Severe acute disseminated encephalomyelitis complicating measles infection

Abstract

A 36-year-old man presented with an acute progressive encephalopathy, followed by tetraparesis and was diagnosed with acute disseminated encephalomyelitis (ADEM) complicating infection with measles virus. Despite demonstrating a typical rash and other early symptoms of measles infection, there was uncertainty around the initial diagnosis. Cerebrospinal fluid analysis and MRI of the brain and spinal cord were consistent with severe ADEM. He required treatment on intensive care but responded favourably to immunosuppressive therapy.

This case highlights the importance of recognising acute measles infection, familiarity with the neurological complications and the potential for good outcome. Healthcare professionals must continue to play an active role in educating the public on the importance of maintaining herd immunity through universal immunisation.

Background

Measles is a highly contagious virus and produces typical clinical symptoms in susceptible individuals exposed to the disease.¹ The neurological sequelae of measles infection are uncommon but well recognised and include primary measles encephalitis, acute (postinfectious) disseminated encephalomyelitis (ADEM), measles inclusion body encephalitis and subacute sclerosing panencephalitis,² the latter two of which are nearly always fatal.

We report the case of an immunocompetent adult who developed severe ADEM following infection with measles. Measles infection was considered early on the basis of a maculopapular rash and Koplik spots, but there remained clinical uncertainty until laboratory confirmation. With the rising incidence of measles across Europe,³ this case highlights the need for clinicians to remain vigilant of this rare but potentially life-threatening disease and its neurological complications which may be less familiar to the current generation.

Furthermore, we demonstrate the extensive MRI abnormalities which can be seen in ADEM and their evolution together with the favourable outcome that can be achieved with prompt immunosuppressive treatment.

Case presentation

A 36-year-old right-handed aviation technician with no significant medical history presented to the emergency department with a 48-hour history of headache, confusion and fluctuating consciousness on a background of 5 days of flu-like illness and a widespread rash. There was no history of unwell contacts or recent foreign travel. A full vaccination history was not available at the time of admission.

On initial clinical assessment the was afebrile. A fading widespread erythematous maculopapular rash noted together with a small number of grey-white spots on the buccal mucosa. He was confused (Glasgow Coma Scale E₄ V₄ M₆) but there was no meningism or other focal neurological signs. The patient was treated for suspected meningoencephalitis with intravenous aciclovir and ceftriaxone. Despite treatment he became increasingly encephalopathic, developed apnoeic episodes and was transferred to the intensive care unit where he was intubated and ventilated. He was extubated 48 hours later but required a tracheostomy and remained encephalopathic. Repeat neurological examination revealed hypotonia, profound global weakness in all limbs, absent deep tendon reflexes and impaired sensation in the lower limbs.

CT head on admission was normal. Subsequent MRI head showed bilateral T2 hyperintensities in the deep grey matter and subcortical white matter typical of ADEM and MRI whole spine showed longitudinal predominantly grey matter changes in the spinal cord, which is less commonly reported. Following cerebrospinal fluid (CSF) analysis, a clinical diagnosis of post-measles ADEM was made. Virology results returned later and were consistent with acute/recent measles infection.

Investigations

Initial blood tests showed a white cell count (WCC) of 9.7×10⁹ L, C reactive protein of 39 mg/L with normal renal and liver function tests. Chest radiograph and urine dipstick testing were normal. HIV serology returned negative.

Cerebrospinal fluid analysis demonstrated a marked pleocytosis with a WCC of 418×10⁶/L (81% lymphocytes) with a negative gram stain and culture, raised protein of 1.8 g/L and borderline low glucose of 2.6 mmol/L (serum 5.8 mmol/L).

Throat swab confirmed measles by real-time transcription PCR and serology returned positive for measles IgG and IgM antibodies. Initial CSF testing returned a low positive measles PCR signal but this was concluded to be a false positive as repeat PCR testing was negative and no measles RNA was detected in the CSF.

Serial brain MRI scans revealed initially bilateral hyperintensity on T2 sequences involving the striatum (figure 1) and subsequently the posterior limb of the internal capsule (PLIC) extending into the midbrain and corresponding with the descending corticospinal tracts (figure 2). One month later, MRI brain demonstrated signal changes in the centrum semiovale (figure 3) with resolution of the striatal and PLIC signal abnormality. MRI of the spinal cord revealed longitudinally extensive cord signal hyperintensity involving the central grey matter with associated cord expansion and no enhancement postcontrast (figure 4), which had largely resolved at on follow-up MRI 1 month later (figure 5).

Figure 1.

Initial MRI brain (day 3) with axial T2 (A) and coronal fluid-attenuated inversion recovery (FLAIR) sequence (B) showing bilateral mildly hyperintense signal in the striatum (white arrows).

Figure 2.

FLAIR MRI (day 9) showing bilateral hyperintensity within the posterior limbs of internal capsules (white arrows). (A—coronal, B—axial).

Figure 3.

Axial T2 MRI demonstrating progressive hyperintense signal demonstrated in the centrum semiovale bilaterally over serial examinations (white arrows). (A—day 9; B—1 month later).

Figure 4.

Initial MRI C-spine (day 3) showing longitudinally extensive cord signal hyperintensity (white arrows) involving the central grey matter (dashed arrows) with associated cord expansion. No enhancement postcontrast (arrow head). (A—sagittal T2; B—sagittal short-T1 inversion recovery (STIR); C—axial T2; D—axial T1 post-contrast).

Figure 5.

MRI (1-month follow-up) showing the hyperintensity in the central grey matter and abnormal cord expansion has now resolved (white arrows) (A—axial T2; B—sagittal STIR).

Treatment

Once the diagnosis of postinfectious ADEM was established, the patient was started on corticosteroids (intravenous methylprednisolone 1000 mg/day for 5 days), followed by a tapering dose of oral prednisolone.

Following discussion with virology, precautionary treatment with intravenous antiviral therapy (ribavirin) was commenced simultaneously with corticosteroids to cover the possibility of active viral infection of the central nervous system and to the potential for viral replication in the presence of immunosuppressive treatment.

Intravenous immunoglobulin 0.4 g/kg per day was given for 5 days following intravenous corticosteroid treatment due to lack of initial clinical response. Following intravenous immunoglobulins treatment, the patient made progressive clinical improvement and was successfully weaned from respiratory support.

Outcome and follow-up

After discharge from intensive care, the patient made significant progress with sustained improvement in his mobility and cognition with the help of intensive neurorehabilitation, although at the time of discharge continued to have problems with short term memory.

Following the diagnosis of measles, the patient’s vaccination history was reviewed and it transpired he had not completed the full UK measles vaccination programme, having missed his second dose of the measles, mumps and rubella (MMR) vaccine for unknown reasons. Shortly after the patient was admitted, his 11-month-old daughter was subsequently diagnosed with measles, just a few weeks before her first MMR vaccination was due. Fortunately, her symptoms were mild, and following consultation with Public Health England, it was concluded that that she was infected by the patient, while the source of his infection was never determined.

After a telephone discussion with the patient 3 months following discharge from the neurorehabilitation unit, he was back home with his family. He described ongoing functional recovery and planned for a phased return to his former employment in the near future.

Discussion

With the widespread availability of a preventative vaccine, the incidence of measles worldwide is falling, but it still responsible for the death of over 100 000 people each year,¹ most commonly from secondary bacterial pneumonia. One or more complications occur in up to 30% of patients infected with measles virus.² Although rare, this case highlights that the neurological sequelae associated with measles are severe, yet clinicians are often unfamiliar with these complications.³ Furthermore, rapidly progressive deterioration is common resulting in significant disability or death,³ so early recognition and treatment of reversible syndromes is crucial.

The neurological complications of measles virus infection are summarised in table 1. We highlight the different clinical, epidemiological, radiological and laboratory features in these distinct conditions. In this case, primary measles encephalitis was considered alongside ADEM the differential diagnosis. However, the evolution of neurological symptoms following improvement of the measles virus prodrome and exanthem, radiological appearances, absence of measles virus RNA in the CSF and improvement following immunosuppressive treatment all favoured a clinical diagnosis ADEM.

Table 1.

Neurological complications of measles infection^{3 14 15}

	Incidence	Clinical setting and disease onset	Clinical signs	Measles virus detection in central nervous system	Cerebrospinal fluid	MRI features	Treatment
Primary measles encephalitis	1–3:1000	During active measles infection	Fever, headache, encephalopathy, seizures	RNA can be isolated in CSF	Lymphocytic pleocytosis (marked), raised protein, normal glucose	T2 hyperintensities, brain oedema	Supportive; ribavirin may be used
Acute disseminated encephalomyelitis	17:40:00	Within weeks to months after measles infection	Encephalopathy, sensory disturbance, weakness	Not detected	Lymphocytic pleocytosis (moderate), raised protein, normal glucose	Multifocal T2 hyperintensities in brain and spinal cord	Corticosteroids; intravenous immunoglobulins; plasma exchange
Measles inclusion body encephalitis	Unknown	Within 1 year of measles infection in immunocompromised children (and rarely adults)	Encephalopathy, refractory seizures, rash	Antibody titre rises in CSF with disease progression; definitive diagnosis by RNA detection on brain biopsy	Usually normal at presentation; mild pleocytosis and raised protein can be seen	Normal at presentation, later oedema and atrophy	Supportive; cessation of immunosuppressive agents; ribavirin may be used
Subacute sclerosing panencephalitis	417:40:00	Measles infection in the first 2 years of life. Disease onset 3–20 years after infection.	Behavioural problems, cognitive decline, myoclonus, intractable seizures, ocular manifestations including necrotising retinitis	High antibody titre in CSF; RNA detectable on brain biopsy in some cases	Normal	Demyelination particularly temporal and parietal lobes, later diffuse cortical atrophy and ventricular dilatation	Supportive; anticonvulsant medication

ADEM is a rare and rapidly progressive autoimmune disease, typically in response to a preceding infection. It is characterised by inflammation and demyelination in the brain and spinal cord, particularly the white matter.⁴ ADEM is well documented in the paediatric population but cases occur more sporadically in adults. It is typically a monophasic illness and although there is no standardised treatment, high dose corticosteroids are the widely accepted first-line treatment. Intravenous immunoglobulin and plasma exchange are reserved for the most severe or refractory cases.

Radiological appearances of ADEM typically demonstrate bilateral but asymmetric lesions of the cerebral white matter, with lesions of the subcortical grey matter less common but well reported. Spinal cord lesions (myelitis) are also recognised,⁵ however the predominant involvement of the spinal cord grey matter in this case is rare.⁶

In the paediatric population cases of ADEM are reported following infection with, and vaccination for, measles virus.⁴ The incidence of ADEM following measles infection is 1 in 1000 cases, more common than following rubella or varicella infection. Historically postmeasles ADEM was associated with mortality rates as high as 25% and 25%–40% of survivors were left with permanent neurological morbidity. Outcomes have significantly improved, however they appear to be worse in adults.⁷

Immunisation with the live attenuated measles virus vaccine provides long-term protection that not only protects the individual vaccinated but also reduces the spread of measles infection by lowering the number of susceptible individuals in the population, a concept known as herd immunity.⁸ For this to be achieved a high level of population immunity is needed. Because measles is highly infectious,>95% immunity is necessary to interrupt endemic transmission.⁸ To obtain this level of population immunity, two doses of the vaccine are required.⁸ Seroconversion rates vary with age, but on average over 90% are immune following their first MMR, rising to well over 95% after second MMR.^{9 10} Therefore, the failure to fully vaccinate enough of the population may mean herd immunity has not been achieved.

In 2017, WHO declared that measles had been eliminated from the UK.¹¹ However, in 2019, the status was revoked with re-emergence of measles transmission. The relatively low rate of measles infection in recent decades may lead to under recognition of acute measles infection and its complications among frontline medical staff. Measles infection should be considered in patients with a widespread maculopapular rash and a prodrome of flu-like symptoms, and healthcare professionals need to remain vigilant for Kopliks spots as a pathognomonic early sign.

Re-emergence represents a major public health concern to the UK. There are a number of reasons for this re-emergence. Following the now discredited 1998 Lancet paper suggesting a link between autism and the MMR there was a sharp drop in the early 2000s in the uptake of the MMR. This means there will be many older children and young adults in the UK will have an incomplete or absent measles vaccination history.¹² In addition, global travel to and from countries where vaccination programmes may be lacking continues to increase.¹³ Given this, clinicians should encourage UK residents to take up the NHS offer of catch up vaccines for under-18s or those eligible on a risk assessment basis.

While cases of measles across the UK and other developed counties rise, we can anticipate the number of neurological complications to follow. Medical professionals need to be familiar with these clinical syndromes as with prompt recognition and treatment a good outcome is possible.

Learning points.

• With the re-emergence of Measles in the UK, doctors should remain vigilant for the disease, and consider the diagnosis in a patient with a widespread maculopapular rash.

• Measles has significant neurological sequelae.

• Acute disseminated encephalomyelitis (ADEM) is a severe complication of measles infection but can have a favourable outcome if recognised early and treated with immunosuppressive therapy.

• ADEM, while characteristically a disease of the white matter, can affect predominantly the grey matter of the central nervous system.

• UK clinicians should be promoting the measles vaccination including catch up vaccinations to those with an incomplete vaccination record.