TITLE

CLINICAL PROFILE OF SSPE: SERIES OF 42 PATIENTS WITH SHORT REVIEW.

Contributors: 1. Prashant K Singh* 2. Anjani K Sharma** 3. R.K.Sureka ** 4. Susant Bhuyan* 5. Vikas Gupta *

*Senior Resident, **Professor Department of Neurology, Sawai Man Singh Medical College, Jaipur Rajasthan, Pin-302004

Address for correspondence:

Dr Anjani Kr. Sharma 36, Ram Gali 7 Raja Park, Jaipur, Rajasthan, Pin-302004 Phone No. 09414072331 E-mail Id anjanijpr@gmail.com

ABSTRACT: This prospective study was planned to analyse the clinical and investigative profile of 42 patients suffering from subacute sclerosing panencephalitis(SSPE). Their diagnosis was

based on a detailed history, clinical examination, presence of anti-measles antibodies in Cerebrospinal Fluid (CSF) and typical electroencephalogram (EEG) pattern. The findings were described as average, mean and percentages. The average age of the patients was 9.5 years (range 5 to 19 yrs). 33 (78%) were males and 9 (22%) were females, a ratio of 3.6:1. The average duration of symptoms before presentation was 5.2 months. History of measles infection was present in 26 patients (63%) while measles vaccination was done in 15 (35.7%) patients. Most of the patients 39(92%) presented in SSPE clinical stage II (44%) and III (48%). Myoclonus was noted in 40 (96%). The EEG of 36 (90%) patients was typical of SSPE.

Key words: SSPE, anti-measles antibodies, myoclonus, periodic discharges.

INTRODUCTION SSPE is a rare late complication of measles, caused by persistent and non-productive infection by measles virus of neurons and glia. The pathogenesis of SSPE is related to defective measles virus maturation in neural cells. The virus remains in intracellular form and spreads by cell to cell contact1. SSPE is characterised by progressive mental deterioration, motor decline, and myoclonus leading to death within 13 years of onset. It is essentially a disease of childhood and commonly occurs at 515 years of age. The natural history of SSPE is characterized by a highly variable temporal course ranging from a fulminant form with acute onset, rapid progression and death within a few weeks, to a protracted course after several years with phases of stabilization and even improvement to some extent2. The key features for diagnosis are clinical manifestation, typical EEG abnormalities and CSF serology. We are presenting clinical and demographic profile of 42 patients along with short review.

MATERIAL AND METHODS This was a prospective study conducted at neurology department of Sawai Man Singh Medical College and Hospital, Jaipur, a tertiary care teaching hospital in Rajasthan. The patients represent a population from Rajasthan and adjoining states in north-west India. The study period was from October 2007 to September 2011. All patients compatible with the clinical diagnosis of SSPE were included. Diagnosis was based on the characteristic clinical features of progressive cognitive and/or behavioural changes, myoclonic jerks,

electroencephalographic evidence of periodic complexes, and raised anti-measles antibody in cerebrospinal fluid (CSF) and /or serum. A total of 42 patients of SSPE were analysed. Demographic data regarding age at onset, presenting features, duration of symptoms, measles vaccination, history of measles and rural or urban background were recorded. A thorough

physical and systemic examination was done. The nervous system examination included mental state, motor and sensory deficits, ophthalmologic examination as well as clinical staging. Laboratory data, electroencephalographic changes, imaging characteristics and CSF examination as well as serum and/ or CSF measles antibody status was studied.

RESULTS Demographic profile: The total number of patients was 42. The age ranged from 5-10 years while mean age of onset was 9.5 yrs. Most of the patients (93%) were of childhood or adolescence age. Three (7.14%) patients were in adult age group (age >18 years). Thirty five (83%) patients were males and 7 (17%) were females, the male to female ratio was 5:1. Fourteen patients were from urban and 28 from rural background, a ratio of 1:2. Majority of patients 26 (62%) were from low socioeconomic status. Past history of measles was present in 26 (62%) of patients, 12 (30%) denied such history whereas it was unknown in another four patients. Out of 26 patients with definite history of measles, 14(53.8%) patients had measles infection at age of 2 years or less. History of measles vaccination was present in 15 (35.7%) patients. 27 (64.28%) patients were not immunised. The mean interval between measles infection and onset of symptoms of SSPE was 5.4 yrs.

Table 1: Demographic profile

Age group 0-5 5-10 10-18 >18 Socio-economic status a. b. c. Low income group Mid income group High income group 26 (62%) 14 (33.33%) 02 (4.6%) 28 (66.66%) 14 (33.33) Patients No (%) 0 (0) 22 (51.85) 17 (40.74) 3 (07.4)

Rural Urban

Clinical profile The mean duration of symptoms was 5.2 months ranging from 20 days in a single patient of acute fulminant SSPE up to one year in others. The presenting manifestations were scholastic decline (74%), myoclonus (63%), behavioural changes including apathy, irritability, abnormal talks (59%), walking difficulty (56%) either due to ataxia or myoclonus, and seizures (37%). While three patients had speech difficulty in form of dysphasia, dysarthria and mutism, two patients had visual complaint and urinary incontinence. No patient presented with chorea or athetosis. The three patients with adult onset SSPE had presenting features in form of myoclonus, apathetic behaviour, walking difficulty and visual disturbances.

Table 2: Clinical Profile Presenting symptoms

Scholastic/cognitive decline Myoclonus 34 (81.48%) 40 (95.23 %)

Neurological findings
Ophthalmological abnormalities a. Impaired saccades, pursuits, nystagmus, restriction of EOM 28 (66.6%) 16 (32%)

Walking difficulty Seizures

37 (88.88%) 23 (54.75%)

b. c.

Optic disc pallor Visual acuity

08 (19%) 03 (7.14%)

Behavioural changes Visual disturbances Urinary disturbances Speech impairment

25 (59.5%) 28 (66.6%) 22 (52 %) 20 (48%)

d.

Chorio-retinitis

01 (2.3%) 33 (79 %) 23 (54.76 %) 23 (54.76 %) 05 (11.1%) 05 (11.1%)

Pyramidal signs Cerebellar signs Extrapyramidal system Vegetative state Decerebrate rigidity

Ophthalmological findings were present in 28(66%) patients. Eye movement abnormalities were most common (32%) followed by disc pallor, diminished visual acuity and chorioretinitis. Among other neurological abnormalities 33 (78%) patients had pyramidal signs in form of spasticity, brisk reflexes and extensor plantar response. Extrapyramidal features in form of tremor, rigidity, dystonia, and dyskinesia as well as cerebellar signs (nystagmus and ataxia), were reported in 23 (54.76%) patients. Most of the patients 39(92%) presented in SSPE clinical stage II (44%) and III (48%), only 3 patients (8 %) presented in clinical stage IV and none in Stage I. During the course of illness myoclonus was noted in 40 (96%) patients, out of which 36 (90%) had generalised myoclonus, and 4 (10%) had focal myoclonus. The frequency of myoclonus ranged from 2 to 15 per minute. Effect of sleep on myoclonus was observed in 33

patients; frequency of myoclonus decreased during sleep in six (19%), disappeared in eight (23%) and remained unchanged in majority of the patients 19(58%). Imaging All the patients underwent brain imaging. CT head was done in 28 patients while 22 had MRI of brain both imaging was available in 8 patients. CT scan was normal in 23(83%) , 3 patients had cerebral atrophy, two patients had asymmetrical/ unilateral involvement in form of right parietal and corona radiate arachnoid cyst in left temporal lobe. MRI of brain was normal in 10 patients, 7 patients showed diffuse cerebral atrophy, one of them showed cerebellar atrophy as well. Bilateral periventricular white matter hyperintensities were found in five patients. Laboratory studies On CSF analysis total cell count was raised (>5 cells) in 3 patients (7%). CSF Proteins were increased (>45mg/dl) in 5 (11%). CSF sugar level was normal in all the patients. Antimeasles antibody test was performed in CSF as well as serum of 15 patients. The titres were raised in 10 patients in CSF and 12 patients in serum. The EEG of 36 (90%) patients was typical of SSPE. Periodic complexes were present in 41(97.6%) of patients. These were true periodic in 75.20% of patients and quasi-periodic in 23.8% of patients. The amplitude ranged from 200 to 800 V, the average being 300 to 400 V, duration of the discharges was from 200 msec to 1.5 second. Background slowing was seen in 22 out of 42 patients (52.3%). The interval between individual discharges ranged from 3 to 20 second. Effect of sleep was studied in 28 patients, 22 patients (52.38 %) showed no change, disappearance of discharges was seen in three (7.14%) patients and further slowing of background was seen in another three (7.14%) patients hypodensities and one patient showed incidental

Discussion and Review of Literature Incidence of SSPE is reported to be around 21 cases per million populations in India by Saha et al3.Worldwide incidence is 4-11 cases of SSPE every 1, 00,000 cases of measles. The disease is more prevalent in males than in females3, 4. Important risk factors associated with SSPE include younger age at measles onset, rural dwelling, poverty, overcrowding, low level of parental education, a higher number of siblings, and a higher birth order3, 5. SSPE is largely a disease of childhood and early adolescence. The average age of presentation worldwide is between 5 and 15 years with the mean age being 9-10 years2. In the present study patients age varied from 5 to 19 yrs and the mean age of presentation was 9.5 yrs consistent with the above data3. Patients were almost equally distributed in age group below (52%) and above (48%) 10 yrs of age. The M:F ratio of 5:1 with majority of the patients (2/3) of rural background and low socioeconomic status was in concordance with previous published series. Twenty six (63 %) of patients had history of measles. Interval between onset of measles and SSPE was also variable and ranged from 7 months to 10 years, with an average of was 6.6 years. Definitive history of immunisation for measles was present in only 7 (16.6%) patients. Previous studies reported immunisation in approximately 41% of their patients. Measles immunisation does not sufficiently prevent measles and its complications. Enver Simsek et al. highlighted that immunisation failure against measles was due to irregular vaccination, age of vaccination, higher maternal measles neutralizing antibody titres, and lack of the booster dose in the pre-school years. Interference by passive (maternal) neutralizing measles antibody has been considered the primary obstacle to the successful immunization of young infants with attenuated measles vaccine6, 7, 8. Because of this reason World Health Organization (WHO) and the United Nations Childrens Emergency Fund (UNICEF) have recommended that all children should be offered a second opportunity for the measles vaccination9.

The clinical profile of our study has been compared with previous studies in the table (3) Table 3: Comparison of clinical features of SSPE in different series

Signs and symptoms

S Praveen Kumar 10

OP Lekhra 11

Khwaja GA 12

Kini et al13

Nagaraja14

Present study

Scholastic/ cognitive decline

29.3 %

58.97%

100%

73%

76.2% (cognitive+beh aviour)

81.84%

Myoclonus Seizures

93% 65%

33.33% 5%

100% 38.8%

94% 24%

76.6% 38.7%

95.23% 55.55%

Behaviour /Personality changes Ophthalmological Abnormalities Pyramidal signs

8%

73%

76.2%

59.5%

24%

15.4%

8.2%

9.7

16.2%

66.6%

37%

38.8%

43.1%

79%

Extrpyramidal features Cerebellar signs

17%

19.4% 5.5%

10% -

55% 55%

Rarely patients of SSPE may presen with psychosis15, catatonia16, pseudotumor cerebri17, acute dessiminated encephalomyelitis18, status epilepticus19, epilepsia partialis continua20 and transcortical aphasia21 In our series the majority of patients 92% were in Stage II and III at the time of diagnosis. None of our patients presented in clinical stage I. This reflects delay either due to ignorance of the parents to notice subtle changes in behaviour and cognition or lack of clinical suspicion by the treating paediatrician at periphery. Saha et al had majority of their patients in stage II of the disease.22

Table 4: MODIFIED JABBOUR STAGES

Stage IA Stage IB Stage IIA Behavioral, cognitive and personality change only. Myoclonic Spasms: focal and not periodic. Further mental deterioration. Myoclonic spasms: periodic, generalized, frequently causing drop spells precluding ambulation

Stage IIB

Apraxias, agnosias, language difficulties. Motor signs: spasticity, ataxia. Ambulation with assistance only.

Stage IIIA

Speaking less, visual difficulties. Sits up. Myoclonic spasms frequent (Every 35 seconds). May have seizures.

Stage IIIB

No spontaneous speech, poor comprehension, blind. Myoclonic spasms. Bedridden, dysphagia. EEG background delta. Other abnormal movements: chorea, ballismus.

Stage IV

No myoclonic spasms. EEG low voltage with no periodic slow wave complexes. Patient in a vegetative state.

CT was normal in majority of our patients (more than two-third); asymmetry in two patients in form of right parietal and corona radiata hyperintensities was noted. Most common abnormalities on CT were diffuse cerebral atrophy and white matter density changes. MR imaging is a superior method in detecting white matter abnormalities and picked up additional abnormalities in 5 (12%) of our patients and consistent with those reported in the literature. Asymmetry on MRI was found in one patient in form of asymmetrical right cortical atrophy. Prominent cerebellar atrophy was noted in one patient on MRI; such finding has not been reported in literature, although patients with SSPE often have cerebellar ataxia. Widespread periventricular hyperintensities and cerebral atrophy were noted in many patients with stage II and III disease. Abnormal MRI findings were significantly more frequent in the later stages, and a normal initial cranial MRI does not exclude SSPE10. Yilmaz K24 et al correlated study of FDG PET, MRI/CT, electroencephalography, and clinical features in SSPE in 16 patients. They concluded that FDG PET imaging can indicate affected brain regions in SSPE more confidently and earlier than MRI.

SSPE is one of the few conditions where EEG is highly diagnostic. The characteristic EEG complexes are called R-complexes which are bilateral symmetrical and synchronous generalised, stereotyped high amplitude delta waves occurring at fairly regular intervals of 515 seconds, and have a constant relationship to myoclonus. These have been classically described in stage II of SSPE. The anatomical origin of these periodic complexes is still debatable. The possible hypothesized sites of origin are cortex, deep thalamic or mesencephalic-reticular region or involvement of both grey and white matter resulting in a disturbance of the normal cortico-subcortical electrical interaction10, 25. The presence of raised titres of anti-measles antibodies in the plasma and CSF is diagnostic for SSPE; levels >1:256 in serum and >1:4 in CSF is considered diagnostic. In our patients we have found raised CSF cell count in three (7%) of patients and increased in CSF protein in 5 (11%) with normal CSF sugar in rest of the patients. Such finding of raised cells and protein has been noticed previously also by Nagaraja14 et al and Thakare26 et al. Enzyme-

linked immunosorbent assay of CSF for measles virus IgG has a sensitivity of 100%, a specificity of 93.3%, and a positive predictive value of 100% in individuals with a clinical picture suggestive of SSPE. Some studies have found elevation of soluble CD8 in CSF and decreased serum b2-microglobulin associated with clinical worsening27.

Table 5: Diagnostic criteria of SSPE28

Clinical EEG CSF Measles antibody Brain biopsy Progressive, subacute metal deterioration with typical signs like myoclonus Periodic, stereotyped, high voltage discharges Raised gammaglobulin or oligoclonal pattern Raised titre in serum (>1:256) and/or cerebrospinal fluid (>1:4) Suggestive of panencephalitis

Definitive: criteria 5 with three more criteria; probable: three of the five criteria.

Despite available investigations and advances in field of SSPE it may still be difficult at times to diagnose cases of SSPE in routine clinical practice as about 17.9% of patients have atypical or uncommon presentations.29 The severity of EEG changes, clinical picture or neuroimaging do not reliably indicate prognosis. Spontaneous remissions rates of 5-10 % have been reported in literature. 10% showed a fulminant or prolonged course. Death is usually inevitable within years of the onset of symptoms 27, 30. The pharmacologic management of SSPE can be divided into disease modifying agents and symptomatic therapies. Among the disease modifying agents isoprinosine and interferon are the most widely studied. Isoprinosine, a derivative of inosine, is thought to disrupt viral replication while interferons are believed to increase IL-1 antagonism, enhance the cellular immune response, and activate natural killer lymphocytes27. Mixed response with IVIG, amantadine, corticosteroids, and acyclovir have been reported in isolated case series27.

Gascon et al (1993) studied combined oral Isoprinosine and intraventricular alpha-interferon therapy for SSPE. Out of eighteen patients, eight (44%) had treatment-induced remissions as compared to about 5% spontaneous remission in the literature23. However in another study Eroglu E reported that long term follow up of 16 to 160 months in patients treated with oral isoprenosine and alpha-interferon plus isoprenosine found that isoprinosine alone or in combination with intraventricular interferon did not change the prognosis in long-term follow-up periods31. While Sato K et al (2009) reported some serious complication of intraventricular interferonalpha and ribavarin in form of malfunction of the Ommaya reservoir, septic meningitis and chemical encephalopathy32. Recently, intraventricular ribavirin therapy has been proposed as novel antiviral chemotherapy for SSPE by achieving ribavarin concentration in CSF that can completely inhibit replication of measles virus33.

Newer perspectives using specific antivirals such as short interfering RNA (siRNA) or small molecule inhibitors are being explored34. Some authors have tested the ability of newer immunomodulators, such as anti-CD20 antibodies, to reduce the humoral response against measles virus27. In conclusion it is necessary to have index of suspicioun to prevent delay in diagnosis. EEG is highly diagnostic for SSPE however anti-measleas antibody titre in CSF/Serum may further increase the yield. The currently available treatment modalities like oral antiviral and intraventricular alpha interferon have not shown promising results and need further evaluation. Other emerging therapies such as intraventricular ribavirin and

immunomodulators may have hope for future management.

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