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Adult-onset subacute sclerosing panencephalitis
  1. Sruthi S Nair,
  2. K V Vysakha,
  3. Ramshekhar N Menon,
  4. Soumya Sundaram
  1. Neurology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Thiruvananthapuram, India
  1. Correspondence to Dr Soumya Sundaram, Neurology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Thiruvananthapuram 695011, India; ssdr.soumya{at}gmail.com

Abstract

Subacute sclerosing panencephalitis (SSPE) is a lethal slow viral disease of the central nervous system caused by a defective measles virus. The onset is mostly in childhood, manifesting clinically as decline in academic performance, behavioural changes, motor dysfunction and myoclonus. Adult-onset SSPE is rare and can present as rapidly progressive dementia. We present a young man of Indian origin with adult-onset SSPE with rapidly progressive dementia but no localising neurological signs. The diagnostic clues were parieto-occipital white matter changes on MR brain scan and history of childhood fever with rash. High titres of antimeasles antibody in cerebrospinal fluid confirmed the diagnosis. The long latency from primary measles virus infection to symptom onset can be misleading in adults. SSPE should be considered in adults with dementia, especially in tropical countries where vaccination coverage is suboptimal.

  • dementia
  • infectious diseases
  • MRI
  • myoclonus

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Introduction

Subacute sclerosing panencephalitis (SSPE) is a lethal slow viral disease of the central nervous system (CNS) produced by a defective measles virus. Measles virus is an RNA virus that spreads to the brain during or immediately after an acute infection. A mutation in the virus prevents its eradication by the immune system and this sets the stage for SSPE.1 The latency from acute infection is around 5 to 15 years and hence SSPE is mostly a disease of childhood. Children with SSPE present with intellectual decline, myoclonus, seizures and motor dysfunction culminating in akinetic mutism and coma.1 2 Presentation in adults is rare and more variable. SSPE presenting with dementia in adults can pose a diagnostic challenge owing to the long latency from the primary infection and wide differential diagnosis.

Case report

A 35-year-old Indian man had insidious onset, progressive cognitive decline over 6 months. The informant was his wife who noted that at the onset, he made mistakes in his work at a paint factory. He made errors in mixing ingredients, packing paints and delivering, could not issue the correct balance to customers, and could not identify the correct paint colours from display. He would forget conversations, misplace objects and repeatedly asked the same questions. At home, he had difficulty with daily tasks such as shaving, dressing and cutting nails and failed to do them in the correct sequence. He could not use a mobile phone or use the television remote control appropriately. Spontaneous speech was abnormal with reduced fluency and he had progressive difficulty in reading and writing. He could recall childhood events, names of relatives and friends and could navigate within the house. Later he required coaxing for most daily activities and had little interaction with family members and relatives. He ate a non-vegetarian diet, and had no addictions, systemic symptoms or prolonged medication intake. In his early childhood, there had been an undocumented fever with rash, and his immunisation status was unknown. He was first of two siblings born to non-consanguineous parents and his younger brother and parents were healthy. There was no family history of dementia or other neurological illnesses.

On examination, he was conscious, alert and cooperative. General systemic examination was normal. His Mini-Mental State Examination score was 17 of 30, losing 5 points in orientation, 2 in recall, 5 in attention and 1 in copying. On Addenbrooke’s cognitive examination-III he scored 68 out of 100, with marked impairment in tasks of attention, memory, verbal fluency and visuospatial function. Bedside neuropsychological testing found his digit span reduced to 4 forwards and 2 backwards; lexical and category fluency were reduced (4/7 for both) and he could not do trail A and B tests. Rey auditory verbal learning test showed poor immediate and delayed recall (3/15 and 0/15, respectively). He had reduced spontaneous speech, impaired complex comprehension, alexia and agraphia. Auditory gnosis was normal. He could recognise but not name any object from the semantic battery (picture recognition). He had poor facial recognition, left–right confusion and colour anomia. Praxis was normal. The remaining neurological examination was normal, including ocular movements, visual acuity and optic fundus examination. There were no myoclonic jerks, parkinsonism, gait abnormalities, spasticity, cerebellar signs or other motor dysfunction.

We evaluated him for a rapidly progressive multidomain cognitive decline without other localising features. Figure 1 summarises the investigative approach and differentials considered at each step. Blood investigations were normal, including full blood count, biochemistry, autoimmune markers (antinuclear, anti-dsDNA, antineutrophil cytoplasmic and antiphospholipid antibodies), antithyroid antibodies and autoimmune encephalitis panel (anti N-methyl-d-aspartate receptor and voltage-gated potassium channel antibodies) and paraneoplastic screening (serum cancer antigen 19.9, carcinoembryonic antigen and alpha-fetoprotein). Whole-body positron-emission tomography scan was normal. MR scan of brain showed T2 and Fluid-attenuated inversion recovery (FLAIR) hyperintensities over bilateral parieto-occipital white matter (figure 2). Cerebrospinal fluid (CSF) showed 15 cells/mm3 (100% lymphocytes) with protein of 0.42 g/L and CSF/blood sugar ratio of 0.65. CSF thyroid peroxidase antibodies were 5 IU/mL (normal range, 0–60). Electroencephalogram (EEG) showed intermittent background slowing without epileptiform discharges or periodic complexes (figure 3).

Figure 1

Flow chart showing the stepwise investigative approach and differential diagnosis considered in this patient with a rapidly progressive dementia. CSF, cerebrospinal fluid; ESR, erythrocyte sedimentation rate; EEG, electroencephalography; FLAIR, fluid-attenuated inversion recovery; NMDA, N-methyl-d-aspartate receptor; PET, positron emission tomography; SSPE, subacute sclerosing panencephalitis; VGKC, voltage-gated potassium channel.

Figure 2

MR scan of brain (A) axial FLAIR and (B) axial T2 images shows periventricular w/hite matter hyperintensity over parieto-occipital region, (C) no enhancement in axial T1W postgadolinium images. (D) ASL image showing reduced perfusion over bilateral parieto-occipital regions. ASL, arterial spin labelling.

Figure 3

Electroencephalography (awake record) showing background slowing (sweep speed 30 mm/s).

Adult-onset SSPE seemed likely in view of childhood fever with rash and parieto-occipital white matter lesions. CSF contained high titres of antimeasles IgG antibodies using ELISA (1:625 dilution), confirming SSPE. We started isoprinosine 1000 mg/day and amantadine 200 mg/day. Over the next 16 months, he developed cortical blindness and infrequent myoclonus, but remained ambulant.

Discussion

SSPE is a lethal progressive neurological disorder that manifests after a latent period of 6–8 years following measles infection.2 The worldwide prevalence of measles infection and subsequent SSPE has declined by over 90% in the five decades since the introduction of a highly effective measles vaccination. However, its incidence remains high in developing countries, ranging from 0.5 to 21 per million as compared with approximately 0.01 per million population in the USA.1 In communities with optimal vaccination coverage, SSPE may result from clinical or subclinical infection in infants before being vaccinated, or from vaccination failure.3

An acute measles virus infection triggers an initial cell-mediated immune response for the eradication of the virus. A humoral response is activated later for long-term protection. However, some people have an inadequate cellular response that fails to eradicate the virus.1 The measles virus reaches brain during the acute infection either through the cerebral endothelial cells or through inflammatory cells. The virus can remain dormant in the cells for many years and the persistent viral infection can result in significant mutations in the viral genome. Chronic brain infection by the mutated measles virus ensues subsequently and trans-synaptic transmission might play a role in the spread of virus in the CNS.2

SSPE manifesting after aged 18 years (adult-onset) is extremely rare. It is more common in males and has myriad clinical manifestations that make the diagnosis challenging. In children, the disease typically progresses through four stages.4 Behavioural changes and intellectual decline in the first stage are followed by frequent myoclonic jerks and seizures. Worsening cognition and extrapyramidal dysfunction occur in the third stage and culminate in akinetic mutism and coma in the final stage.4 These stages are less well-defined in adults.1 Myoclonus (23%–64%) and behavioural/cognitive dysfunction (18%–46%) are the most common manifestations.5 6 Myoclonic jerks in SSPE are typically described as periodic dystonic myoclonus recurring every 4 to 8 seconds.7 Visual symptoms are frequent and highly characteristic and may be cortical (cortical blindness and haemianopia) or ophthalmological (chorioretinitis, optic neuritis, papillitis, maculopathy and retinopathy) in origin.8 Extrapyramidal and pyramidal dysfunction occur later in the course. Outcomes range from fulminant (death in 6 months) to spontaneous remission (rare).1

SSPE is an uncommon cause for rapidly progressive dementia (table 1). The priority is to exclude potentially treatable conditions, such as neurological infections (neurosyphilis, Whipple’s disease, HIV dementia), inflammatory disorders (autoimmune encephalitis, neurosarcoidosis, Behçet’s disease), neoplasm, toxins, nutritional, metabolic and vasculopathy (primary angiitis of CNS).9 10

Table 1

Differential diagnosis of rapidly progressive dementia in this clinical context

MR brain scan findings in SSPE include ill-defined T2 and FLAIR white matter hyperintensities with or without cortical involvement, and classically involving parieto-occipital regions. Corpus callosum and basal ganglia hyperintensities and cortical atrophy can occur while mass effect and enhancement are uncommon. MR imaging may be normal early in the disease course. The key diagnostic clue in this case, was the parieto-occipital white matter involvement.11

EEG can be diagnostic in SSPE but may initially show only background slowing. Later, long interval high amplitude periodic complexes (every 4–10 seconds) occur, time-locked with myoclonic jerks and known as the ‘Radermecker complex’. Electrophysiological data implicate a shift in cortical excitability and a self-triggering mechanism for the periodic discharges and dystonic myoclonus.7 The absence of periodic complexes in our patient relates to the absence of myoclonus.

The diagnostic criteria proposed by Dyken et al require histopathological confirmation for definite diagnosis of SSPE. A probable diagnosis requires three out of the five criteria to be satisfied: (1) progressive cognitive deterioration, (2) EEG showing periodic long interval high voltage discharges, (3) CSF showing elevated gammaglobulins or oligoclonal bands, (4) raised titres of antimeasles antibody in serum and CSF and (5) histopathology.12

There is no effective therapy for SSPE though many antiviral drugs have been tested to try to slow the disease progression. The most promising among them in small studies has been a combination of intraventricular interferon plus oral isoprinosine.2 Ribavirin, amantadine, cimetidine, glucocorticoids and even plasma exchange have been tried without conclusive benefit.1 2

SSPE should be a differential diagnosis for progressive dementia, even in older patients. The diagnosis in adults can be challenging owing to the long latency from measles infection. Clinical pointers for diagnosis include myoclonic jerks, visual symptoms and history of measles infection or incomplete immunisation. Re-emergence of measles outbreaks in developed nations underlines the need to follow immunisation schedules stringently across the world to prevent this fatal complication.

Key points

  • Subacute sclerosing panencephalitis (SSPE) is a lethal complication of measles infection and is vaccine preventable.

  • Adult-onset SSPE is rare and can present with isolated dementia.

  • Adults with SSPE typically have visuoperceptual problems and chorioretinitis, myoclonic jerks time-locked with periodic complexes in electroencephalogram, and parieto-occipital white and grey matter hyperintensities with cortical atrophy on MR brain scan.

Further reading

  • Mead S, Rudge P. CJD mimics and chameleons. Pract Neurol. 2017;17(2):113–121. doi:10.1136/practneurol-2016-0 01 571

  • Geschwind MD. Rapidly progressive dementia. Continuum (Minneap Minn). 2016;22:510–537. doi:10.1212/CON.0000000000000319

  • Joseph F, Dawson K, Betmouni S, et al. The Bath Advanced Neurology Course 2003: progressive neurological decline in pregnancy. Pract Neurol 2005;5:168–175.

Ethics statements

References

Footnotes

  • Contributors SSN did the study design, acquisition of data, drafting and final approval of manuscript. KVV was involved in diagnostic evaluation and management of the patient, acquisition and interpretation of data, and critical revision of manuscript. RNM was involved in critical revision and final approval of the manuscript. SS helped in study concept, design, drafting, critical revision and final approval of the manuscript.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed by Jason Warren, London, UK.

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