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Ahead of print publication

Persisting irritability with fever is not always meningitis

1 Department of Pediatrics, Pondicherry Institute of Medical Science, Puducherry, India
2 Department of Pediatrics, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India
3 Department of Pediatrics and Neonatology, Aarupadai Veedu Medical College and Hospital, Puducherry, India

Date of Submission23-Oct-2020
Date of Decision10-May-2021
Date of Acceptance11-Apr-2021
Date of Web Publication07-Jan-2022

Correspondence Address:
Rohit Bhowmick,
Department of Pediatrics, Pondicherry Institute of Medical Science, 605014.
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jpn.JPN_283_20



Krabbe disease is a neuro-regressive disorder commonly seen in the infantile age group. The authors report a four-month-old male baby with persisting irritability despite adequately treated for meningitis. The authors wish to highlight the importance of systematic evaluation that leads to the diagnosis of Krabbe disease, which can be challenging in the early infantile age group.

Keywords: Globoid cell leukodystrophy, infantile krabbe, irritable infant, neurodegenerative disorder

How to cite this URL:
Fathima H, Bhowmick R, Kasinathan AN, Bhat VB. Persisting irritability with fever is not always meningitis. J Pediatr Neurosci [Epub ahead of print] [cited 2023 Dec 1]. Available from: https://www.pediatricneurosciences.com/preprintarticle.asp?id=335199

   Introduction Top

Krabbe disease (KD), also known as globoid cell leukodystrophy, is a storage disorder of the peripheral and central nervous system secondary to the accumulation of galactosylcerebroside in the myelin sheath.[1] It is clinically classified based on the age of onset and includes the early infantile form (1–12 months), late infantile form (1–3 years of age), juvenile, and adult onset. The infantile form is the most common and accounts for 85–90% of cases.[2] Unexplained irritability, poor feeding, gastroesophageal reflux, stiff limbs, and loss of acquired milestones are the typical clinical features in the infantile form.[2] The authors report a four-month-old male baby who was referred as a case of partially treated meningitis and where it later turned out to be KD.

   Case Report Top

A four-month-old male child was referred to our hospital with irritability and a diagnosis of partially treated meningitis. The patient was born to a third-degree consanguineous couple with an uneventful perinatal period. He developed fever, new onset of irritability, and poor feeding for five days. An initial diagnosis of bacterial meningitis was made in another hospital. Cerebrospinal fluid (CSF) analysis revealed elevated protein (168 mg/dl); however, other biochemical, cellular, and microbiological parameters were within normal limits. He was treated with intravenous (IV) antibiotics and acyclovir for 14 days and then discharged. Six days post-discharge, he was brought to our hospital with fever, intermittent stiffness of the trunk and limbs, which were suggestive of dystonia. His poor feeding and excessive irritability persisted with disturbed sleep. Family history revealed the death of an elder sister at five months of age. The deceased sibling had global developmental delay and succumbed to death after refractory status epilepticus without a diagnosis.

On examination, the child was irritable with persistent crying and recurrent opisthotonic posturing and dystonia. General examination revealed no neurocutaneous markers, optic atrophy, microcephaly, or organomegaly. The child was visually inattentive with no fixation to bright light. Development assessment revealed severe global developmental delay (developmental quotient, 25%). On neurological examination, bipyramidal signs such as spasticity, exaggerated deep tendon reflexes, and positive Babinski were striking. Repeat CSF analysis revealed persistently elevated protein (284 mg/dl) with acellularity. The CSF and blood culture were sterile, ruling out meningitis. An MRI brain revealed bilateral dentate nucleus hyperintensity, which was suggestive of KD [Figure 1] and was confirmed by homozygous pathogenic variation in exon 12 of the Galactocerebrosidase (GALC) gene by Sanger sequencing. The child was initiated on neuro-rehabilitative protocol, and reproductive counseling was offered to the parents.
Figure 1: T2-weighted MRI image showing bilateral dentate nucleus hyperintensity

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   Discussion Top

KD is an autosomal recessive neurodegenerative disorder involving β-GALC. The index child merited attention because of unexplained irritability mimicking meningitis, consanguinity among parents, and a history of sibling loss with global developmental delay and convulsions. The clinical features of infantile onset of KD depend on the residual enzyme activity and include four stages.[3] Stage I is characterized by episodic crying with feeding difficulty after an apparent state of near normalcy. Stage II is neurological, with marked decorticate posturing and opisthotonos. Seizures, deafness, dysautonomia, and blindness become prominent in Stage III. Stage IV is characterized by profound hypotonia with vegetative state and no volition. Unlike infantile onset forms, sudden onset vision loss and gait instability are the features of juvenile-onset KD. Spastic paraparesis may be the only presentation of adult-onset KD, highlighting the heterogenous age-dependent clinical phenotype.[3] The high protein content of the cerebrospinal fluid in KD is a clue to the diagnosis and is secondary to the breakdown of myelin in the CSF. Bilateral hyperdensities in the thalamus are one of the hallmarks of KD as per a CT brain.[4] Bilateral T2 periventricular white matter hyperintensity with cerebellar dentate nucleus involvement are typical findings in an MRI brain.[5] Biochemical estimation of enzyme galactosylceramidase in the leukocytes is slowly replaced by genetic sequencing for the GALC gene on chromosome 14q24.3-q32.1. Currently, enzyme replacement therapy (ERT) and hematopoietic stem cell transplantation (HSCT) are the only available therapeutic approaches for the management of KD.[6] HSCT helps in improving the survival outcome and also delays the onset of spasticity in children without neurological manifestations. This is possible if detected early by using newborn screening or genetic analysis of the chorionic villus sample in the affected fetus.

To conclude, we wish to highlight the meningitis-like presentation of a child with KD. Detailed family history and dentate nucleus changes in the cerebellum in MRI are valuable clues to the diagnosis.

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There are no conflicts of interest.

   References Top

Carol A, Graziano E, Cardile V. History, genetic, and recent advances on Krabbe disease. Review article. Gene 2014;555:2-13.  Back to cited text no. 1
Orsini JJ, Escolar ML, Wasserstein MP, Caggana M. Krabbe disease. In: Adam MP, Ardinger HH, Pagon RA, et aleditors. GeneReviews® [Internet]. Seattle, WA: University of Washington; 1993-2021 [2000 Jun 19; updated 2018 Oct 11]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1238/. [Last accessed on 2021 Jun 23].  Back to cited text no. 2
Escolar ML, West T, Dallavecchia A, Poe MD, LaPoint K. Clinical management of krabbe disease. J Neurosci Res 2016;94:1118-25.  Back to cited text no. 3
Kwon JM, Matern D, Kurtzberg J, Wrabetz L, Gelb MH, Wenger DA, et al. Consensus guidelines for newborn screening, diagnosis and treatment of infantile krabbe disease. Orphanet J Rare Dis 2018;13:30.  Back to cited text no. 4
Gerard GV, Ryan J, Urgel DL. Krabbe disease in a 6-month old male presenting with neurodevelopmental regression and psychomotor delay: A case report. Eurorad2017. doi: 10.1594/ EURORAD/CASE.14919.  Back to cited text no. 5
Adriana C, Eleonora G, Giovanna P, Rosanna A,Venera C. Chaperones as potential therapeutics for Krabbe disease: Review article. J Neurosci Res2016;94:1220-30.  Back to cited text no. 6


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