Severe Cerebellar Atrophy Research Articles

Proton magnetic resonance spectroscopic imaging in patients with cerebellar degeneration.

Using proton magnetic resonance spectroscopic imaging, we studied the cerebellum of 9 patients with cerebellar degeneration and of 9 age-matched normal control subjects. This technique permits the simultaneous measurement of N-acetylaspartate, choline-containing compounds, creatine/phosphocreatine, and lactate signal intensities from four 15-mm slices divided into 0.84-ml single-volume elements. Because patients with cerebellar degeneration often show substantial atrophy on magnetic resonance imaging (MRI), we specifically chose to analyze the spectroscopic signals only from tissue that did not have an atrophic appearance on the MRI. The spectroscopic findings showed a significant reduction of N-acetylaspartate in all parts of the cerebellum, a significant correlation with MRI scores of cerebellar atrophy, and a significant correlation with clinical rating scores of cerebellar disturbance. Our method of analysis suggests the presence of a neurodegenerative process in cerebellar areas that do not appear to be atrophic on the MRI. Some limitations of proton magnetic resonance spectroscopic imaging in the present study were related to the partial field inhomogeneity characteristics of the posterior fossa, the anatomical location of the cerebellum, and the particularly severe cerebellar atrophy in some of the patients.

Severe cerebellar atrophy following acute cerebellitis

The clinical course and serial magnetic resonance imaging findings of a 4-year-old girl with acute cerebellar ataxia due to acute cerebellitis are described. Multifocal white matter lesions visualized by magnetic resonance imaging in both cerebellar hemispheres in the acute phase disappeared in the convalescent phase. Cerebellar signs became less prominent within 2 weeks, but mild ataxic gait remained. During the follow-up period of 32 months, there was a gradual development of cerebellar atrophy along with a recurrence of cerebellar ataxia.

Primary degeneration of the granular layer of the cerebellum. A study of 14 patients and review of the literature.

Primary degeneration of the granular layer of the cerebellum is an autosomal recessive disorder exhibiting characteristic clinical features: hypotonia, strabismus, delayed motor development, nonprogressive ataxia, delayed language development with dysarthria and mental retardation. We studied fourteen children, seven of each gender. Neuroimaging tests including pneumoencephalography, computed tomography (CT) and magnetic resonance imaging (MRI) showed severe cerebellar atrophy in all. MRI best demonstrated the cerebellar lesion, revealing great uniformity amongst the cases. Vertebrobasilar angiography was performed in two cases and showed marked hypoplasia of the cerebellar arteries, predominantly the posterior inferior cerebellar artery (PICA) and its branches. Necropsy was performed in three cases; cerebellar atrophy with loss of granular cells and diverse abnormalities of the Purkinje cells was found in two. The third, the sister of one of the other two cases, had a similar but shorter clinical course and died at three months of age. Her sister, who died at 5 years of age, presented a severe cerebellar atrophy with typical changes in the granular cell layer and Purkinje cells. In the third patient, who lived three months, only focal cerebellar folial atrophy with no microscopic changes in the granular cell layers was present. Though this case cannot objectively be included in the cerebellar atrophy syndrome with granular cell loss, her family history and clinical picture suggest the same disease. The findings observed in our series and the study of cases described in the literature, suggest that there are several forms of this disease which differ mainly in severity and neurological evolution. The cerebellar lesion seems to be a progressive atrophic process with the most severe changes during the early years of life.

Regional cerebral blood flow measured with N-isopropyl-p-[123I]iodoamphetamine single-photon emission tomography in patients with Joseph disease

Regional cerebral blood flow (rCBF) was measured in five Japanese patients who were clinically diagnosed as having Joseph disease, also called Machado-Joseph disease or Azorean disease, using N-isopropyl-p-[123I]iodoamphetamine (IMP) and single-photon emission tomography (SPECT). Cerebellar atrophy was evaluated by a five-step rating scale as defined on X-ray computed tomography (X-CT). Compared with ten age-matched normal controls (mean cerebellar CBF +/- SD: 66.9 +/- 6.6 ml/100 g/min), rCBF in patients with Joseph disease was significantly decreased in the cerebellum (mean +/- SD: 50.2 +/- 7.3 ml/100 g/min). No significant relationship, however, was found between the decrease in rCBF in the cerebellum and the degree of cerebellar atrophy on X-CT. rCBF in the cerebellum was minimally decreased in one patient who had severe cerebellar atrophy and in two patients with moderate atrophy. These data may support the findings that Purkinje cells in the cerebellum are almost normal in Joseph disease, and that the granular and molecular layers remain intact in spite of cortical atrophy of the cerebellum. It is concluded that [123I]-IMP SPET is able to identify pathological and metabolic changes in the cerebellum that do not appear on X-CT or magnetic resonance imaging, and thus is useful for the diagnosis of Joseph disease.

Phenytoin overdosage and cerebellar atrophy in epileptic patients: clinical and MRI findings.

Mild overdosage of phenytoin produces reversible cerebellar symptoms (nystagmus, double vision, dysarthria and ataxia). Several case reports suggest that relatively mild and relatively short intoxication can lead to cerebellar degeneration. We observed 11 patients who had episodes of abnormally increased serum levels, most of which developed clinical signs of cerebellar dysfunction. All of these patients were examined with a 1.5-tesla whole-body system (Magnetom, Siemens). Five patients had normal cerebellar structures, although 3 of them had a history of clinical intoxication and all had at least one episode of increased serum level of diphenylhydantoin. The remaining 5 had moderate to severe cerebellar atrophy. Two of them never experienced signs of clinical intoxication. There was no correlation between degree of atrophy and severity of clinical symptoms and elevation of serum DPH levels. There was no correlation between cerebellar atrophy, duration of epilepsy and frequency of seizures.

Diagnostic criteria and genetics of the PEHO syndrome.

The PEHO syndrome (progressive encephalopathy with oedema, hypsarrhythmia, and optic atrophy) is a recently recognised disorder of unknown biochemical background. Diagnostic features have been found in neuroradiological and neuropathological studies, which show characteristic severe cerebellar atrophy. In combined neuroradiological and ophthalmological studies, 10 out of 21 possible PEHO patients fulfilled the criteria for true PEHO syndrome. All were abnormal at birth showing hypotonia, drowsiness, or poor feeding. Head circumference was normal, but usually dropped to 2 SD below average during the first year of life. Visual fixation was either absent from birth or lost during the first months of life. Nine patients had peripheral oedema in early childhood. The mean age of onset of infantile spasms was 4.9 months. All patients were extremely hypotonic and no motor milestones were reached. Patellar reflexes were brisk. Brain stem and somatosensory evoked potentials were abnormal in each case studied, cortical responses of somatosensory evoked potentials could not be elicited, and motor conduction velocities became delayed with age. Altogether 19 PEHO patients were found in 14 Finnish families. Autosomal recessive inheritance is likely.

Radiologic correlates of reaction time measurements in olivopontocerebellar atrophy.

We measured simple visual and auditory reaction time (RT) and movement time (MT) in 32 patients with olivopontocerebellar atrophy (OPCA) in comparison to 32 control subjects. In addition, we followed 2 approaches to radiologic assessment by computed tomographic scans: subjective (by inspection of films) and objective (by measurement of 4 radiologic ratios at the level of the posterior fossa and 1 ratio at the supratentorial level). All OPCA patients had various degrees of cerebellar atrophy and lengthened RT and MT in comparison to their controls. There were no significant differences in RT and MT performances in patients with mild-moderate versus those with severe cerebellar atrophy as assessed by inspection of their films. OPCA patients with severe versus mild-moderate atrophy evaluated by 3 measures, i.e., brainstem, brachium pontis and fourth ventricle ratios, presented few significantly lengthened RT and MT performances. In contrast, patients with severe atrophy revealed by the midbrain ratio had significantly lengthened RT and MT performances compared to those with mild-moderate atrophy assessed by this ratio on 7 of 8 measures; the 8th measure showed a borderline significant difference. This could be explained by the fact that atrophy at the midbrain level is the only one which involves dopaminergic, noradrenergic and glutamatergic structures and pathways.

Cerebellorubral degeneration after resection of cerebellar dentate nucleus neoplasms: evaluation with MR imaging.

The authors describe the magnetic resonance (MR) findings in seven patients who developed severe cerebellar symptoms and atrophy of the contralateral red nucleus following removal of unilateral neoplasms in the deep nuclei of the cerebellum. For most patients, pre- and postoperative spin-echo MR images were obtained with long repetition times (TRs) at 1.5 T. The long TR images obtained before surgery demonstrated unilateral masses involving the dentate nucleus. Long TR images obtained after surgical resection of the dentate nucleus showed increased signal intensity in all of seven contralateral red nuclei, three of seven ipsilateral superior cerebellar peduncles, and two of seven contralateral inferior olivary nuclei. Three other patients who underwent surgery for cerebellar neoplasms without resection of the dentate nuclei showed no postoperative brain stem changes on MR images. The authors speculate that the changes in the contralateral red nuclei are due to cerebellorubral degeneration (since well-described neural tracts interconnect the dentate nucleus and the contralateral red nucleus). Injury of the dentate nucleus may result in degeneration of distant neural connections.

MR of progressive neurodegenerative change in treated Menkes' kinky hair disease

MR examinations of a male child with Menkes' kinky hair disease, a genetic disorder of copper metabolism, at four months and 30 months, document the progression of neurodegenerative changes despite parenteral copper therapy. These changes include severe cortical and cerebellar atrophy, deranged cerebral vasculature, and subdural fluid collection.

Cell Loss in the Inferior Olive of the Staggerer Mutant Mouse is an Indirect Effect of the Gene

Staggerer (sg) is an autosomal recessive mutation in mouse that causes severe cerebellar atrophy. In this mutant, the Purkinje cell (PC) number is reduced by about 75% and the remaining Purkinje cells have a reduced dendritic arbor and an ectopic location. Previous analysis of staggerer chimeras has demonstrated that the Purkinje cell phenotypes are all direct consequences of the cell-autonomous action of the staggerer gene. The two major afferents to the Purkinje cell are also affected. Virtually all of the granule cells die by the end of the first postnatal month. This death, however, has been shown to be an indirect consequence of mutant gene action. The second major afferent system is from the cells of the inferior olive that project to the main trunks of the Purkinje cell dendrite via the climbing fiber system. Quantitative studies of cell number in the inferior olive have shown that the number of cells is reduced by about 62% in adult sg/sg mutants. We report here the results of our quantitative analysis of three staggerer chimeras. beta-glucuronidase activity was used as an independent cell marker. Our findings demonstrate that inferior olive cell death in staggerer mutant mice is an indirect effect of staggerer gene action. Thus, as for the granule cells, the loss of olivary neurons most likely results from a target related cell death.

Muscle pathology in Marinesco-Sjögren syndrome

Three of 4 adult patients with Marinesco-Sjögren syndrome (MSS; 2 males and 2 females, aged 26–31 years) in 2 families became non-ambulant because of slowly progressive muscular weakness rather than cerebellar ataxia. Other clinical features in these 4 patients were typical for MSS: bilateral cataracts from infancy, mental retardation, severe cerebellar atrophy, multiple skeletal abnormalities and hypergonadotropic hypogonadism. EMG demonstrated a myopathic pattern and serum CK was mildly elevated. Muscle biopsies from these 3 patients showed myopathic changes including a marked variation in fiber size, an increased number of fibers with centralized nuclei, and scattered necrotic and regenerating fibers. Fiber type analysis with myosin ATPase staining showed type 1 fiber predominance, type 2B fiber deficiency and mild increase in type 2C fibers. Muscle biopsy changes and the clinical course indicate that our MSS patients suffered from a chronic dystrophic process similar to that in congenital muscular dystrophy.

Cockayne Syndrome

Two siblings with Cockayne syndrome (CS) had extremely severe and early onset cachectic dwarfism, developmental delay, cataracts, microcephaly, peripheral neuropathy, and spastic quadriplegia. In order to study the inherited DNA-repair defect known to be present in cultured CS cells, a lymphoblastoid line was established from the younger sibling. Tissue culture studies revealed the line to have a hypersensitivity to the lethal effects of 254-nm ultraviolet radiation (UV) equivalent to that of lymphoblastoid lines from CS patients who had either the usual severity or a very mild form of CS. Autopsy of the older sibling at six years of age showed the brain to be severely atrophic, with particularly severe cerebellar atrophy. There was a marked reduction in the number of granule cells in the cerebellum and irregular patchy myelination throughout the brain. Many astrocytes contained either a large, bizarre-shaped nucleus or multiple nuclei. Some Purkinje cells of the cerebellum and pyramidal neurons of the hippocampus were binucleated. It is suggested that the DNA-repair defect of CS causes abnormalities in nuclear DNA replication and cell division which result in cell death and in the observed nuclear abnormalities.

The value of computerized tomography in the diagnosis of cerebellar atrophy.

Computerized tomography was performed in 31 patients presenting clinical signs of cerebellar degeneration. CT abnormalities consistent with cerebellar atrophy were found in all cases but one. Specific patterns of abnormality were found in olivo-ponto-cerebellar degeneration and in alcoholic atrophy. The CT findings in spino-cerebellar degeneration were varied, ranging from severe diffuse cerebellar atrophy to normality, possibly according to age and duration of symptoms.

Role of the staggerer gene in determining Purkinje cell number in the cerebellar cortex of mouse chimeras

Staggerer ( sg) is a mutation in mice which causes severe cerebellar atrophy. Virtually all of the granule cells degenerate by the end of the first postnatal month. The Purkinje cells are also affected. They are reduced in number, ectopic in location, reduced in size and show a regional variation in their cytological appearance. The appearance of the cerebellar cortex of Staggerer ↔ wild-type chimeric mice has demonstrated that the reduced size, ectopia, and regional variation are always traits of cells whose nucleus is of sg/sg genotype and thus are due to factors intrinsic to the affected cell. This report is a quantitative analysis of the cerebellar cortex of two Staggerer chimeras. Sections were chosen from serially sectioned half cerebella. Using β-glucuronidase activity as an independent marker of a cell's genotype, cells were scored as belonging to 1 of 3 cell classes: wild-type Purkinje cell, wild-type Golgi cell, and Staggerer medium-to-large neuron. The results confirm that the total number of cells in the chimera (all 3 classes) is greater than that found in a homozygous Staggerer but less than that found in a wild-type. Further, the distribution of the two genotypes strongly suggests that the decreased number of cells in Staggerer and in the chimera is due to an intrinsic defect in the Staggerer cells and not to a general (extrinsic) compromising of cerebellar development. Possible implications for normal cerebellar development are discussed.

Neuroaxonal dystrophy (Seitelberger's disease) with late onset, protracted course and myoclonic epilepsy

We present the pathologic findings, including electron microscopy, in one of two affected brothers with severe progressive myoclonus epilepsy, beginning in our patient at the age of 10 and leading to death at age 23. At autopsy there was widespread and marked neuroaxonal dystrophy, severe cerebellar atrophy, and tract degenerations in the gracilis columns and the lateral corticospinal tracts in the spinal cord. There was no increased pigmentation in the globus pallidus or reticular zone of the substantia nigra, on gross or microscopic examination. We regard this case as an example of a juvenile form of neuroaxonal dystrophy (Seitelberger's disease). The absence of pallido-nigral hyperpigmentation distinguishes this disease from Hallervorden-Spatz disease, which we regard as a separate disease entity.

THE PRESENT STATUS OF OUR KNOWLEDGE OF THE PATHOLOGICAL HISTOLOGY OF THE CORTEX IN THE PSYCHOSES

When we review the principal facts of the newer histological investigations of the paralysis process, we can conclude that this process is so well differentiated that it can be separated from all other diseases of the central nervous system. Our knowledge of the pathological anatomy is of extreme value for the clinical symptomatology of paralysis, as it allows us to diagnose cases of an atypical and extraordinary character. Further, the newer findings indicate that the process cannot be entirely accounted for by the inflammatory process in the blood vessels. More often independent degenerative changes are seen in the nervous tissue which go hand in hand with the inflammatory changes. The histological investigations of the other organs of the body make it more probable that the paralytic process is not only a disease of the central nervous system, but a disease of the entire body. But more investigations are needed to prove this point. Focal or circumscribed degeneration of the medullated sheath of the axis cylinders, particularly in the cortex, which can approach even the focal lesions of multiple sclerosis, is a frequent accompanying change in the paralytic process of the central nervous system. It is possible to differentiate a third type of paralysis which can be added to the typical cases and atypical localized forms (Lissauer's paralysis) the stationary paralysis which is characterized by a particularly mild process in the histological and clinical picture. The paralysis on the ground of hereditary lues is associated frequently with characteristic changes in the cerebellum, particularly the abnormal form and multiple nuclei of the Purkinje cells. This characteristic finding of the Purkinje cells is so frequently found, and in so many cases, that it is impossible to class them with isolated double nucleated cells found in the cerebellum of cases of other mental diseases. It is not entirely clear from whence these cells originate. From the fact that they are occasionally found in paralysis in middle life, and after late acquired syphilis in relation to a severe cerebellar atrophy, and are similar to the cells in juvenile paralysis, at present one cannot conclude that their presence indicates paralysis hereditaria tarda. Thorough examination of particularly atrophic cerebellum in adult paralysis is necessary before we can arrive at any conclusion. The investigations of Sibelius indicate, possibly, that in the central nervous system of paralytics, who have acquired syphilis, that frequently developmental anomalies are present. And possibly this means that there is a specific predisposition towards a later paralysis when accompanied with syphilis.