Subacute sclerosing panencephalitis is the most devastating consequence of an often remote measles infection. Subacute sclerosing panencephalitis occurs almost exclusively in children and usually years after the primary measles infection. The long latency of its development, its aspecifi c presentation, and the fact that laboratory and imaging fi ndings can be deceptively normal all make for a diffi cult diagnosis, and the disease is often misdiagnosed or diagnosed late, only after a long list of diff erential diagnoses has been excluded. Once diagnosed, subacute sclerosing panencephalitis is not easily treated, but progresses relentlessly until death. While subacute sclerosing panencephalitis cannot be cured, it can be prevented through measles vaccination, and it has become a very rare disease, most likely through the worldwide use of eff ective vaccines. Here, we report the case of an adult patient who was admitted to our hospital with a rapidly progressive encephalopathy and behavioural changes.
The patient was born at a military hospital in rural southern India in 1985 and migrated to Canada in 2009. Her past medical history was unremarkable, and she received routine childhood vaccinations, including measles vaccination at age 1 year. As an adult she had mild environmental asthma and suff ered miscarriages at 18 gestational weeks in 2012 and at 12 gestational weeks in 2013. Her prenatal serology was typical: positive measles IgG (30·5 IU/mL); positive rubella IgG (87·2 IU/mL); positive varicella IgG; negative hepatitis B surface antigen; negative syphilis antibody screen; cervical swabs negative for Chlamydia trachomatis, Neisseria gonorrhoeae, bacterial vaginosis, and trichomonas; and negative HIV serology.
She became pregnant for the third time and at 21 weeks' gestation she and her husband travelled to the state of Tamil Nadu in India, where they stayed in a small village and visited the port city of Tuticorin. During her stay she was exposed to chickens and wild pigeons on her parents' property and had several mosquito bites. She drank only bottled water and avoided raw fruits and vegetables as much as possible. She did not take malaria prophylaxis. Her 4 week stay was noteworthy only for a mild upper respiratory illness with coryza, cough, rhinorrhoea, and malaise for several days, which had resolved by the time she returned to Canada. 7 days after her return to Canada she developed mild confusion and intermittently unbalanced gait. Over the next few days she developed diffi culty with common tasks such as starting and driving her car. 5 days after the onset of her initial symptoms, she developed bizarre behaviour, disorientation, disturbed sleep, and incomprehensible speech. Her husband brought her to the hospital for further evaluation, where she was seen 7 days after symptom onset.
In the emergency room, she was found to be afebrile and haemodynamically stable with no abnormalities on routine blood tests, including a normal complete blood count and diff erential. The neurology service was consulted. In the neurological exam, the patient was unable to recall and name routine objects and had diffi culty following commands. The motor exam showed normal strength with mildly increased tone, which was more noticeable in the right compared with the left extremities, and brisk deep tendon refl exes throughout. In the cerebellar exam, the patient had diffi culties with rapid alternating move ments in both arms and a wide-based gait with a tendency to veer to the left. The rest of the neurological and physical examination was normal, which included ultrasound and biophysical profi le assessment of her pregnancy. She was admitted to the neurology service for further investigation.
Results from an extensive diagnostic investigation during her hospital stay showed few abnormalities. Cerebrospinal fl uid was tested on three occasions and showed no abnormalities in cell counts, protein content, and glucose content (table 1). The cerebrospinal fl uid was negative for oligoclonal bands. Several infectious and autoimmune causes were investigated in cerebrospinal fl uid and found to be negative: viral MRI of the brain showed no abnormalities in the fi rst weeks after symptom onset (fi gure 1), and results from electro encephalogram (EEG) registrations showed no epileptiform changes.
The patient was treated empirically for viral encephalitis and bacterial meningitis until the appropriate test and cultures were reported negative. A working diagnosis of autoimmune encephalitis was then made and she was treated with high dose intravenous methylprednisolone. 3 days after admission to hospital, she became somnolent and developed bilateral upgoing plantar refl ex responses. The patient became hypoxic shortly afterwards because of an aspiration pneumonia; she was intubated and admitted to the intensive care unit, and given broad spectrum antibiotics for possible infectious causes. She became comatose despite treatment with intravenous immunoglobulins, plasmapheresis, rituximab, and anti seizure medications. At 31 weeks gestation, she developed hypertension and pre-eclampsia was suspected. Because of this complication, the child was delivered by emergency caesarean section. She was delivered of a healthy boy, and the hypertension resolved soon afterwards. She then developed acute tubular necrosis, which was confi rmed with a renal biopsy, and was started on haemodialysis. She remained comatose and repeat cranial MRI showed diff use hyperintensity in the brainstem and cerebral cortex, brain oedema, and brain herniation (fi gure 1). She died soon afterwards, 6 weeks after symptom onset.
Gross examination of the brain showed generalised oedema and central herniation with associated temporo-occipital acute cerebral infarction. Diff use encephalitis with associated astrocytic gliosis and neuropil loss was present in multiple areas of the cortex and thalamus. The brain had numerous eosinophilic viral inclusions, which were both nuclear and cytoplasmic. Transmission electron microscopy images 
showed that the intranuclear inclusion bodies comprised viral nucleo capsid fi laments typical of paramyxoviruses (fi gure 2). Results of RT-PCR testing showed strongly positive results for measles virus. The virus strain was classifi ed as a genotype D6 by genotyping done at the National Microbiology Laboratory in Winnipeg, MB, Canada. Results from sequencing of the virus at the Alberta Provincial Laboratory in Calgary, AB, Canada, showed that there were several mutations in the wild-type virus consistent with previously described mutations in cases of subacute sclerosing pan encephalitis. 1 The autopsy revealed a left breast fi broadenoma and uterine changes secondary to the patient's pregnancy and caesarean section. The kidneys were autolytic; no viral inclusions were identifi ed. No noteworthy pathological changes were identifi ed in other organ systems.
The diff erential diagnosis of a subacute encephalopathy in pregnancy is broad. A detailed clinical discussion was published in 2005. 2 
inclusion body encephalitis, and subacute sclerosing panencephalitis. 3 Primary measles encephalitis takes place during primary infection with onset typically during the rash phase of illness. Primary measles encephalitis aff ects one to three in 1000 patients with measles. The underlying patho physiology seems to be a primary viral infection of CNS, because the cerebro spinal fl uid usually has high titres of measles antibodies. 4 Vaccination and primary encephalitis are not clearly related; investigators of a case series from 1963 to 1971 reported only 45 cases of primary encephalitis within 6-15 days of vaccination out of 50·9 million doses. 5 Furthermore, fi ndings from a prospective 14 year followup study from 1982 to 1996 showed that four of 1·8 million individuals had neurological complications attributed to the measles vaccine. Two cases of measles encephalitis after vaccination were reported in patients who were immunocompromised and two other infants younger than 1 year developed encephalitis 9-13 days after vaccination that could not be attributed to any specifi c cause. 6 Acute post-measles encephalitis is the most common CNS sign of measles virus infection and takes place immediately after resolution of the primary infection. This disease is an autoimmune-mediated infl ammatory disorder and occurs in one individual per 1000 cases of measles 7 and in one to three per 10 million live measles vaccinations. 8 The mortality associated with acute postmeasles encephalitis is up to 25% in adults and 5% in children and the fi rst-line treatment is high dose steroids with subsequent intravenous immunoglobulin.
Measles inclusion body encephalitis is associated with immunodefi ciency (such as in patients with HIV infection) and can occur within 1 year of primary measles infection or vaccination. Measles inclusion body encephalitis has a mortality rate of 75% and survivors are often left with neurological defi cits. 3, 9 Disease pathogenesis is not completely understood, but is thought to involve infection of cerebral endothelial cells, and subsequent slow spread of the infection to CNS cells such as glial cells and neurons. One case of measles inclusion body encephalitis caused by a vaccine strain was reported in a child who was subsequently diagnosed with immunodefi ciency. 10 Viral mutations typically found in subacute sclerosing panencephalitis are also found in the measles inclusion body encephalitis. 11 Subacute sclerosing panencephalitis is the most severe consequence of measles infection and happens after a longer latency period. In subacute sclerosing panencephalitis, mutated and defective measles virus proliferate within CNS cells. 12 The favoured view is that the virus mutates after invading the CNS, where it is incapable of generating infectious virions. Viral genome replication and translation of viral proteins takes place and presumably spreads to other neurons by axonal transport. 13 Symptoms typically occur 6-8 years after primary infection. 14 Because subacute sclerosing panencephalitis develops some years after natural measles infection, and the typical symptoms of cognitive decline and behavioural changes develop slowly, the disease is diffi cult to diagnose. The symptoms typically progress to dementia, general convulsions, coma, and death over a period of 1-3 years. 15, 16 Many cases of the disorder probably remain undiagnosed because of the diffi culty of diagnosis and the variable practices in brain biopsies and autopsies.
Most patients with subacute sclerosing pan encephalitis had their primary measles infection when younger than 2 years; 2 those who are infected with measles virus when younger than 1 year are 16 times more likely to develop subacute sclerosing pan encephalitis. 2 The disease most commonly aff ects children, although it can occur in adults. In adults, the mean age at presentation is 25 years (with the oldest patient aged 35 years) and ocular symptoms are more common than in children. 2 Clinical presentation of the disease is quite variable, but is usually characterised by progressive dementia, abnormal movements, and myoclonic jerks. An attempt to classify subacute sclerosing panencephalitis into four clinical stages has been made (appendix). 17 Impaired immune responses seem to predispose individuals to the development of subacute sclerosing panencephalitis. Immaturity of the immune system in the fi rst 2 years of life is thought to prevent a successful cell mediated immune response that would eradicate the virus, which allows the mutated virus to enter a persistent dormant state in CNS cells. 18 The viral isolates associated with subacute sclerosing pan encephalitis were investigated in a series of 11 cases. 19 Genotypes D7 and D1 were the most common isolates, which were present in four of 11 cases each. One of the 11 reported cases (diagnosed in Glasgow, UK in 1999) was caused by the genotype D6 isolate, the same genotype found in the patient described in this Grand Round. Genotype D6 is known to be responsible for outbreaks of disease in many European countries from 1996-2002. 20 A review 12 in 2002 assessed subacute sclerosing panencephalitis cases in the USA. Among the PCR-proven cases, genotype D3 viral subtype was the most prevalent, followed by several cases of genotype E. Genotype D6 had not been reported in Canada since 1997, 21 and has not been seen anywhere in the world since 2007, 22 which supports our contention that our patient was infected decades ago.
Review of case reports in families suggests a genetic susceptibility of subacute sclerosing panencephalitis, because the disease has been reported in twins, 23 siblings, 23, 24 and members of the same extended family. 25 Several studies have reviewed the genetics of patients with subacute sclerosing panencephalitis and of the viral strains implicated. However, such research is diffi cult in view of the rarity of the disease, and its results should be regarded as hypothesis-generating rather than confi rmatory of genetic susceptibility. The programmed cell See Online for appendix Grand Round death-1 (PD-1) gene is thought to contribute to genetic susceptibility to subacute sclerosing pan encephalitis. A statistically signifi cant diff erence in PD-1 gene polymorphisms has been found in patients with subacute sclerosing panencephalitis and healthy controls in Turkey. 26 PD-1 is a co-inhibitory molecule and a member of the CD28 family that acts as a negative immunomodulator in the suppression of T lymphocytes. 27 Results from a study 28 from Japan suggest that mutations in toll-like receptor 3 (TLR3) are positively associated with the disease. TLR3 recognises the dsRNA of measles virus and triggers the immunological cascade that results in the production of type 1 interferon, which is important for viral clearance. 28 Mutations in TLR3 are proposed to decrease the recognition of measles virus and the production of interferon. Mutations in the sodium channel α-1 subunit gene, which are implicated in epilepsy, are thought to increase cerebral neuron vulnerability to measles infection. 29 Measles virus is a member of the Morbillivirus genus, family Paramyxoviridae. The genome consists of a single strand non-segmented RNA of negative polarity and is about 16 kb long. 13, 14 Measles viral strains that are associated with subacute sclerosing panencephalitis have defective envelope associated proteins; specifi cally haemagglutinin, fusion, and matrix protein. 30 Proteins encoded by the matrix gene are essential for viral replication; therefore, crucial mutations impair the ability of the virus to produce viral progeny outside of the infected cell. 31, 32 The D6 isolate, the cause of subacute sclerosing panencephalitis in the patient described in this Grand Round, had mutations characteristic of the disease strains for these essential viral proteins. 19, 33 The risk of subacute sclerosing panencephalitis is estimated to be 0·2-1·0 per 100 000 measles cases worldwide with a higher risk in males (male-to-female ratio 2-4:1). 34 The disease is more common in rural areas and in poor communities. Authors of an epidemiological study 34 of subacute sclerosing panencephalitis done in Germany reported a risk of developing the disease after measles infection before 5 years of age of between one in 1700 and one in 3300. Most case reports of subacute sclerosing panencephalitis are described in non-vaccinated patients; however, similar to the patient described in this paper, some reports describe cases of the disease despite adequate vaccination. 35 ,36 A 7-year-old patient had rapid onset of subacute sclerosing panencephalitis with a documented vaccination history of measles, mumps, and rubella (MMR) vaccination at 15 months. The patient was presumed to have been exposed to measles before his vaccination, which might have been the case in our patient. 35 Alternatively vaccine failure has been reported in a small number of patients, who were typically immunised before 12 months of age and did not seroconvert. 37 Subacute sclerosing panencephalitis during pregnancy is very rare. Our review of the scientifi c literature yielded 21 prior cases (table 2). The most recent case report 46 describes two 20-year-old patients with similar clinical signs and biochemical and radiological investigations to the patient described here. The diagnosis of presumed subacute sclerosing panencephalitis was made on the basis of clinical judgment of the care providers and the patients were treated; one patient was given interferon alfa-2b for 5 weeks and the other was given intrathecal interferon alfa-2 and inosinepranobex for 8 weeks; no clear benefi ts were seen before both patients succumbed to illness. Most other reported cases were not diagnosed until after death; most patients were treated for a presumed infectious and paraneoplastic encephalopathy. Only two case reports of subacute sclerosing panencephalitis in pregnancy presented with typical symptoms: a 30-year-old woman at 30 weeks' gestation (pregnant three times, with one livebirth) and a 27-year-old woman at 24 weeks' gestation (pregnant once, with one livebirth). 2, 41 Both patients presented with visual symptoms and subsequently developed confusion, hemianopia, and focal seizures. Cerebrospinal fl uid test results showed expected pleocytosis and oligoclonal bands. Findings from EEGs in both cases showed non-specifi c slowing and no radiological abnormalities in MRI. Despite the typical presentation, both cases presented diagnostic challenges and were treated empirically for infectious and infl ammatory causes. At autopsy, both patients tested positive for the measles genotype D1 isolate.
The youngest reported patient with subacute sclerosing panencephalitis in pregnancy was a 14-year-old girl who had a history of 1 year onset of progressive unilateral visual impairment. At 31 weeks' gestation, she had rapid progressive cognitive decline in 1 week. Test results showed periodic spikes and slow wave complexes on EEG and a cortical abnormality in brain MRI. 16 Patients who presented in their late 20s and 30s had a rapid neurological decline with mean survival of 1-2 months. 16 One report 41 describes an 18-year-old woman who developed post-partum fulminant subacute sclerosing panencephalitis. A few days after delivery, she developed rapidly progressing confusion and akinetic mutism followed by hyperpyrexia, tachycardia, hypertension and tachycardia, and eventual death. However, she might have shown early symptoms during the second and third trimesters of her pregnancy.
Pregnancy is known to alter the immune response of women, which can potentially aff ect susceptibility to some infectious diseases. Although many studies suggest systemic suppression of immunity takes place, which is mainly related to progesterone, this has not been proven. An immunomodulatory eff ect probably takes place, which results in a diff erent response to Grand Round microorganisms and infl ammatory cascade, and is probably associated with the onset of subacute sclerosing panencephalitis during pregnancy. 52 Most children born to mothers with subacute sclerosing panencephalitis have been free of the disease and medical complications. One report 17 described a newborn baby who had measles during the perinatal period and developed subacute sclerosing panencephalitis during the fi rst year of life. A case report 47 from Germany describes the outcome of 13 infants of maternal subacute sclerosing panencephalitis cases. Intrauterine death occurred in four cases, two infants died in the fi rst days of life and remaining children were reported as healthy. Importantly, this study had no longterm follow-up and it is therefore unknown if later complications occurred. The child born to the patient in this Grand Round is healthy at age 1 year, and continues to be followed up by a paediatrician.
Misdiagnosis of subacute sclerosing panencephalitis as infection or autoimmune encephalitis, as was the Attempts to formulate diagnostic criteria for the disease have been made; however, the gold standard for diagnosis is a positive brain biopsy suggestive of panencephalitis. Measles antibody detection using indirect immunofl uorescent assay has been successful in establishing cerebrospinal fl uid to serum ratios. 37, 54 Cerebrospinal fl uid analysis for both anti-measles virus IgG titres and intrathecal synthesis of virus-specifi c IgG index is diagnostic for subacute sclerosing panencephalitis. 37, 54 Intrathecal synthesised IgG is typically markedly elevated with oligoclonal bands; however, IgG might not be solely specifi c for measles virus but to other viruses at lower titres. Detection of anti-measles IgM in cerebrospinal fl uid has been suggested to lead to an extended course of subacute sclerosing panencephalitis. Measles RNA is rarely identifi ed, but it is diagnostic for subacute sclerosing panencephalitis. 37, 54 Investigators of one study 55 found that patients with the disease had cerebrospinal fl uid-to-serum ratios between 1:80 and 1:5. This represents the antibody index, which calculates the cerebrospinal fl uid-to-serum antibody ratio that could diff erentiate between blood-derived and brain-derived pathogenesis. Normalisation of cerebrospinal fl uid-to-serum ratios that account for albumin and total IgG has been introduced to improve the specifi city and sensitivity of diagnosis. 56, 57 Cerebrospinal fl uid was not tested for measles-specifi c antibody in the patient described in this paper, but the measles IgG titre in serum was relatively high in the absence of a reported recent infection or vaccination; in hindsight this result might have been a clue to the diagnosis.
Diagnostic criteria proposed by Dyken in 1985 58 suggest that three of the fi ve criteria are needed for a diagnosis of probable subacute sclerosing panencephalitis. Diagnostic criteria described in 2010 59 defi ne major and minor criteria needed for diagnosis (panel). 58 The sensitivity and specifi city of these criteria have not been assessed in either the general population or pregnant women, because the disease is very rare. Results from EEG analysis of patients with subacute sclerosing panencephalitis in India showed 98% of patients had delta burst patterns that were most commonly seen in the second stage of the disease. 60 Periodic slowing seemed to be a common EEG fi nding in earlier stages of disease. Changes in MRI imaging are non-specifi c and, as was the case in the patient here, only present when the disease is advanced. 2 Diff usion weighted MRI has been assessed as an aid to diagnosis of subacute sclerosing panencephalitis. The apparent diff usion coeffi cient values from six diff erent areas of the brain were signifi cantly higher in the patients with subacute sclerosing panencephalitis and enabled diff erentiation of disease stages. 61 Treatment effi cacy in subacute sclerosing panencephalitis cannot easily be established in clinical trials because the disease is rare. Although there is no known cure for the disease, several therapies, which might delay progression of disease or provide symptomatic relief, have been tested in non-randomised settings. In the Infectious Disease Society of America (IDSA) guidelines, intrathecal ribavirin is classed as level C-III level of evidence with no known effi cacy for other treatment regimens investigated, such as interferon alfa, intravenous immunoglobulin, and isoprinosine. 62, 63 The use of isoprinosine, inter ventricular interferon alfa, and ribavirin with ¹⁸F-fl uorodeoxyglucose PET have been investigated in various case reports. Cortical metabolism was preserved and neurological prognosis was good at 3 years after diagnosis. 64 One report 65 noted an improvement of myoclonus with carbamazepine use, although this treatment had no eff ect on mortality.
In the past 10 years, fewer cases of subacute sclerosing panencephalitis have been reported, which corresponds to a decreased incidence of primary measles infection. Epidemiological data have shown that successful vaccination programmes have directly and indirectly protected the population against the disease through eradication and prevention of measles transmission. 14, 22, 34, 66 Subacute sclerosing panencephalitis is related to wild-type measles infection, usually before age 2 years. Since the introduction of the measles vaccine, the disease has become exceedingly rare in North America. In Alberta, Canada, subacute sclerosing panencephalitis became reportable in 1983 and six cases were reported between 1983 and 1994. A monovalent live measles vaccination programme was introduced in Alberta in July, 1970, and the universal infant MMR programme was introduced in 1982. 67 The MMR second dose campaign for children aged 4-6 years was introduced in 1996 and a catch-up programme (age 14-15 years) was introduced between 1997 and 1998. 68 In India, an immunisation programme was introduced in 1978 as a WHO Expanded Programme of Immunization initiative. 69 This programme gained momentum in 1985, and was expanded in a phased manner to become a universal immunisation programme covering all districts by 1990. The programme consisted of seven vaccines for preventable diseases, including measles. Two doses of measles vaccine were given to children at age 9-12 months and a second dose at 15-18 months. 69 A dose of MMR at 5 years of age can be recommended depending on the district. Measles deaths in India decreased from 106 000 in 2005 to 65 000 in 2010 after a measles catch-up campaign that provided vaccination for 135 million children. 70 In Japan, the addition of a mass immunisation campaign in 1982 resulted in a gradual reduction in subacute sclerosing pan encephalitis cases from 24 cases reported in 1981 to 15 in 1985. 66 Similar trends have been reported in Israel. 14 These fi ndings emphasise the importance of herd immunity in the maintenance of a population free of measles, because infants are susceptible to measles infection until the MMR vaccination can be given at 12 months old.
The outcome of our patient draws attention to the most serious complication of measles infection. Diagnosis of subacute sclerosing panencephalitis is diffi cult because of the broad diff erential and rarity of the disease. Subacute sclerosing panencephalitis should be considered in the diagnosis of progressive encephalitis, especially in view of increased migration and global travel. Although no treatment exists for the disease, early diagnosis and therapeutic intervention with offlabel treatment candidates could help in the development of a management strategy.
Perhaps the most important lesson learned from our patient is the importance of the prevention of subacute
Citations were identifi ed through PubMed searches with no publication date restrictions using the search terms (including variations), "subacute sclerosing panencephalitis (SSPE)", "SSPE AND pregnancy", "SSPE AND adult", combined with study fi lters for case reports, case series, cohort studies, review articles, and original research. Additional articles were identifi ed from the reference lists of identifi ed papers. Only papers published in English were reviewed. The fi nal reference list was generated on the basis of originality, quality, and relevance. sclerosing panencephalitis through immunisation and prevention of measles virus infection. Mass immunisation campaigns in many countries have resulted in the rapid reduction of primary measles infection and subsequent reduction of cases of subacute sclerosing panencephalitis. In the USA, the incidence of the disease has dropped from 0·61 to 0·01 per million people per year. 14 Areas with successful vaccination programmes have had a steady decline in subacute sclerosing panencephalitis. Primary prevention of measles infection through the creation, improvement, and continuation of vaccination programmes remains our best chance to prevent this devastating disease.
MHC, BM, and MWK all participated in the care of the patient and wrote the fi rst draft of the manuscript. JTJ did the brain autopsy, identifi ed the virus, submitted tissue for PCR analysis, and helped prepare the pathology text, pathology fi gures, and the pathology fi gure legends. AN helped to prepare the pathology text, pathology fi gures, and the pathology fi gure legends. KC, KF, JM, KP, RT, and SW took part in the investigations for the patient. All authors contributed to the writing and revision of the manuscript.
We declare no competing interests.