SPECT
Six studies included patients with HIE, four reported low cerebral perfusion in the basal ganglia in patients with HIE 7) (Iwaibara 2010), and low cerebral perfusion in the lentiform nucleus and thalamus in half (3/6) of the patients with severe HIE. Tranquart et al. reported low corpus striatum-to-cerebellum activity ratio in cerebral perfusion8), Kapucu et al. reported low striatal-to-occipital cortex ratio in cerebral perfusion8) and Oshima et al. reported low cerebral perfusion in the entire brain9). Three studies reported cerebral perfusion of parasagittal lesions9–11) (Oshima 1993) (Konishi, 1994) (Shah 2001). Konishi et al. reported low cerebral perfusion of a wide area of the brain, except in the basal ganglia, brain stem and the sensory cortex, in three cases with HIE that suffered severe neurological prognosis, despite no remarkable MRI abnormality10). Oshima et al. reported low cerebral perfusion in the parasagittal region in cases with mild HIE9). Shah reported low cerebral perfusion of parasagittal lesions in 5/12 cases11). (Table 1)
Table 1
SPECT studies on neonatal HIE and CP during 1991–2020
SPECT | Objects | n | | |
1990(livanainen)16) | pediatric patients with various neurological diagnosis | 60 | | |
1993 (M Oshima)9) | HIE | 11 | 123I-IMP | Diffuse↓, Parasagital↓ |
1994 (C H Kao)16) | CP; perinatal asphyxia with MR and involved limbs | 13 | 99mTc-ECD | motor cortex ↓, Occipital lobe ↓ |
1994 (Y Konishi) 10) | HIE; 41–44 post-conceptional weeks | 10 | 123I-IMP | Diffuse without somatosensory ↓, BG↓, brainstem ↓ |
1995(Yamada)12) | CP; ATE | 12 | 123I-IMP | Thalamus ↓corpus striatum ↓orbitofrontal ↓pericentral gyrus areas ↓prefrontal ↓medial temporal areas ↓ |
1996(Sztriha L)45) | CP (7 five with porencephalic cyst), stroke (2), HHES (3), TBI (2) | 14 | 99mTc-ECD | |
1998(Lee) 13) | CP; SD(35) SQ (11), spastic HEMI(2) ATE(2), mixed(1) | 51 | 99mTc-ECD | temporal lobe 53% ↓, BG ↓, Thalamus ↓, cerebellum ↓, extratemporal cortex ↓ |
1998(Kapucu) 8) | HIE; mild (6), moderate (10), severe (4) | 20 | 123I-IBZM | ST/OC(striatal to occipital cortex)↓ |
2000(Yim) 14) | CP; bilateral spastic | 36 | 99mTc-ECD | Thalamus or cerebellar cortex ↓ |
2001(Valkama)19) | VLBW; birth weight < 1,500 g, gestation age < 34 weeks | 34 | 99mTc-ECD | cerebellar cortex |
2001(Tranquart) 46) | HIE 39.2w | 12 | 123I-IMP | Striatum/cerebellum activity ratios ↓ |
2001 (S Shah)11) | HIE; Sanart 2–3 | 24 | 99mTc-ECD | Parasagital↓ |
2006(Okumura)15) | CP; ATE due to kernicterus | 3 | SPECT | all hypoperfusion BG related to cortical area ↓ |
2010(Klaus Borch)18) | Premature babies; 26-32W | 13 | 99mTc-ECD | Periventriclular |
2010 (Iwaibara) 7) | HIE; Sanart 2–3 | 13 | 99mTc-ECD | lentiform nucleus ↓ Thalamus ↓ |
2012(Lee)21) | CP; SQ(11), HEMI(6), SD(3) | 20 | | The neurologic improvement occurred significantly in patients with diplegia or hemiplegia rather than quadriplegia. Autologous CB infusion is safe and feasible, and has yielded potential benefits in children with CP. |
2016(Rana)17) | CP; Spastic(91%), Asphyxia(69.6%) White matter change including PVL(73.2%) | 56 | 99mTc-ECD | cortex↓, sub cortex↓ |
Seven papers included patients with CP, and five reported low cerebral perfusion in the thalamus area. Yamada et al. reported low cerebral perfusion in the cortex and corpus striatum, in addition to the thalamus12). Lee et al. reported low cerebral perfusion of the cortex, basal ganglia and cerebellum, in addition to the thalamus13). Yim et al. reported low cerebral perfusion in the cerebellum in addition to the thalamus14). Okumura reported low cerebral perfusion of the basal ganglia connecting to the cortex15). Kao reported low cerebral perfusion of occipital lesions in cases with visual disturbances and relevant cortical area in children with spastic quadiplesia16). Rana reported low cerebral perfusion of the cortex and a subcortex lesion17). (Table 1)
Two articles provided information on neonates that were born with very low birth weight (VLBW); Borch reported that 13 VLBW cases with Periventricular Leukomalacia (PVL) had low cerebral blood flow in periventricular white matter lesions18). Valkama reported low cerebral blood flow of the cortex, thalamus and cerebellum19).(Table 1)
In 1990 Iivanainen reported that SPECT was useful for the diagnosis of degenerative brain diseases (82%) 20), And that it was more sensitive than Electroencephalogram (EEG), CT and MRI. (Iivanainen 1990). Konishi reported that SPECT is better than other tests if done during the first week of life10). Shah reported that the relationship between findings in a SPECT exam and neurological sequelae at three months of age had a positive predictive value of 75% (brain ultrasonography (USG) 60%) and negative predictive value of 100%༈USG 76%༉11). Okumura suggested that SPECT might be useful in cases of kernicterus when no remarkable findings can be demonstrated on an MRI scan15).
However, two studies suggested that SPECT might not be the most appropriate test for neonatal HIE because of limited image resolution and risk of exposure to radiation. Indeed, there have been no reports of SPECT studies with neonates since 2016 with one exception – for the study of epilepsy10,19).
Of interest, SPECT was useful in one study to demonstrate cerebral perfusion in children with CP after stem cell therapy21). Diverse neurological domains improved in five patients (25%) as assessed by developmental evaluation tools as well as by fractional anisotropy values in brain MRI-diffusion tensor imaging (DTI). The neurologic improvement was significant in patients with diplegia or hemiplegia rather than quadriplegia. The procedure was generally well-tolerated, although five patients experienced temporary nausea, hemoglobinuria, or urticaria during the intravenous infusion of the autologous umbilical cord blood (UCB) transfusion. They concluded that autologous UCB infusion is safe and feasible, and has yielded potential benefits in children with CP accompanied with improvement cerebral perfusion21).
PET
A total of 18 studies were reviewed to assess the benefit of PET for assessment of glucose matabolism. Fourteen studies used Fludeoxyglucose (18F) PET, two assessed GABA-A receptor binding using 18F PET 22–23) and two other groups reported cerebral blood flow24–25) (Table 2).
Table 2
PET studies on neonatal HIE and CP during 1991–2020
PET | | | | Result |
1991 (Kerrigan JF)31) | SQ, SD, HEMI, Ate | 23 | 18F-FDG-PET | Cortex↓ (SD), BG↓, Thalamus↓ ༈Ate༉ |
1993(Suhonen-Polvi) 47) | HIE | 14 | 18F-FDG-PET | Sensorimotor cortex↓ cases with delayed development; subcortical lesion ↓, Thalamus ↓, cerebellum ↓, brainstem↓(neonatal period and 3 mo) |
1995 (M Blennow)26) | HIE | 6 | 18F-FDG-PET | Prefrontal Cortex3/6↑, BG3/6↑, |
1995 (Kucukali I)24) | SD | 3 | Germanium68/gallium68 PET using 15O | Whole brain |
1995(H Suhonen-Polvi) 27) | HIE and hypoglycemia | 9 | 18F-FDG-PET | |
1996 (Azzarelli B)28) | HIE | 12 | 18F-FDG-PET | most severe HIE; BG↓ Thalamus↓ brainstem↓ |
1997 (Rosenbaum)25) | HIE | 26 | CBF with cesium fluoride scintilation detectors PET | |
2006 (Wong VC) | CP | 4 | 18F-FDG-PET body acupuncture | brain glucose metabolism showed a > 10% increase in the frontal, parietal, temporal, and occipital cortices and cerebellum after a short course of tongue and body acupuncture |
2007 (Batista CE) 29) | CP (Ate) | 1 | 18F-FDG-PET | severe cases; BG↓, Thalamus↓, early days after HIE; Transient BG↑ (Ate) |
2007 (Lee JD)21) | SD due to PVL | 30 | cerebral GABAr PET by 18F-Fluoroflumazenil | |
2013 (Park HJ) 23) | HEMI (human?) | 6 | 18F-Fluoroflumazenil-PET | |
2013 (Sharma A) 34) | CP and MR | 1 | PET-CT | Six months following Autologous Bone Marrow Derived MNCs therapy, PET-CT scan showed significant increase in metabolic activity in all four lobes, mesial temporal structures and left cerebellar hemisphere, also supported by clinical improvement in IQ, social behavior, speech, balance and daily functioning. |
2013 (Min K)6) | CP | 96 | 18F-FDG-PET | Compared with the EPO (n = 33) and Control (n = 32) groups, the pUCB (n = 31) group had significantly higher scores on the GMPM and BSID-II Mental and Motor scales at 6 months. 18F-FDG-PET/CT showed differential activation and deactivation patterns between the three groups. |
2015 (Sharma A) 35) | CP | 1 | PET | |
2015 (Sharma A) 5) | CP | 40 | PET | Overall, at six months, 95% of patients showed improvements. The study population was further divided into diplegic, quadriplegic, and miscellaneous group of cerebral palsy. On statistical analysis, a significant association was established between the symptomatic improvements and cell therapy in diplegic and quadriplegic cerebral palsy. PET-CT scan done in 6 patients showed metabolic improvements in areas of the brain correlating to clinical improvements. |
2017 (Rah WJ) 33) | CP | 57 | 18F-FDG-PET | The administration of G-CSF as well as the collection and reinfusion of mPBMCs were safe and tolerable. 42.6% of the patients responded to the treatment with higher neurodevelopmental scores than would normally be expected. Although we observed metabolic changes to the cerebellum, thalamus and cerebral cortex in the 18F-FDG brain PET-CT scans, there were no significant differences in such changes between the mPBMC and placebo. |
2020 (Fowler EG)30) | Spastic CP | 9 | 18F-FDG-PET | Cortex↓, cerebellar↑ in children with less SVMC |
2020 (Gu J)4) | CP | 39 | 18F-FDG-PET | 9 patients received treatments and completed the scheduled assessments. No significant difference was shown between the 2 groups in AE incidence.Additionally, significant improvements in ADL, CFA, and GMFM were observed in the hUC-MSC group compared with the control group. In addition, the standard uptake value of 18F-FDG was markedly increased in 3 out of 5 patients from the hUC-MSC group at 12 months after transplantation. |
For those using Fludeoxyglucose (18F) PET, four studies investigated cases with HIE, of whom three reported glucose metabolism of the basal ganglia and the thalamus. Blennow reported that none of those with low glucose metabolism and half (3/6) of those with high glucose metabolism in the basal ganglia region at two and a half days after birth26).(M Blennow,1995) Suhonen-Polvi et al. reported low glucose metabolism in the cortex, basal ganglia and thalamus in cases with neurological sequaela during the first week of life and three months of life. The repeated PET study showed that the uptake of FDG was markedly high and increased in all brain sections of infants with normal development (n = 11), whereas those with delayed development (n = 4) had significantly lower values (P < or = 0.005). 27). (Suhonen-Polvi H 1995) Azzarelli reported low glucose metabolism of the brain stem region in addition to basal ganglia and thalamus, in severe cases in which 10/12 infants died at the age of 2 to 12 weeks28). (Azzarelli B, 1996)
When it comes to children with CP, 2/3 papers reported cases with spastic diplegia with low glucose metabolism of the cortex29–30).(Batista CE 2007)(Fowler EG 2020) Two papers reported children with athetoid CP (“dyskinetic cerebral palsy”) who were found to have low glucose metabolism in the basal ganglia29,31).(Kerrigan JF 1991)(Batista CE,2007) Batista reported that neonates with athetoid CP with transient high glucose metabolism in the basal ganglia 29).(Batista CE,2007) Human umbilical cord derived mesenchymal stromal cell (UC-MSC) therapies for individuals with CP showed improvement in motor function and increase in glucose metabolism by PET-CT scan4) (Gu et al. 2020).
Virginia et al. reported that the brain glucose metabolism was more than 10% higher in the frontal, parietal, temporal, and occipital cortices and cerebellum after a short course of tongue and body acupuncture in CP using PET32).
Cell therapy
Recently, PET and SPECT have been used for the investigation of the effectiveness of cell therapies. We identified six clinical studies for CP from 18 articles on PET and one from 17 articles who studied on SPECT since 2013.(Table 3) PET and SPECT were performed before and after cell therapies for cases with cerebral palsy. Six articles on PET consist of one by human umbilical cord derived mesenchymal stromal cells(hUC-MSC)4), one mobilized peripheral blood mononuclear cells (mPBMCs) 33), three autologous bone marrow mononuclear cells (BMMNCs) 5, 34–35), one allogeneic umbilical cord blood6). Four of six paper reported that PET-CT scan showed much increase of glucose metabolism and one of six no significant change of glucose metabolism after cell therapy. One article on SPECT reported that two from five cases showed improvement of cerebral perfusion in the thalamus by SPECT after autologous cord blood treatment13). Most studies were performed using intrathecal (IT) (n = 3) and intravenous (IV)(n = 4) injection. Administration was once in 6 studies and four times in one study. As with adverse events, allogeneic UCB with rhEPO showed ten serious adverse events that required the hospitalization of nine patients among the 105 recruited participants. A 25-month-old female died after allogeneic UCB with rhEPO at 14 weeks post-treatment. (Table 3)
Table 3
References related to change of PET or SPECT score for neonatal HIE and CP after cell therapy
Reference Number | Disease | N | Route | Cell Type | Cell number | Results | Adverse events |
PET 2013(Sharma)35) | CP and MR | 1 | IT | Auto BMMNC | 1 × 1 × 106 CD34 + cells | Six months following Autologous Bone Marrow Derived MNCs therapy, PET-CT scan showed significant increase in metabolic activity in all four lobes, mesial temporal structures and left cerebellar hemisphere, also supported by clinical improvement in IQ, social behavior, speech, balance and daily functioning. | None reported |
PET 2013 (Min )6) | CP | 96 | IV | alloUCB with rhEPO | 1 × 3 × 107/kg total nucleated cells (TNCs) | Compared with the EPO (n = 33) and Control (n = 32) groups, the pUCB (n = 31) group had significantly higher scores on the GMPM and BSID-II Mental and Motor scales at 6 months. 18F-FDG-PET/CT showed differential activation and deactivation patterns between the three groups. | Ten serious adverse events that required hospitalization of nine patients were reported among the 105 recruited participants; similar between the three groups. The death of a 25-month-old female in the pUCB group at 14 weeks post-treatment. She was quadriplegic with spasticity from profound hypoxia with involvement of the central gray matter and brainstem. She had severe motor impairment and was unable to control her head. She was medically stable post-treatment with continuous neurological improvement up until the 3-month follow-up evaluation. During routine seizure follow-up, she was found to be neurologically stable. The same day she died during sleep with no apparent cause, and determined not to be related to the treatment. |
PET 2015(Sharma) 35) | CP | 1 | IT | Auto BMMNCs | 1 × 3.3 × 107 total nucleated cells (TNCs) | On repeating the Functional Independence Measure (FIM), the score increased from 90 to 113. A repeat PET-CT scan of the brain six months after intervention showed progression of the mean standard deviation values towards normalization which correlated to the functional changes. At one year, all clinical improvements have remained. | None reported |
PET 2015(Sharma) 5) | CP | 40 | IT | BMMNCs | 1 × 10.23 × 106 CD34 + cells | Overall, at six months, 95% of patients showed improvements. The study population was further divided into diplegic, quadriplegic, and miscellaneous group of cerebral palsy. On statistical analysis, a significant association was established between the symptomatic improvements and cell therapy in diplegic and quadriplegic cerebral palsy. PET-CT scan done in 6 patients showed metabolic improvements in areas of the brain correlating to clinical improvements. | At the time of the procedure, there were no complications recorded. During the hospital stay, a few patients did show minor procedure related adverse events-15% a spinal headache, 7.5% nausea, 30% vomiting, 12.5% pain at the site of injection, and 2.5% diarrhea. These events were self-limiting and relieved within one-week using medication. The only major adverse event noted related to cell transplantation was seizures - in 2 patients. |
PET 2017 (Rah)33) | CP | 57 | IV | mPBMCs | 1st 4.63 ± 2.88 × 108/kg 2nd 6.20 ± 1.94× 108/kg TNCs, | 42.6% of the patients responded to the treatment with higher neurodevelopmental scores than would normally be expected. Although we observed metabolic changes to the cerebellum, thalamus and cerebral cortex in the 18F-FDG brain PET-CT scans, there were no significant differences in such changes between the mPBMC and placebo. | Transient hemoglobinuria (n = 3) and abdominal pain (n = 1) were reported during the mPBMC infusion, and these were resolved with supportive treatments. |
PET 2020 (Gu)4) | CP | 39 | IV | hUC-MSCs | 1 × 4.6 ± 0.50 × 107 MSC cells | 9 patients received treatments and completed the scheduled assessments. Additionally, significant improvements in ADL, CFA, and GMFM were observed in the hUC-MSC group compared with the control group. In addition, the standard uptake value of 18F-FDG was markedly increased in 3 out of 5 patients from the hUC-MSC group at 12 months after transplantation. | No significant difference between hUC-MSC and control in AE incidence. Serious adverse events were not observed. Upper respiratory infections were reported most frequently (52.6%). Diarrhea (31.6%) fever (36.8%) with a high incidence. |
SPECT 2012 (Lee) 21) | CP | 20 | IV | Auto UCB | 1 × 5.5 ± 3.8 (0.6 ~ 15.65) × 107 TNCs | The neurologic improvement occurred significantly in patients with diplegia or hemiplegia rather than quadriplegia. Autologous CB infusion is safe and feasible, and has yielded potential benefits in children with CP. | Infusion was generally well-tolerated, even without premedication, although 3 patients experienced temporary nausea and hemoglobinuria, and 2 patients experienced hemoglobinuria and urticaria, but these were easily controlled with peniramine or intravenous hydration. |