The Cerebellar Cognitive Affective Syndrome in Ataxia-Telangiectasia.

Ataxia-telangiectasia (AT) is an autosomal recessive, multisystem disease causing cerebellar ataxia, mucocutaneous telangiectasias, immunodeficiency, and malignancies. A pilot study reported cognitive and behavioral manifestations characteristic of the cerebellar cognitive affective / Schmahmann syndrome (CCAS). We set out to test and further define these observations because a more comprehensive understanding of the spectrum of impairments in AT is essential for optimal management. Twenty patients (12 males; 9.86 ± 5.5 years, range 4.3 to 23.2) were grouped by age: AT-I (toddlers and preschoolers, n = 7, 4.3-5.9 years), AT-II (school children, n = 7, 5.9-9.8 years), AT-III (adolescents/young adults, n = 6, 12.6-23.2 years). Standard and experimental tests investigated executive, linguistic, visual-spatial, and affective/social-cognitive domains. Results were compared to standard norms and healthy controls. Cognitive changes in AT-I were limited to mild visual-spatial disorganization. Spatial deficits were greater in AT-II, with low average scores on executive function (auditory working memory), expressive language (vocabulary), academic abilities (math, spelling, reading), social cognition (affect recognition from faces), and emotional/psychological processing. Full Scale IQ scores were low average to borderline impaired. AT-III patients had the greatest level of deficits which were evident particularly in spatial skills, executive function (auditory working memory, sequencing, word/color interference, set-shifting, categorization errors, perseveration), academic achievement, social cognition (affect recognition from faces), and behavioral control. Full Scale IQ scores in this group fell in the impaired range, while language was borderline impaired for comprehension, and low average for expression. Cognitive deficits in AT at a young age are mild and limited to visual-spatial functions. More widespread cognitive difficulties emerge with age and disease progression, impacting executive function, spatial skills, affect, and social cognition. Linguistic processing remains mildly affected. Recognition of the CCAS in children with AT may facilitate therapeutic interventions to improve quality of life.

The cerebellar cognitive affective/Schmahmann syndrome scale.

Cerebellar cognitive affective syndrome (CCAS; Schmahmann's syndrome) is characterized by deficits in executive function, linguistic processing, spatial cognition, and affect regulation. Diagnosis currently relies on detailed neuropsychological testing. The aim of this study was to develop an office or bedside cognitive screen to help identify CCAS in cerebellar patients. Secondary objectives were to evaluate whether available brief tests of mental function detect cognitive impairment in cerebellar patients, whether cognitive performance is different in patients with isolated cerebellar lesions versus complex cerebrocerebellar pathology, and whether there are cognitive deficits that should raise red flags about extra-cerebellar pathology. Comprehensive standard neuropsychological tests, experimental measures and clinical rating scales were administered to 77 patients with cerebellar disease-36 isolated cerebellar degeneration or injury, and 41 complex cerebrocerebellar pathology-and to healthy matched controls. Tests that differentiated patients from controls were used to develop a screening instrument that includes the cardinal elements of CCAS. We validated this new scale in a new cohort of 39 cerebellar patients and 55 healthy controls. We confirm the defining features of CCAS using neuropsychological measures. Deficits in executive function were most pronounced for working memory, mental flexibility, and abstract reasoning. Language deficits included verb for noun generation and phonemic > semantic fluency. Visual spatial function was degraded in performance and interpretation of visual stimuli. Neuropsychiatric features included impairments in attentional control, emotional control, psychosis spectrum disorders and social skill set. From these results, we derived a 10-item scale providing total raw score, cut-offs for each test, and pass/fail criteria that determined 'possible' (one test failed), 'probable' (two tests failed), and 'definite' CCAS (three tests failed). When applied to the exploratory cohort, and administered to the validation cohort, the CCAS/Schmahmann scale identified sensitivity and selectivity, respectively as possible exploratory cohort: 85%/74%, validation cohort: 95%/78%; probable exploratory cohort: 58%/94%, validation cohort: 82%/93%; and definite exploratory cohort: 48%/100%, validation cohort: 46%/100%. In patients in the exploratory cohort, Mini-Mental State Examination and Montreal Cognitive Assessment scores were within normal range. Complex cerebrocerebellar disease patients were impaired on similarities in comparison to isolated cerebellar disease. Inability to recall words from multiple choice occurred only in patients with extra-cerebellar disease. The CCAS/Schmahmann syndrome scale is useful for expedited clinical assessment of CCAS in patients with cerebellar disorders.awx317media15678692096001.

Cerebellar Contribution to Social Cognition.

Emotion attribution (EA) from faces is key to social cognition, and deficits in perception of emotions from faces underlie neuropsychiatric disorders in which cerebellar pathology is reported. Here, we test the hypothesis that the cerebellum contributes to social cognition through EA from faces. We examined 57 patients with cerebellar disorders and 57 healthy controls. Thirty-one patients had complex cerebrocerebellar disease (complex cerebrocerebellar disease group (CD)); 26 had disease isolated to cerebellum (isolated cerebellar disease group (ID)). EA was measured with the Reading the Mind in the Eyes test (RMET), and informants were administered a novel questionnaire, the Cerebellar Neuropsychiatric Rating Scale (CNRS). EA was impaired in all patients (CD p < 0.001, ID p < 0.001). When analyzed for valence categories, both CD and ID missed more positive and negative stimuli. Positive targets produced the highest deficit (CD p < 0.001, ID p = 0.004). EA impairments correlated with CNRS measures of deficient social skills (p < 0.05) and autism spectrum behaviors (p < 0.005). Patients had difficulties with emotion regulation (CD p < 0.001, ID p < 0.001), autism spectrum behaviors (CD p < 0.049, ID p < 0.001), and psychosis spectrum symptoms (CD p < 0.021, ID p < 0.002). ID informants endorsed deficient social skills (CD p < 0.746, ID p < 0.003) and impaired attention regulation (CD p < 0.144, ID p < 0.001). Within the psychosis spectrum domain, CD patients were worse than controls for lack of empathy (CD p = 0.05; ID p = 0.49). Thus, patients with cerebellar damage were impaired on an EA task associated with deficient social skills and autism spectrum behaviors and experienced psychosocial difficulties on the CNRS. This has relevance for ataxias, the cerebellar cognitive affective/Schmahmann syndrome, and neuropsychiatric disorders with cerebellar pathology.

Metalinguistic deficits in patients with cerebellar dysfunction: empirical support for the dysmetria of thought theory.

The cerebellar cognitive affective syndrome (CCAS) includes disruption of linguistic processing such as verbal fluency, verbal working memory, grammar, and speech perception. We set out to examine linguistic capabilities in patients with cerebellar lesions to determine which domains are spared and which impaired and to evaluate the underlying cognitive structure of these deficits. Forty-four patients with cerebellar disease were compared to 40 healthy controls on the Oral Sentence Production Test (OSPT) which assesses production of sentences with correct syntactic structure and semantic quality. Twenty-five of these cerebellar patients and 25 controls received the Test of Language Competence-Expanded (TLC-E) that assesses metalinguistic ability. The OSPT failed to reveal differences between patients and controls. In contrast, all cerebellar patients were impaired on each of the four TLC-E subtests. Differences between isolated cerebellar and complex cerebrocerebellar patients were nonsignificant. These results confirm and extend prior observations of the TLC-E in patients with cerebellar lesions and suggest three separate but related language impairments following cerebellar dysfunction: (1) disruption in automatic adjustment of intact grammatical and semantic abilities to a linguistic context in sentence production, (2) disruption in automatic adjustment to a linguistic context in sentence interpretation, and (3) disruption of cognitive processes essential for linguistic skills, such as analysis and sequential logical reasoning. These findings are consistent with the unifying framework of the universal cerebellar transform and the dysmetria of thought theory and provide new insights into the nature of the cognitive impairments in patients with the CCAS.

Growth retardation and growth hormone deficiency in patients with Ataxia telangiectasia.

BACKGROUND: Ataxia telangiectasia (A-T) is a devastating human recessive disorder characterised by progressive cerebellar ataxia, immunodeficiency, genetic instability, and cancer susceptibility. In addition, many patients suffer from growth failure. METHODS: We analyzed growth and IGF-1/BP3 levels of 24 A-T-patients compared with an age-matched group of healthy controls (n = 36). RESULTS: Ten (41.7%) A-T patients and none of healthy controls had an IGF-1 level below the 3rd percentile for age. The growth hormone (GH) stimulation tests revealed a severe GH deficiency with no increase of >5 ng/ml in six of the ten A-T patients. The IGF-1 generation tests revealed normal increases in IGF-1 values in all patients. CONCLUSION: Our results show that a disturbance in the GH/IGF-1 axis was present in 58.3% of A-T patients. Low levels of GH were the result of reduced central GH secretion. GH treatment may be a therapeutic option for A-T patients with severe growth failure.

Cognitive phenotype in ataxia-telangiectasia.

BACKGROUND: Pediatric cerebrocerebellar neurodegenerative disorders such as ataxia-telangiectasia (AT) have not been examined in detail for neuropsychologic changes. Such studies may contribute to the further understanding of ataxia-telangiectasia and to the role of the cerebrocerebellar system in the development of cognitive function in childhood. METHODS: Twenty-two patients with the classic phenotype of ataxia-telangiectasia were grouped into early stage cerebellar disease (group AT-I) versus late stage cerebrocerebellar disease (group AT-II) and examined for neurocognitive features. Results were compared with those of healthy control subjects and with standard norms. RESULTS: Patients in AT-I group scored low average compared with standard norms on all tests and were impaired compared with healthy control subjects for verbal intelligence quotient (P < 0.001), vocabulary and comprehension (P = 0.007), processing speed (P = 0.005), visuospatial processing (P = 0.020), and working memory (P = 0.046). Patients in AT-II group scored below average compared with standard norms on all tests and were impaired compared with control subjects for attention (P < 0.001), working memory (P < 0.001), and abstract reasoning (P < 0.001). Comprehension scores were lower for patients in AT-II than in AT-I group (P = 0.002), whereas vocabulary scores showed no difference between groups (P = 0.480). CONCLUSION: Cognitive impairments in ataxia-telangiectasia present early, coinciding with cerebellar pathology and are characteristic of the cerebellar cognitive affective syndrome. Widespread and deeper cognitive deficits manifest in later stages of ataxia-telangiectasia when additional noncerebellar pathology develops. These results are the first indications of distinct cerebellar and extracerebellar and/or subcortical contributions to the range of cognitive domains affected in ataxia-telangiectasia and need to be confirmed in future studies.

Degeneration of the cerebellum in Huntington's disease (HD): possible relevance for the clinical picture and potential gateway to pathological mechanisms of the disease process.

Huntington's disease (HD) is a polyglutamine disease and characterized neuropathologically by degeneration of the striatum and select layers of the neo- and allocortex. In the present study, we performed a systematic investigation of the cerebellum in eight clinically diagnosed and genetically confirmed HD patients. The cerebellum of all HD patients showed a considerable atrophy, as well as a consistent loss of Purkinje cells and nerve cells of the fastigial, globose, emboliform and dentate nuclei. This pathology was obvious already in HD brains assigned Vonsattel grade 2 striatal atrophy and did not correlate with the extent and distribution of striatal atrophy. Therefore, our findings suggest (i) that the cerebellum degenerates early during HD and independently from the striatal atrophy and (ii) that the onset of the pathological process of HD is multifocal. Degeneration of the cerebellum might contribute significantly to poorly understood symptoms occurring in HD such as impaired rapid alternating movements and fine motor skills, dysarthria, ataxia and postural instability, gait and stance imbalance, broad-based gait and stance, while the morphological alterations (ie ballooned neurons, torpedo-like axonal inclusions) observed in the majority of surviving nerve cells may represent a gateway to the unknown mechanisms of the pathological process of HD.

Neurodegeneration in ataxia telangiectasia: what is new? What is evident?

This article summarizes evident and recent findings on the characteristics of the neurological phenotype in ataxia telangiectasia (AT), reviews neuropathological and neuroradiological findings, and outlines therapeutic treatment options. In addition, this review offers an overview of current hypotheses on mechanisms of neurodegeneration in AT and discusses their relevance in clinical neurology. The obvious features of neurodegeneration in AT-cerebellar ataxia and dysarthia-are accompanied by a variety of further disabling disease symptoms. Review of the literature outlines a complex pattern of central nervous degeneration in AT that might have been underestimated so far. Neurodegeneration in AT is closely related to the absence or partial lack of the ataxia telangiectasia-mutated (ATM) kinase. ATM is a central player in maintaining cellular homeostasis. Systemic review of the literature reveals a subset of cellular targets hypothesized to count responsible for degeneration in ATM-deficient neurons. Further systematic cliniconeurological, pathoanatomical, and neuroradiological studies are required to understand the structural basis of this neurodegenerative disease. This better understanding has implications for the treatment of AT patients. Second, biochemical and molecular biological studies aimed at deciphering the pathomechanisms of this progressive disorder are necessary for the development of promising future therapies.

Rare brain biopsy findings in a first ADEM-like event of pediatric MS: histopathologic, neuroradiologic and clinical features.

Pediatric MS tends to present more often with an acute onset and a polysymptomatic form of the disease, possibly with encephalopathy and large tumefactive lesions similar to those observed in some cases of acute disseminated encephalomyelitis (ADEM), which makes it more difficult to differentiate between an explosive and severe onset of MS vs. ADEM. An ADEM-like first demyelinating event can be the first attack of pediatric MS, but international consensus definitions require two or more non-ADEM demyelinating events for diagnosis of MS. In our patient KIDMUS MRI criteria for MS (Mikaeloff et al. J Pediatr 144:246-252, 2004a; Mikaeloff et al. Brain 127:1942-1947, 2004b) were negative at first attack, but Barkhof criteria for lesion dissemination in space in adults (Barkhof et al. 120:2059-2069, 1997), Callen modified MS-criteria and Callen MS-ADEM criteria for children (Callen et al. Neurology 72:961-967, 2009a; Callen et al. Neurology 72:968-973, 2009b) were positive suggesting pediatric MS. As the clinical course was devastating with non-responsiveness upon high-dose immune modulatory therapy and due to the absence of an alternative diagnosis other than demyelinating disease brain biopsy was performed. Brain biopsy studies or autopsy case reports of fulminant pediatric MS patients are extremely rare. Histopathology revealed an inflammatory demyelinating CNS process with confluent demyelination, indicating the likelihood of a relapsing disease course compatible with an acute to subacute demyelinating inflammatory disease. This pattern was corresponding to the early active multiple sclerosis subtype I of Lucchinetti et al. (Ann Neurol 47(6):707-717, 2000).

Spinocerebellar ataxia type 2 (SCA2): identification of early brain degeneration in one monozygous twin in the initial disease stage.

Spinocerebellar ataxia type 2 (SCA2) is a progressive autosomal dominantly inherited cerebellar ataxia and is assigned to the CAG repeat or polyglutamine diseases. Recent morphological studies characterized the pathoanatomical features in heterozygous SCA2 patients and revealed severe neuronal loss in a large variety of cerebellar and extra-cerebellar brain sites. In the present study, we examined the brain pathoanatomy of a monozygous twin of a large Hungarian SCA2 family with pathologically extended CAG repeats in both SCA2 alleles. This unique patient was in the initial clinical stage of SCA2 and died almost 3 years after SCA2 onset. Upon pathoanatomical investigation, we observed loss of giant Betz pyramidal cells in the primary motor cortex, degeneration of sensory thalamic nuclei, the Purkinje cell layer, and deep cerebellar nuclei, as well as select brainstem nuclei (i.e., substantia nigra, oculomotor nucleus, reticulotegmental nucleus of the pons, facial, lateral vestibular, and raphe interpositus nuclei, inferior olive). All of these degenerated brain gray matter structures are known as consistent targets of the underlying pathological process in heterozygous SCA2 patients. Since they were already involved in our patient within 3 years after disease onset, we think that we were for the first time able to identify the early brain targets of the pathological process of SCA2.

Extracerebellar MRI-lesions in ataxia telangiectasia go along with deficiency of the GH/IGF-1 axis, markedly reduced body weight, high ataxia scores and advanced age.

Ataxia telangiectasia (AT) is a rare autosomal recessive disorder characterized by progressive ataxia, neurodegeneration, immunodeficiency, and cancer predisposition. Pathoanatomical studies reported a degeneration of cerebellar Purkinje cells as the striking feature of the disease. Although recent studies suggested the involvement of extracerebellar structures such as the brainstem and basal ganglia, this has rarely been studied in human AT. Thus, we performed a detailed cliniconeuroradiological investigation of 11 AT patients, aged 8 to 26 years by collecting clinical neurological data, ataxia scores, growth status, body mass index (BMI), growth hormone (GH), and insulin-like-growth factor 1 (IGF-1) and correlated them to extracerebellar neuroimaging findings in human AT. Neuroimaging was done by cranial and spine magnetic resonance imaging (MRI) with T1- and T2-weighted spin-echo and fluid attenuated inversion recovery sequences. We compared clinical and neuroradiological findings of six patients with IGF-1 levels and BMI below the third percentile to five patients with normal IGF-1 serum levels and BMI above the third percentile. Three of the six first mentioned patients older than 20 years and two patients older than 12 years showed noticeable high Klockgether ataxia scores above 25 points. Three of these patients presented with marked hyperintense lesions in the cerebral white matter of T2-weighted MR images. Interestingly, all six patients suffered from marked spinal atrophy. Two of the patients presented with severe extra-pyramidal symptoms, but only one patient showed associated MRI abnormalities of the basal ganglia. MRI in patients with normal IGF-1 levels showed the expected cerebellar lesions in four patients, whereas spinal atrophy was found only in two patients. There was no affection of the cerebral white matter or basal ganglia in this group. We conclude that central cerebral white matter affection, spinal atrophy, and extrapyramidal symptoms are more often present in patients with pronounced deficiency of the GH/IGF-1 axis accompanied by markedly reduced body weight and high ataxia scores. This may point to a major role of IGF-1 and nutritional status in neuroprotective signaling.