Clinical report 1
A 6-year-old girl of Filipino origin presented to the emergency department in July 2001 with an eight-day history of progressive weakness and abnormal movements. The movements consisted of sudden head drops described by parents as brief sleeping episodes and new onset of dropping objects. She had also been noted to have a fine tremor, fidgetiness, unsteady gait and frequent falls. Her behavior was described as more irritable and emotionally labile. Parents had noted a longer history of difficulty understanding her speech, decreased recall of the names of common objects, and requiring help to feed/use washroom. Past medical history revealed measles infection at four months of age in the Philippines and that she received standard Canadian immunizations upon immigration at age two years.
On exam the child was pleasant and cooperative but was not able to comply with two step commands. She did not know her parent's first names, her phone number or address. Cranial nerve, motor and sensory exam were all normal. A fine intention tremor was evident in the upper extremities. Every 5–10 seconds the child would have a brief myoclonic movement of the whole body with head flexion, eye closure and arm extension. She would often fall during these myoclonic jerks but otherwise her gait and balance appeared intact.
A video EEG confirmed the presence of high amplitude periodic discharges [See Additional file 1] associated with head drops. Investigations from the CSF were normal except for oligoclonal banding and markedly elevated measles virus IgG at 7100 mIU/ml consistent with the diagnosis of SSPE. The diagnosis was confirmed within 3 weeks of initial presentation. A Brief Assessment Examination showed a score of 18 with 60 being the greatest impairment (see below). An initial MRI was normal but within three months a second MRI showed diffuse cerebral atrophy and a hyperintense lesion in the left temporal lobe on T2 weighted images.
Treatment with high dose valproic acid and clonazepam significantly improved the myoclonic seizures. Isoprinosine was started immediately (100 mg/kg divided qid) upon diagnosis but by one month later on admission for insertion of the Ommaya reservoir and initiation of intraventricular interferon-alpha (IFN-α) 2B her clinical state had deteriorated. She was minimally responsive, no longer vocalizing needs, had few purposeful movements and poor head control. Despite this the treatment with intraventricular IFN-α 2B was initiated at 1 million units per day for 2 weeks, then weekly for six weeks, then every other week for three months. No improvement in the child's function occurred but no further deterioration was noted. Other symptomatic treatments included g-tube feeding, physiotherapy, glycopyrrolate to decrease oral secretions. Mild thrombocytopenia and fevers with injections occurred but did not interfere with the treatment. Due to a lack of clinical improvement, the interferon and isoprinosine were discontinued after five and eighteen months respectively.
Gradually the clinical picture progressed to diffuse rigidity, brisk reflexes with clonus and multifocal myoclonus. The child remained stable albeit in a state of minimal responsiveness, with no communication or purposeful movement until she died of a respiratory illness in March 2004, two and a half years after her diagnosis. No autopsy was performed.
Clinical report 2
A 14-year-old boy born in Canada presented in late 1997, at seven years of age, with staring spells, diagnosed as absence epilepsy but over the next year developed atonic seizures consisting of head drops, myoclonic seizures, and then generalized tonic clonic seizures lasting approximately two minutes. Approximately one year after the onset of his seizures he was losing skills such as tying his shoelaces, and dressing himself and needed to be transferred out of a regular classroom.
His past medical history was significant for being born at 26 weeks gestation, and having mild respiratory distress syndrome and then bronchopulmonary dysplasia. No intracranial pathology was detected clinically or by head ultrasound at that time. Since infancy there had been no significant illnesses. There was no history of measles disease or contact in the first year of life. His immunization record confirmed that all immunizations had been appropriately given including MMR in June 1992 at the age of 21 months and measles booster at 6 years of age.
Clinical examination revealed a head circumference of 53.7 cm (80th percentile). Cranial nerves were intact including a normal fundoscopic exam. There was mild hypotonia and normal power. Deep tendon reflexes were generally brisk. Plantars were upgoing bilaterally.
Initial EEG demonstrated generalized 3 Hz spike wave and polyspike and wave. A subsequent EEG five months later showed marked abnormality with no normal rhythmicity and intermittent projected activity consisting of high voltage delta and multifocal sharp waves in bursts with attenuation of faster frequencies. These occurred at times in a quasi periodic fashion approximately every five seconds throughout the recording. In addition there were multiple independent spikes and sharp waves. MRI showed high signal in the periventricular white matter. CBC, electrolytes, calcium, magnesium, liver function tests, renal function tests, lactate, ammonia, creatine kinase, plasma and urine amino acids, urine organic acids, very long chain fatty acids, mucopolysaccharides and oligosaccharides were all normal. Skin biopsy did not show any inclusions on electron microscopy. Toxicology screen normal. The major findings of note were in the cerebrospinal fluid obtained in April 1999. Nucleated cell count was 3 × 106/L and protein was 662 mg/L. CSF IgG was 212 mg/L (nr 0–64) and CSF IgG/albumin ratio was 1.91 (nr 00-0.23). CSF measles titre was 2460 mIU/ml (nr = 0). The diagnosis of subacute sclerosing panencephalitis was made in April 1999. Given the lack of infant measles infection, the history of prematurity and the atypical EEG the diagnosis of SSPE was only arrived at after extensive investigation into all neurodegenerative disease.
He was not treated with specific antiviral therapy. At the time of his most recent visit, age 131/2 years, he was having seizures every three weeks consisting of clonic movements of the face and both arms lasting up to one minute. He was using a wheelchair outside the home. On examination he remained very interactive socially and appropriately verbally responsive to simple questions. He was somewhat disinhibited. Cranial nerves were intact. Fundoscopic exam showed peripheral diffuse retinal atrophy consistent with previous retinal choroiditis. There was a mild right dystonic hemiparesis superimposed on a moderate spastic diplegia. In addition there was marked cerebellar tremor in the upper limbs, significant dysmetria and gait ataxia. This child recently died due to respiratory illness and no autopsy was performed.
Clinical report 3
A 14 year old girl born in Canada presented in March 1996 at six years of age with a history of a respiratory infection two months prior to her presentation. From that time she had been lethargic, slow to complete school assignments and unable to understand simple requests around activities of daily living. Her sleep pattern had also become disturbed. One month later she began to have drop attacks. The only other symptom of note was headache for five days. Her chest x-ray demonstrated bronchopneumonia and she was treated Erythromycin at her local hospital. A CT scan and EEG were reported to be normal
Her past medical history revealed that she was the product of a normal delivery at 38 weeks, weighing 2.5 kg. At 13 months of age she contracted pneumococcal meningitis but had a complete recovery from this. Because of her meningitis, she had not received her MMR immunization. At 14 months of age she contracted measles. Subsequently she had recovered from her illnesses and her development had been entirely normal.
Clinical examination revealed a lethargic but cooperative girl. There was bilateral papilloedema and focal chorioretinitis. Cranial nerves were otherwise intact. The motor examination was entirely normal. She had a mildly asymmetric gait but there was no ataxia.
EEG showed multiple independent spikes and background slowing. Her MRI was normal. Lumbar puncture revealed a pressure of 36 mmHg but in March 1996 the CSF glucose (3.7 mmol/L) protein (195 mg/L) leukocyte count (3 × 10-6/L) were normal. CSF measles PCR was negative. Initial treatment included clonazepam, valproate and dexamethasone. Over the next two weeks she deteriorated dramatically to the point where she would give only one word answers, demonstrated marked ataxia and significant decline in cognition. Myoclonic seizures were evident. A further EEG revealed periodic complexes. Plasma measles IgG by enzyme immunoassay was 4.34 (EIA units cutoff value < 0.7). CSF measles PCR was negative. No virus was cultured but the CSF measles IgG by enzyme immunoassay was 3.58 EIA units (nr = 0).
Within one month of her presentation she had deteriorated to the point where there were periods of time when she appeared not to be aware of her surroundings and was ataxic to the point where she needed to be fully supported when walking. She had only occasional words and continuing myoclonia. She was treated with intravenous ribavirin 100 mg/kg/day as a q 6 h regimen and ribavirin levels were measured both in the plasma and CSF. It was felt that the levels obtained in the CSF were not adequate to inhibit viral replication, and therefore, it was decided to give intraventricular ribavirin using an Ommaya reservoir. The dose was gradually increased over ten days from 1 mg/kg/day to 10 mg/kg/day. This treatment did not produce any reversal in her clinical symptoms and signs and was discontinued.
At the time of her last visit, age 13 years, the major issues were that she was sleeping through most of the day, being awake for a total of 4–6 hours per day in periods of half to one hour. Her seizures had continued to be a major problem but had improved significantly on a small dose of topiramate. Clinical examination revealed no interaction and evidence of a severe spastic quadriparesis. There was evidence of decerebrate posturing.
Clinical report 4
A 16 year old boy born and raised in Iraq until 6 years of age, presented with a diffuse red rash on his upper extremities and trunk in September 1998, followed by a rapid change in behavior over the next three months. He was described as having memory problems, social isolation and poor concentration. He then developed myoclonic jerks of the extremities and was admitted for investigation four months after his rash.
At one year of age the child had suffered a measles-like illness. Family claimed he had received immunizations upon entering Canada but this was not confirmed.
On examination the child manifested significant mental status changes. He was disoriented in all spheres and unable to read, write or speak. Formal motor and sensory exams were not able to be performed given his mental status. There were almost continuous myoclonic seizures.
EEG demonstrated quasi-periodic bursts of high voltage slow wave activity at intervals of 4–9 seconds which correlated with myoclonic jerks seen in the patient. The EEG background was otherwise normal. MRI showed focal signal abnormalities in the left occipital lobe without enhancement. Serum and CSF showed elevated levels of measles IgG (exact values not available) in January 1999. A brain biopsy did not clearly delineate findings of SSPE.
The child was treated with isoprinosine 1 gram tid from diagnosis until death. He also received, via an Ommaya reservoir, intra-venticular IFN-α 1 million units twice a week for two weeks, then three times a week for three weeks and then once a week for a month and then it was discontinued. Seizures were treated with valproic acid 750 mg tid.
He was transferred to a pediatric rehabilitation centre after his diagnosis and in October 1999 he was brought back to hospital with generalized body rigidity, fever and agitation. He developed adult respiratory distress syndrome and renal failure due to rhabdomyolysis. Creatine kinase levels were 47,000. The specific cause for his sudden deterioration was not clear with infection, malignant hyperthermia or dystonic spasm directly related to SSPE considered. He died within two weeks of re-admission and no autopsy was performed.