Kluver–Bucy syndrome in a girl with anti-NMDAR encephalitis
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.263181
Source of Support: None, Conflict of Interest: None
The Kluver–Bucy syndrome (KBS) is a rare neurobehavioral disorder characterized by hyperorality, hypersexuality, short-term memory loss, placidity, hypermetamorphosis, visual agnosia, mutism, and seizures., At least three main symptoms are required to make a diagnosis of KBS. This condition was first described in 1939 by Heinrich Kluver and Paul Bucy in a rhesus monkey following removal of a portion of temporal lobes and rhinencephalon. The first human case was described by Terzian and Ore in 1955, following bilateral temporal lobectomy for epilepsy surgery. The pathogenesis of KBS is secondary to dysfunction of temporal lobes, particularly amygdale, hippocampus, and white matter tracts., Any infiltrative, infectious, degenerative disorder, infarct, and surgical resection of temporal lobe can lead to KBS. Disruption of pathways connecting the dorsomedial thalamus to the prefrontal cortex and/or other limbic areas may also lead to KBS. Most cases of KBS have been reported in adults. In children, KBS has been reported in association with herpes encephalitis, Listeria monocytogenes meningoencephalitis, metabolic/hypoxic encephalopathy, congenital temporal lobe malformations, and following surgical resection of temporal lobes. We describe a case of KBS in a girl with autoimmune encephalitis.
A 10-year-old, right-handed girl presented with acute-onset febrile illness followed by behavioral changes, irrelevant speech, and change in her preference to Hindi over Punjabi language unusual to her previous self. She stopped recognizing parents and indicating for daily needs. She had 2 episodes of seizures on day 3 of illness followed by unresponsiveness. She was managed as suspected viral encephalitis. She received antiepileptics, acyclovir, and ventilator support and regained consciousness by day 10. Over the next 4 weeks, she continued to improve, became ambulatory, started recognizing parents, and speaking again.
At 6 weeks of illness, the parents reported new-onset behavioral feature as marked disinhibition, putting everything into mouth, reduced speech, and inability to recognize family members and objects. She started repeatedly kissing and touching inappropriately. Her sleep duration was reduced to a mere 3–4 hours per day. She had markedly impaired recent memory, speech, visual agnosia, inattention, and facial stereotypies with repeated grimacing and pouting. Rest of the neurological examination was unremarkable.
Her first lumbar cerebrospinal fluid (CSF, on day 7 of the illness) analysis showed 300 cells with lymphocytic predominance and normal glucose and protein. Bacterial cultures were sterile. Herpes simplex virus DNA polymerase chain reaction (PCR) was negative in CSF. Magnetic resonance imaging (MRI) of the brain showed hyperintensities in bilateral temporal as well as frontal lobes, and the opercular areas [Figure 1].
She presented to our hospital at 8 weeks of illness; suspecting autoimmune limbic encephalitis, she was treated with methyl prednisolone 30mg/kg/day for 5 days followed by oral prednisolone for 4 weeks. The CSF was analyzed for antibodies-mediated autoimmune encephalitis (anti-N-methyl-D-aspartate receptor (NMDAR), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR), Hu, Yo, Ri, CV2, amphiphysin, and Caspr2) and showed anti-NMDA receptor antibodies. In view of the poor response, intravenous immunoglobulin (IVIg) 2g/kg was given. Partial improvement in dyskinesia and sleep wake cycle was noted. Screening for tumor was negative. Intravenous rituximab weekly at 375mg/m 2, four dosages, were given and she showed gradual improvement. At 6 months of follow-up, she continues to have short-term memory impairment; rest of her symptoms have subsided.
The combination of hyperorality, amnesia, hypersexuality, and visual agnosia was suggestive of KBS with anti NMDA receptor encephalitis in our patient., The typical presentation of anti-NMDA receptor encephalitis is an initial phase of neuropsychiatric features, followed by neurological complications such as encephalopathy, seizures, agitation, mutism, and typical orofacial-lingual dyskinesia. Recovery is usually rapid with aggressive immunomodulatory therapy; however, sometimes the disease course can be protracted. Cognitive and behavioral dysfunctions can persist with impaired executive functioning, impulsivity, abnormal sleep pattern, and amnesia for the entire illness.
Presence of significant bilateral temporal lobe changes in MRI were mimicking herpes simplex encephalitis (HSE) in the index patient; however, herpes simplex virus deoxyribose nucleic acid polymersae chain reaction (DNA PCR) was negative [Figure 1]. Secondary autoimmune phenomenon is known with viral encephalitis, particularly with HSE, as 14–25% of children with HSE show a relapsing course., Pruss et al., detected anti-NMDA receptor antibodies in 13 (30%) of the 44 patients with HSE.
Pediatric KBS has been described with viral encephalitis, tuberculous meningitis, focal cortical malformations, surgical resection of temporal lobes, and hypoxic ischemic encephalopathy.,, Autoimmune limbic encephalitis shares some of the features with KBS. Only two pediatric cases of KBS with probable autoimmune limbic encephalitis have been reported., In these two cases, in whom CSF and serum antibodies for autoimmune encephalitis were negative, treatment with immunomodulators showed resolution of symptoms [Table 1].
It is known since decades that resection of medial temporal lobes leads to KBS. Pathogenesis of KBS is related to structural or functional dysfunction of the medial temporal lobe, hippocampus, and amygdala; however, the exact molecular pathogenesis is not known.
In the index patient, the presence of anti-NMDA receptor antibodies throws light on the pathophysiology of KBS. NMDA receptors, along with AMPA and kainate receptors, mediate glutamatergic synaptic transmission and play a prominent role in synaptic plasticity, learning, and behavior. Anti-NMDA receptor antibodies cause selective, reversible decrease in NMDA receptor surface density, synaptic localization, and currents in vitro. Continued exposure to NMDA receptor autoantibodies leads to the internalization of NMDA receptors in the hippocampal neurons within the rat brain., On incubation of CSF from patients with NMDA receptor antibodies, the density of receptors on the neuronal surface reduces, which suppresses the induction of long-term synaptic potentiation, the cellular mechanism underlying the learning and memory processes. Mice exposed to NMDA receptor antibodies showed impaired spatial memory. Brain tissue from mice with memory disturbances had decreased content of NMDA receptor protein in the hippocampal area shown by immunohistochemistry, which is consistent with the fact that anti-NMDA receptors antibodies affect the expression and function of hippocampus.
Within the human brain, these antibodies target NMDA receptors in the hypothalamus, forebrain, and limbic system, resulting in decreased receptor expression on the postsynaptic neuronal surface. The net result of downregulated NMDA receptors is reduction in gamma-aminobutyric acid release, leading to disinhibition of excitatory pathways., The end-result include alterations in mood, sleep, appetite, seizures, amnesia, involuntary movements, and autonomic instability., This effect may functionally mimic surgical resection of temporal lobes.
In conclusion, the dysfunction of NMDA receptor mediated functions of hippocampus and frontal lobe result in clinical features mimicking KBS in individual with anti-NMDA receptor encephalitis.
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