Postnatal Brain Growth Patterns in Pontocerebellar Hypoplasia.

BACKGROUND: Pontocerebellar hypoplasia (PCH) is a rare group of disorders mainly affecting the cerebellum and pons. Supratentorial structures are variably involved. We assessed brain growth patterns in patients with the most frequent forms of PCH, namely PCH1B (OMIM#614678) and PCH2A (OMIM#277470), since in these types of PCH, pre- and postnatal neurodegeneration is established by neuropathological profiling. To assess the influence of the different pathomechanisms on postnatal growth patterns, we included CASK-associated microcephaly and PCH (MICPCH, OMIM#300749) patients in our analyses, as MICPH mimics PCH on magnetic resonance imaging (MRI) but represents a developmental disorder including abnormal neuronal migration. METHODS: A total of 66 patients were included: 9 patients with PCH1B, 18 patients with PCH2A, 6 patients with MICPCH, and 33 age- and gender-matched hospital-based controls. Segmentation of the vermis and cerebellum was performed manually, as were measurements of the thickness of the head of the caudate nucleus, the width of the anterior horn, and lateral ventricle size. RESULTS: The cerebellum was severely hypoplastic at birth in all patients, and postnatal growth was nearly absent. In patients with PCH1B/2A, we found relative sparing of the vermis compared with the cerebellar hemispheres. In addition, PCH1B and PCH2A cases demonstrated thinning of the head of the caudate nucleus, an associated increase in anterior horn width, and an increase in lateral ventricle size. None of these features were seen in the MICPCH group. CONCLUSIONS: Our findings confirm the progressive nature including caudate nucleus atrophy in PCH1B and PCH2A. In MICPCH, the relative sparing of supratentorial structures confirms its different pathomechanism.

[Multisemic atrophy: a description of the clinical case of olivopontocerebellar atrophy against the background of stenosing atherosclerotic vascular lesions].

Features of the onset, the course of the disease causes difficulties in the early diagnosis and formulation of the correct diagnosis. Olivopontocerebellar atrophy is characterized by a broad polymorphism of clinical manifestations. There is a need to develop new methods of symptomatic and neuroprotective treatment, as well as the optimization of non-drug therapy.

Differentiating Genetic Forms of Pontocerebellar Hypoplasia From Acquired Lesions Resembling Pontocerebellar Hypoplasia: Clinical, Neurodevelopmental, and Imaging Insight From 19 Extremely Premature Patients.

It is well established that extreme prematurity can be associated with cerebellar lesions potentially affecting the neurologic prognosis. One of the commonly observed lesions in these cases is pontocerebellar hypoplasia resulting from prematurity, which can pose challenges in distinguishing it from genetically caused pontocerebellar hypoplasia. This confusion leads to unacceptable and prolonged diagnostic ambiguity for families as well as difficulties in genetic counseling. Therefore, it is crucial to identify the clinical and neuroradiologic features allowing to differentiate between acquired and genetic forms of pontocerebellar hypoplasia in order to guide clinical practices and improve patient care. In this regard, we report in the present manuscript the clinical, developmental, and radiologic characteristics of 19 very premature children (gestational age <28 weeks, now aged 3-14 years) with cerebellar lesions and discuss the causal mechanisms. Our findings support the notion that a combination of specific clinical and radiologic criteria is essential in distinguishing between acquired and genetic forms of pontocerebellar hypoplasia.

The Use of FDG PET Parametric Imaging in the Diagnosis of Olivopontocerebellar Atrophy.

Olivopontocerebellar atrophy is a rare neurodegenerative syndrome associated with 2 distinct disorders: multiple system atrophy and spinocerebellar ataxia. We present a case involving a 66-year-old man with adult-onset progressing cerebellar signs reflective of a cerebellar syndrome with no significant family history and unremarkable genetic testing for spinocerebellar ataxia. This case was found to be most consistent with sporadic olivopontocerebellar atrophy, which falls under the multiple system atrophy category. This diagnosis can be made using F-FDG PET/CT scanning and with MRI in some cases. However, in this case, relatively new PET/CT quantification and parametric imaging software was used for analysis, CortexID Suite.

[Early onset epileptic encephalopathy caused by mitochondrial arginyl-tRNA synthetase gene deficiency: report of two cases and literature review].

Objective: To summarize the clinical features of two early onset epileptic encephalopathy (EOEE) patients with arginyl-tRNA synthetase (RARS2) gene variations and to review related literature. Methods: The clinical data and genetic features of two pontocerebellar hypoplasia type 6 (PCH6) patients with RARS2 variation diagnosed by the Department of Neurology, Beijing Children's Hospital from January 2017 to December 2018 were analyzed retrospectively. A literature search with "RARS2" "pontocerebellar hypoplasia type 6" and "early onset epileptic encephalopathy" as key words was conducted at China national knowledge infrastructure (CNKI), Wanfang Data Knowledge Service Platform and PubMed (up to May 2020), literature about RARS2 gene variation patients and their complete clinical data were chosen and reviewed. Results: The onset age of the two cases (1 male, 1 female) were 2 months and 29 days respectively and the early onset symptom of them was epileptic encephalopathy. The main symptoms included seizures, development delay, microcephaly and lactic acidosis. In addition to these symptoms, the female also had dyspnea, hypoglycemia and metabolic acidosis after birth. Brain magnetic resonance imaging (MRI) of the two patients were normal at first. Follow up at four-month (case 1) and eight-month (case 2) MRI showed atrophy of cerebral and cerebellar, but the pons was not affected. All four heterozygous variations in RARS2 gene revealed by whole-exome sequencing (p.Arg560His and p.Arg6His from case 1, p.Arg254Trp and p.Phe5Ser from case 2) were novel. No eligible reports were found in Chinese journals, while 17 reports were found in English literature. Excluded cases with incomplete data together with these two cases, a total of 34 patients from 20 families were found. All patients had developmental delay while 94% (32/34) patients showed the initial symptoms within 3 months, 93% (28/30) patients were diagnosed as epilepsy, 89% (25/28) patients had progressively microcephaly and 52% (16/31) cases did not show the pons atrophy on brain MRI. Twenty of 28 cases (71%) were refractory epilepsy. There were 31 types of gene variations and most of them were missense variations (21/31, 68%). Conclusions: The majority of PCH6 cases caused by RARS2 gene variation show the initial symptoms within 3 months, characterized by EOEE, most of them are refractory epilepsy, accompanied by developmental delay, microcephaly and increased lactic acid. Brain MRI indicates progressive cerebral or pontocerebellar atrophy.

New Radiologic Findings of Hypertrophic Olivary Degeneration in 2 Patients with Brainstem Lymphoma.

BACKGROUND: Hypertrophic olivary degeneration (HOD) is a rare neurological condition of trans-synaptic degeneration caused by disruption of the dentatorubro-olivary pathway. We present new radiologic findings of HOD in 2 cases of brainstem lymphoma. CASE DESCRIPTION: A 35-year-old woman (Case 1) and a 69-year-old man (Case 2) presented with remarkably similar clinical courses. The primary lesion was located at the dorsal pons extending to the midbrain. Pathologic diagnosis of diffuse large B-cell lymphoma was obtained after surgical resection. Complete remission of the primary lesion was achieved by treatment with 3 courses of high-dose methotrexate and radiotherapy. Arterial spin-labeling and T2-weighted imagings showed high signal intensity in the inferior olive (IO) at some time after the operation. Slight contrast enhancement in the IO was also found in Case 1. These radiologic findings nearly misled us into a diagnosis of recurrence of lymphoma. Signal intensity in the IO on arterial spin-labeling imaging changed with time. Normalized regional cerebral blood flow (rCBF) in the IO was defined as a percentage of rCBF to the global cerebral blood flow calculated using automated software. Chronologic change in normalized rCBF in the IO revealed a large peak in Case 1, but only a mild increase in Case 2. Neurological findings demonstrated severe oculopalatal tremor in Case 1 and mild palatal tremor in Case 2. CONCLUSIONS: Hyperperfusion and contrast enhancement in the IO were found in 2 patients with HOD. These findings may be confused with recurrence of malignant tumor.

Unilateral Symptomatic Hypertrophic Olivary Degeneration Secondary to Midline Brainstem Cavernous Angioma: A Case Report and Review of the Literature.

BACKGROUND: Hypertrophic olivary degeneration (HOD) is a rare phenomenon in the dento-rubro-olivary pathway caused by lesion or disruption of the fibers of the Guillain-Mollaret triangle. Hemorrhage of pontine and midbrain cavernous angiomas can rarely lead to HOD portending neurologic deterioration and possible concomitant life-threatening complications; for this reason, it may define a poignant consideration in planning intervention. CASE DESCRIPTION: The patient was a 57-year-old woman with known midbrain-pontine cavernous angioma. For several years, the lesion had been stable, as shown by imaging follow-up, until 10 months before the patient presented with falls, dysarthria, and headache. Imaging showed some decrease in size as well as blood product around the cavernous angioma, suggesting interim period hemorrhage and interval development of HOD. CONCLUSIONS: The literature regarding imaging recommendations for stable cavernous angioma in the midbrain-pontine junction is reviewed. The implication of HOD for patient outcome is discussed and a comment is made on how the development of HOD may affect management of the cavernous angioma.

Topographic brain mapping of the international cooperative ataxia rating scale. A positron emission tomography study.

The International Cooperative Ataxia Rating Scale (ICARS) is a 100-point semiquantitative scale designed primarily to assess cerebellar dysfunction. However, little is known of the metric properties of this scale. We assessed the ICARS by rating the severity of cerebellar dysfunction in 27 patients with spinocerebellar ataxias (SCA), three patients with sporadic olivopontocerebellar ataxia and 24 healthy control subjects. [(18)F]-fluorodeoxyglucose (FDG) positron emission tomography (PET) study was also performed on each subject. The statistical parametric mapping analyses revealed a significant correlation between the ICARS scores and functional impairment of the frontal regions within SCA patients. The glucose metabolism in the cerebellum, thalamus and caudate nucleus had significant differences between SCA patients and healthy control subjects. The results suggested that the clinical severity of SCA patients correlated with the functional impairment in the frontal regions, the targets of cerebellar efferent projections.

A New Patient With Intermediate Severe Salla Disease With Hypomyelination: A Literature Review for Salla Disease.

BACKGROUND: Likely pathogenic variants in SLC17A5 results in allelic disorders of free sialic acid metabolism including (1) infantile free sialic acid storage disease with severe global developmental delay, coarse facial features, hepatosplenomegaly, and cardiomegaly; (2) intermediate severe Salla disease with moderate to severe global developmental delay, hypotonia, and hypomyelination with or without coarse facial features, and (3) Salla disease with normal appearance, mild cognitive dysfunction, and spasticity. PATIENT DESCRIPTION: This five-year-old girl presented with infantile-onset severe global developmental delay, truncal hypotonia, and generalized dystonia following normal development during her first six months of life. Brain magnetic resonance imaging showed marked hypomyelination and a thin corpus callosum at age 19 months, both unchanged on follow-up at age 28 months. Urine free sialic acid was moderately elevated. Cerebrospinal fluid free sialic acid was marginally elevated. Sequencing of SLC17A5 revealed compound heterozygous likely pathogenic variants, namely, a known missense (c.291G>A) variant and a novel truncating (c.819+1G>A) variant, confirming the diagnosis of Salla disease at age 3.5 years. CONCLUSION: We report a new patient with intermediate severe Salla disease. Normal or marginally elevated urine or cerebrospinal fluid free sialic acid levels cannot exclude Salla disease. In patients with progressive global developmental delay and hypomyelination on brain magnetic resonance imaging, Salla disease should be included into the differential diagnosis.

[Analysis of brain images in patients with spinocerebellar degeneration; using statistical parametric mapping (SPM) and easy Z score imaging system (eZIS)].

In order to investigate the cerebral blood flow objectively, the easy Z score imaging system (eZIS), was developed, and has been applied in clinical practice. SPECT with 99mTc-ethyl cysteinate dimer (99mTc-ECD) was performed, and the images were analyzed using the SPM97 and the eZIS Ver. 2 to investigate cerebral blood flow in patients with two types of spino-cerebellar degeneration. We compared the distribution of cerebral blood flow between 13 patients with cortical cerebellar atrophy (CCA) and 26 patients with olivopontocerebellar atrophy (OPCA). In the both groups, cerebellar blood flow was decreased generally. In our evaluation using the eZIS Z score, the scores for the brain stem and cerebellar nucleus in the OPCA group were lower than those in the CCA group. This method facilitates the objective evaluation of cerebral blood flow in patients with spinocerebellar degeneration, and may be useful for analyzing the condition of these disease.

Clinical/metabolic correlations in multiple system atrophy. A fludeoxyglucose F 18 positron emission tomographic study.

OBJECTIVE: To evaluate the regional cerebral metabolic involvement; the relationships among regional brain metabolism, clinical features, and quantitative measures of disease severity; and the patterns of brain involvement that can be related to the different types of onset: striatonigral degeneration vs olivopontocerebellar atrophy. DESIGN: Fludeoxyglucose F 18 positron emission tomography (PET) studies performed in patients with multiple system atrophy (MSA) were evaluated for their clinical features at the onset of the disease and at the time of the PET study. CASES: Seventeen patients diagnosed as having probable MSA and 10 age-matched controls. RESULTS: The hypometabolism in the putamen-pallidum complex and in the cerebellum was the best discriminant for disease classification. The efficacy of levodopa treatment was positively correlated with the metabolic activity of the putamen-pallidum complex. The patients with olivopontocerebellar atrophy type (N = 8) had a prevalent hypometabolism in the cerebellum, while the patients with striatonigral degeneration type (N = 9) had a prevalent impairment in the pallidum-putamen complex. We demonstrated a negative correlation between (1) severity of parkinsonism and metabolic values of putamen and caudate; (2) severity of cerebellar signs and metabolism in the cerebellum; and (3) autonomic dysfunction and metabolic activity in the thalamus, frontal, and temporal regions, bilaterally. CONCLUSIONS: These findings support the selective metabolic reduction in the putamen and cerebellum as a marker of MSA. The clinical/metabolic correlations, demonstrating the expected dependence of extrapyramidal and cerebellar signs by dysfunction of basal ganglia and cerebellum, also support a possible involvement of central nervous system structures in autonomic control.

A comparison of cerebral blood flow and glucose metabolism in olivopontocerebellar atrophy using PET.

OBJECTIVE: In sporadic cases of olivopontocerebellar atrophy (OPCA), to determine whether local cerebral blood flow (lCBF) is reduced, whether lCBF is coupled to local cerebral metabolic rate for glucose (lCMRglc), and whether lCBF measurements are potentially useful in diagnosing OPCA. DESIGN: Positron emission tomography was used with [15O]H2O to measure lCBF and with [18F]fluorodeoxyglucose to measure lCMRglc in 17 patients with OPCA and 21 normal control subjects. RESULTS: In OPCA patients, lCBF was significantly decreased in the cerebellum, but not in the cerebral cortex, basal ganglia, thalamus, or brainstem. In the same patients, lCMRglc was significantly decreased in the cerebellum and brainstem, where the largest changes were observed, and also in the cerebral cortex, basal ganglia, and thalamus. The ratio of lCBF to lCMRglc, an indicator of the coupling of blood flow to metabolism, was similar in OPCA patients and normal subjects for all regions except the brainstem, where the ratio was marginally decreased in OPCA patients. Using logistic discriminant analysis to assess the ability of lCBF and lCMRglc to differentiate OPCA patients from normal subjects, we found the cross-validated sensitivity of absolute lCMRglc as a predictor of OPCA was 82% with a corresponding specificity of 71%; the sensitivity of absolute lCBF was 71% and the specificity 76%. CONCLUSIONS: In sporadic cases of OPCA, lCBF is reduced in the cerebellum, CBF remains coupled to lCMRglc, and the lCBF pattern is a useful predictor of the diagnosis.

Skeletal myoclonus in olivopontocerebellar atrophy: treatment with trihexyphenidyl.

We studied two patients with nonfamilial olivopontocerebellar atrophy with skeletal myoclonus. Palatal or skeletal myoclonus is probably not a coincidental finding but another manifestation of the underlying disease. In both cases, the myoclonus was suppressed by administration of trihexyphenidyl, indicating a cholinergic disorder.

Degenerative neurological disorders associated with deficiency of glutamate dehydrogenase.

The activity of glutamate dehydrogenase, the enzyme of glutamate degradation, was measured in platelets of 27 healthy controls and 85 patients with different degenerative cerebellar and/or basal ganglia disorders. A group of 7 patients was selected with slowly progressive multiple-system atrophy, in whom a clinical diagnosis of olivopontocerebellar atrophy appeared tenable, with decreased activity of glutamate dehydrogenase (38% of the mean control value). In 4 patients data on inheritance were compatible with the genetic pattern of autosomal recessive inheritance, while 3 patients were sporadic cases. In an effort to define this group of patients more precisely, it is suggested that decreased activity of glutamate dehydrogenase induces an increase in extracellular glutamate levels in the central nervous system with subsequent development of excitotoxicity.

The development of infratentorial atrophy in patients with idiopathic cerebellar ataxia of late onset: a CT study.

The development of infratentorial atrophy in six patients suffering from idiopathic cerebellar ataxia of late onset was studied by a retrospective evaluation of consecutive computed tomography (CT) scans. Four patients had evidence of olivopontocerebellar atrophy (OPCA) both on clinical testing and magnetic resonance imaging (MRI). In these four patients, atrophy of the cerebellum and brain stem became visible at the same time and progressed in a roughly parallel manner, whereas in the remaining two the brain stem was left intact. In all patients with OPCA, definite brain-stem atrophy was visible earlier than the appearance of non-cerebellar clinical symptoms. The present data suggest that CT investigations at regular intervals may be of prognostic value in cerebellar ataxias.

Reduced cerebellar blood flow and oxygen metabolism in spinocerebellar degeneration: a combined PET and MRI study.

Fourteen patients with spinocerebellar degeneration (SCD) were subjected to MRI and PET studies. The quantitative MRI data revealed significant cerebellar and pontine atrophy in the patients with olivopontocerebellar atrophy (OPCA), and cerebellar atrophy in the patients with late cerebellar cortical atrophy (LCCA). We failed to demonstrate significant differences in the pons between LCCA patients and normal controls. PET measurements revealed decreases in cerebral oxygen metabolic rate (CMRO2) in the cerebellar hemisphere and vermis in both groups of patients. The markedly decreased cerebral blood flow (CBF) and CMRO2 in the pons were found only in the patients with OPCA. PET data corrected for the tissue shrinkage on the basis of MRI morphometry indicated a net reduction in cerebellar CMRO2 and CBF. The present study has demonstrated that a combination of functional and anatomical data offers further evidence in favour of the current acceptable classification of SCD based on clinicopathological grounds. Our data further suggest that the amount of atrophy in the cerebellum could not fully account for the decreased metabolic rates observed in PET studies.

CT findings in spinocerebellar degeneration.

Thirty-five CT scans were studied from patients with several forms of spinocerebellar degeneration. Atrophy was determined by objective measurements of the number and width of cerebellar sulci, transverse diameter and surface area of the fourth ventricle, brainstem ratio, cerebellopontine angle cistern, and Evans' index. Two-thirds of the patients with Friedreich's ataxia showed moderate cerebellar atrophy and an increase in the surface area of the fourth ventricle. Severe cerebellar atrophy and enlargement of the cerebellopontine angle cistern was seen in patients with olivopontocerebellar (OPC) atrophy and idiopathic cortical cerebellar atrophy. In the OPC atrophy group there was also prominent atrophy of the brainstem and an increase in the fourth ventricle parameters. Alcoholic cerebellar degeneration showed a specific pattern of cerebellar atrophy most prominent in the superior vermis, together with a slight increase in the fourth ventricle surface, a reduction in the size of the brainstem, and an enlargement of the cerebellopontine angle cistern. Supratentorial atrophy was present only in the OPC and alcoholic atrophy groups. In one patient with spastic ataxia, CT was normal but MR imaging revealed prominent atrophy of the spinal cord. These CT patterns appear to be distinctive enough to permit the diagnosis and classification of the various forms of spinocerebellar degeneration.

Olivopontocerebellar atrophy studied by positron emission tomography and magnetic resonance imaging.

We examined 9 patients with olivopontocerebellar atrophy (OPCA) using positron emission tomography and magnetic resonance imaging (MRI). Regional cerebral blood flow and oxygen metabolism were compared with the findings in 10 normal age-matched volunteers. The volumes of the basis pontis and the cerebellar hemispheres were quantitated by MRI to assess the relationship between morphological changes of the pons or cerebellum and the cerebellar circulation and metabolism. In the patients with OPCA, cerebellar hemispheric blood flow and oxygen metabolism were significantly lower than in the normal volunteers. Pontine volume showed a significant correlation with the cerebellar blood flow and the metabolic rate of oxygen. In contrast, the cerebellar hemispheric volume showed no correlation with either of these parameters. Our results suggest that the disruption of pontocerebellar pathway may contribute to the reduction of both blood flow and oxygen metabolism in the cerebellum of OPCA and that detection of cerebellar circulatory impairment without marked cerebellar atrophy by neuroimaging may be suggestive of OPCA.

Glucose metabolism in the cortical and subcortical brain structures in multiple system atrophy and Parkinson's disease: a positron emission tomographic study.

The brain glucose metabolism was studied by PET with 18F-FDG in 11 patients with multiple system atrophy (MSA) and 12 patients with idiopathic Parkinson's disease (PD). Seven of the 11 MSA patients were diagnosed as having olivopontocerebellar atrophy, two had striatonigral degeneration, while two demonstrated Shy-Drager syndrome. The glucose metabolic rates for each region in the PD patients showed no difference from the normal controls. The frontal, temporal and parietal cortical glucose metabolic rates and the caudate, the putaminal, the cerebellar and the brainstem glucose metabolic rates in the MSA patients decreased significantly from the controls. The atrophy of the cerebellum and the brainstem in the MSA patients were scored by MRI. The cerebellar and brainstem glucose metabolism in the MSA patients decreased as the atrophy score in such regions advanced in each group; however, some patients with no atrophy showed a decreased glucose metabolism. Although the cerebellar and the brainstem glucose metabolism decreased in all MSA patients, such a decrease was not observed in the SND patients. The decrease in the glucose metabolism for the non-cortical regions in the MSA patients seems to be due to a diffuse depletion of the neurons not restricted to the nigrostriatal neurons. Deafferentation to the cerebral cortices seems to result in a decreased cortical metabolism. The differences in the glucose metabolism between MSA and PD as assessed by PET may be caused by the pathophysiological differences between MSA and PD, and such differences therefore appear to be useful when making a differential diagnosis between MSA and PD. The relative sparing of the brainstem and cerebellar glucose metabolism is considered to be a feature of patients with SND.