Acute necrotizing encephalopathy (ANE) is a host-mediated phenomenon with viral triggers typically including influenza and parainfluenza viruses.1 It presents with a spectrum of symptoms from vomiting to seizures and coma with the potential to cause long-standing neurocognitive impairment.2 Sporadic forms (ANE) and recurrent/familial forms (ANE1) are now recognized in the literature, with the latter being described after the discovery of mutations in the RANBP2 gene.1 The diagnosis requires exclusion of other causes of encephalopathy, a high index of suspicion from the history (i.e., of recurrent attacks, family history) and diagnostic clues from prompt magnetic resonance imaging (MRI).
Although the association of the H1N1 strain of influenza as a trigger for isolated ANE has been previously described, this is the first case of the H1N1 strain being isolated in the recurrent/familial form, ANE1, with a confirmed missense mutation in RANBP2. This is only the second report of the p.T653I mutation in RANBP2 giving rise to a clinical phenotype of ANE1. In the previous reported case, the pathogenic significance of this specific mutation was not clearly established. Segregation analysis in our family provides further confirmatory evidence that the p.T653I is a pathogenic mutation.
A 28-month-old female child presented with 5 days of fever, lethargy and coryzal symptoms, initially diagnosed as a viral upper respiratory tract infection by her general practitioner. After 72 hours, she developed persistent non-bilious vomiting and presented to a district general hospital. Initial examination revealed that the child was alert and responsive but febrile with signs consistent with an upper respiratory tract infection. No focal neurology was detected at this time and she was managed conservatively with intravenous fluids.
Over the next 6 hours, the vomiting became relentless and the child became visually inattentive, encephalopathic and unresponsive. A computed tomography scan of the head at this time showed early right cerebellar folial swelling. A lumbar puncture was performed and cerebro spinal fluid (CSF) analysis (See Investigations below) was consistent with a working diagnosis of meningoencephalitis. The patient was empirically started on ceftriaxone, acyclovir and clarithromycin and transferred to the regional teaching hospital. Other differential diagnoses considered at the time comprised viral encephalitis, acute disseminated encephalomyelitis and a metabolic encephalopathy. She had no significant past medical history of note and was born at term with an uneventful antenatal and perinatal period. Her immunizations were up to date in keeping with the United Kingdom Immunization schedule.
Of note in her family history, she had an older sibling who had died at the age of 6 months within 12 hours of presenting with fever and seizures. An MRI head scan of the sibling revealed what was thought to be focal cortical dysplasia, corroborated by the initial postmortem report. Both the child’s father and paternal aunt had an illness with vomiting and seizures at 6 and 15 months of age, respectively. The father’s maternal aunt had an episode of encephalopathy during infancy, developed epilepsy at the age of 26 and died in her mid 30s because of breast cancer. Tracing back the old CSF reports of the father, aunt and deceased sibling revealed markedly elevated CSF protein counts.
INVESTIGATIONS AND DIAGNOSIS
Serum ammonia, lactate, liver function tests, electrolytes and renal function were all within normal limits. A full septic screen was performed including a throat swab, urine and blood cultures and serology for Mycoplasma and Borrelia, HIV, EBV, CMV (all eventually negative). Immunology (PHA T-cell stimulation assay, virus specific T-cell responses including to Influenza A) and autoantibody screen (including lupus anticoagulant, antithyroid peroxidase, NMDA-receptor voltage-gated) returned within normal limits. A neurometabolic screen comprising urine organic acids, biotinidase, porphyrins, thyroid function, blood and CSF lactate were normal. An EEG within 24 hours of admission showed generalized slowing. CSF results on admission revealed a CSF white cell count of 18 × 106/L (14 × 106/L lymphocytes and 4 × 106/L neutrophils) and glucose—4.6 mmol/L (normal 5.4 mmol/L). Of note, the CSF protein level was markedly elevated at 3242 mg/L. Influenza (H1N1 viral strain) was isolated on the NPA. The remaining cultures were negative both in blood and CSF including extended viral CSF PCR (HSV, VZV, mumps, Enterovirus, Parechoviruses). Apart from the aforementioned NPA, the rest of the extended respiratory viral PCR was negative (Parainfluenza 1, 2, 3, 4, Adenovirus, Metapneumovirus, RSV, Enterovirus, Parechovirus, Bocavirus).
The child had normal fundi and visual evoked potentials. MRI with diffusion restriction and spectroscopy was performed under general anesthetic within 48 hours of presentation (Fig. 1). Diffusion weighted sequences revealed a central focus of restricted diffusion consistent with necrotizing inflammation in the claustrum and thalami symmetrically. T1 contrast-enhanced images did not demonstrate any pathological enhancement of any of the areas of abnormality on T2 images. T2 gradient echo imaging demonstrated susceptibility within the mammillary bodies consistent with hemorrhagic necrosis. Similar hemorrhagic change was demonstrated in both geniculate bodies.
Spectroscopy revealed a high lactate peak, even in the radiologically normal areas. A diagnosis of mitochondrial cytopathy (e.g. MELAS, MERRF) was considered. Hence, diagnostic muscle biopsy (for mitochondrial respiratory chain defects) and skin biopsy (for pyruvate dehydrogenase) were considered but not performed. In the interim, she was treated with a 2-week course of ceftriaxone and 3-week course of acyclovir. On the basis of the MRI findings and the family history, a clinical diagnosis of familial/recurrent ANE (ANE1) was made and the child was treated with dexamethasone and intravenous immunoglobulin. As the MRI findings were similar to Wernicke’s encephalopathy, thiamine was also given while awaiting confirmatory genetic tests.
Given the known association with ANE1 and mutations in the RANBP2 gene, DNA from the index case was sequenced and found to have the same c.2085C>T, p.T653I missense mutation previously reported.1 Segregation analysis revealed that the father, paternal grandmother and deceased sibling also had the same mutation strongly suggesting that this is a pathogenic autosomal-dominant mutation with reduced penetrance. Genetic testing of POLG/PEO1 genes, mitochondrial mutations (m.9176T>C, m.13513G>A, m.14459G>A; mitochondrial DNA rearrangements) and array comparative genomic hybridization, were normal.
Originally, the neuropathologic report of the deceased sibling concluded that subtle cortical dysplasia was present which had made the child susceptible to febrile seizures. Retrospective review in 2013 did not confirm cortical malformation. There was focal microvascular hemorrhage consistent with ANE in the thalamus and mammillary bodies but not in the brainstem. There was evidence of terminal hypoxic ischemic injury.
A steady clinical improvement of the child ensued over 2 weeks. Despite periods of emotional lability during the acute phase, the child made a complete recovery and remains neurocognitively uncompromised at 8-month follow-up. A repeat MRI showed near complete resolution of the imaging changes with only limited punctate foci of gliosis in the claustrum bilaterally and right superior cerebellar folia. The patient received the inactivated flu vaccine this year and tolerated it well.
ANE is a host-mediated encephalopathy triggered by viral infections, notably influenza A and B. It was initially described by Mizuguchi et al3 in 1995 and has been reported to affect children between the ages of 5 months and 10 years.4 Originally reported in Japan and Taiwan,5 there have been increasing reports of prevalence worldwide. Reported mortality rates approach 30%.5
ANE typically presents with vomiting, seizures and fluctuating consciousness with progression to coma and can result in long-lasting neurologic sequelae in 15%.5 Acutely, important differential diagnoses to consider include meningoencephalitis, toxic/metabolic encephalopathies and acute disseminated encephalopathy. More rare diagnoses include Leigh/Alper’s syndrome and demyelinating/inflammatory diseases such as MS.6 Recently, a case of ANE was reported with a presentation resembling an acute transverse myelitis.7
Identification of mutations in RANBP2 has provided greater insight into its clinical spectrum. Most cases are sporadic but familial clustering provided the platform for identifying a key mutation in the RANBP2 gene, which encodes for a component of the nuclear pore.2 Three missense mutations in RANBP2 have been reported as susceptibility alleles for ANE with an estimated 40% penetrance.1 Hence, the sporadic form is referred to as ANE and the familial/recurrent form being referred to as ANE1 with a degree of overlap between the clinical features, although the latter may have a wider spectrum of clinical manifestations among family members.2,6 ANE1 has been described in American and European populations but only recently in an Asian child.8
The 2 types are also defined by their neuroradiologic and clinical hallmarks. In ANE, these include lesions in the thalami bilaterally, putamina, deep periventricular WM, cerebellum and brainstem.4 There is also hepatic involvement reported in Asian patients with abnormal liver function and/or hepatomegaly.4 In ANE1, T2 and FLAIR weighted MRI hyperintensities have been reported in the external capsules, claustrum, limbic structure, temporal lobes and mammillary bodies.6 Diffusion-weighted imaging reveals restricted diffusion in these areas with diffusion coefficient maps showing low values in the hemorrhagic areas, akin to cytotoxic or ischemic lesions with higher values suggesting peripheral edema.6
It appears that brainstem involvement is the key prognostic factor.6 Currently, early administration of steroids, often within 24 hours and prophylactic use of inactivated vaccines are starting to be adopted as a therapeutic strategy.9
Neilson et al1 studied a large multigenerational family with autosomal-dominant ANE (i.e., “ANE1”). Half of the members who presented with ANE1 had residual debilitating neurological impairment. In 2009, the same group identified a recurrent missense mutation (c.1880C>T) in the RANBP2 gene causing an amino acid substitution (p.Thr585met). In total, 10 families were found to harbor this mutation, arising de novo in 2 of these families). Further missense mutations were found in 2 different families (c.2085C>T; p.Thr653Ile and c.2094A>G; p.Ile656Val). Discovering these independent missense mutations and de novo mutations in only affected families implicated RANBP2 as a susceptibility allele for a familial form of ANE, that is, ANE1.
Gika et al2 reported a 9-year old with ANE1 who was heterozygous for a RANBP2 mutation [c.1880C>T (p.Thr585Met)] and 1 of the cases reported in Ref. . The child had 1 self-limiting attack of ANE at 9 months, a right abducens nerve palsy with slow recovery at 2 years of age and at 9 years suffered postinfluenza A ANE with severe neurocognitive impairment. Her mother had been noted to have post-viral encephalitis and polyneuritis at the age of 19 with a residual foot-drop and was also found to be heterozygous for the same mutation. This case highlighted that the RANBP2 mutation can result in phenotypic ANE or a less severe mono/polyneuropathy. Lönnqvist et al further defined a heterozygous p.T585M mutation in 6 affected members of a 3-generation family with ANE1.6
RANBP2 may be a critical modulator of neuronal activity, glucose catabolism and energy homeostasis.10 Given the absence of a CSF infiltrate, ANE is accepted as a host-mediated phenomenon. A cytokine storm may be pivotal in the pathophysiology of ANE.11 Interleukin-6 (elevated in both serum and CSF) and TNF alpha are pro-inflammatory cytokines that are capable of inducing apoptosis and endothelial injury resulting in the breakdown of the blood-brain barrier.11 Notably in this condition there is a “relative absence” of lymphocytosis despite the raised CSF protein. This could be explained by this proposed breach in the blood-brain-barrier, which could be confirmed by CSF IgG index or albumin quotient (often mixed with oligoclonal bands). An alternative explanation could be intrathecal production in vivo, which could be revealed by measuring intrathecal oligoclonal bands.
1. Neilson DE, Adams MD, Orr CM, et al. Infection-triggered familial or recurrent cases of acute necrotizing encephalopathy caused by mutations in a component of the nuclear pore, RANBP2. Am J Hum Genet. 2009;84:44–51
2. Gika AD, Rich P, Gupta S, et al. Recurrent acute necrotizing encephalopathy following influenza A in a genetically predisposed family. Dev Med Child Neurol. 2010;52:99–102
3. Mizuguchi M, Abe J, Mikkaichi K, et al. Acute necrotising encephalopathy of childhood: a new syndrome presenting with multifocal, symmetric brain lesions. J Neurol Neurosurg Psychiatry. 1995;58:555–561
4. Suri M. Genetic basis for acute necrotizing encephalopathy of childhood. Dev Med Child Neurol. 2010;52:4–5
5. Mizuguchi M. Acute necrotizing encephalopathy of childhood: a novel form of acute encephalopathy prevalent in Japan and Taiwan. Brain Dev. 1997;19:81–92
6. Lönnqvist T, Isohanni P, Valanne L, et al. Dominant encephalopathy mimicking mitochondrial disease. Neurology. 2011;76:101–103
7. Wolf K, Schmitt-Mechelke T, Kollias S, Curt A. Acute necrotizing encephalopathy (ANE1): rare autosomal-dominant disorder presenting as acutetransverse myelitis. J Neurol. 2013;260:1545–1553
8. Lee JH, Lee M, Lee J. Recurrent acute necrotizing encephalopathy in a Korean child: the first non-Caucasian case. J Child Neurol. 2012;27:1343–1347
9. Marco EJ, Anderson JE, Neilson DE, et al. Acute necrotizing encephalopathy in 3 brothers. Pediatrics. 2010;125:e693–e698
10. Aslanukov A, Bhowmick R, Guruju M, et al. RanBP2 modulates Cox11 and hexokinase I activities and haploinsufficiency of RanBP2 causes deficits in glucose metabolism. PLoS Genet. 2006;2:e177
11. Wang GF, Li W, Li K. Acute encephalopathy and encephalitis caused by influenza virus infection. Curr Opin Neurol. 2010;23:305–311