A 7-year old previously healthy girl of non-consanguineous Caucasian parents was admitted due to the first occurrence of a brief self-limiting afebrile focal onset seizure (twitching of the right arm). Retrospectively, the patient reported intermittent abdominal pain and a brief period of intermittent double vision preceding the seizure by ~4-5 h on the day of admission.
Initial blood tests showed a normal hemogram, blood glucose levels (5.8-6.3 mmol/L), coagulation parameters, and renal retention parameters. CRP was mildly elevated to 22 mg/l [n.v. <8] and D-dimers were increased to 3.8 mg/l [n.v. <0.5].
Electroencephalogram (EEG) demonstrated severe bi-hemispheric slowing, especially in the right parieto-occipital region. Shortly after admission, the patient reported a sudden episode of abdominal pain, headache, loss of vision and suffered from another seizure with focal onset with evolution to generalized seizure activity. The seizure, together with the other symptoms, resolved after ~3 min without medical intervention. The cranial MRI (cMRI) performed on the first day of admission was consistent with PRES showing multiple spot-like, partly confluent cortical/subcortical hyperintensities predominantly in the bilateral parietal region on FLAIR/T2-weighed images with slight focal swelling (Figures 2A,B). On diffusion weighted images, the involved cortical ribbon and the adjacent subcortical white matter were hyperintense to a large extent without hypointensity on the ADC map indicating vasogenic edema. Only small cortical sections showed hypointensities on the ADC map in terms of diffusion restrictions. Typical watershed infarcts or microbleedings could not be detected. The patient's blood pressure was relatively low on the first night, with systolic pressures ranging from 98 to 100 mmHg and diastolic pressures ranging from 44 to 47 mmHg with a normal heartbeat rate of 86-125/min. Vasculitis workup was negative as demonstrated by normal von-Willebrand-Antigen, ANAs and p- und c-ANCAs, anti-ds ABs, ENAs, C3, C4. Cerebrospinal fluid showed no cells and normal levels of lactate, glucose, and protein. Microbiological workup and PCR investigations for neurotropic viruses were negative.
Shortly after the admission, several petechiae developed on the forearms and lower limbs. Within the first 5 days of admission, the patient showed progressive petechial bleeding signs, which progressed to the classical and diagnostically groundbreaking palpable purpura (Figure 3), and suffered from another short episode of confusion and blurred vision. Concerning other organ manifestations, urine diagnostics and duplex-sonography of kidneys and gut demonstrated repeatedly normal findings. Arthralgia was not noted.
After the second seizure on the day of admission, the girl suffered from headaches and mild behavioral changes but was overall in a stable condition. The patient was treated with acyclovir and ceftriaxone until a microbial etiology for the symptoms was excluded by blood- and spinal fluid analyses. In the course of the disease, blood pressure became elevated, reaching 150 mmHg systolic on the second day. Therefore, antihypertensive medication was initiated with dihydralazine and gradually extended with ramipril, amlodipine, and repeated doses of nifedipine, resulting in levels around 130/75 mmHg. Repeated abdominal ultrasound showed kidneys and gut normally perfused. Urine workup showed no hematuria, and an albumin/creatinine ratio of 33 mg/g ruled out renal impairment. Extended secondary hypertension diagnostics showed normal findings for ocular fundus, electrocardiogram, echocardiography, and endocrine disorders.
Four days after the seizure, a non-tender purpuric rash appeared on the lower extremity and buttocks/forearms/and on the trunk in loco typico for IgAV (Figure 2). Abdominal pain and nausea returned 2 days later, so intravenous methylprednisone 2 mg/kg/d was administered for 3 days. Daily abdominal ultrasound excluded intussusception. Under combined antihypertensive medication, the patient fully recovered neurologically without any further seizures. Blood pressure decreased to levels of 100 mmHg systolic under continued treatment with ramipril and amlodipine after 1 week.
The benefit of steroids in IgAV has only been shown for abdominal involvement, whereas no studies compare the neurologic outcome with steroids to no or other treatment. As our patient did not show neurological symptoms after the remission of the initial seizure during her entire stay and for the potential additional effects on the blood pressure, we did not administer steroids until the return of abdominal symptoms. Following three courses of i.v. methylprednisone (2 mg/kg), which were well-tolerated, medication was switched to an oral equivalent and tapered. At 1-month follow-up, no neurologic residues were notable, EEG showed slow wave-complexes in the occipital areas and was otherwise normal, renal ultra-sound and urine workup remained without abnormalities. Hypertension diminished, and the antihypertensive medication could be discontinued after a total of 4 weeks. At 6-month follow-up, clinical and neurological examination and urine workup and blood pressure remained normal. EEG findings had significantly improved, showing only mildly slow waves in the occipital region. An externally acquired brain MRI follow-up was normal without residual lesions. Today, with a follow-up of 3 years, the patient remained symptom-free.
Literature search with the aforementioned MeSH terms yielded 325 studies, of which 22 included patients with seizures or PRES associated with IgAV and two studies with IgAV associated with cerebral vasculitis. From these studies, clinical data of a total of 28 patients could be collected. Reports in English and German were evaluated independently by two authors. In addition, citations from reviews were checked, but no further reports could be identified by this (Table 1).
In total, we identified 28 cases with IgAV and reversible encephalopathy. Twenty six cases were associated with seizures, and thereof 14 cases fulfilled all clinico-radiological criteria of PRES. Lava et al. indicated the existence of seven other cases, which, however, were not available in English or did not fulfill the radiologic diagnostic criteria of PRES and were therefore not considered a confirmed PRES diagnosis in this summary. In contrast to the general prevalence of IgAV (male 2:1 female), neurological involvement in pediatric patients was nearly equally contributed, with 13 girls and 13 boys affected, respectively. Two cases of adult males (22 and 42 years of age) and one female patient were found. Berube et al., however, reported a 1.5:1 preponderance of male patients. The mean age of patients was 11.2 years (median 8.0, range 5-42 years), and no ethnic prevalence was found. The clinical spectrum of the given IgAV cohort is summarized in Figure 4.