Subacute sclerosing panencephalitis presenting as severe depression in an adult

Abstract

Subacute sclerosing panencephalitis (SSPE) is a fatal disorder that occurs as a rare complication of childhood measles. Symptoms typically manifest between the ages of 5 and 15. While the incidence of SSPE is declining globally, it is still prevalent in regions where measles remains common and vaccination rates are low due to poverty and lack of health education. Diagnosing SSPE can be challenging, particularly when patients exhibit unusual symptoms. A thorough clinical evaluation, including vaccination history, physical examination, electroencephalogram (EEG) and Cerebrospinal fluid (CSF) analysis, can help in making a diagnosis. We present the case of a young woman in her early 20s who initially experienced depressive symptoms, followed by myoclonus, dementia and visual impairment. The patient was ultimately diagnosed with SSPE based on characteristic EEG findings, neuroimaging results, CSF analysis and elevated serum measles antibody levels.

Background

Subacute sclerosing panencephalitis (SSPE), a progressive encephalitis, is a slow virus disease mediated by the persistence of the measles virus in the central nervous system. Most patients with SSPE have a history of primary measles infection at an early age. The average latent period between measles infection and SSPE is around 8–10 years in most cases but may range from 6 months up to 18 years. A study from South India estimated its prevalence at 2.1 per 1 million population. The relentless course and invariably fatal outcomes underscore the significance of measles vaccination in preventing both the primary infection and severe neurological sequelae that can ensue. The diagnosis is usually not difficult in the typical scenario where the child presents with an intellectual decline followed by generalised myoclonic jerks. Our patient had an atypical presentation, in the form of psychiatric symptoms after two decades of childhood measles infection, which made the diagnosis challenging.

Case presentation

A female in her early 20s was seen by a psychiatrist with complaints of persistent low mood, anhedonia, worsening scholastic performance and suicidal thoughts. She was diagnosed with severe depression and was started on Escitalopram. Her parents initially reported a mild improvement in symptoms, followed by a steady deterioration. Six weeks later, she started having jerky movements, initially involving the right upper limb and subsequently spreading to all four limbs. She complained of blurred vision and difficulty in walking with persistent jerky movements of all four limbs, occurring every 5 s. She was unimmunised except for a BCG vaccination at birth. There was a febrile illness with an exanthem at the age of 2 years but without any obvious complications at that time. On examination, the patient had a mask-like face with an open mouth and constant drooling of saliva. Limb movements were scarce, with a slow myoclonus that recurred every 5 s. On testing, the patient was uncooperative, withdrawn and had fair remote memory with defective recent memory. Her fund of knowledge was limited, and abstract thinking was poor. The vision in both eyes was reduced but she could identify large letters. Mini-mental state examination (MMSE) could not be performed at the time of presentation. There was evidence of bilateral pyramidal tract involvement with pseudobulbar palsy, extrapyramidal signs with a striatal toe along with appendicular and gait ataxia. Fundus examination revealed slate-like pigmentation in the macular region. No fever, neck stiffness, sensory, bowel or bladder symptoms were observed. The examination of the gastrointestinal, respiratory and cardiovascular systems was unremarkable.

Investigations

The routine blood examination revealed mild normochromic anaemia. Renal, liver function tests and serum electrolytes were normal. The Cerebrospinal fluid (CSF) study revealed occasional lymphocytes with raised protein levels and positive oligoclonal bands. MRI of the brain revealed ill-defined hyperintense signals in bilateral parietal and occipital white matter (figure 1B) extending from the subcortical through deep through periventricular regions (figure 1A) without diffusion restriction. Electroencephalogram (EEG) showed a background activity of 3–4 Hz over the posterior head regions, poorly reactive to eye opening with bursts of biphasic and triphasic polyspikes and waves of 1–2.5 Hz recurring at intervals of 5–6 s (periodic long interval diffuse discharges) that were frontally dominant and generalised (figure 2). Serum IgG for rubeola was strongly positive (>250 U/mL). CSF sample showed antimeasles IgG positivity at a dilution of 1:625. Dyken’s diagnostic criterion was applied, leading to the diagnosis of SSPE.

Figure 1.

MRI brain T2/FLAIR sequence demonstrating periventricular white matter hyperintensities (A) and ill-defined hyperintense signals in bilateral parietal and adjacent occipital white matter (B). FLAIR, fluid-attenuated inversion recovery.

Figure 2.

EEG showing a background activity of 3–4 Hz with bursts of biphasic and triphasic polyspikes and waves of 1–2.5 Hz recurring at intervals of 5–6 s, suggestive of periodic long interval diffuse discharges. EEG, electroencephalogram.

Differential diagnosis

Considering the presence of dementia and myoclonus in a young patient, the differential diagnoses considered were Progressive myoclonic epilepsy, Autoimmune encephalitis, Wilson’s disease, Neuropsychiatric lupus, Creutzfeldt Jakob disease and Post-rubella panencephalitis, in addition to SSPE. Serum ceruloplasmin level was normal. The antinuclear antibody profile and the CSF panel for autoimmune encephalitis were also negative.

Treatment

The patient was managed with good nursing care and valproate and clonazepam were used to control myoclonic jerks. Baclofen was started because of the spasticity of limbs. Ribavirin and Amantadine in combination were employed to halt the progression of the disease. She had a hospital stay of approximately 6 weeks, and, at the time of discharge, there was an improvement in her levels of consciousness, memory and comprehension (MMSE score of 16).

Outcome and follow-up

The patient was asked to review every 3 months, and on her first follow-up, she had a reduced frequency of myoclonic jerks with an improvement in dysphagia. She was ambulatory and only mildly dependent on her daily activities. At a 6-month follow-up, there was a notable improvement in her memory and cognition, with an MMSE score of 20, and she could communicate normally with her caregivers. However, there was an increase in the frequency of myoclonic jerks and mild worsening of dysphagia. After 9 months, there was an episode of hospitalisation due to severe pneumonia. The patient had to shift to a liquid-based diet due to steady worsening of dysphagia with frequent nasal regurgitation. There was also a worsening of myoclonic jerks that warranted support for her daily activities.

Discussion

SSPE is a rare progressive CNS disorder, caused by the mutant measles virus, first described by Dawson.¹ It usually affects children and younger adults with a slight male preponderance. The average age of SSPE diagnosis is approximately 12 years and the median duration from the onset of measles to the development of neurological symptoms is 9.5 years (ranging from 2.5 to 35 years).² The measles vaccine has a protective effect against SSPE by reducing the risk of measles infection in individuals. Consequently, the incidence of SSPE is higher in countries with a high vaccination gap. The administration of the measles vaccine in patients who had a subclinical measles infection has no impact on altering the course or progression of the disease. Children who contract measles infection in the first year of their lives have a 16 times greater risk of developing SSPE than those who are infected at the age of 5 or later. The Central nervous system (CNS) manifestations are explained by neuronal and oligodendrocyte death caused by an exaggerated immune response mediated by CD4 and CD8 positive T cells along with antibody-secreting B cells against the persistent measles virus.³ An autoimmune theory, where antibodies against the virus cross-react with myelin antigens, resulting in demyelination, is also being discussed.⁴ The typical history involves a patient going through four clinical stages. The first stage, which may last from weeks to years, consists of the insidious onset of personality changes, strange behaviour and decline in scholastic performance in children. There is no disability in the initial stages. Myoclonic jerks that occur approximately every 5–10 s are the hallmark of the second stage. The patient would have severe mental decline and long tract signs. The affected person would have moderate disability often requiring assistance for walking. Further neurological deterioration occurs in the third stage with the patient developing autonomic dysfunction and decorticate rigidity, along with the disappearance of myoclonus. The patient assumes a vegetative state with akinetic mutism and disordered breathing in the fourth stage. Death usually occurs at the third or fourth stage from severe autonomic dysfunction resulting in arrhythmias, respiratory failure or aspiration pneumonia⁵ Approximately 10% of patients with SSPE can have atypical presentations in the form of predominant psychiatric syndrome, seizures, early age of onset, visual loss and other focal symptoms.⁶ The characteristic ophthalmologic manifestation of SSPE is chorioretinitis with macular involvement.⁷ Visual loss could be due to chorioretinitis, optic neuritis, retinal atrophy in a long-standing disease or bilateral involvement of the visual cortex. Congenital and neonatal measles infections are generally associated with early-onset SSPE with a short latency period. A similar case of SSPE presenting as depression was reported by Datta et al.⁸ A high index of suspicion is required to diagnose SSPE with atypical features. CSF antibody tests, EEG and neuroimaging have specific findings in SSPE that can aid in diagnosis. Normal protein levels with markedly elevated immunoglobulin levels or the presence of oligoclonal bands is the characteristic finding of the CSF study. The demonstration of high titres of measles IgM and IgG antibodies in CSF and serum is the gold standard for the diagnosis of SSPE. EEG in SSPE is characterised by periodic complexes that consist of a generalised and synchronous burst of sharp-slow wave discharges. The typical discharge has a duration of 0.5–2 s, high voltage and is repetitive (occurring every 4–15 s).⁹ MRI is far superior to CT of the brain for the demonstration of lesions. The parietooccipital region is predominantly affected in the initial stages whereas the subcortical, periventricular and cortical grey matter are affected later. The involvement of the brain stem, cerebellum and basal ganglia is rare.¹⁰ The T2-weighted images and fluid-attenuated inversion recovery images show hyperintensities in the involved areas. Other MRI sequences like Diffusion-weighted imaging and Apparent Diffusion Coefficient mapping are helpful in identifying smaller lesions if conventional sequences do not reveal any abnormality.¹¹ Dyken’s criteria¹² for the diagnosis of SSPE are as follows: (a) progressive subacute mental deterioration with myoclonus and other typical findings; (b) EEG showing periodic stereotypic high voltage discharges; (c) oligoclonal bands in the CSF and/or elevated gamma globulins in the CSF (≥ 20% of total protein); (d) brain biopsy showing panencephalitis; (e) and elevated antimeasles antibodies in the serum (≥ 1:256) and/or in the CSF (≥1:4). Three or more criteria must be satisfied for a definite diagnosis of SSPE.

Treatment is usually limited to good nursing care. Anticonvulsants like carbemazepine, valproate, levetiracetam and clozapam can be used to control myoclonus and drugs like baclofen can be used to reduce spasticity.^{13 14} Immunomodulators like Isoprinosine, interferon A and antivirals like Ribavirin may help in halting the progression of the disease. Interferon alpha can be administered subcutaneously, intrathecally or via the intraventricular route. Isoprinosine is an oral medication with immune-stimulant properties given at a dose of 100 mg/kg in three to five divided doses. Ribavirin, used in combination with interferon or Isoprinosine, is administered either orally or intrathecally.¹⁵ A newer drug inhibiting the F protein of the measles virus that facilitates transneuronal spread has also been developed. SSPE has a dismal prognosis, and death usually occurs between 1 and 3 years after diagnosis. Increasing CSF measles antibody titres may offer a longer survival according to a few reports.³

Patient’s perspective.

I could hardly remember the time of hospitalisation and the phase prior to that. My mother tells me that it was so tough that I couldn’t even swallow foods on my own. Doctors had told me the prognosis is not good and I am sort of adjusted to that now.

Learning points.

• A high index of suspicion is required to diagnose SSPE with atypical presentations and variable age of onset. A proper history and clinical examination are key in making the diagnosis.

• SSPE should be considered in the differential diagnosis of a patient with intellectual impairment, myoclonus, variable pyramidal and extrapyramidal features with or without a prior history of measles.

• SSPE is a preventable disease, highlighting the importance of universal measles vaccination.

Ethics statements

Patient consent for publication

Consent obtained directly from patient(s).