Peripheral nervous system involvement in SSPE as a parainfectious manifestation - A case report

doi:10.21203/rs.3.rs-2846096/v1

Background

Rapidly progressive encephalopathy in a young adult has a range of differentials requiring an exhaustive workup. We present a man with a history of encephalopathy with neuropathy and a rare diagnosis.

Case presentation

A 40 year-old man presented with a 6-month history of cognitive dysfunction and an asymmetric gradually progressing ascending quadriparesis with the involvement progressing in the order of motor, sensory, autonomic and bulbar. MRI of the brain showed diffuse atrophy. Nerve conduction studies revealed sensorimotor neuropathy affecting all four limbs. CSF showed a negative autoimmune panel and no signs of an infectious etiology. The patient was started on plasma exchange with a provisional diagnosis of an immune mediated disorder.

A nerve biopsy showed axonolysis and demyelination. EEG showed delta wave slowing and periodic discharges. A possibility of SSPE was considered, although peripheral neuropathy is an atypical presenting feature, following which the measles IgG antibodies titers in CSF and serum were found to be raised at 377.2 U/mL and 197 U/mL respectively. He had persistent sepsis and several episodes of respiratory distress requiring invasive mechanical ventilation. He was started on intrathecal interferon with a period of objective stability after which the sensorium gradually deteriorated and the outcome was fatal.

Conclusions

Subacute sclerosing panencephalitis (SSPE) is a progressive disorder caused by a persistent defective measles virus and causes death several years after the measles infection. It is suspected based on characteristic clinical features, EEG findings and demonstration of measles antibodies in CSF. The diagnosis is made based on Dyken's criteria. SSPE can present in an atypical fashion with peripheral nerve involvement. Neuropathy may occur due to para-infectious demyelination with no cellular infiltration seen on the nerve biopsy. A high index of suspicion aids diagnosis in rarer presentations.

Subacute sclerosing panencephalitis

adult onset

Dyken’s criteria

demyelination

periodic discharge on EEG

peripheral asymmetric neuropathy

measles antibodies titers

Rapidly progressive encephalopathy in a young adult has a range of differentials requiring an exhaustive workup. Subacute sclerosing panencephalitis (SSPE) is a progressive disorder caused by a persistent defective measles virus and causes death several years after the measles infection. It is suspected based on characteristic clinical features, EEG findings and demonstration of measles antibodies in CSF. The diagnosis is made based on Dyken's criteria.

A 40-year-old man was asymptomatic six months before presentation when he developed a week-long period of insomnia and behavioral issues, followed by a gradually progressive asymmetric onset flaccid quadriparesis. The left lower limb was affected first, followed by the right a week later and the upper limbs a month later. He developed truncal weakness, fecal and urinary incontinence with urinary retention over the next two months. Five months after the onset of the illness, he developed dysphagia, dysarthria and a diminution of vision in both eyes. There was no history of ataxia, dysmetria, fever, headache, neck stiffness or dry mouth, or recent dog bite. The patient was a known case of hypertension and had a history of bilateral tubercular pleural effusion. At presentation, he was alert and answering questions, with quadriparesis and areflexia. Fundoscopy revealed bilateral optic nerve pallor, and nerve conduction studies were consistent with a demyelinating neuropathy.

Evaluation and hospital course

The patient had a subacute course presenting as cognitive and behavioral issues followed by polyradiculoneuropathy suggesting involvement of both central and peripheral nervous systems. Infectious, toxic, metabolic, nutritional, neoplastic, inflammatory and autoimmune causes were considered. Other possibilities included mitochondrial and neurodegenerative diseases which could progress rapidly, such as adrenoleukodystrophy with associated myeloneuropathy.

The patient was thoroughly worked up with these differentials, and his investigations are detailed in Table 1. MR imaging revealed diffuse cerebral atrophy without any meningeal or parenchymal lesion or contrast enhancement. (Figure 1) A PET scan revealed uptake in the lungs and was consistent with ventilator-associated pneumonia.

A few days after admission, the patient developed respiratory distress, possibly due to bulbar and diaphragmatic weakness, for which he required invasive mechanical ventilation. He was started on pulse methylprednisolone. He also received five cycles of plasma exchange, considering an immune-mediated illness because of rapid progression. The patient’s EEG showed delta slowing, while the nerve biopsy showed demyelination, as seen in figure 2. Symptoms did not improve on oral steroids. The patient started having intermittent fever due to hospital-acquired pneumonia and was treated with antibiotics and supportive care in parallel to investigating the primary cause.

One month after admission, the patient had a seizure and a repeat EEG revealed periodic discharges (Figure 3). Measles IgG antibody index was positive (Table 2). The patient was started on intrathecal interferons. He showed a transient period of objective stability, after which the sensorium deteriorated. Repeat IgG index after four weeks revealed a reduction in titers. (Table 2) The patient had a relentlessly progressive course and succumbed to the primary illness and sepsis before a brain biopsy could be done.

Rapidly progressive cognitive decline with progressive lower motor neuron quadriparesis is rare.

Our patient did not have myoclonic jerks at any time during his illness. However, since the patient had a rapidly progressive cognitive decline with seizures and the EEG had periodic discharges, a possibility of SSPE was considered (1), confirmed by CSF anti-measles antibody titers. SSPE, though considered in the etiologic list of rapidly progressive cognitive decline, has not been commonly associated with radiculoneuropathy. We found one case in which the measles virus nucleocapsid and antigen were demonstrated in the peripheral nerve in SSPE. (2) However, in our case, the nerve biopsy revealed bland demyelination without inflammation (Figure 2). We extracted RNA from the nerve biopsy sample, performed a PCR for measles RNA, and found it negative.

So we believe our patient probably had para-infectious demyelination of the radicles and nerves, with no active nerve inflammation due to measles antibodies in the CSF and the circulation. The measles IgG antibody index was positive, and following four weeks of interferon therapy along with Isoprinosine led to a reduction in the antibody titer. (3)

Most of the patients diagnosed with SSPE die within five years of diagnosis. In a large case series of 118 patients, it was found that 20% of patients died in less than a year of symptom onset, as did our patient, who survived for just eight months after symptom onset. (4) However, this series found substantial improvement spontaneously or with treatment in more than half of the included patients. There is no cure for SSPE; most treatments aim at symptomatic management and are only occasionally beneficial. (5) Our patient rapidly progressed through stages of SSPE, given that he presented first with behavioral decline, showed progressive unresponsiveness, and eventually succumbed to the disease. (6) Literature has shown modest benefits of administering intrathecal interferons in terms of increasing survival time and improving responsiveness in patients like ours, but mortality benefits remain unclear. (7) Our patient started responding clinically and immunologically; however, he succumbed due to ongoing sepsis.

SSPE can present in an atypical fashion with peripheral nerve involvement.
Neuropathy may occur due to para-infectious demyelination with no cellular infiltration seen on the nerve biopsy.
A high index of suspicion is essential to diagnose the condition.
Early diagnosis can avoid inappropriate treatment with immunomodulation

Ethics approval and consent to participate

As per institute regulations, ethics approval is not needed for individual case reports. Written informed consent for participation was obtained from all participants.

Consent for publication

Written informed consent for publication was obtained from all participants.

Availability of data and materials

Not applicable

Competing interests

None

Funding

None

Authors' contributions

PN and BB worked up the case, reviewed patient charts, and prepared the first draft of the manuscript. JAG, MT, DV, RKS and AE observed and treated the patient throughout his hospital course and provided relevant clinical insights for the preparation of this report. SD, MCS and VS procured and interpreted the neuropathological investigations; MB procured and interpreted the microbiological investigations. AG procured and interpreted the neuroimaging and radiological investigations for the patient. MBS procured and interpreted the electroencephalogram findings of the patient. AE supervised and edited the first draft of the manuscript. All authors read and approved the final draft of the manuscript.

Acknowledgements

None

Saha V, John TJ, Mukundan P, Gnanamuthu C, Prabhakar S, Arjundas G, et al. High incidence of subacute sclerosing panencephalitis in south India. Epidemiol Infect. 1990 Feb;104(1):151–6.
Shankar SK, Taly AB, Arunodaya GR, Nagaraja D, Jayakumar PN, Ravi V. Peripheral neuropathy in subacute sclerosing panencephalitis - Immunohistochemical and ultrastructural evidence. Clin Neuropathol. 1998 Jan;17(1):15–8.
Garg RK. Subacute sclerosing panencephalitis. Postgrad Med J. 2002 Feb 1;78(916):63–70.
Risk WS. The Variable Natural History of Subacute Sclerosing Panencephalitis: A Study of 118 Cases From the Middle East. Arch Neurol. 1979 Oct 1;36(10):610.
Rocke Z, Belyayeva M. Subacute Sclerosing Panencephalitis. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 [cited 2022 Jun 11]. Available from: http://www.ncbi.nlm.nih.gov/books/NBK560673/.
Fisher D, Defres S, Solomon T, Measles-Induced, Encephalitis. QJM Mon J Assoc Physicians. 2014 May 26;108.
Anlar B, Aydin OF, Guven A, Sonmez FM, Kose G, Herguner O. Retrospective evaluation of interferon-beta treatment in subacute sclerosing panencephalitis. Clin Ther. 2004 Nov;26(11):1890–4.

Table 1: Investigative workup a week after presentation

Parameter	Observation
Hb	13.90 g/dL
WBC count	26.96 x 10^3/μl
Platelet count	369.00 x 10^3/μL
PT/INR	14.40 s/1.07
aPTT	44.40 sec
Urea/Creatinine	42/0.7 mg/dL
Bilirubin	0.37 mg/dL
ALT/AST	182/68
ALP	227 U/L
Total protein	7.0 g/dL
Albumin/globulin	3.2 g/dL /3.8 g/dL
Lipid profile	Normal
Vitamin B12	686.00 pg/mL
TSH	1.49 μIU/mL
T3	75 ng/dL
T4	7.1 μg/dL
HIV 1,2, HBsAg, anti HCV, VDRL	Negative
ANA, anti ds-DNA, ENA profile, ANCA	Negative
aCL –IgG, aCL - IgM	Negative
Anti LKM 1, ASMA	Negative
Lyme Serology	Negative
CSF Examination
CSF cell count	Nil
CSF protein	38 mg/dL
CSF glucose/Corresponding RBS	60 mg/dL
GeneXpert, AFB, TBPCR	Negative
Cryptococcal antigen	Negative
CSF VDRL	Non-reactive
CSF Malignant Cytology	Negative
CSF CMV PCR	Negative
VZV DNA	Negative
Bone marrow aspirate/biopsy/flowcytometry	Cellular bone marrow; adequate trilineage hematopoiesis
Nerve biopsy	Figure 2

EEG

Figure 3

NMO/MOG antibody	Negative
Anti ganglioside panel	Negative

Table 2: Measles (Rubeola) IgG Antibodies

Measles (Rubeola) IgG Antibodies
	One month after presentation	Two months after presentation
Serum IgG Measles	197 U/mL	193.5 U/mL
CSF IgG Measles	377.2 U/mL	177.2 U/mL
Serum Total IgG	541 mg/dL	712.00 mg/dL
CSF Total IgG	2.08 mg/dL	2.55 mg/dL
CSF/Serum Quotient Reference	2.47 [Positive >1.5]	1.3 [Equivocal (1.30-1.50)]

No competing interests reported.

Peripheral nervous system involvement in SSPE as a parainfectious manifestation - A case report

Status:

Version 1

Abstract

Figures

Background

Case Presentation

Discussion and Conclusions

Declarations

Ethics approval and consent to participate

Consent for publication

Availability of data and materials

Competing interests

Funding

Authors' contributions

Acknowledgements

References

Tables

Additional Declarations

Status:

Version 1