Ananthanarayanan Kasinathan

Topiramate Therapy in Alternating Hemiplegia of Childhood

To the Editor: In a recent publication from our centre, we had highlighted novel features in a child with Alternating hemiplegia of childhood (AHC) [1]. We would like to share our experience with the use of topiramate in the management of an another genetically confirmed child with the same disorder. A 14-mo-old girl presented with concerns of global developmental delay (6–8 mo) and paroxysmal episodes of tonic/dystonic spells of the neck and upper limb since three months of age. She was first born to non-consanguinous parents after an uneventful perinatal period. Her family history was unremarkable. At eight months of age, she developed recurrent episodes of flaccid hemiparesis of either side of the body. These episodes were acute with no effect on consciousness and used to subside by two days. On examination, the child had normal head circumference with normal consciousness and flaccid weakness of left upper limb more than lower limb. The clinical possibilities considered at admission were Alternating hemiplegia of childhood; mitochondriocytopathy and GLUT1 deficiency. Magnetic resonance imaging of the brain was unremarkable. Electroencephalography was normal. Blood lactate was 2.3 mmol/L. CSF: serum glucose ratio was 0.8. Next generation sequencing revealed a heterozygous missense variation in exon 17 of the ATP1A3 gene {c.2401G > G/A;p.Asp801Asn} and its pathogenicity was confirmed by insilico analysis. The child was started on first line flunarizine therapy, however, the episodes were refractory. The child was then initiated on topiramate therapy, following which there was dramatic improvement in paroxysms. On 6 mo follow-up, posttopiramate therapy, child has language predominant delay with no further episodes of dystonic spells or flaccid hemiparesis. AHC is a devastating disease and challenging to manage. Flunarizine has demonstrated promising results with efficacy in 76% patients [2]. Topiramate has also been proposed as a promising alternative in flunarizine refractory AHC. The use of topiramate was first proposed byDi Rosa et al. in a 12-y-old girl with family history of migraine with sustained response over 18 mo follow-up [3]. The pharmaco-therapeutic mechanism of topiramate in AHC is unknown but may be related to inhibition of non NMDA, especially the AMPA mediated excitatory neurotransmission [4]. However, the drug efficacy is difficult to evaluate owing to the ‘roller-coaster’ course of AHC, with periods of aggravation and improvement. In conclusion, we would like to highlight the promising role of topiramate in Alternating hemiplegia of childhood.

Ocular Flutter in Scrub Typhus

A 9-year-old boy presented with a subacute febrile illness with bursts of conjugate horizontal saccadic oscillations on visual fixation (Figure and Video; available at www.jpeds.com) and cerebellar ataxia. Examination revealed hepatosplenomegaly and scrotal eschar. Magnetic resonance imaging of the brain was normal and lumbar cerebrospinal fluid showed lymphocytic pleocytosis (70 cells, protein 105 mg/dL). IgM enzyme-linked immunosorbent assay for scrub typhus was positive. Intravenous doxycycline and dexamethasone for 5 days resulted in complete recovery. Ocular flutter is bursts of conjugate horizontal saccades without intersaccadic interval, occurring on visual fixation, irrespective of gaze direction and eye closure. Ocular movements are present in full direction, hence ocular flutter may lead to troublesome oscillopsia. Ocular flutter is usually present with ataxia and myolconus and rarely can be isolated phenomenon. Ocular flutter is considered as a milder version of opsoclonus; ocular flutter or saccadic intrusions are usually horizontal, whereas opsoclonus are multidirectional. Pathogenesis of ocular flutter is related to dysfunction of omnipause neurons in the paramedianpontine reticular formation or fastigial nucleus of cerebellum. Damage to the GABAergic omnipause neurons or malfunction of glycine receptors causing a decrease in the efficacy of omnipause neuron-mediated inhibition leads to ocular flutter. Hydrocephalus, midbrain glioma, demyelinating disorders, enterovirus encephalitis, Lyme disease, autoimmune encephalitis, heredodegenerative disorders, and head trauma are reported with ocular flutter. Ocular flutter in an index child is a rare clinical feature of scrub typhus cerebellitis. Immune-mediated pathogenesis (anti-GQ1b, antiGADAntibodies) complements the role of steroids in early recovery. ■

Recurrent Streptococcus pneumoniae meningitis and Mondini dysplasia: Association or causation?

Mondini dysplasia is a developmental disorder of the inner ear structures and it is a rare cause of recurrent bacterial meningitis in children. A 10-year-old boy presented with acute febrile encephalopathy and right ear pain. In the past, he had suffered from two distinct episodes of pyogenic meningitis. On examination, he had signs of meningeal irritation and right ear sensorineural deafness. Magnetic resonance imaging of the brain and computerized tomography of the temporal bone was suggestive of Mondini dysplasia in the right ear. Our case highlights the need for (a) screening of hearing loss at the bedside by Rinne and Weber test in case of recurrent bacterial meningitis (b) searching for an underlying inner ear malformation if there is a hearing loss.

Siblings with L2 Hydroxy Glutaric Aciduria

Two male siblings aged 9 and 16 y born to nonconsanguineous Punjabi parents, presented with complaints of infantile-onset developmental delay and progressively increasing limb tremulousness. On examination, both children had moderate intellectual impairment and macrocephaly (Head circumferences: 58 cm and 57.5 cm respectively) along with action-exacerbated limb tremulousness (upper >lower). Their neuroimaging revealed signature features of L2 Hydroxy glutaric aciduria (Figs. 1 and 2). Urinary Gas Chromatography Mass Spectroscopy (GC-MS) of both children displayed grossly elevated 2 Hydroxy glutaric acid levels. Targeted gene sequencing performed in the younger

Apathy - Forme Fruste of Autoimmune Encephalitis

To the Editor: A previously healthy, 2-y-old boy presented with new-onset behavioral change for the past two months. Parents noticed that he became quiet and distant, indifferent with unusual or minimal response to the questions posed. He soon preferred to stay in bed and with little impetus to eat, drink or speak. His sleep cycle was, however, not altered. His interaction with parents and peers had gradually reduced. For the fifteen days prior to admission, he developed peculiar, repetitive, nose picking behavior and minimal intermittent twisting movements of the limbs. On examination, he was self-absorbed, indifferent, socially withdrawn and lacked all emotional reactions. He was visually attentive and mute. Repetitive nose picking and intermittent dystonia were observed. Cranial nerves, fundus and rest of the neurological examination were normal. Magnetic Resonance Imaging of the brain was unremarkable. Cerebrospinal fluid analysis was acellular with mildly elevated protein (62 mg%), normal sugar (68 mg%) and strongly reactive anti-NMDAR antibodies. He was initiated on a combination therapy with Intravenous Immunoglobulin and pulse methyl prednisolone. At 4 wk follow up, the motor stereotypies and dystonia resolved with marked reduction in apathy. However, the child was hyperactive, had an altered sleep-wake cycle, and persistent speech deficits. Hewas given Rituximabweekly (375mg/ m) for four weeks. He showed complete resolution of all symptoms at 8 wk follow-up. At the two-year follow-up, the child was symptom free; was in first standard; had good scholastic skills; normal peer relationship; and no residual motor, speech or behavioral deficits. Anti-NMDAR encephalitis is a neuroimmune syndrome characterized by profound psychiatric and cognitive deficits [1]. Unlike adults, where psychotic symptoms are dominant, manic features inclusive of irritability; behavioral outburst and hyperactivity are commoner in children [2]. Light-switch mental status with rapid fluctuations in sensorium is another salient presenting feature [3]. The index child merits discussion because of the prominent apathetic features at onset. Apathy as a feature of Limbic encephalitis and Hashimoto thyroiditis has been well reported in adults. However, literature review of the three largest published series in children did not yield any mention [2, 4, 5]. The added findings of motor stereotypies; mild dystonia; and normal neuroimaging were pointers to the underlying diagnosis. Our case highlights the relatively rare apathetic presentation of pediatric AntiNMDAR encephalitis.

Post-Herpetic Autoimmune Encephalitis

To the Editor: A previously healthy 8-y-old boy presented with fever, generalized seizures, and progressive lethargy for the past 4 d. On examination, he had altered sensorium, meningismus, and brisk muscle stretch reflexes. There were no focal motor deficits or papilledema. A clinical diagnosis of acute meningoencephalitis was considered. Cerebrospinal fluid examination showed 268 cells (74% lymphocytes), normal glucose, elevated protein (217 mg%), absence of red blood cells and positive Herpes simplex virus (HSV)-DNAPCR. Themagnetic resonance imaging (MRI) brain was suggestive of changes seen in herpes encephalitis (Fig. 1). Electroencephalograph showed bilateral slowing with no epileptiform discharges. Intravenous acyclovir (60 mg/kg/day) was administered for 21 d. At discharge, he had residual cognitive and speech impairment. Two weeks later (nearly 40 d after the onset of encephalitis), he returned with severe behavioral abnormalities; rapid on-off state between responsiveness and nonresponsiveness (light-switch mental status); mutism with intermittent echolalia; hyperorality; social disinhibition; acral dyskinesia; and irritable insomnia. A clinical diagnosis of herpes relapse or secondary immune-mediated disorder was considered. A repeat electroencephalography showed diffuse slowing. A repeat cerebrospinal fluid examination showed no cells, normal biochemistry, negative HSV DNA-PCR and strongly reactive anti-N-methyl-D-aspartate receptor (NMDAR) antibodies on cell based assay (Fig. 1c). He recovered significantly with intravenous pulse methylprednisolone and immunoglobulin therapy. Our case highlights the importance of recognizing postherpetic autoimmune encephalitis in children as the treatment is entirely different and needs to be initiated early for improved neurological outcome. Anti-NMDAR antibodies are being increasingly described in children with herpes encephalitis and can mimic a viral encephalitis relapse [1]. This immune activation and generation of anti-NMDAR antibodies is possibly related to the virus-induced neuronal destruction exposing the NMDAR or polyspecific B-cell activation occurring in the course of herpes-related central nervous system inflammation [1]. This secondary (postherpetic) anti-NMDAR encephalitis is associated more frequently with movement disorders than with seizures. The presence of new behavior abnormalities, insomnia, light switch mental status, movement disorder, mutism and absence of seizures are pointers to an underlying autoimmune phenomenon as in the index case [2, 3]. The clinical suspicion is supplemented by negative HSV DNA PCR, poor response to acyclovir and lack of new lesions in MRI [4]. The key to management is timely commencement of immune-modulatory therapy to improve neurological outcomes. A better understanding of this subgroup of herpes encephalitis triggered anti-NMDAR antibodies is needed for more targeted therapy. * Naveen Sankhyan drnsankhyan@yahoo.co.in

Child with Isolated Motor Delay: Look at the Neuroimage

To the Editor: A 4-y-old boy, born to non-consanguineous parents, presented with isolated motor delay since infancy. He was born at term with an uncomplicated perinatal period. There was no history of loss of attained milestones or seizures. On examination, he had a motor age of 9–10 mo; normal cognitive, language and social milestones; normal head size; proximal muscle weakness, areflexia, bilateral contractures at elbow, wrist, knee and ankle joints. Birth and family history were unremarkable. Investigations revealed, mildly elevated serum creatine kinase (963 U/L) and bilateral diffuse white matter changes on magnetic resonance imaging (MRI) of the brain. Based on suggesting findings on the MRI brain (Fig. 1) and the detection of a homozygous nonsense variation in exon 2 of the LAMA2 gene (chr6:129371200; C > T) on next generation sequencing, a diagnosis of merosin deficient congenital muscular dystrophy (CMD) was concluded. Merosin deficient CMD is a severe muscle disease caused by complete or partial merosin deficiency. Affected children present with delayed motor development, proximal muscle weakness, hypotonia, and joint contractures [1]. Most of the patients with partial merosin deficient CMD are due to LAMA2 gene mutations and usually presents with normal intelligence, but rarely may have mild intellectual disability and epilepsy. The diagnosis is usually made by clinical history, muscle biopsy, and characteristic changes on MRI of the brain. The MRI changes usually appear between 6 to 12 mo of life and give an important diagnostic clue to the diagnosis [1]. Diffuse cerebral white matter changes and prominent lateral ventricles are common findings on the MRI of the brain. Subcortical and periventricular white matter is commonly affected while corpus callosum and internal capsule are spared [2]. Apart from characteristic white matter changes, some patients may have subtle occipital cortex and cerebellar changes [3]. White matter changes do not progress with increasing age [4]. MRI based differential diagnosis includes megalencephalic leukoencephalopathy with subcortical cysts, vanishing white matter disease, molybdenum co-factor and sulfite oxidase deficiency and certain mitochondrial respiratory chain defects [5]. Clinical features, age of onset and specific features on the MRI, helps in differentiating these disorders. MRI of the brain should be done in all children with suspicion of congenital muscular dystrophy to look for markers of merosin deficiency and associated cerebral malformations. A careful attention to the clinical profile and neuro image may give a clue to the diagnosis of this condition, prompting genetic confirmation.

Unusual cause of west syndrome

Schimmelpenning-Feuerstein-Mims syndrome is a congenital neurocutaneous disorder, comprising of organoid epidermal nevus with a broad spectrum of multiorgan dysfunction (neurologic, skeletal, cardiovascular, ophthalmic, and urologic) secondary to postzygotic mutation in the early embryonic period. Predominant neurological manifestations include epilepsy, intellectual impairment, and focal deficits. Here, we report a 3-year-old girl who presented with epileptic spasms and had a characteristic linear sebaceous nevus. This report not only highlights the importance of early diagnosis of this condition but also emphasizes the need for multiorgan screening in children with seizures and nevi.

Unusual Cause of Altered Mentation – Acute Cerebellitis

To the Editor: A 4-y-old girl presented to the emergency with a three-day history of fever, loose stools, generalized seizures and altered sensorium. She had extreme irritability, mutism, insomnia, and no expression of awareness. She had lost the ability to visual fixate and follow. On examination, she had poor arousal and awareness with altered sleep wake cycle; mutism; continuous, oro-lingual and acral dyskinesia. She had generalized hypotonia, brisk muscle stretch reflexes, but no meningeal or cerebellar signs. Cerebrospinal fluid (CSF) analysis revealed 80 cells (80% polymorphonuclear cells) with hypoglycorrhachia (30 mg%) and normal protein (60 mg%). The CSF bacterial culture was sterile. Viral polymerase chain reaction for; Herpes, Enterovirus/Flavivirus/Paramyxovirus was negative; and scrub typhus serology were negative. The CSF for anti-N-methyl-D-aspartate receptor antibodies was negative. Based on neuroimaging findings (Fig. 1), demyelination was ruled out and a diagnosis of acute cerebellitis was concluded. The child was treated with Ceftriaxone, Azithromycin, Ampicillin, Clonazepam and Melatonin. By two weeks, her irritability had reduced, her sleepwake cycle was restored and she had started responding to commands. At two-months follow-up, she was walking but ataxic, had dysarthria and dysmetria. At last follow-up at one year after the acute illness, there is complete resolution of cerebellar signs and child is neurologically normal with a development quotient of 96. Acute cerebellitis is a multifaceted disease with a variable clinical course ranging from self-limiting disorder to fulminant course and death [1]. It typically presents with rapid onset cerebellar dysfunction in the form of ataxia, headache, vomiting, altered mental status, and coma in late stages. Altered mentation in children with cerebellitis is usually attributed to raised intracranial tension secondary to obstructive hydrocephalus or tonsillar herniation. Remarkably, this child presented with predominant changes in mentation with profound insomnia, mutism and prominent dyskinesias. This clinical phenotype challenges the classic role of cerebellum in motor coordination and throws light on non-motor higher order brain functions of the cerebellum. Such functions include cognition, language, emotional behavior (fear) and sleep [2]. This newer role of cerebellum has further been validated by animal models and functional studies on cerebellar circuitry in humans [3]. There are scant reports in the pediatric literature on the atypical non motor higher order dysfunctions of cerebellum following rotavirus infection and surgery [4]. The absence of cerebellar signs at admission followed by ataxia, at two months follow-up, emphasizes the predominant encephalopathic presentation. Our case highlights the clinical non-motor dysfunctions of acute cerebellar inflammation. * Pratibha Singhi doctorpratibhasinghi@gmail.com

KCNQ2 Epileptic Encephalopathy in Early Infancy

To the Editor: A 12-mo-old boy was first seen at 50 d of life for repeated focal tonic seizures and excessive lethargy. He was term born, second in birth order to a nonconsanguineous couple with an uneventful perinatal period. At 18 h of life, he had repeated episodes of focal tonic seizures and excessive irritability with a clinical response to phenobarbitone therapy. At 50 d of life, the child was readmitted with multiple polymorphic seizures (focal tonic seizures, versive eye movements, and occasional multifocal clonic jerks). By 8 mo, the child had developed frequent therapy-resistant seizures with no gain of developmental milestones. A trial of Phenytoin, Valproate, Topiramate, Vigabatrin and Levetiracetam were ineffective. Family history was not contributory. Physical examination revealed no facial dysmorphism, a small head (OFC between −2 to −3 Z score), hypertonia, hyperreflexia, and visual inattention. EEG showed a severely abnormal background with multifocal interictal epileptiform discharges (IEDs). MRI brain was unremarkable. CSF Pipecolic acid and CSF Glycine were within normal range. Next generation sequencing for Early Infantile Epileptic Encephalopathy genes (60 Genes) revealed a heterozygous missense variation in exon 6 of KCNQ2 gene (chr20:62,070,967; A > A/G; c.911 T > T/C). The mutation was later validated by Sanger sequencing. Parental studies were unremarkable suggesting a possible de-novo mutation. The child responded to oral Carbamazepine and Benzodiazepines with complete seizure control. On follow-up at 24 mo, the child had a profound developmental failure with poor visual attention, microcephaly, spastic quadriparesis and was seizure free for 10 mo after starting Carbamazepine. KCNQ2 related epileptic encephalopathy (OMIM 613720) is characterized by a quotidian frequency of seizures that are predominantly tonic, pharmacoresistant and resultant profound intellectual deterioration [1]. The clinical presentation of our child is comparable to existing literature with the onset of epilepsy in first week, profound developmental deficits and intractable epilepsy [2, 3]. EEG is characterized by an age-dependent evolving pattern with burst suppression followed by multifocal interictal epileptiform discharges (IEDs). Reversible basal ganglia and thalamus signal changes in MRI may give a clue to the diagnosis. Sodium channel blockers, especially Carbamazepine and Phenytoin are the drugs of choice for effective seizure control [4]. The child we report also had a dramatic response to Carbamazepine. Targeted gene sequencing forms the mainstay of diagnosis in infants with early onset refractory epilepsy as it not only has prognostic implications but also paves way for prenatal detection and counseling. Early use of sodium channel blockers like Carbamazepine, that are usually avoided in infants, may improve the otherwise dismal outcome in KCNQ2 encephalopathy. * Pratibha Singhi doctorpratibhasinghi@gmail.com