Familial encephalopathy with neuroserpin inclusion bodies (FENIB) presenting as catatonia: A case report in a psychiatry setting

INTRODUCTION Catatonia has always been in the limelight of psychiatric nosological systems and now has been assigned a special chapter in DSM-5.[1] Catatonia secondary to general medical condition, more commonly called as organic catatonia, is being increasingly recognised in the recent years.[2] Few studies have also described the symptom profile, etiological aspects, and treatment response of organic catatonia.[3,4] FENIB is a rare hereditary degenerative condition of the central nervous system.[5] Individuals with this condition exhibit low attention and focus, diminishing work or academic performance, and language difficulties and eventually endure a deterioration in intellectual capacities (dementia).[6] There have reports of additional symptoms, such as uncontrollable, erratic muscular spasms, seizures, mood changes including apathy, despair, and hostility.[7,8] Eventually, the afflicted individuals need thorough supportive conservative medical care and management of comorbid conditions (myoclonus, seizures etc.). The key pathological finding in FENIB is the presence of neuronal inclusion bodies distributed throughout the gray matter of the cerebral cortex and in certain subcortical nuclei.[5] However, FENIB presenting as catatonia is not yet reported, and probably ours is the first case report in this regard, suggesting to include FENIB in the list of etiological conditions of organic catatonia. CASE DESCRIPTION The index patient was a 24-year young female, studied till 9th standard, from a nuclear family, of lower middle socioeconomic status, second in birth order, born out of full-term normal vaginal delivery, maintained well during childhood, and attained all the developmental milestones normally for her age with poor scholastic performance. As per the informants (parents), she was able to do all household chores, was able to understand the concept of money, and reportedly was fast in grasping all the concepts. She failed in her 10th standard, and thereafter, she did not wish to study further. She used to help with all the household chores efficiently until around 2016, would interact with family members, and would be euthymic. In 2016, when she was around 17 years of age, with apparently no precipitating event, she started to avoid doing household chores, had reduced interaction with family members, had decreased emotional reaction on hearing any sad or happy news, and would not actively participate in any family discussion which was quite unlike her premorbid self. She would be seen sitting idle in front of the television for the whole day in the same place. She would keep looking in one direction for a period of 2 to 3 minutes without blinking. She would not bathe, brush, and eat by herself; would eat only when served; and did not show much change in facial expressions. On many occasions, she noted to wear her clothes upside down and would not bother much about the same; during her menstrual cycle, the patient would not take care of her hygiene. Over the years, she gradually started to respond in very few sentences or just by nodding her head in yes or no. Due to gradual worsening of her condition, she was brought to our outpatient psychiatric services in October 2023 and a diagnosis of Catatonia was considered with possibility of an underlying psychotic illness (schizophrenia with predominantly negative symptoms). When rated on Busch Francis Catatonia Rating Scale (BFCRS), she scored 14, but on administering 2 mg intravenous lorazepam (Lorazepam Challenge Test), it was negative (no change in BFCRS score). A working diagnosis of catatonia and simple schizophrenia was kept, after which she was planned for electroconvulsive therapy (ECT). She was started on Tab. Aripiprazole 5 mg OD. However, in the next few days, her catatonic signs and symptoms worsened (posturing, staring, negativism, closing her mouth on being fed, resisting any possible body movement, and even started to pass urine and faces in her clothes). Ten effective modified ECTs were administered, and she was admitted to our inpatient psychiatric services for diagnostic clarification. Following ECTs, she had gradual reduction in the catatonic signs, and BFCRS score reduced to 4 [Table 1].Table 1: Rating on the Bush Francis Catatonia Rating Scale on serial evaluation and response to ECTIn ward observation and serial mental state examination, she was found to behaving oddly, would be seen smiling inappropriately, would not understand any commands, and continued to pass urine and stool in her clothes and appear unbothered by it. She was found to have severe inattention, echolalia and echopraxia (repetition of same words and actions), perseveration (continuous type abnormally prolongs or repeats a behaviour without interruption), utilization behaviour (she tried holding any object handed near to her), grasp reflex present, and frontal release signs. In neurological examination, she had brisk deep tendon reflexes (3+), and plantar reflex was flexor. Rigidity was present in all the four limbs (4/5); however, it could be due to catatonic negativism. Fundus examination was normal. Tab aripiprazole 5 mg was stopped in the first week, and after 2 weeks of stopping ECTs, she had relapse of catatonia with BFCRS score rising up to 17. ECTs were restarted, and after 7 ECTs, catatonia improved [Table 1]. Neurology consultation was taken in view of suspicion of organicity as there was the presence of diffuse cerebral atrophy on MRI (brain) at the young age of 24 years. All the metabolic parameters including serum ceruloplasmin and blood levels for heavy metals were normal. Following which blood investigation for whole genome exome sequencing was sent (report usually takes 1 month time). She was kept on weekly maintenance ECTs as every time a gap of 5 days of ECT was given, she had relapse of catatonic signs and she was discharged from inpatient psychiatric facilities. Around 1 month later, she developed an episode of generalized tonic clonic seizures (lasting for 2 to 3 minutes) and was unconscious for 20 to 25 minutes. Electroencephalogram (EEG) revealed seizure activity, and she was started on phenytoin 300 mg/day. The whole genome exome report revealed that she had a heterozygous variant of uncertain significance in exon 9, SERPINI1 gene (variant – c.1178G.C, p.Arg393Pro, Depth-64x; Genomin nomenclature – Chr 3;g.167543056G>C), which had an autosomal dominant inheritance and was diagnosed with familial encephalopathy, with neuroserpin inclusion bodies. Family members were counselled about the diagnosis and future expectations from treatment. Genetic testing of parents could not be done due to financial constraints. There was no family history of epilepsy of similar symptoms in parents or in any relatives. The absence of similar symptoms in parents could possibly be due to de novo mutation resulting in a pathogenic variant, as has been reported in a few case reports.[9] Due to frequent relapse of catatonia, she had been kept on maintenance ECTs every fortnightly and phenytoin 300 mg/day from neurology. On follow-up until date, she is maintaining reasonably well and able to do self-care activities but is having gradual cognitive decline as evident from assessment of Hindi Mini-Mental State Examination Scale ranging from 15 to 17 always (which is the natural course of the disease – FENIB). DISCUSSION The index case highlights the importance of evaluating for organic cause in patients presenting with catatonia with unusual presentation. The patient initially presented with symptoms suggestive of negative symptoms of schizophrenia and subsequently presented with catatonia, which almost simulated the presentation of catatonic schizophrenia.[10] However, after a thorough investigation and the hunch of the possibility of organic cause (due to frequent relapse of catatonia when ECTs were stopped/spaced in the absence of any gross psychotic/positive symptoms along with cognitive impairment at a young age), we were able to reach to the diagnosis of FENIB. In many secondary and tertiary care psychiatric settings in low and middle-income countries, the facilities to perform a thorough organic workup are not available, and hence, many a time, many patients with unusual presentation with catatonia are labelled/misdiagnosed as schizophrenia/psychosis, and are treated with multiple antipsychotics/other types of treatment strategies.[11-13] The age of onset, rate of progression, and severity of FENIB varies depending on the specific mutation in the neuroserpin gene.[5] The symptoms of FENIB may become apparent as early as the first decade or as late as the fifth or sixth decade of life. Our knowledge of FENIB is limited by the fact that only a few families with FENIB have been described.[6,14,15] In late onset illness, affected individuals typically experience declining cognitive function that affects their ability to work. In addition to deficits in attention, concentration, and language usage, an impaired ability to judge the spatial relationship between objects (poor visuospatial skills). A striking finding is perseveration, a condition marked by uncontrolled, repetitive behaviors such as continually repeating a word, phrase, or gesture, present in the index case.[5] Daily living skills are gradually lost, and they become increasingly dependent on family or other care givers. Eventually, most will require comprehensive care in a skilled nursing facility. Other symptoms may include tremor, motor restlessness, dystonia (sustained muscle contractions associated with abnormal, uncontrolled movements and postures), and occasionally seizures.[8] The rate of decline is relatively slow, and with adequate supportive care, patients may survive for many years or even decades.[5] When FENIB begins earlier in life, from the first to third decade, there are additional neurological symptoms and the disease may progress quite rapidly. Seizures may be the first manifestation, including a syndrome called progressive myoclonic epilepsy (PME).[7,8] The seizures may be difficult to control with medication, and episodes of status epilepticus or persistent, repetitive seizures may occur, sometimes resulting in death. In general, an earlier age of onset is associated with more severe symptoms, and the patient may survive for only a few years.[16] Cognitive deficits have been mostly reported in frontal and frontal-subcortical areas in the reported cases across the globe.[6] Few case reports suggest that patients with G392R and G392E variants have onset of symptoms at the age of 7–8 yrs and 11–13 years, respectively (i.e., childhood onset FENIB) and often present with PME and gradual cognitive decline.[9] In the index case, the onset of symptoms started around the age of 17 years and had G393 variant in exon 9 of chromosome 3. The treatment of FENIB is directed toward the specific symptoms that are apparent in each individual. Individuals with progressive dementia often experience frustration, anxiety, and depression due to their decreasing ability to function in certain aspects of their lives.[5] These frustrations may be minimized by maintaining a stable home environment and a structured routine that does not place excessive demands on the affected individual. Eventually, most individuals with FENIB require comprehensive medical care as provided in a nursing home. Genetic counselling is recommended for affected individuals and their families.[5] Catatonia as presenting symptom in a case of FENIB has not been reported yet, and therefore, ours is the first case to report this finding, which resolved with ECT, further highlighting the role of ECT in the management of organic catatonia not responding to lorazepam. As evident from the recent literature review, FENIB is limited to a handful of case reports, suggesting the need for more research on this disorder.[9] A close collaboration between psychiatrists, neurologists, and physicians is needed to diagnose and manage patients with FENIB. Declaration of patient consent The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.