A 19-month-old girl, born to consanguineously married parents, who was developing typically, presented with excessive irritabilityand decreased sleep for the past 40-50 days.Child had received diphtheria-pertussis-tetanus(DPT) booster dose 50 days back. Initially the symptoms were attributed to vaccination, but irritability kept gradually increasing. Child gradually regressed in language and cognition. She was not able to speak and on admission was able to only coo.There was behavioural change in the child in the form of new onset head banging, throwing of previously favourite toys and was avoiding going to the mother.Child was not mingling well with others, did not play like before, was not showing interest in surroundings and there was cognitive decline in the form of not showing body parts and not recognizing mother. However, child was able to walk without support, and there was no motor regression. There was no history of seizures, fever, vision disturbance, involuntary movements, abnormal eye move-ments, and ataxia. Child had an uneventful birth history and family history. On examination, child was extremely irritable and crying inconsolably. Child had pallor and vitals were stable. There was no lymphadenopathy and organomegaly. There were dried crusted rashes with excoriation over trunk and limbs, with hyperpigmentation. Neurological examination did not show any cranial nerve involvement or motor weakness. There was no muscle twitching/fasciculation/neuromyotonia with spasticity, the best elicited power was 4/5 in all limbs,with brisk deep tendon reflexes with ankle clonus with bilateral extensor plantar response. Sensory and cerebellar examination was normal. Meningeal signs were absent.

Possibility of autoimmune encephalitis, connective tissue disorder and malignancy, possible lymphoma with paraneoplastic manifestations were considered as differential diagnosis. Peripheral smear examination, erythrocyte sedimentation rate and C-reactive protein were within normal units, and serum anti-nuclear antibody was negative. Magnetic resonance imaging of brain and nerve conduction study were normal. CSF analysis revealed one lymphocyte, normal protein and sugar, and positive oligoclonal bands. Electroencephalogram revealed diffuse slowing. Autoimmune encephalitis panel done by indirect immuno-fluorescence technique in transfected cells was positive for Caspr2 antibody in the serum and negative in the CSF.

Chest X-ray, ultrasound abdomen, computed tomography (CT) chest, CT abdomen, and bone marrow aspiration done to rule out the possibility of malignancy were non-contributory. Child was treated with intravenous methylprednisolone for 5 days with intravenous immunoglobulin 2g/kg, and showed clinical improvement within 72 hours. The child’s irritability decreased and gradually child started sleeping well, started showing interest in surroundings, regained previous vocabulary of nearly 100 words, speaking two word phrases and was interacting well. The skin lesions resolved within 10 days after starting immuno-suppressive therapy. After administration of intravenous methylprednisolone for five days, child was treated with oral prednisolone 2 mg/kg bodyweight per day for 6 months and was gradually tapered and stopped as child was completely asymptomatic and was gaining new milestones. Child has been on follow-up for the last one year. At age of 29 months, the child has achieved age-appropriate developmental milestones.

CASPR2–mediated limbic encephalitis is characterized by the onset of cognitive deficits, psychiatric disturbances, seizures, peripheral nerve hyper-excitability, neuropathic pain and insomnia in association with detection of Caspr2 antibodies in serum or cerebrospinal fluid, with or without underlying malignancies. There is strong male predominance with risk of malignancy in adults [3].

CASPR2 is a membrane protein expressed in the central and peripheral nervous system, which is essential for proper localization of voltage-gated potassium channels (VGKC) [4]. The most common presenting symptoms in adults are cognitive disturbance (26%), seizures (24%), peripheral nerve hyper-excitability (21%) and neuropathic pain (18%) [3]. Fewer than 10 pediatric cases have been reported with CASPR2 autoimmunity, so the phenotypes and immunotherapy responsiveness is less well-defined in children [4]; though, encephalopathy, seizures, neuropsychiatric symptoms, neuropathic pain and cramps are described as clinical features in children, with a median age of onset of 13 years [5,6]

Children with CASPR2 autoimmunity are under-recognized because neuropathic pain and symptoms of peripheral nerve hyperexcitability are difficult to characterize in children [5]. Peripheral nerve hyperexcitability has been documented in patients with CASPR2 autoimmunity[1]. One of the limitations of our case report is that we could not document the presence of neuromyotonia or evidence of peripheral nerve hyperexcitability in this child by electrophysiology.

The sub acute onset of behavioral disturbance, cognitive and speech regression should be considered as clinical clues to suspect autoimmune encephalitis in children; and CASPR2 mediated autoimmune limbic encephalitis should be considered as a cause of irritability with intractable itching/neuropathic pain in a child, as its recognition is important because they respond well to immunosuppressive therapy.

1. Khadilkar S, Soni G, Patil S, Huchche A, Faldu H. Autoimmune encephalitis: An update. J Assoc Physicians India. 2017;65:62-9.

2. Tuzun E, Dalmau J. Limbic encephalitis and variants: Classification, diagnosis and treatment. Neurologist. 2007; 13:261-71.

3. Van Sonderen A, Arino H, Petit-Pedrol M, Leypoldt F, Kortvelyessy P, Wandinger KP, et al.The clinical spectrum of Caspr2 antibody–associated disease.Neurology. 2016; 87: 521-8.

4. Hacohen Y, Singh R, Rossi M, Lang B, Hemingway C, Lim M, et al. Clinical relevance of voltage-gated potassium channel–complex antibodies in children. Neurology. 2015; 85:967-75.

5. López-Chiriboga AS, Klein CJ, Zekeridou A, McKeon AB, Dubey D, Flanagan EP,et al. LGI1 and CASPR2 neuro-logical autoimmunity in children.Ann Neurol. 2018;84:473-80.

6. Nosadini M, Toldo I, Tascini B, Bien CG, Parmeggiani L, De Gaspari P,et al. LGI1 and CASPR2 autoimmunity in children: Systematic literature review and report of a young girl with Morvan syndrome. J Neuroimmunol. 2019;335: 577008.