucocyte counts, reduced glucose, and increased protein levels, whereas non-infectious causes are often associated with normal opening pressures, normal glucose levels, increased protein levels, and increased leukocyte counts.²²

Other markers for other non-infectious causes of myelitis should also be considered. Aquaporin-4, myelin oligodendrocyte glycoprotein antibodies, and oligoclonal bands on cerebrospinal fluid were tested and were negative in our case, as were serum antinuclear antibodies, extractable nuclear antigens, cerebrospinal fluid and serum for paraneoplastic autoantibodies, and autoantibodies to glial fibrillary acidic protein.²²

Radiological features

The imaging features seen in this female patient with monkeypox infection differ from features seen in other common viral encephalitis. For example, the most common cause of viral encephalitis is HSV, which typically has involvement of the mesolimbic system, insular cortex, and cingulate gyrus, affecting one or both cerebral hemispheres.²³ In 2020, there were several documented cases of COVID-19 encephalitis, in which commonly described findings include venous sinus thrombosis, grey matter signal changes, and microhaemorrhages.²⁴ Other non-infectious differential diagnoses to consider in our case would include Creutzfeldt-Jakob disease, autoimmune encephalitis, and hypoxic–ischaemic injury. However, the clinical picture and radiology seen in this case are not typical for these diagnoses.

In this female patient, the initial MRI examination showed diffuse T2 hyperintensities throughout the cerebral white matter, with further hyperintensities in both thalami, the left middle cerebellar peduncle, and the brainstem. There was also diffuse T2 hyperintensity of the cerebral cortices. These appearances were considered suspicious for an encephalitic process.

10 days after treatment, new signs of areflexia and reduced lower limb power prompted repeat MRI examination. This showed increased T2 and FLAIR hyperintense signal change in the cerebral white matter. In addition to the established signal change in the thalami, new hyperintensities in the posterior limb of the left internal capsule and splenium of the corpus callosum were also identified. There was increased diffuse cerebral and new cerebellar cortical swelling with some patchy areas of low apparent diffusion coefficient signal, implying restricted diffusion (figure 1). These findings were suggestive of an acute phase of encephalitis. Previously noted lesions in the left middle cerebellar peduncle and brainstem were again evident. However, they had increased in size and now also showed regions of isointense and low apparent diffusion coefficient signals consistent with reduced diffusivity. There was no evidence of any intracranial, pathological contrast enhancement.

Spinal imaging was also done (figure 3), which displayed long segments of T2 and short-tau inversion recovery hyperintense signal and cord swelling along the whole length of the spinal cord, involving both grey and white matter tracts. Post-contrast imaging showed patchy foci of enhancement in the cervical spine and avid enhancement of the cauda equina nerve roots. These imaging features were consistent with LETM and are likely to correspond with the acute deterioration of the patient.

Follow-up MRI imaging done 9 days later showed reduced cortical swelling with some modest reduction in the volume of intracranial T2 and FLAIR signal change. There was also a reduction in signal change and swelling of the spinal cord, with some improvement in cord enhancement. Enhancement of the cauda equina nerve roots remained unchanged.

Treatment options

The optimal antiviral treatment for monkeypox disease and associated complications is not known, but options include tecovirimat,25, 26 cidofovir, brincidofovir, and vaccinia immunoglobulin. The current recommendations for treatment of monkeypox disease in the UK were published on Sept 20, 2022.²⁷ In this patient, oral or nasogastric tecovirimat were initiated (intravenous tecovirimat was not available in Europe at the time) when encephalitis was suspected as tecovirimat has been shown to cross the blood–brain barrier in animal studies. However, no human data for cerebrospinal fluid penetration of the drug has been published.²⁵ Because of the new neurological symptoms in our patient, a second antiviral cidofovir was administered. Although cidofovir does not show good penetration of the blood–brain barrier, there might be synergy between antivirals.²⁶ Brincidofovir, an oral lipid prodrug of cidofovir, has been shown to be synergistic with tecovirimat in both cell culture and mouse orthopoxvirus models,²⁸ but brincidofovir is not readily available in the UK. These murine studies have shown encouraging findings for the use of tecovirimat, and future trials will seek to confirm them in humans. Furthermore, many patients who have been admitted to or treated in hospitals have been recruited to observational studies that will provide detailed outcome data.

Because of the LETM and substantial neurological symptoms our patient had, which were thought to be secondary to a post-infectious, autoimmune event, and because of the poor prognostic markers, we proceeded to treat her with methylprednisolone and plasmapheresis, as they have previously been shown to be beneficial in acute CNS inflammatory demyelinating disease.²⁹ At her 3-month follow-up, plasmapheresis did not appear to have reactivated monkeypox infection, and could therefore be a safe approach in similar patients.

Conclusion

Because of negative outcomes of the cases of encephalitis in Spain,² we would like to highlight the positive outcome in our case with an unusual presentation of neurological sequelae of monkeypox infection. We believe the care of our patient was helped by fast involvement of appropriate national multidisciplinary teams and early initiation of antiviral therapy, alongside active management of transverse myelitis.

Future research

There is a clear need for ongoing epidemiological surveillance to establish whether the current monkeypox outbreak will lead to transmission into novel animal reservoirs, allowing it to become endemic in countries outside of Africa. Current treatment options have not been evaluated in human clinical trials and ongoing efforts to evaluate the use of these drugs are currently happening. Vaccination with smallpox vaccines has formed an important part of the public health response to date, but how efficacious this will be against monkeypox virus remains unclear.

Declaration of interests

We declare no competing interests.