We present a previously healthy 6-month-old boy who was admitted to our hospital with lethargy, hypotonia and focal clonic seizures 6 days following diptheria, tetanus toxoid and whole-cell pertussis vaccination. A diagnosis of acute necrotising encephalopathy was made with the aid of MRI, including diffusion-weighted imaging and proton MR spectroscopy.
The association of diptheria, tetanus toxoid and whole-cell pertussis (DTPw) vaccination with acute necrotising encephalopathy (ANE) has not been previously reported in the literature. ANE has been predominantly reported in Japan, Taiwan and, less frequently, Korean children [1, 2]. We present a unique case of a non-Asian child with ANE following DTPw vaccination.
A previously healthy 6-month-old boy had hyperpyrexia and irritability after the second dose of DTPw vaccination. On the 6th day after vaccination his symptoms had progressed and he was admitted to our hospital with lethargy, hypotonia and focal clonic convulsions. His body temperature was 36.3°C. On laboratory examination, white blood cell value was 12,000/mm3. Biochemical analysis and cultures of blood, urine and cerebrospinal fluid (CSF) were unremarkable. There was no familial history of acute encephalitis and genetic analysis to look for a mutation of the RANBP2 gene was not performed.
On the 3rd day of admission, brain MRI showed symmetrical increased signal intensities (SI) in both thalami and posterior limb of the internal capsule (PLIC) on fluid-attenuated inversion recovery (FLAIR) and T2-weighted sequences (Fig. 1). Increased SI on T1-weighted images in the right thalamus suggested haemorrhage (Fig. 1); however, there were no corresponding hypointense areas on T2-gradient-echo sequence to support this. T1-W contrast-enhanced images showed no enhancement in the swollen thalami. There was increased SI on diffusion-weighted imaging (DWI) and apparent diffusion coefficient (ADC) sequences in both thalami, apart from an area with decreased ADC in the right thalamus corresponding to haemorrhage or cytotoxic oedema (Fig. 1).
One week after the first MRI study, brain MRI and DWI were repeated and brain proton spectroscopy (MRS) was obtained. There was partial improvement, but with persistent moderate increased SI on T2-W and DWI sequences, and increased ADC (Fig. 2). Hyperintensity on the T1-W sequence had disappeared (Fig. 2). We obtained multivoxel and single voxel proton MRS using echo times of 31 ms, 136 ms, and 272 ms. The voxel location for single-voxel MRS was set at the right thalamus. We measured high lipid-lactate complex peak intensities at 0.8–1.5 parts per million (ppm) and glutamate/glutamine complex peak intensities at 2.0–2.5 ppm on single voxel short-echo-time proton MRS (TE 31 ms) (Fig. 2). N-acetyl aspartate (NAA) peak was within the normal range.
Fifteen days after admission, his clinical symptoms had regressed and he was discharged. Bilateral thalamic lesions regressed within 6 months. On follow-up MRI the thalami appeared mildly heterogeneous and diffusely smaller than normal and the PLIC were asymmetrical and partially myelinated (Fig. 3). His neurological and psychological evaluations showed psychomotor retardation and cerebral palsy.
The aetiology and pathogenesis of ANE remain unclear. About 90% of patients with ANE have a history of viral infection. Influenza A and B virus, Epstein-Barr virus, measles, herpes simplex, human herpes virus-6, rubella and varicella virus are reported in the literature as possible viral agents . DTPw vaccination has not been previously reported in association with ANE. Vaccination with DTPw has recognised neurological adverse events, but ANE has not been previously included in this list.
According to the literature, differential diagnoses for ANE include Leigh encephalopathy, glutaric acidaemia, methyl malonic aciduria, infantile bilateral strial necrosis, Wernicke encephalopathy, carbon monoxide poisoning, central pontine/extrapontine myelinolysis, acute disseminated encephalomyelitis, Reye syndrome, acute haemorrhagic leukoencephalitis, arterial or venous infarct, severe hypoxia, and traumatic injury . We excluded these diseases based on clinical and laboratory examinations, and imaging findings. ANE typically involves the bilateral thalami, pons, brainstem, periventricular white matter and cerebellum.
Neuropathologically, ANE lesions show oedema, petechial haemorrhage and necrosis, suggesting local breakdown of the blood brain barrier (BBB) . According to published clinical and neuropathological data, possible pathogenesis may be simple alteration of vessel wall permeability without disruption (mild cases) or vessel wall necrosis (severe cases) . Transudation of serum with resulting parenchymal oedema may indicate the vasogenic nature of the oedema. Decreased ADC levels in ANE may be due to haemorrhage (as a result of local breakdown of the BBB) or cytotoxic oedema [2, 3]. Local breakdown of the BBB may be due to cytokine release from virus-stimulated glial macrophages. It is known that production of cytokines such as IL-6 and TNF-α increase due to DTPw and diphtheria, tetanus toxoid and acellular pertussis (DTPa) vaccination too. DTPw is a more IL-6 inducer than DTPa and whole-cell vaccination has a strong effect on macrophage activation [4, 5]. Increased IL-6 and TNF-α levels due to DTPw vaccination may cause alteration of vessel wall permeability and local breakdown of the BBB. Cytotoxic and vasogenic oedema on DWI and increased lipid complex peak and glutamate/glutamine complex peak intensities on short echo-time MRS, as in our case, may be secondary to these neurotoxic effects.
There are few reports regarding DWI and MRS findings of ANE in the literature. Harada et al.  described DWI and lactate production in ANE. They detected decreased ADC values and low lactate peak in a patient with ANE. Goo et al.  detected bilateral thalamic high SI on DWI and decreased ADC values in two cases with ANE. They found lipid-lactate complex peak and glutamate/glutamine complex peak on short-echo-time MRS . Albayram et al.  presented DWI findings of a case with ANE. They detected low ADC values within the thalamic lesion, and increased ADC values surrounding it .
Increased lipid peak on short-echo-time MRS may result from cell membrane damage or disintegration. Glutamate is an excitatory neurotransmitter but can cause excitotoxic neuronal damage if excessive amounts are released into the synaptic cleft .
The prognosis of ANE is usually poor. However, in some patients, ANE has a good prognosis with reversible involvement of the brain and they recover completely or have mild sequelae . The presence of haemorrhage, localized atrophy or cystic encephalomalacia in the brain lesions was reported as a significant prognostic imaging finding observed in patients with ANE by Kim JH et al.  In addition, patients who have restricted water diffusion in thalamic lesions on the ADC map and glutamate/glutamine complex and mobile lipid on MRS generally have severe sequelae or high mortality [1, 3, 8]. Our case had pathological findings on brain MRI, DWI and MRS and he developed cerebral palsy.
In conclusion, ANE may be seen secondary to DTPw vaccination. We suggest that in patients with neurological symptoms after DTPw vaccination, ANE should be kept in mind and detailed neuroradiological imaging methods must be performed, including brain MRI, DWI and MRS.
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Aydin, H., Ozgul, E. & Agildere, A.M. Acute necrotizing encephalopathy secondary to diphtheria, tetanus toxoid and whole-cell pertussis vaccination: diffusion-weighted imaging and proton MR spectroscopy findings. Pediatr Radiol 40, 1281–1284 (2010). https://doi.org/10.1007/s00247-009-1498-9