Chronic Pregabalin Abuse with Subacute Encephalopathy Mimicking Autoimmune Encephalitis
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.333486
Source of Support: None, Conflict of Interest: None
Keywords: Abuse, autoimmune encephalitis, movement disorders, pregabalin, toxicity
Pregabalin is a gabapentinoid increasingly prescribed for many painful conditions and anxiolysis. Pregabalin toxicity due to acutely consuming large quantities results in reduced consciousness, myoclonic encephalopathy. Pregabalin abuse due to consumption of supratherapeutic dose over months to years leads to self-injury and somnolence. The abuse potential of pregabalin is increasingly identified particularly in western countries, where the drug is listed either for restricted use or in the process of restricting its use. The extent of pregabalin abuse in India is not clear due to lack of high-quality data; however, three previous case reports along with our case report, all reported during 2013 to 2018 indicate increasing pregabalin abuse in India. We report a unique case of chronic pregabalin abuse with subacute neuro-psychiatric symptoms mimicking autoimmune encephalitis.
A 31-year-old gentleman, right handed, a PhD scholar as well part-time employee at a start-up company, presented with the history of the involuntary dropping of objects from the hand of two years duration, bizarre behavioral changes of three months duration, intermittent winking of the right eye and abnormal oro-facial movements of three months duration. He also gave a history of abnormal rapid jerky involuntary movements of both hands (R > L). He had unsteady gait with fall tendency to either side of one-month duration. His wife also noticed frequent dropping of objects from his hand during last two years associated with sudden jerky transient movements of the hand.
He has psoriasis since childhood, for which he is not on any medications currently. He also gave a history of recurrent oral ulcers in childhood, had long-term remission, and however recurred with above neurological symptoms. He is a smoker, alcoholic, consumes marijuana occasionally, uncontrolled over-eating. Even on repeated enquiry, he denied any other substance abuse. Personal history is significant for the failure of a previous love affair, erectile dysfunction, and depression. His father also has a history of recurrent oral ulcers and previously had epilepsy His wife was diagnosed with SLE and APLA syndrome.
He had consulted many physicians; was diagnosed previously as a psychiatric disorder and started on SSRI and antipsychotics. He underwent MRI during his previous consultation, reported as normal. He came to our hospital seeking the second opinion. His parents showed several recorded videos during the course of this new onset illness, which revealed different kinds of abnormal movements in him. During the examination, several myoclonic jerky movements witnessed involving both upper and lower limbs, as well oro-facial muscles. He was profusely sweating during all his visits to outpatient department, throughout in-patient period. He had bilateral gaze-evoked nystagmus (L > R), impaired tandem gait, generalized brisk deep tendon reflexes. His previous MR imaging reviewed, which showed subtle T2/FLAIR hyperintensities of right cerebellar white matter, right cingulate gyrus, left posterior limb of internal capsule [Figure 1]. He was satisfying the diagnostic criteria for possible autoimmune encephalitis (subacute onset of altered mental status/psychiatric symptoms, MRI features suggestive of encephalitis and reasonable exclusion of alternative causes). In view of the history of psoriasis and recurrent oral ulcers, family history of recurrent oral ulcers, autoimmune encephalitis was first among the differential diagnoses.
He was advised admission and detailed evaluation including repeat MRI during his first visit. Though he was admitted to the hospital, immediately after reaching ward he reported paranoid ideas and absconded from the hospital on the same day. He was advised 1 gram of methylprednisolone IV injection for 5 days. His parents were able to convince the patient to carry out the injectable treatment, to which he was highly reluctant but could not avoid parents' request.
After the fifth dose of IV methylprednisolone, his symptoms reduced significantly, hence his parents convinced him to seek medical attention promptly. Excellent response to steroids strengthened our suspicion for autoimmune encephalitis in him. He was admitted to hospital for the second time, underwent extensive autoimmune workup (blood and CSF studies), repeat high-resolution MRI. The follow-up MRI did at an interval of 2 weeks showed subtle T2/FLAIR hyperintensity involving left cerebellar hemisphere white matter, left middle cerebellar peduncle, left parieto-occipital white matter [Figure 2], left thalamus. After discharge from the hospital, he had a recurrence with worsening of symptoms, frequent falls, became severely disabled and not able to carry out his daily activities. He revisited outpatient department, and was clinically diagnosed as paroxysmal kinesiogenic dyskinesia. Sodium valproate was started with reasonable improvement in symptoms. While awaiting blood, CSF reports, and PET scan, he finally admitted to consuming 30 tablets of 75 mg pregabalin daily (total dose of 2,250 mg/day) since last 2 years. He claims to feel 'psychedelic effects' (he revealed that he had gathered information about the pregabalin drug on internet), 'high' while on medication, makes him calm, and can slip to sleep easily during the night. He claims no such neuropsychological symptoms since he started pregabalin abuse. His all blood and CSF investigations, PET-CT and EEG were normal. Serum pregabalin levels were not done. He stopped pregabalin abuse abruptly and was observed in the hospital for three days during which time he was completely asymptomatic. He and his family members underwent several sessions of counselling. During one-month follow-up, he had successfully abstained from the drug abuse and remained asymptomatic.
Pregabalin is a drug approved for many disabling long-term conditions like epilepsy, post-herpetic neuralgia, fibromyalgia, neuropathic pain, diabetic neuropathy, and generalized anxiety disorder. Acute pregabalin toxicity/acute self-poisoning is a clinical syndrome secondary to consumption of the supratherapeutic dose of pregabalin in short duration. The dosage for acute pregabalin toxicity described in the literature varies from 600mg to 11.5 g. Chronic pregabalin toxicity/pregabalin abuse is due to un-indicated long-term consumption of the therapeutic/supratherapeutic dose of pregabalin.
Pregabalin has a relatively simple pharmacokinetic profile, rapidly and extensively absorbed with the oral bioavailability of more than 90%, is not bound to plasma protein, undergoes negligible metabolism, excreted primarily by renal excretion. While acute pregabalin accumulation reported in renal failure patients, its accumulation in healthy adults not reported. We describe a case of chronic pregabalin abuse since two years, developing neuro-psychiatric syndrome due to subacute (3 months duration) toxicity. To the best of our knowledge, we are first to describe changes in brain parenchyma in MR imaging, mimicking autoimmune encephalitis. Myoclonic encephalopathy secondary to pregabalin toxicity is previously described; however, we describe a case with varied abnormal movement disorders, which include – tremor, asterixis, tics, fasciculations, dyskinesia, choreoathetosis, ataxia. The subacute (3 months) onset of neuro-psychiatric symptoms in our patient who used to abuse the same dosage of the drug since 2 years remains elusive.
A systematic review by Schjerning O, et al., in 2016 described nine cases of pregabalin abuse consuming supra-therapeutic dosage, with the mean age of 34 years (age range 19-47 years), most were diagnosed with psychiatric disease. Pregabalin also found to be a co-abuse substance along with other abusive drugs, particularly heroin.
Concern for abuse/misuse of pregabalin rose due to a recently increased prescription of pregabalin., The United States of America (USA) and the United Kingdom (UK) have identified the problem of pregabalin abuse and taking appropriate step to control its misuse. The United States Drug Enforcement Administration (DEA) placed pregabalin and all products containing pregabalin into Schedule V of the Controlled Substances Act in 2005. Both Pregabalin and gabapentin misuse are increasingly being reported in the UK, which has led to the proposal by Advisory Council on the Misuse of Drugs (ACMD) to classify these drugs as Class C drugs (i.e., controlled drugs). Similar trends reported from other countries like Germany, Finland, and USA. Realizing the abuse potential and increasing reports of the misuse of the drug, pregabalin was agenda Item 5.1 in thirty-ninth meeting of WHO Expert Committee on Drug Dependence in November 2017. Ojanpera I, et al., noted clearly increasing trend in fatal toxicity index (FTI) with pregabalin in Finland, they also identified pregabalin as emerging drug of abuse.
There are only three cases of pregabalin misuse/abuse reported from India so far [Table 1]. The prevalence of pregabalin abuse is probably undermined. Low level of suspicion among neurologists/psychiatrists/emergency physicians could be one of the contributory factors for non-detection of pregabalin toxicity/abuse. Even with a limited number of reports of increasing abuse of pregabalin, the Drug Controller General of India (DGCI) should consider restricting the availability of this medicine to reduce misuse. This is increasingly relevant to India, as one legitimate prescription can be used by many to buy medicines at multiple stores on the same day without any questions being asked by the issuing pharmacists. An alternative suggestion would be to stamp “drugs delivered” on the prescription by pharmacists, so that same prescription cannot be misused.,,
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[Figure 1], [Figure 2]