Subacute Sclerosing Panencephalitis in a 63-Year-Old Woman Presenting as Generalized Choreoathetosis

Abstract

The persistence of measles virus infection in childhood and early adolescence can rarely lead to a fatal progressive neurodegenerative disorder known as subacute sclerosing panencephalitis (SSPE), characterized by behavioral disturbances and intellectual disability followed by myoclonic jerks and occasional negative myoclonus. Movement disorders are rarely presenting manifestations in SSPE. We herein report a 63-year-old woman with generalized choreoathetosis as the presenting manifestation of stage-I SSPE. Our case was atypical for the patient's age and clinical presentation with generalized choreoathetosis and bilateral putaminal and caudate nucleus signal hyperintensity. Though highly uncommon, neurologists should keep SSPE as a differential diagnosis among patients with movement disorders. Measles-endemic countries should be more vigilant to the atypical and rare presentations of SSPE, such as generalized choreoathetosis.

Introduction

The persistence of measles virus infection in childhood and early adolescence can rarely lead to a fatal progressive neurodegenerative disorder known as subacute sclerosing panencephalitis (SSPE), characterized by behavioral disturbances and intellectual disability followed by myoclonic jerks and occasional negative myoclonia. ¹ SSPE has been documented worldwide, but it is considered a rare disease in the West, with fewer than ten cases reported annually in the United States. ² The incidence decreased significantly after the advent of an efficient measles vaccination. In developing nations, the incidence of SSPE is still relatively higher yet varies. For example, Saha et al. ³ estimated an annual incidence of 21 per one million inhabitants in south India. However, detailed global surveillance data on the prevalence and incidence of SSPE is unknown. A recent report from UK-SSPE surveillance showed the re-emergence of SSPE after 15 years in the United Kingdom and an increased risk of SSPE in several European countries following measles outbreaks.^4,5

Measles-induced neurological syndromes include primary encephalitis, acute post-measles encephalitis, measles inclusion body encephalitis, and, most importantly, SSPE. ⁶ The relative rarity of SSPE and the atypical presentations can be mistakenly interpreted, leading to a significant diagnostic delay. ⁷ SSPE is a neurological disorder of childhood and early adolescence, with very few cases reported so far in adults,^8,9 making it a significant diagnostic challenge for clinicians. In this sense, Garg et al., ¹⁰ in a literature survey of 39 reported adult-onset SSPE cases worldwide, found only 11 cases with more than 35 years of onset. SSPE follows primary measles infection by months to several years, with a mean of approximately seven years and a gradually progressive course leading to death within a few years. ⁸

We herein report a 63-year-old female with generalized choreoathetosis as the presenting manifestation of stage-I SSPE.

Case Presentation

A 63-year-old woman with type-2 diabetes and arterial hypertension was admitted to the emergency department with generalized abnormal movements, urinary and fecal incontinence, and sleep disturbances for the last three months. A sudden episode of slurring of speech with left-sided weakness a month before admission was also reported in history.

The patient appeared drowsy and disoriented on the initial examination. The general examination did not reveal icterus, cyanosis, edema, and clubbing, except for mild to moderate pallor. She had a blood pressure of 130/90 mmHg, pulse rate of 93/minute, respiratory rate of 18/minute, and capillary blood glucose of 130 mg/dl. Her mini-mental state examination (MMSE) score was 26/30. Neurological examination revealed involuntary, random, purposeless, asymmetric (left more than right) flowing movements from one muscle group to another involving both distal and proximal limbs muscles, aggravated by action or excitement, classic Jack in the box tongue and lip-smacking, suggestive of choreoathetosis. In addition, she also had myoclonic jerks predominantly involving the limb muscles. The remaining examination was normal except for anisocoria, tetraparesis (MRC -4/5), generalized hyporeflexia, and bilateral extensor plantar responses.

Encephalitis (infectious, post-infectious, autoimmune, and paraneoplastic), metabolic disorders, hepatic encephalopathy, Hashimoto’s encephalopathy, mitochondrial disorders with encephalopathy, diabetic striatopathy, atypical demyelinating disorders, and Creutzfeldt-Jakob disease were considered among differential diagnoses. Blood cell count, ammonia level, and renal, thyroid, and liver function parameters were normal. Autoimmune and paraneoplastic encephalitis profile, including anti-thyroid antibodies, was negative. Her ANA was weakly positive (1:100) with a speckled pattern. Cerebrospinal fluid (CSF) cultures and polymerase chain reaction assay for the detection of neurotrophic viruses (herpes simplex virus 1 and 2, human herpesvirus 6 and 7, Epstein Barr virus, cytomegalovirus, enterovirus, parvovirus B19, varicella-zoster virus, human parechovirus, adenovirus, and severe acute respiratory syndrome coronavirus-2) were negative as well as neurotuberculosis, neurosyphilis, neuroborreliosis, Japanese encephalitis, and dengue. In addition, serologies for HIV 1 and 2, cytomegalovirus, and hepatitis B and C were negative. Rapid diagnostic kit tests for Plasmodium falciparum and vivax were negative. Serum and CSF lactate and pyruvate levels and serum creatine kinase levels were within normal range, making any possibility of mitochondrial diseases less likely. Further extensive investigations failed to demonstrate any associated concealed neoplastic process.

In the subsequent days, generalized choreoathetosis and drowsiness slightly improved; only occasional myoclonic jerks remained. However, after a couple of days, intravenous lacosamide (100 mg twice daily) and valproate (500 mg three times a day) were started due to a focal seizure. Her drowsiness after the episode of focal seizure aggravated and an emergency non-contrast computed tomography was performed to rule out a possible underlying cerebrovascular incident, which turned out to be normal. In the following days, her mental status worsened, with a drastic fall in her MMSE score to 16/30. In the meantime, the IgG-measles antibody panel returned positive with a CSF/serum measles-specific IgG of 2.34 and serum-measles-virus IgG of 170 (Table 1). In most central nervous system infections, the intrathecal immune response is characterized by a delayed oligoclonal and polyclonal response with IgG predominance produced by memory B cells.^11,12 In this case, the ratio between CSF/serum measles-specific IgG is the quotient used for interpretation.^11,12 A ratio of more than 1.5 is indicative of measles-specific antibody production in the CSF.^11,12 In order to diagnose intrathecal immunoglobulin synthesis, clear discrimination between blood-derived and brain-derived proteins in CSF is required; hence, paired estimation of serum and CSF antibodies is essential and more important than the absolute values.^11,12

Table 2.

Dyken's criteria for diagnosing subacute sclerosing panencephalitis. ¹³

Definite: criteria 5 with three more criteria
Probable diagnosis: three of the five criteria.
1. Clinical - Progressive, subacute mental deterioration with typical signs like myoclonus.
2. Electroencephalogram: Periodic, stereotyped, high-voltage discharges.
3. Cerebrospinal fluid: Raised gamma globulin or oligoclonal pattern.
4. Measles antibodies: Raised titer in serum (≥1:256) and/or cerebrospinal fluid (≥1:4).
5. Brain biopsy: Suggestive of panencephalitis.

Table 1.

Laboratory investigations of patient's serum and cerebrospinal fluid.

Investigations	Results
Serum
Anti-nuclear antibody	Weakly positive (1:100), speckled pattern
C-reactive protein	Negative
Total IgG	1097 mg/dL (N, 700-1600)
Cerebrospinal fluid
Lactate	1.67 mmol/L (N, 1.2-2.1)
Pyruvate	.07 mmol/L (N, .03-.15)
Protein	48 mg/dL (N, 15-60)
Glucose	41 mg/dL (N, 20-45)
Oligoclonal bands	No Bands
Cell count	<1/cc (N, <5)
Total IgG	2.53 mg/dL (N, 0-3.4)
Serum and cerebrospinal fluid
Anti-N-methyl D-Aspartate receptor antibody	Negative
Anti-AMPA (GLUR 1 & GLUR 2) antibody	Negative
Anti-GABA-B antibody	Negative
Anti-GAD 65 antibody	Negative
Anti-voltage gated potassium complex antibody	Negative
Anti-LGT antibody	Negative
Anti-CASPR2 antibody	Negative
Measles
Cerebrospinal fluid IgG measles	80 U/mL
Serum IgG measles	73.5 U/mL
Cerebrospinal fluid IgG /serum IgG quotient	Positive (2.34) (positive >1.5)

A brain MRI revealed mild hyperintense-signal on T2-weighted and fluid-attenuated inversion recovery images involving caudate and putamen with mild diffusion restriction, which was also appreciated in the left temporal cortex (Figures 1A and B). On the electroencephalogram, periodic complexes of bilaterally symmetrical triphasic slow waves were seen at regular intervals (Figures 1C and D). A diagnosis of SSPE was confirmed as per Dyken's criteria ¹³ (Table-2), and clinical stage-I progressing into stage II was considered as per the modified Jabbour classification. ¹⁴ Importantly, during thorough history taking, our patient's vaccination status was questionable, with an unknown history of infection.

Figure 1.

Brain magnetic resonance imaging reveals bilateral putaminal and caudate nucleus signal hyperintensity on the T2-weighted sequence (A) with mild diffusion restriction on the diffusion-weighted image (B). Figures C and D show bilaterally symmetrical triphasic slow waves at regular intervals.

Table 3.

Previously reported patients with movement disorders heralding subacute sclerosing panencephalitis.

Authors	Age/Sex	General Symptoms	Immunization Status/measles Infection	Serum biochemical parameters	Cerebrospinal fluid parameters	Neurological presentation	Neurological evaluation	Treatment	Outcome
Turaga et al. 31	8 yr/female	Cognitive decline with memory and calculation deficit and poor scholastic performances	Immunized/infected at one year	Not reported	Antimeasles IgG antibodies were positive	Sudden flexion of head and trunk without loss of consciousness and generalized jerk involving the entire body	Isolated lesions in basal ganglia with hyperintensity on T2-weighted images and hypointensity in T1-weighted images. Electroencephalogram showed a semi-periodic burst suppression pattern	Not reported	Sudden death
Kundu et al. 32	8 yr/female	Drowsy and responded poorly to simple commands	Not immunized/infected at 1.5 years	Normal	Slightly elevated protein and elevated antimeasles IgG antibody	Hemiplegic gait with periodic myoclonic spasms and exaggerated deep tendon reflexes with extensor plantar reflex	T1-weighted image hypointensity and T2-weighted image hyperintensity in the left lentiform nuclei with Periventricular degeneration. Electroencephalogram revealed generalized epileptiform discharges	Valproate and amantidin	Discharged with counseling
Goswami et al. 33	8 yr/female	Unresponsive and apathetic, she could not recognize her parents	Not immunized/no history of infection	Raised antimeasles antibody titers	Raised antimeasles antibody titers	Dystonic storm	Magnetic resonance imaging revealed discrete, scattered hyperintensities involving the left globus pallidus and bilateral occipital lobes. Electroencephalogram showed generalized quasi-periodic high-amplitude generalized slow waves (left more than right)	Trihexyphenidyl hydrochloride, lorazepam, midazolam, carbamazepine, and isoprinosine	Discharged
Cornelius et al. 34	10 yr/female	Conscious-oriented with poor attention span, difficulties in doing simple arithmetic tasks, and speech slow, monotonous with reduced word output	Immunized/unknown history of infection	Normal	Raised antimeasles antibody titers	Akinetic rigid syndrome	T2-weighted/fluid-attenuated inversion recovery sequences revealed hyperintensities in the putamen and sub-cortical frontal white matter. Electroencephalogram showed periodic complexes	Valproate and clonazepam	Progressive deterioration
Tandra et al. 35	10 yr/male	Conscious but unaware of self or environment, poor comprehension and impaired memory recall, slurred speech, inappropriate laughter, and poor scholastic performances	Not immunized	Raised antimeasles antibody titers	Raised antimeasles antibody titers	Choreoathetosis, prominent orolingual dyskinesia, and periodic, shock-like sudden negative myoclonus	Hyperintensities in bilateral putamen and medial temporal regions and left cortical temporal regions. Lactate doublets in MR-spectroscopy. Electroencephalogram revealed periodically synchronized large-amplitude complexes	Valproate and isoprinosine	At the six-month follow-up, the patient continued to have cognitive decline, myoclonic jerks, choreoathetosis, and motor regression
Serin et al. 36	11 yr/male	Alert, fully oriented and cooperated	Not reported	Elevated Antimeasles antibody titers	Elevated Antimeasles antibody titer Positive IgG Oligoclonal bands	Brisk bilateral deep tendon reflexes, weakness of right upper and lower limbs with hemidystonia	T2-weighted sequences revealed hyperintensity in bilateral basal ganglia and parieto-occipital region (predominant on the left side). Electroencephalogram revealed periodic generalized epileptiform discharges	Isoprinosine and beta-interferon	Not reported
Kamate et al. 37	12 yr/female	Sudden extension of head and neck without loss of consciousness, alert with cognitive impairment	Immunized/no history of infection	Not reported	Elevated Antimeasles antibody titers	Generalized myoclonic jerks involving neck and trunk and exaggerated deep tendon reflexes with intermittent dystonia	Isolated hyperintensities in left lentiform nuclei on T2-weighted/fluid-attenuated inversion recovery Electroencephalogram: long interval, generalized, periodic, epileptiform discharges	Not reported	Not reported
Kalane et al. 38	12 yr/male	Increased spasticity with brisk tendon reflexes in both upper and lower limbs bilaterally Poor scholastic performances	Not immunized/doubtful history of infection at two years	Normal	Elevated Antimeasles antibody titers	Low amplitude myoclonic jerks in limbs and cognitive decline	Left putaminal hyperintense lesion on T2-weighted/fluid-attenuated inversion recovery images with diffused brainstem and bilateral cerebellar peduncular involvements. Electroencephalogram showed high amplitude, periodic bursts of slow and sharp waves at intervals of 5-8 seconds on a slow background	Not reported	Not reported
Bozlu et al. 28	12 yr/male	Unremarkable	Unknown	Raised measles IgG antibody titers	Elevated measles IgG antibody titers	Slurring of speech with decreased volume and speed, generalized rigidity, left hemidystonia, bradykinesia, impaired postural reflexes, and mask-like facies. Brisk deep tendon reflex, progressive development of dystonia	Magnetic resonance imaging was normal. Electroencephalogram revealed irregular background activity with generalized slow-wave discharges	Inosiplex, intravenous immunoglobulin, and carbamazepine	Improvement in speech, bradykinesia, and myoclonus
Akdal et al. 39	12 yr/male	The patient was mute and occasionally smiled, with frequent unexplained falls, poor scholastic performances	Immunized/infected at 1.5 years	Raised antimeasles antibody titers	Raised antimeasles antibody titers and five oligoclonal IgG bands	Myoclonic jerks of the face with frequent negative myoclonus, mild cogwheel rigidity predominantly on the left limbs, and brisk muscle stretch reflexes with bilateral plantar symmetric flexion	T2-weighted images revealed hyperintense lesions in the left lentiform nucleus with lesions in the left caudate and right lentiform nucleus. 15-month follow-up magnetic resonance imaging revealed diffuse periventricular white matter lesions and atrophic changes. Electroencephalogram revealed 1-1.5 Hz periodic high amplitude sharp and slow wave complexes	Not reported	Not reported
Sawaishi et al. 25	13 yr/male	Alert but poorly responded to simple commands and needed help in daily life	Not immunized/infected at three years	Elevated serum antimeasles antibody titers	Six oligoclonal IgG bands and elevated antimeasles antibody titers	Parkinsonian-type gait interrupted by periodic generalized myoclonic spasm, increased deep tendon reflexes, bradykinesia, and increased muscle rigidity	T2-weighted images revealed high signal intensities in caudate and cerebellar dentate nuclei	Isoprinosine, valproate and levodopa	The patient became vegetative on follow-up
Misra et al. 27	13 yr/male	Unremarkable	Unknown/no history of infection	Normal	Raised IgG, positive oligoclonal bands, and elevated antimeasles IgG titers	Parkinsonian features with left-sided predominant pyramidal signs. Later, spontaneous periodic generalized myoclonus with significant behavioral changes, mental slowness, and apathy	Brain magnetic resonance imaging was normal. EEG showed paroxysmal generalized bursts and slow wave discharges in a pseudo-periodic pattern (every 8-10 seconds) with generalized slow background	Levodopa and carbidopa without benefit	Not reported
Misra et al. 27	15 yr/male	Unremarkable	Immunized/no history of infection	Elevated antimeasles antibody titers	Raised cell count with mildly elevated protein, elevated immunoglobulins, positive oligoclonal bands of IgG, and elevated antimeasles antibody titers	Diminished attention span, impaired recent memory, dyscalculia, generalized parkinsonian features without resting and intentional tremor, and positive truncal and gait ataxia without appendicular ataxia. Generalized myoclonus with cognitive involvement eight weeks later	Brain magnetic resonance imaging, electromyography, and nerve conduction study were normal Electroencephalogram revealed periodic (every 5 seconds) generalized burst high amplitude (2-3 Hz) slow wave discharges on a slow background	Levodopa and carbidopa without benefit	Not reported
Almeida et al. 40	15 yr/male	Jerks in arms and legs, difficulties in swallowing, poor scholastic performances	Immunized/no history of infection	Positive IgG antibodies for measles, rubella, and herpes simplex virus	Slightly elevated protein and increased total IgG	Unmotivated laughing with intermittent myoclonus, grasping, snouting, paratonia in upper limbs with tongue tremor, and dystonia in limbs. The mini-mental-state examination was 10/30	T2-weighted/FLAIR images revealed hyperintensities in the caudate and putamen bilaterally with high-pointed signals in T1-weighted images Electroencephalogram showed generalized periodic activity at 5-6 Hz with asymmetric background activity, which was more disorganized in the right hemisphere and concomitant to myoclonus	Valproate	Sudden death
Reddy et al. 41	18 yr/female	Slurring of speech, difficulty in swallowing, needed help to walk	Immunized/no history of infection	Raised antimeasles antibody titers	Elevated Antimeasles antibody titers	Abnormal slow, jerky movements of limbs (proximal more than distal), trunk, and neck	Magnetic resonance imaging was normal Electroencephalogram showed periodic high amplitude generalized slow wave discharges	Intrathecal interferons, Isoprinosine, valproate, lorazepam, trihexyphenidyl, and levodopa	Not reported
Ondo et al. 42	26 yr/female	Evidence of numerous bruises and cuts from her frequent falls with an otherwise normal general examination She was unresponsive but awake during the movements with proper orientation	Not reported/no clear history of measles	Normal	Elevated IgG levels, 6-7 oligoclonal bands, and raised antimeasles antibody titers	Bradykinesia with dystonia, brisk deep tendon reflex with bilateral extensor plantar reflexes. Sensory impairment except for painful stimuli. Right-sided monocular blindness	Magnetic resonance imaging was normal SPECT study revealed increased activity in the bilateral caudate nucleus (right more than left). Electroencephalogram revealed episodes of generalized high amplitude delta activity alternating with 10-12 seconds periods of theta activity	Carbamazepine, amantadine and prednisone	Initially, she demonstrated dramatic improvement in mental status, all motor functions, and complete resolution of monocular blindness. she died two weeks later
Ghosh et al. 43	36yr/male	Rapidly progressive behavioral abnormalities and visual difficulties for the last three to four months	Questionable vaccination status	Raised antimeasles IgG antibodies	Increased cell count, elevated total protein, elevated lactate Elevated antimeasles antibody	Multidomain cognitive impairment with subcortical myoclonus	Magnetic resonance imaging showed non-enhancing bilaterally symmetrical altered intensity lesions. Hyperintensity on T2WI and FLAIR sequence involving thalamus and brain stem Electroencephalogram revealed periodic discharges suggestive of Radermecker complex	Not reported	Discharged with follow up

The clinical presentation and brain MRI pattern could be reminiscent of Creutzfeldt-Jakob disease. However, we ruled out this possibility as there was no prior history before admission of neuropsychiatric symptoms (dementia, behavioral abnormalities, and deficits involving higher cortical function, including aphasia, apraxia, and frontal lobe syndromes), and the raised titer of measles antibody in serum and CSF. 14-3-3 Protein result was not available to us because of resource constraints.

She became immobile and bedridden with significantly reduced speech, communication, and self-care abilities with a Modified Rankin Scale of 4 (moderately severe disability). Her MMSE score maintained between 13-16/30 without further deterioration. Subsequently, a discharge with home-care nursing was planned with maintenance therapy on lacosamide, valproate, ribavirin, isoprinosine, and modafinil.

Discussion

Movement disorders are rarely presenting manifestations in SSPE. We reviewed all published cases of movement disorders heralding SSPE, using PubMed, MEDLINE, Science Direct, Embase, and CrossRef, and found 17 cases with a mean age of 14 years at diagnosis (range 8-36 years) (Table 3). Only three adult cases were found in this search. Despite the rarity of movement disorders during the early stages of SSPE, they seem more common in pediatric SSPE cases. Noteworthy to mention that in a cross-sectional study of 50 children with SSPE, 28 (56%) had movement disorders, with seven in whom movement disorders were the presenting manifestations of the disease. ¹⁵

Choreiform movements in SSPE are classically seen in more advanced disease stages. However, our case is unique because the patient is the oldest published suffering SSPE and because of the clinical presentation with generalized choreoathetosis and bilateral putaminal and caudate nucleus signal hyperintensity. ¹⁶

Our patient had, however, two manifestations deviant from SSPE. First was the bilateral putaminal and caudate nucleus hyperintensities with diffusion restriction. The main brain imaging characteristics of SSPE encompass minor subcortical focal changes during clinical stage-I, periventricular and subcortical white matter involvement during clinical stage II with callosal white fiber atrophic changes in stage III, and extensive cortico-subcortical, cerebellar as well as diffuse brainstem involvement during stage-IV.^17,18,19 Interestingly, several reports have mentioned that, though highly uncommon, basal-ganglia involvement occurs most of the time without any underlying cortical or subcortical lesions.^20,21 Diffuse tensor imaging (DTI) studies in SSPE have revealed significant changes in white matter far earlier than conventional MRI, with clinical stage II showing structural alterations using that technique. ²² Second was the presence of triphasic waves on the electroencephalogram. However, although rare, triphasic waves can be seen in SSPE.^23,24 Despite all of this, the diagnosis of SSPE stood tall after the amalgamation of history, especially the clinical features, physical examination, and investigations.

So far, studies in SSPE have not been able to provide conclusions on the mechanism and spread of the measles virus in the brain, and it demands further research and deeper understanding to deliver more efficacious therapeutics leading to definitive treatment for SSPE. According to Sawaishi et al., ²⁵ basal ganglia lesions in SSPE are mostly confined within the putamen and areas of the caudate but spare globus pallidus and thalamus. Migration of lesions from putamen to caudate has also been reported, reflecting that caudate involvement might be accompanied by putamen lesions or vice versa. ²⁶ Besides, the case of an early parkinsonian syndrome in SSPE with substantia nigra involvement followed by sequential spread to caudate and putamen emphasizes upon migratory neurotropic nature of measles within the nigrostriatal connectome.^27,28 Several other studies have also reflected the anterograde and retrograde axonal transport of measles passing trans-neuronally to next-order neurons.^29,30

Conclusions

Measles-endemic countries should be more vigilant to the atypical and rare presentations of SSPE, such as generalized choreoathetosis. Though highly uncommon, neurologists should keep SSPE as a differential diagnosis among patients with movement disorders.

ORCID iDs

Ritwick Mondal https://orcid.org/0000-0002-4288-7661

Shramana Deb https://orcid.org/0000-0003-3383-4063

Julian Benito-Leon https://orcid.org/0000-0002-1769-4809