Psychosis in the aftermath of stroke: Pyridoxine-responsive homocystinuria in an adolescent

Sir, Homocystinuria is a rare autosomal recessive disorder of methionine metabolism, most commonly due to cystathionine β-synthase (CBS) deficiency, with an estimated incidence of 1 in 100,000–200,000 live births.[1] It has multisystem involvement, with classic features such as ectopia lentis, marfanoid skeletal changes, osteoporosis, and thromboembolic events. Neurocognitive impairment and psychiatric disturbances are also common in untreated cases. Neuropsychiatric manifestations range from affective and obsessive—compulsive symptoms to personality disorders, with studies reporting prevalence rates of nearly 50%.[2] Acute psychosis as a presenting feature is rare and often overlooked. About half of CBS-deficient patients respond to pyridoxine (vitamin B6), which lowers plasma homocysteine and improves systemic and psychiatric symptoms.[3] Pyridoxine-responsive homocystinuria is often missed on neonatal screening and may present later in adolescence with varied clinical features. We report a case of acute psychosis in a patient with a prior cerebrovascular accident (CVA) secondary to homocystinuria, who showed marked improvement with pyridoxine therapy. A 17-year-old male undergraduate from an urban, lower-middle socioeconomic background, with a non-vegetarian diet, presented with one month of behavioral and perceptual disturbances. The onset was subacute, marked by irritability, social withdrawal, academic decline, disturbed sleep, and episodes of self-talk in response to unseen voices. He also developed suspiciousness toward family members, impairing personal care, and daily functioning. Initially taken to faith healers, he was eventually brought for psychiatric evaluation. During admission, he reported hearing threatening voices attributed to neighbors and displayed pronounced suspiciousness toward physicians and patients. He was born of a non-consanguineous union, with normal birth history and milestones. Scholastic performance had been good prior to illness. There was no seizure, abnormal movement, family history of neurological, or psychiatric illness. Examination: Height 168 cm, weight 63 kg, BMI 22 kg/m², with no dysmorphic features. Neurological evaluation showed no deficits despite a past history of left-sided weakness. Fundus and cardiovascular examinations were normal. Mental status revealed poor rapport, muttering behavior, persecutory delusions, persistent auditory hallucinations, distractible attention, intact orientation and memory, impaired judgment, and poor insight. Investigations: Baseline labs, thyroid profile, vitamin B12, vitamin D, ceruloplasmin, and autoimmune screening were normal. Magnetic resonance imaging (MRI) brain, electroencephalogram (EEG), and coagulation profile were unremarkable [Figure 1]. He was started on olanzapine 5–10 mg/day, which improved sleep but not psychosis. A metabolic screen revealed markedly elevated serum homocysteine (41 μmol/L; ref 4.5–15 μmol/L), macrocytosis (MCV >100 fl), and raised mean corpuscular hemoglobin (MCH). A diagnosis of homocystinuria-associated psychosis was made, and pyridoxine 200 mg twice daily was started.Figure 1: MRI brain (axial T1/T2/FLAIR sequences) showing normal brain parenchyma with no focal lesions, mass effect, or abnormal signal intensityDifferential Diagnoses: Considered possibilities included early-onset schizophrenia, post-stroke psychosis, mood disorder with psychotic features, autoimmune encephalitis, Wilson’s disease, and vitamin B12 or folate deficiency. Primary psychotic disorders were considered due to persecutory delusions and hallucinations, but were deemed unlikely given the abrupt onset, absence of prodromal negative symptoms, and poor response to antipsychotics. Post-stroke psychosis was excluded by normal neuroimaging, and the delayed onset after the cerebrovascular event. Autoimmune and metabolic encephalopathies were ruled out by normal EEG, MRI, and autoimmune screening. The presence of marked hyperhomocysteinemia, macrocytosis, and rapid, sustained remission with pyridoxine supported homocystinuria-associated psychosis. Course: Within days, hallucinations and delusions subsided, with restoration of self-care, social interaction, and sleep. Four weeks later, serum homocysteine normalized 6.8 (<10 μmol/L). He continued on olanzapine 10 mg and pyridoxine 200 mg/day. Follow-up showed complete remission, resumption of academics, and no residual paranoia. Homocystinuria, most often due to CBS deficiency, manifests with ocular, skeletal, vascular, and neuropsychiatric features. Psychosis is an unusual but documented presentation. The pathophysiology of psychiatric symptoms is complex. Homocysteine metabolism is tightly linked to folate and vitamin B12 pathways, generating S-adenosylmethionine (SAM), a key methyl donor for neurotransmitters, nucleic acids, and receptor regulation.[4,5] In CBS deficiency, accumulation of homocysteine and SAM impairs methylation reactions, disrupting monoamine synthesis, and receptor function. Oxidative derivatives such as homocysteic acid act as potent N-methyl-D-aspartate (NMDA) receptor agonists, producing excitotoxicity and disturbed neurotransmission, explaining acute psychotic features.[6] Our patient, with prior stroke due to homocystinuria, presented with acute psychosis resistant to antipsychotics. Elevated homocysteine and macrocytosis suggested underlying metabolic disturbance. High-dose pyridoxine led to rapid resolution, consistent with pyridoxine-responsive homocystinuria. Approximately 50% of CBS-deficient patients retain residual enzyme activity, accounting for this response. This case highlights key points: (1) acute psychosis can be a presenting feature of homocystinuria, even in the absence of classical systemic signs; (2) lack of antipsychotic response should raise suspicion of metabolic etiologies; and (3) pyridoxine responsiveness makes this a reversible cause of psychosis. Given the overlap between hyperhomocysteinemia and disorders like schizophrenia and depression, metabolic screening should be considered in adolescents with atypical or treatment-resistant psychosis. Early recognition can prevent complications such as recurrent stroke, cognitive decline, and premature mortality. Declaration of patient consent The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given his consent for his images and other clinical information to be reported in the journal. The patient understands that his name and initials will not be published and that due efforts will be made to conceal his identity, but anonymity cannot be guaranteed. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.