LETTERS
Steroid-Responsive Myoclonus in Adult-Onset Subacute Sclerosing Panencephalitis To the Editor: Subacute sclerosing panencephalitis (SSPE) is a rare inflammatory disease of the central nervous system caused by persistence of measles virus. The interval between primary measles and onset of SSPE is often protracted, averaging 6 years.1 The illness usually affects children and adolescents, although onset in adulthood is not uncommon.2 Typical course is heralded by intellectual and behavioral deterioration followed by myoclonic or other types of seizures and culminates in coma and ultimately death in several months.3 Despite this seemingly bleak prognosis, at least half of the patients experience substantial improvement or clinical plateaus, and an estimated 1 in 5 patients survive more than 4 years.4 Currently, treatment is aimed at either seizure control (with valproate, clonazepam, etc.) or disease modification (mainly with isoprinosine, alone or in combination with a-interferon), though frequently both. Steroids are less commonly used as diseasemodifying agents, albeit with inconsistent results,1 and rarely for seizure control. We report successful treatment of refractory myoclonic seizures with prednisolone in a patient with adult-onset SSPE. Case Report A 21-year-old man was admitted to the neurology department of our hospital in June 2011 with complaints of gradually progressive abnormal
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jerky movements of limbs, ataxia, and frequent falls, over the past year. A psychiatry referral was sought with us for management of concurrent intellectual and behavioral problems. Assessment revealed that, 2 years earlier, he developed difficulty concentrating in the classroom, misunderstood instructions, and required frequent reminders. He gradually lost interest in studies and dropped out of school. His behavior became childish, stubborn, and irritable. Motor symptoms appeared 1 year after the onset, worsened progressively, and led to the current hospitalization. Family members were unable to recall a history of measles or details of immunization. There was no family history of myoclonic jerks. Physical examination was normal except for several small bruises over both elbows and knees. Neurological examination revealed ataxic gait, myoclonic jerks in both upper and lower limbs, slurred speech, and verbal perseveration. His Mini-Mental State Exam (MMSE) score was 16/30. Routine blood investigations, serum B12, and folic acid were within normal limits. Special investigations, including thyroid function test, VDRL, enzyme-linked immunosorbent assay (ELISA) for HIV, serum ceruloplasmin, and slit-lamp examination failed to reveal any abnormality. Biochemical and cytological examination of cerebrospinal fluid (CSF) was within normal range. Antimeasles IgG antibody estimation by ELISA method was negative in CSF but positive in serum. T2-weighted magnetic resonance imaging (MRI) of brain showed punctuate hyperintensities in subcortical and periventricular deep white matter in both cerebral
hemispheres, and electroencephalogram (EEG) revealed characteristic periodic spike and slow-wave discharges, occurring every 7 sec, time-locked with myoclonic jerks. A diagnosis of SSPE was made, and discussion was held with family members regarding prognosis and available treatment options. They did not consent to intraventricular interferon therapy, and isoprinosine was locally unavailable. It was therefore decided to treat patient symptomatically with sodium valproate (1,000 mg/day) and clonazepam (1 mg/day). In absence of any improvement, dose of valproate was increased after a week to 1,200 mg/day; however, the patient developed hyperammonemia, manifested by confusion, tremors, worsening of ataxia, and raised serum ammonia levels, necessitating dose reduction back to 1,000 mg/day. The patient was discharged after resolution of hyperammonemia. At follow-up, dose of clonazepam was increased to 2 mg/day, but this resulted in oversedation without any improvement in myoclonus. As myoclonic jerks continued unabated for 2 months, corticosteroid was considered as add-on therapy, to which the family consented. Prednisolone was started at 40 mg/day, resulting in gradual but marked reduction in intensity and frequency of seizures. While valproate and clonazepam were continued, prednisolone was slowly tapered after 3 months. Despite this, myoclonic seizures continued to improve and completely subsided after 3 more months, in February 2012. There was no further clinical deterioration, and, in fact, the patient showed
J Neuropsychiatry Clin Neurosci 25:4, Fall 2013
SHARMA and BISWAS noticeable improvements in cognitive functioning, as well; his MMSE score was 23/30 in September 2012. There were no significant adverse effects of prednisolone except increased appetite and weight gain, which subsided gradually after its discontinuation. Discussion Diagnosis of SSPE is based on presence of any three of the following: characteristic clinical course, EEG findings, elevated antimeasles IgG in serum and/or CSF, elevated immunoglobulins in CSF, and isolation of virus in brain biopsy.4 Our patient presented with a characteristic history and EEG findings suggestive of SSPE and had elevated titres of antimeasles IgG in serum. Although unusual, low or undetectable levels of antimeasles IgG in CSF have been reported in a number of patients with SSPE;5,6 however, serum levels are nearly always elevated.6 In uncertain cases, presence of antimeasles IgM in CSF supports the diagnosis of SSPE;5 however, this facility was not available at our center. There has been considerable debate regarding treatment of SSPE. Although isoprinosine and a-interferon are reported to be the most effective disease-modifying agents, their response rate is, at best, modest.7 Other antiviral or immunomodulatory agents tried in individual cases are ribavirin, amantadine, natural interferon, intravenous immunoglobulin, and corticosteroids.1,7 In particular, myoclonic seizures are notoriously difficult to manage with conventional antiepileptics.8 In a few instances, trihexyphenidyl8 and carbamazepine9 have been used to control these resistant seizures. We considered using corticosteroids in our patient when myoclonus did not respond to maximally-tolerated doses of valproate and clonazepam.
Although steroids have been used to treat intractable seizures in childhood epilepsies,10 in SSPE, their use seems to be limited to ophthalmologic complications,11 fulminant presentation,12 or later stage of illness as last-resort option;7 rarely has it been used for treating refractory myoclonic seizures. Of interest is the fact that not only did our patient’s myoclonic jerks subside, but his hitherto declining cognitive functioning also showed noticeable improvement. This improvement must be interpreted with caution, as spontaneous improvement is known to occur in SSPE;4 however, a clear temporal correlation between initiation of prednisolone and clinical improvement in our case indicates otherwise. Similar response has been observed by previous authors,13,14 although the role of steroids was not explicitly acknowledged, possibly because of small sample size. Good response in our case may be attributed to subacute course of illness and use of steroid relatively early in disease (i.e., Stage 2).4 It is unclear whether neurological damage in SSPE is due to direct effects of virus or action of the host’s immune system against virus-laden brain cells,15 and it might be assumed that therapeutic actions of steroids involve the latter. It is possible that other patients might obtain benefit from steroids given earlier in the course of their illness, by improving seizure control and possibly disease modification. Although it is premature to draw conclusions from a single report, nevertheless, this case is important as it broadens the scope of treatment in SSPE. Vivek Sharma, M.D. Dept. of Psychiatry Kailash Hospital Greater Noida, Uttar Pradesh, India
J Neuropsychiatry Clin Neurosci 25:4, Fall 2013
Devdutta Biswas, M.D. Dept. of Psychiatry Hindu Rao Hospital New Delhi, India Correspondence: Dr. Vivek Sharma; e-mail: doc.v.sharma@hotmail. com References 1. Gutierrez J, Issacson RS, Koppel BS: Subacute sclerosing panencephalitis: an update. Dev Med Child Neurol 2010; 52:901–907 2. Singer C, Lang AE, Suchowersky O: Adult-onset subacute sclerosing panencephalitis: case reports and review of the literature. Mov Disord 1997; 12:342–353 3. Jabbour JT, Duenas DA, Sever JL, et al: Epidemiology of subacute sclerosing panencephalitis (SSPE): a report of the SSPE Registry. JAMA 1972; 220:959–962 4. Risk WS, Haddad FS: The variable natural history of subacute sclerosing panencephalitis: a study of 118 cases from the Middle East. Arch Neurol 1979; 36:610–614 5. Lakshmi V, Malathy Y, Rao RR: Serodiagnosis of subacute sclerosing panencephalitis by enzyme-linked immunosorbent assay. Indian J Pediatr 1993; 60:37–41 6. Chung BHY, Ip PP, Wong VC, et al: Acute fulminant subacute sclerosing panencephalitis with absent measles and PCR studies in cerebrospinal fluid. Pediatr Neurol 2004; 31:222–224 7. Gascon GG; International Consortium on Subacute Sclerosing Panencephalitis: Randomized treatment study of inosiplex versus combined inosiplex and intraventricular interferon-alpha in subacute sclerosing panencephalitis (SSPE): International Multicenter Study. J Child Neurol 2003; 18:819–827 8. Nunes ML, da Costa JC, da Silva LF: Trihexyphenidyl and isoprinosine in the treatment of subacute sclerosing panencephalitis. Pediatr Neurol 1995; 13:153–156 9. Yi git A, Sarikaya S: Myoclonus relieved by carbamazepine in subacute sclerosing panencephalitis. Epileptic Disord 2006; 8:77–80 10. Kurian M, Korff CM: Steroids in pediatric epilepsy: infantile spasms and beyond. Epileptologie 2011; 28:15–20
http://neuro.psychiatryonline.org
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LETTERS 11. Tandon R, Khanna S, Sharma MC, et al: Subacute sclerosing panencephalitis presenting as optic neuritis. Indian J Ophthalmol 1999; 47:250–252 12. Faivre A, Souraud JB, McGonigal A, et al: Fulminant adult-onset subacute sclerosing panencephalitis: a case report. BMJ Case Rep 2009; pii: bcr09.2008.0922
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13. Cobb WA, Morgan-Hughes JA: Non-fatal subacute sclerosing leucoencephalitis. J Neurol Neurosurg Psychiatry 1968; 31:115–123 14. Di Trapani G, Mazza S, Tomassetti P, et al: Clinical-electrophysiological correlations in a long-term case of subacute sclerosing panencephalitis with partial
clinical improvement. Eur Neurol 1991; 31:23–29 15. Boos J, Esiri MM: Subacute and chronic encephalitis, in Viral Encephalitis: Pathology, Diagnosis, and Management. Boston, MA, Blackwell Scientific Publishers, 1986, pp 266–291
J Neuropsychiatry Clin Neurosci 25:4, Fall 2013
Steroid-Responsive Myoclonus in Adult-Onset Subacute Sclerosing Panencephalitis To the Editor: Subacute sclerosing panencephalitis (SSPE) is a rare inflammatory disease of the central nervous system caused by persistence of measles virus. The interval between primary measles and onset of SSPE is often protracted, averaging 6 years.1 The illness usually affects children and adolescents, although onset in adulthood is not uncommon.2 Typical course is heralded by intellectual and behavioral deterioration followed by myoclonic or other types of seizures and culminates in coma and ultimately death in several months.3 Despite this seemingly bleak prognosis, at least half of the patients experience substantial improvement or clinical plateaus, and an estimated 1 in 5 patients survive more than 4 years.4 Currently, treatment is aimed at either seizure control (with valproate, clonazepam, etc.) or disease modification (mainly with isoprinosine, alone or in combination with a-interferon), though frequently both. Steroids are less commonly used as diseasemodifying agents, albeit with inconsistent results,1 and rarely for seizure control. We report successful treatment of refractory myoclonic seizures with prednisolone in a patient with adult-onset SSPE. Case Report A 21-year-old man was admitted to the neurology department of our hospital in June 2011 with complaints of gradually progressive abnormal
E30
http://neuro.psychiatryonline.org
jerky movements of limbs, ataxia, and frequent falls, over the past year. A psychiatry referral was sought with us for management of concurrent intellectual and behavioral problems. Assessment revealed that, 2 years earlier, he developed difficulty concentrating in the classroom, misunderstood instructions, and required frequent reminders. He gradually lost interest in studies and dropped out of school. His behavior became childish, stubborn, and irritable. Motor symptoms appeared 1 year after the onset, worsened progressively, and led to the current hospitalization. Family members were unable to recall a history of measles or details of immunization. There was no family history of myoclonic jerks. Physical examination was normal except for several small bruises over both elbows and knees. Neurological examination revealed ataxic gait, myoclonic jerks in both upper and lower limbs, slurred speech, and verbal perseveration. His Mini-Mental State Exam (MMSE) score was 16/30. Routine blood investigations, serum B12, and folic acid were within normal limits. Special investigations, including thyroid function test, VDRL, enzyme-linked immunosorbent assay (ELISA) for HIV, serum ceruloplasmin, and slit-lamp examination failed to reveal any abnormality. Biochemical and cytological examination of cerebrospinal fluid (CSF) was within normal range. Antimeasles IgG antibody estimation by ELISA method was negative in CSF but positive in serum. T2-weighted magnetic resonance imaging (MRI) of brain showed punctuate hyperintensities in subcortical and periventricular deep white matter in both cerebral
hemispheres, and electroencephalogram (EEG) revealed characteristic periodic spike and slow-wave discharges, occurring every 7 sec, time-locked with myoclonic jerks. A diagnosis of SSPE was made, and discussion was held with family members regarding prognosis and available treatment options. They did not consent to intraventricular interferon therapy, and isoprinosine was locally unavailable. It was therefore decided to treat patient symptomatically with sodium valproate (1,000 mg/day) and clonazepam (1 mg/day). In absence of any improvement, dose of valproate was increased after a week to 1,200 mg/day; however, the patient developed hyperammonemia, manifested by confusion, tremors, worsening of ataxia, and raised serum ammonia levels, necessitating dose reduction back to 1,000 mg/day. The patient was discharged after resolution of hyperammonemia. At follow-up, dose of clonazepam was increased to 2 mg/day, but this resulted in oversedation without any improvement in myoclonus. As myoclonic jerks continued unabated for 2 months, corticosteroid was considered as add-on therapy, to which the family consented. Prednisolone was started at 40 mg/day, resulting in gradual but marked reduction in intensity and frequency of seizures. While valproate and clonazepam were continued, prednisolone was slowly tapered after 3 months. Despite this, myoclonic seizures continued to improve and completely subsided after 3 more months, in February 2012. There was no further clinical deterioration, and, in fact, the patient showed
J Neuropsychiatry Clin Neurosci 25:4, Fall 2013
SHARMA and BISWAS noticeable improvements in cognitive functioning, as well; his MMSE score was 23/30 in September 2012. There were no significant adverse effects of prednisolone except increased appetite and weight gain, which subsided gradually after its discontinuation. Discussion Diagnosis of SSPE is based on presence of any three of the following: characteristic clinical course, EEG findings, elevated antimeasles IgG in serum and/or CSF, elevated immunoglobulins in CSF, and isolation of virus in brain biopsy.4 Our patient presented with a characteristic history and EEG findings suggestive of SSPE and had elevated titres of antimeasles IgG in serum. Although unusual, low or undetectable levels of antimeasles IgG in CSF have been reported in a number of patients with SSPE;5,6 however, serum levels are nearly always elevated.6 In uncertain cases, presence of antimeasles IgM in CSF supports the diagnosis of SSPE;5 however, this facility was not available at our center. There has been considerable debate regarding treatment of SSPE. Although isoprinosine and a-interferon are reported to be the most effective disease-modifying agents, their response rate is, at best, modest.7 Other antiviral or immunomodulatory agents tried in individual cases are ribavirin, amantadine, natural interferon, intravenous immunoglobulin, and corticosteroids.1,7 In particular, myoclonic seizures are notoriously difficult to manage with conventional antiepileptics.8 In a few instances, trihexyphenidyl8 and carbamazepine9 have been used to control these resistant seizures. We considered using corticosteroids in our patient when myoclonus did not respond to maximally-tolerated doses of valproate and clonazepam.
Although steroids have been used to treat intractable seizures in childhood epilepsies,10 in SSPE, their use seems to be limited to ophthalmologic complications,11 fulminant presentation,12 or later stage of illness as last-resort option;7 rarely has it been used for treating refractory myoclonic seizures. Of interest is the fact that not only did our patient’s myoclonic jerks subside, but his hitherto declining cognitive functioning also showed noticeable improvement. This improvement must be interpreted with caution, as spontaneous improvement is known to occur in SSPE;4 however, a clear temporal correlation between initiation of prednisolone and clinical improvement in our case indicates otherwise. Similar response has been observed by previous authors,13,14 although the role of steroids was not explicitly acknowledged, possibly because of small sample size. Good response in our case may be attributed to subacute course of illness and use of steroid relatively early in disease (i.e., Stage 2).4 It is unclear whether neurological damage in SSPE is due to direct effects of virus or action of the host’s immune system against virus-laden brain cells,15 and it might be assumed that therapeutic actions of steroids involve the latter. It is possible that other patients might obtain benefit from steroids given earlier in the course of their illness, by improving seizure control and possibly disease modification. Although it is premature to draw conclusions from a single report, nevertheless, this case is important as it broadens the scope of treatment in SSPE. Vivek Sharma, M.D. Dept. of Psychiatry Kailash Hospital Greater Noida, Uttar Pradesh, India
J Neuropsychiatry Clin Neurosci 25:4, Fall 2013
Devdutta Biswas, M.D. Dept. of Psychiatry Hindu Rao Hospital New Delhi, India Correspondence: Dr. Vivek Sharma; e-mail: doc.v.sharma@hotmail. com References 1. Gutierrez J, Issacson RS, Koppel BS: Subacute sclerosing panencephalitis: an update. Dev Med Child Neurol 2010; 52:901–907 2. Singer C, Lang AE, Suchowersky O: Adult-onset subacute sclerosing panencephalitis: case reports and review of the literature. Mov Disord 1997; 12:342–353 3. Jabbour JT, Duenas DA, Sever JL, et al: Epidemiology of subacute sclerosing panencephalitis (SSPE): a report of the SSPE Registry. JAMA 1972; 220:959–962 4. Risk WS, Haddad FS: The variable natural history of subacute sclerosing panencephalitis: a study of 118 cases from the Middle East. Arch Neurol 1979; 36:610–614 5. Lakshmi V, Malathy Y, Rao RR: Serodiagnosis of subacute sclerosing panencephalitis by enzyme-linked immunosorbent assay. Indian J Pediatr 1993; 60:37–41 6. Chung BHY, Ip PP, Wong VC, et al: Acute fulminant subacute sclerosing panencephalitis with absent measles and PCR studies in cerebrospinal fluid. Pediatr Neurol 2004; 31:222–224 7. Gascon GG; International Consortium on Subacute Sclerosing Panencephalitis: Randomized treatment study of inosiplex versus combined inosiplex and intraventricular interferon-alpha in subacute sclerosing panencephalitis (SSPE): International Multicenter Study. J Child Neurol 2003; 18:819–827 8. Nunes ML, da Costa JC, da Silva LF: Trihexyphenidyl and isoprinosine in the treatment of subacute sclerosing panencephalitis. Pediatr Neurol 1995; 13:153–156 9. Yi git A, Sarikaya S: Myoclonus relieved by carbamazepine in subacute sclerosing panencephalitis. Epileptic Disord 2006; 8:77–80 10. Kurian M, Korff CM: Steroids in pediatric epilepsy: infantile spasms and beyond. Epileptologie 2011; 28:15–20
http://neuro.psychiatryonline.org
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LETTERS 11. Tandon R, Khanna S, Sharma MC, et al: Subacute sclerosing panencephalitis presenting as optic neuritis. Indian J Ophthalmol 1999; 47:250–252 12. Faivre A, Souraud JB, McGonigal A, et al: Fulminant adult-onset subacute sclerosing panencephalitis: a case report. BMJ Case Rep 2009; pii: bcr09.2008.0922
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13. Cobb WA, Morgan-Hughes JA: Non-fatal subacute sclerosing leucoencephalitis. J Neurol Neurosurg Psychiatry 1968; 31:115–123 14. Di Trapani G, Mazza S, Tomassetti P, et al: Clinical-electrophysiological correlations in a long-term case of subacute sclerosing panencephalitis with partial
clinical improvement. Eur Neurol 1991; 31:23–29 15. Boos J, Esiri MM: Subacute and chronic encephalitis, in Viral Encephalitis: Pathology, Diagnosis, and Management. Boston, MA, Blackwell Scientific Publishers, 1986, pp 266–291
J Neuropsychiatry Clin Neurosci 25:4, Fall 2013
