Casuistic Use of High-Dose Methylprednisolone in a Child with Acute Encephalopathy due to Metabolic Crisis in HIBCH DeficiencyAbstract
3-hydroxyisobutyryl-CoA hydrolase deficiency (HIBCHD) is a rare metabolic disease. Early symptoms include poor feeding, seizures, hypotonia and impaired psychomotor development. Acute metabolic crisis can cause encephalopathy with high risk of neurological sequelae or death. Casuistic, we here report a nine-year old Danish girl with HIBCHD treated with intravenous high-dose methylprednisolone when presenting with encephalopathy during acute metabolic crisis. Presentation of acute encephalopathy with basal ganglia changes seen on MRI was regarded as acute disseminated encephalomyelitis (ADEM) leading to intravenous high-dose methylprednisolone treatment. The effect of methylprednisolone was profound, not only on the acute neurological symptoms, but also accelerated the development of the child. After re-evaluation of MR images, Whole Genome Sequencing (WGS) confirmed the diagnosis HIBCHD. The high-dose methylprednisolone treatment regime was repeated in a following severe metabolic crisis presenting with acute encephalopathy, dystonia and spasticity. The child survived and after rehabilitation neurological sequelae are present but considerably reduced. We consider if high-dose methylprednisolone should be recommended in children with acute metabolic crisis and encephalopathy due to HIBCHD. Since influenza A virus was the triggering cause to metabolic crisis with encephalopathy, vaccination should be considered in HIBCHD.
Keywords:
Child; Encephalopathy; Metabolic disease; Metabolic crisis; Leigh syndrome
Introduction
HIBCHD, 3-hydroxyisobutyryl-CoA hydrolase deficiency, is a rare metabolic disease [1]. HIBCHD is autosomal recessively inherited and caused by pathogenic variants in the HIBCH gene leading to deficient breakdown of valine. The 3-hydroxyisobutyryl-CoA hydrolase is responsible for hydrolysis of 3-hydroxyisobutyryl-CoA, the fifth step in valine catabolism, as well as the hydrolysis of 3-hydroxypropionyl-CoA, an intermediate in a minor pathway of propionate metabolism. The enzyme defect causes accumulation of several toxic intermediary products in the breakdown of valine, including methylacrylyl-CoA, which inhibits several mitochondrial enzymes and mitochondrial energy generation. This explains why the disease mimics mitochondrial disease [1]. HIBCHD has an estimated incidence of 1:130,000 among East Asians and 1:550,000 in Europeans [2]. In total, 31 HIBCH gene variants was reported in 2021 in 34 different patients presenting a broad phenotypic spectrum ranging from early death to movement disorder with survival into adulthood [3].
Magnetic resonance imaging (MRI) abnormalities are characteristic with bilateral involvement of the basal ganglia with varying degrees of white matter atrophy. During metabolic crisis, cerebral cytotoxic edema may evolve, and the MRI shows decreased diffusion with bilateral hyperintense T2 signal in the putamen and/or brainstem. The subthalamic nucleus, substantia nigra, caudate nucleus, globus pallidus, dorsomedial thalamus and cerebellar dentate nuclei may also be involved [4]. The crisis may lead to permanent MRI changes and neurological compromise [5].
There is no cure for HIBCHD. A low-protein diet with reduced valine may be used [6]. However, there is little evidence regarding the efficacy of nutrition therapy for HIBCHD and mitochondrial disease in general [7]. Infections, vomiting and fasting can lead to metabolic decompensation with dehydration, metabolic acidosis, severe illness and encephalopathy, coma and convulsions. In case of acute illness, regular food is paused and emergency regime is initiated with special dietary products mixed in a glucose polymer solution. Emergency regimen is either oral or intravenous, depending on the patient's condition [8].
Our case is a nine-year old Danish girl with HIBCHD treated with high-dose methylprednisolone during acute metabolic crisis. After her second metabolic crises, Whole Genome Sequencing (WGS) confirmed the diagnosis HIBCHD. Before WGS diagnostics, the basal ganglia changes seen on MRI was regarded as acute disseminated encephalomyelitis (ADEM) leading to initiation of high-dose methylprednisolone treatment. The effect of prednisolone was profound on not only the acute neurological symptoms, but also accelerated the development of the child.
Patient and Methods
The parents have given written informed consent. The patient was the second child of healthy non-consanguineous parents from Sri Lanka. There is a healthy older sister with normal development. She was born in Denmark at 39 weeks of gestation after a normal pregnancy. The birth was uneventful. Apgar score at 1 and 5 minute was 10. Her birth weight was 3.700 g, length 52 cm.
She had normal psychomotor development until ten months of age, where she had a period with prolonged fever with altered consciousness and seizures. She was admitted to the hospital under the suspicion of febrile seizures. After this febrile episode, the parents observed slowing of her development and regression in some areas. She began to squint. She learned to walk after the age of two. She had a very slow language development. She easily got tired, could not follow her peers, and she was kept home on days when the kindergarten was going on an excursion.
When the patient was three years old, she was hospitalized with fever and limping on her left leg. Virus screening was positive for influenza A. Ultrasound and X-ray of the lower extremities was normal. Biochemically, there was no signs of infection. During the next weeks, she became encephalopathic with complete loss of gait function.Cerebrospinal fluid (CSF) protein was 0.11 g/l (ref. 0.15 - 0.45 g/l) with normal level of leucocytes (2 × 106 /l) and erythrocytes (<300 x106 /l). PCR and culturing was negative for virus and bacteria. Capillary lactate was increased 3.5 mM. Cerebral MRI showed symmetrical hyperintense abnormalities bilaterally in basal ganglia on FLAIR and T2-weighted sequence, corresponding to restricted diffusion (Figure 1; bottom row). Spinal MRI was normal. Cerebral MRI findings and the acute presentation with increasing encephalopathy, was interpreted as ADEM. The patient was treated with high dose intravenous methylprednisolone 30 mg/kg/day for 5 days. Oral corticosteroid treatment was continued at 2 mg/kg/day for two weeks with gradual tapering over 4 weeks. The patient responded well to treatment. Motor skills and language development became even better than before the crisis. She became able to run, had a better balance and could climb stairs. The patient could neither run nor climb stairs independently before the acute crisis. The patient’s vocabulary expanded and she became capable of making sentences.
Bottom row: MRI at metabolic crisis due to HIBCHD at age 3 years. These T2W and FLAIRS sequences show symmetrical high-signal changes in globus pallidus and corpus striatum. There is restricted diffusion with high signal on DWI b1000 and reduced signal on ADC corresponding to intracellular cytotoxic edema and developing necrosis. The patient was treated with high-dose methyl prednisolone. Middle row: Repeated MRI three month after metabolic crisis. Compared to the first MRI, the signal at T2W and FLAIR, DWI b1000 and ADC sequences is now reduced corresponding to less intracellular cytotoxic edema; an indication of cellular improvement although chronic manifestations. Upper row: MRI from metabolic crisis at age six with severe encephalopathy. Again significant high signal changes on T2W and FLAIR corresponding to acute intracellular cytotoxic edema and developing necrosis.
Three months later, the limb returned. The MRI showed slightly diminished changes bilaterally in globus pallidus, however, the impression of restriction of diffusion was unchanged (Figure 1). Whole Genome Sequencing (WGS) showed compound heterozygosity for two pathogenic variants in the HIBCH gene associated with 3-hydroxy-isobutyrol-coA hydrolase deficiency (HIBCH): a missense variant in exon 12: c. 1007G>A; p. (Cys336Tyr) inherited from her father and a missense variant in exon 4: c.289G>A;p.(Gly97Arg) inherited from her mother. The patient started on a special low-protein diet with a specific reduction of valine; levocarnitine (100 mg/kg/day), Q10 supplementation and reduced fasting time. There was normal examination of eyes and vision.
At the age of 6 years, the patient was hospitalized with fever and encephalopathy despite dietary emergency regimen. Again, virus screening was positive for Influenza A virus. Emergency regimen with IV glucose was initiated alongside levocarnitine, Tamiflu and high-dose prednisolone. Compared to earlier MRI, there was significantly increased high signal changes with restriction of diffusion in basal ganglia (Figure 1; upper row). Despite treatment, her level of consciousness decreased, and she needed assisted ventilation for 5 days. After extubation, she was severely encephalopathic with no eye contact, no response to sounds or call, no language - only primitive screaming, increasing dystonia and spasticity. The patient was unable to eat and drink and a percutaneous endoscopic gastrostomy (PEG) tube was inserted. Over the next month, she became less encephalopathic. She was transferred to a neurorehabilitation center. At this stage, the patient could follow movements with her eyes, could communicate with vocal sounds and could laugh. Recognition was impaired. She had severe dystonia, had uncoordinated swallowing, and was fed via the PEG tube.
One year after the third metabolic crisis, she was discharged from neurorehabilitation center to home. During that year, the patient did not achieve independent walking. She had a baclofen pump inserted due to spasticity. Feeding was primarily via PEG tube. She was dependent on others in activities of daily life. The language skills recovered with minor dysarthria left, although vocabulary was reduced. Rehabilitation is still ongoing. The baclofen pump is now weaned off. The treatment of dystonia has been stopped. She is capable of standing and walking a few steps with support. Her language skills are almost normalized. Her cognition including memory skills also seems to develop positively. She has started special school; she is socially active and is increasingly independent on caregivers.
Results and Discussion
HIBCH is a rare metabolic disease and may cause signs and symptoms consistent with Leigh syndrome. Leigh syndrome is a neurodegenerative disease with variable symptoms, caused by genetically heterogeneous mitochondrial dysfunction, accompanied by bilateral central nervous system lesions [9]. The cerebral findings are to some extent dependent on the genetic background that cause the mitochondrial dysfunction. Typically in HIBCH, as in other mitochondrial disorders with dysfunction in oxidative phosphorylation, the changes are localized to the basal ganglia (90%), thalamus (42%) - and/or in the brainstem (62%), where symmetrical hyperintense changes are found on T2W and FLAIR sequences. The findings are due to necrosis and is associated with demyelination, vascular proliferation and gliosis [7]. In acute phases, diffusion restriction is often seen in the same affected brain regions. Restricted-diffusion patterns on MRI typically results from failure of energy-dependent adenosine triphosphate production in cell membranes resulting in intracellular cytotoxic edema, usually implying cell death [10]. There is increasing evidence, that chronic inflammation plays a role in mitochondrial diseases [11]. In this case, MRI findings was interpreted as ADEM. However, ADEM typically presents with bilateral, poorly marginated, asymmetrical white matter lesions with additional involvement of gray matter of thalamus and basal ganglia [12]. In addition, resolution of MRI abnormalities favors ADEM [11, 12].
In this patient, the first metabolic crisis occurred when the patient was ten months old. After a period of fever and uncomplicated febrile convulsions her development became slower, she lost skills and began to squint. Early-onset mitochondrial disorders including those presenting with Leigh and Leigh-like syndrome can present with squint together with loss of previously acquired skills often after a minor febrile illness [13]. The patient was not treated with high-dose methylprednisolone at this stage.
At her second metabolic crisis, presenting with limping and encephalopathy, our patient was treated with high-dose prednisolone. She achieved better walking function and balance. She became able to run and her language developed. Cerebral imaging also showed improvement. Figure 1 shows less pronounced diffusion restriction in the basal ganglia when comparing the MRI obtained in the acute setting with MRI done 3 months later (Figure 1 bottom and middle row). After the first metabolic crisis with no treatment, the patient's development deteriorated with almost arrested language development. Independent walking was first achieved after the age of two. After treatment with high-dose methylprednisolone at the second metabolic crisis, the patient's psychomotor development was significantly improved and her language skills became better, developing from a child with sparsely developed speech, to a child with near normal language development. The authors cannot explain this significant clinical improvement and consider this as an effect of high dose methylprednisolone. No other medicine or diet regime were introduced. High-dose methylprednisolone was also given at the third metabolic crisis. This time the encephalopathy was more profound with coma, dystonia and spasticity. However, after long rehabilitation the language skills have recovered, dystonias are vanished while some spasticity has remained corresponding to permanent brain damage. It is not possible to say, whether the patient would have endured even more profound disabilities or died, if not treated with methylprednisolone.
Prednisolone is a potent anti-inflammatory drug. The use of prednisolone in mitochondrial diseases is debated, since evidence is based on case reports, and beneficial effect seems divergent, not only between, but also within the same mitochondrial disease [14]. However, in some mitochondrial diseases as MELAS, mitochondrial myopathy and mitochondrial leucoencephalopathy corticosteroid treatment appears beneficial [15]. All tough the complete pathogenesis in mitochondrial diseases is not understood, the effect of corticosteroid is supposed to be anti-inflammatory and immune modulating along with a direct effect on the mitochondria via specific glucocorticoid receptors [11, 14-16].
The two major metabolic crises in the patient were triggered by Influenza A. Other viral infections including corona virus, did not result in the same serious symptoms and could be handled with oral emergency regime without the development of encephalopathy. This may be purely coincidental, since no cases have been reported in patients with metabolic crisis due to HIBCH deficiency and Influenza A virus infection. In general, immune system dysfunction is a well-documented possible sequalae of genetic mitochondrial dysfunction, although, the mechanism is poorly understood [15]. Encephalopathy is the most common major neurological association with Influenza virus. Some studies show that the risk of encephalopathy is higher in children with pre-existing neurological problems [17]. Depending on the severity of the encephalopathy, cerebral edema of the cerebral cortex, symmetric involvement of the thalami, basal ganglia and brainstem can be seen [17].
In conclusion, high-dose methylprednisolone should be considered in patients with HIBCHD with severe metabolic crisis, characteristic MRI abnormalities and encephalopathy. In this case, Influenza A was the trigger of severe metabolic crises; hence, vaccination should be considered in patients with HIBCHD.
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Publication Dates
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Publication in this collection
24 Feb 2025 -
Date of issue
2025
History
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Received
30 June 2024 -
Accepted
29 Jan 2025
