Mario-Ubaldo Manto

The wide spectrum of spinocerebellar ataxias (SCAs)

Spinocerebellar ataxias (SCAs) are a clinically heterogeneous group of disorders. Current molecular classification corresponds to the order of gene description (SCA1-SCA 25). The prevalence of SCAs is estimated to be 1–4/100.000. Patients exhibit usually a slowly progressive cerebellar syndrome with various combinations of oculomotor disorders, dysarthria, dysmetria/kinetic tremor, and/or ataxic gait. They can present also with pigmentary retinopathy, extrapyramidal movement disorders (parkinsonism, dyskinesias, dystonia, chorea), pyramidal signs, cortical symptoms (seizures, cognitive impairment/behavioral symptoms), peripheral neuropathy. SCAs are also genetically heterogeneous and the clinical diagnosis of subtypes of SCAs is complicated by the salient overlap of the phenotypes between genetic subtypes. The following clinical features have some specific values for predicting a gene defect: slowing of saccades in SCA2, ophthalmoplegia in SCA1, SCA2 and SCA3, pigmentary retinopathy in SCA7, spasticity in SCA3, dyskinesias associated with a mutation in the fibroblast growth factor 14 (FGF14) gene, cognitive impairment/behavioral symptoms in SCA17 and DRPLA, seizures in SCA10, SCA17 and DRPLA, peripheral neuropathy in SCA1, SCA2, SCA3, SCA4, SCA8, SCA18 and SCA25. Neurophysiological findings are compatible with a dying-back axonopathy and/or a neuronopathy. Three patterns of atrophy can be identified on brain MRI: a pure cerebellar atrophy, a pattern of olivopontocerebellar atrophy, and a pattern of global brain atrophy. A remarkable observation is the presence of dentate nuclei calcifications in SCA20, resulting in a low signal on brain MRI sequences. Several identified mutations correspond to expansions of repeated trinucleotides (CAG repeats in SCA1, SCA2, SCA3, SCA6, SCA7, SCA17 and DRPLA, CTG repeats in SCA8). A pentanucleotide repeat expansion (ATTCT) is associated with SCA10. Missense mutations have also been found recently. Anticipation is a main feature of SCAs, due to instability of expanded alleles. Anticipation may be particularly prominent in SCA7. It is estimated that extensive genetic testing leads to the identification of the causative gene in about 60–75 % of cases. Our knowledge of the molecular mechanisms of SCAs is rapidly growing, and the development of relevant animal models of SCAs is bringing hope for effective therapies in human.

Effects of anti–glutamic acid decarboxylase antibodies associated with neurological diseases

Glutamic acid decarboxylase (GAD) catalyzes the conversion of glutamic acid into GABA. GAD autoantibodies (GAD‐Ab) have been described in diabetes mellitus and in diseases involving the central nervous system such as stiff‐person syndrome and cerebellar ataxia. However, the pathogenic role of GAD‐Ab in neurological diseases remains a matter of debate.

Modulation of motor cortex excitability by sustained peripheral stimulation: The interaction between the motor cortex and the cerebellum

The excitability of cortical neurons in the motor cortex is determined by their membrane potential and by the level of intracortical inhibition. The excitability of the motor cortex as a whole is a function of single cell excitability, synaptic strength, and the balance between excitatory cells and inhibitory cells. It is now established that a sustained period of somatosensory stimulation increases the excitability of motor cortex areas controlling muscles in those body parts that received the stimulation prior to excitability testing. So far, it has been supposed that the sensorimotor cortex was the anatomical substrate of these excitability changes, which could represent an early change in cortical network function before structural plasticity occurs. Recent experimental studies highlight that the cerebellum, especially the interpositus nucleus, plays a key role in the adaptation of the motor cortex to repeated trains of stimulation. Interpositus neurons, which receive inputs from both sensorimotor cortex and the spinal cord, are involved in somesthetic reflex behaviors and assist the cerebral cortex in transforming sensory signals to motor-oriented commands by acting via the cerebello-thalamo-cortical projections. Moreover, climbing fibers originating in the inferior olivary complex and innervating the nucleus interpositus mediate highly integrated sensorimotor information derived from spinal modules. It appears that the interpositus nucleus is a main subcortical modulator of the excitability changes occurring in the motor cortex, which may be a substrate of early plasticity effective in motor learning and recovery from lesion.

On the cerebello-cerebral interactions

The question of which type of information and how it is being processed by the puzzling cerebellar circuitry remains open. Numerous works have highlighted and delineated the roles of cerebellar pathways in various parameters of motor control, such as timing of motor commands. Recent anatomical and functional data on a possible genuine cerebellar contribution in the processing of ‘cognitive’, behavioral and emotional information have not yet generated a consensus. Despite an apparent homogeneous and uniform cytoarchitecture, the actors of the cerebellar orchestra do play different roles depending on the anatomical inputs/outputs of the cerebellar regions. The numerous interactions between the cerebellum and the cerebral cortex remain a major field of research. Fundamental questions related to the cerebro-cerebellar networks, such as the modulation of corticomotoneuronal discharges in various contexts, have not been fully addressed, or only indirectly, with recent methods. Complexity of circuitries and non optimal theoretical frameworks continue to hamper our understanding of cerebellar operations.

Clinical symptoms of cerebellar disease and their interpretation

The observations of Gordon Morgan Holmes (22 February, 1876–29 December, 1965) on the effects of cerebellar lesions on motor function were incisive, insightful, and have well survived the test of time. While new discoveries, both clinical and basic science, have clearly added to our understanding, many of the fundamentals, as described by Holmes, appear in any contemporary clinical or basic neuroscience text. Holmes’ contributions underlie our modern thinking about cerebellar deficits. Cerebellar Classics III features Holmes’ Croonian Lectures III and IV as delivered on June 15 and 20, 1922, respectively. In Lecture III he deals with how the cerebellum may modulate more complex movements and how these are modified in the compromised patient; he covers a wide range of examples. In Lecture IV Holmes completes his detailed descriptions of deficits correlated with lesions, and engages in an overview of the previous three Lectures with a particular emphasis on theories of cerebellar function as seen in his clinical experience and cases, clarifying the roles of the cerebellum in motor control. As he did for Cerebellar Classics II, Professor Mitchell Glickstein offers us a unique view into the thinking of Holmes on his topics and how his ideas reflected his time in Cerebellar classics III. Glickstein includes commentary on how Holmes’ views interfaced with that of some of his contemporaries and with later scientists, and he revisits some of the more interesting clinical comments made by Holmes. We trust that our readers have enjoyed this opportunity to reacquaint themselves with these truly classic contributions of Sir Gordon Holmes.

Interaction between repetitive stimulation of the sciatic nerve and functional ablation of cerebellar nucleus interpositus in the rat

It is established that cerebellar nuclei exert a significant effect on the excitability of spinal neurons. However, their output is heterogeneous. Conditioning trains of dentate nucleus stimuli are known to modify the post-synaptic potentials evoked in motoneurons by stimulation of group Ia and Ib afferents in appropriate peripheral nerves. The role of the interpositus nucleus in the modulation of the excitability of rat spinal cord remains unclear. We investigated the interactions between tetrodotoxin (TTX)-induced inactivation of the interpositus cerebellar nuclei and repetitive electrical stimulation of the ipsilateral sciatic nerve (proximal segment) in the anesthetized rat. TTX (10 microM) was administered in cerebellar nuclei by the technique of microdialysis (coordinates of the extremity of the guide related to bregma: AP: -11.6, L: +2.3, V: -4.6). Peripheral stimulation consisted of trains of electric stimuli at a rate of 10 Hz, which were repeated every second during 1 hour. Stimulus intensity was adjusted to produce constant somatosensory evoked potentials. H-reflex, F-wave and M responses of the plantaris muscles were analysed ipsilaterally. H-reflex recruitment curve, Hmax/Mmax ratios, F-wave persistence and mean F/mean M ratios were studied. Functional blockade of cerebellar interpositus nucleus reduced the slope of H-reflex recruitment curve without affecting the Hmax/Mmax ratio, and depressed both F-waves persistence and mean F/mean M ratios. Concomitant repetitive stimulation of the sciatic nerve counteracted the depression of the H-reflex recruitment curve, without interacting with F-waves depression. Our results (1) show that TTX-sensitive sodium channels in cerebellar nucleus interpositus modulate the H-reflex recruitment, and (2) reveal an interaction between TTX-sensitive sodium channels in cerebellar nuclei and afferent repetitive activity not described so far.

Myorhythmia associated with Hodgkin’s lymphoma

Sirs: Myorhythmia is defined as a coarse alternating tremor present at rest and during movement that is slower than parkinsonian tremor [8]. Its frequency rate may vary from 50 to 180 cycles/min, with a clustering of most cases either at 120 or at 180 cycles/min. Myorhythmia may involve a single limb, more than one limb, a combination of limbs and face, palate, head, jaw, neck, tongue, eyes or trunk [8]. The term extremity myorhythmia is used when limb muscles are involved [8]. Myorhythmia has been associated with brainstem or thalamic vascular disease, trauma, chronic alcoholism-nutritional deficiency, Whipple’s disease, and phenytoin intoxication [7–8]. One case was recently reported to be associated with Hashimoto’s encephalopathy [3]. We describe a patient exhibiting extremity myorhythmia as a paraneoplastic symptom. A 66 year-old right-handed man complained of diplopia, speech difficulties, loss of balance, nausea and vomiting of acute onset, in the absence of arthralgia. He had a history of prostatic hypertrophy, hypertension and hyperlipemia. Current medication included indapamide 2.5 mg/d and atorvastatin 20 mg/d. He had no family history of neurological disease. He was admitted in our department 17 days after the onset of symptoms. On admission the patient was afebrile, with a blood pressure of 140/70 mm Hg and a heart rate of 92/min. He had multiple eye movement abnormalities including a gaze-evoked and downbeat nystagmus, a saccadic ocular pursuit, and skew deviation. There was no paralysis of vertical gaze. Optic fundi were normal. A scanning dysarthria was present. The patient had upper and lower limb ataxia, bilateral adiadochokinesia predominating on the left side, ataxia of the trunk while sitting and marked instability when standing. He could not walk without aid. Tendon reflexes were brisk bilaterally, plantar response was flexor on the left and equivocal on the right side. The only sensory abnormality was a diminished vibration sense at the toes, bilaterally. Erythrocyte sedimentation rate was 31 mm/h, with a normal level of C-reactive protein. Blood cell count, electrolytes, liver and renal function tests were normal. Thyroid function tests were normal. Levels of anti-thyroglobulin and anti-peroxisomal antibodies were 70 UI/mL (normal 0–150) and 34 UI/mL (normal 0–80), respectively. Antinuclear antibodies were absent. CT of the chest showed sequelae of pleurisy. No enlarged node was detected by chest and abdominal CT. Prostate biopsy specimens showed no evidence of tumor cells. No periodic acid Schiff (PAS)-positive macrophages were found on duodenal biopsies samples. The EEG showed a diffuse slowing at 6.5–7.5 Hz without epileptiform discharges. Brain CT and brain MRI were normal. CSF analysis showed 40 red cells/mm3, 7 white cells/mm3 (94 % lymphocytes), 83 mg/dL proteins (normal 30–65) and a normal IgG index. Search for oligoclonal IgG bands was negative. CSF cultures for bacteria were negative. CSF PCRs for enterovirus, herpes simplex virus (HSV 1, HSV 2), zoster virus (VZV), cytomegalovirus, Epstein-Barr virus were negative. Anti-neuronal antibodies were first evaluated in the patient’s serum and CSF 20 days after the first neurological symptoms. Immunofluorescence was performed using paraformaldehyde-fixed frozen sections of rat cerebellum as previously described [6]. Anti-Hu, anti-Yo, anti-Ri, anti-Amphiphysin and anti-CV2 were clearly negative. However, the serum (end point dilution: 1/500) and the CSF (end point dilution 1/100) showed a granular labeling of Purkinje cell cytoplasms with nuclear sparing and fine dotted pattern in the molecular layer typical of anti-Tr antibodies (Fig. 1). Anti-Tr specificity was confirmed by immunocompetition in a reference laboratory (F. Graus, Barcelona, Spain). A new serum sample obtained two months later was completely negative as was a new CSF sample obtained 6 months after the beginning of the neurological symptoms. CSF analysis showed normal cell count, protein level, and IgG index. Thirteen months later, a whole body PET-FDG revealed increased uptake in several abdominal nodes. LETTER TO THE EDITORS

The Saga of Zones in the Cerebellar Cortex as Reflected in the Corticonuclear System: Prologue (1897–1929)

The concept of zones in the cerebellar cortex is wellunderstood today. These patterns are reflected in afferents to the cortex, such as the spinocerebellar pathways, and the efferents arising from the cortex, such as the corticonuclear pathways. One of the most important features of cerebellar circuity is the close antomofunctional relationship between afferents and efferents. The olivo-cortico-nuclear organization is matching the distribution of climbing fiber collaterals to cerebellar nuclei and the inhibitory nucleo-olivary projections. This has been demonstrated in particular for the so-called intermediate cerebellum. The corticonuclear pathways are of particular interest due to the long lines of research that provided the basis for their discovery. It is essential to remember that the concept (a concept is something formulated from ideas or examples) of zones in the cerebellar cortex was not an extant thought that simply needed to be proved. Rather, this concept was a result of research that, over decades, produced progressively more detailed patterns of fiber projections; collectively, these patterns gave rise to the concept/hypothesis of cerebellar cortical zones that were subsequently proved to exist. Experiential observations, spanning about 75 years, laid the framework for the hypothesis of cortical efferent zones and the definitive proof that they existed. During this period, there were descriptions of connections whose significance was not understood at the time, experimental side trips that went nowhere and even clouded the picture, and experimental results that in retrospect were quite insightful. CEREBELLAR CLASSICS VI begins this saga of exploration and discovery with a brief overview of selected early studies and features a 1929 paper that provided important, and fundamental, insights into the question of just how precisely arranged is the relationship between the cerebellar cortex and its nuclei. To the best of our knowledge one of the first detailed studies that focused on the patterns of cerebellar corticonuclear fibers was the dissertation of I. A. Klimoff, On the Conduction Paths of the Cerebellum; Experimental-anatomical Observations, 1897 (Fig. 1). This work, prepared at the Imperial University of Kazan, offered an extensive review of the extant literature and invoked the names of many prominent scientists of the period such as Edinger, Flechsig, von Monakow, Deiter, Gudden, and Ferrier and Turner. In what we would now call the literature review, Klimoff described the patterns of selected cerebellar connections based on what is seen in preparations relying largely on fiber stains. On the experimental side of his work, Klimoff used the Marchi method to ascertain the projections of cerebellar lesions. Regarding the lesions of the cortex, Klimoff generally

The Saga of Zones in the Cerebellar Cortex as Reflected in the Corticonuclear System: A Different Approach, a Specific Hypothesis, and the Proof Begins (Voogd, 1969)

In the interval between the mid-to-late 1940s and the mid-tolate 1960s, there were a number of research papers that utilized anatomical and physiological techniques (for example [1–5]) to describe the patterns of cerebellar corticonuclear projections. The physiological techniques were contemporary for the day and the anatomical methods relied on the relatively new silver impregnation of Nauta and Gygax [3]. All of these authors referenced the studies of Jansen and Brodal [8, 9] which used the Marchi method. In these works, the corticonuclear patterns were generally described as forming “longitudinal zones,” “cortico-nuclear zones,” or “functional zones.” This terminology represented a clear movement to recognize, formalize, and rationalize the basic features of the patterns that were described by Jansen and Brodal. While these studies (excluding Jansen and Brodal), on cat, rat, and monkey, provided some additional detail of the patterns of the corticonuclear fiber projection as regarding a so-called zonal organization, they differed in other important respects. In fact, the deviation from the pattern of Jansen and Brodal was variously described as “significant” or “to differ in certain important respects.” First, even though lesions were shown as small and frequently oriented parallel to potential cortical zones, degeneration was distributed to wide areas of the cerebellar nuclei, in some experiments to all nuclei on the ipsilateral side. The reasons of this incongruity were unclear, not explained, and noted by subsequent investigators. Second, despite the fact that Weidenreich [12] and others such as Ogawa [10] and Ono and Kato [11] recognized four nuclei on each side, these contemporary authors described projections into only the medial, interpositus, and lateral nuclei. It is true that Jansen and Brodal described projections to generally the same three nuclei. However, in their 1942 paper, they clearly describe divisions of the interpositus into the anterior and posterior parts and a tendency for degeneration, in some cases, to favor more caudal versus more rostral parts of this “interposed” nucleus. While more detail of the corticonuclear system was provided, these results did not clarify or advance the concept of a global zonal plan. Perhaps the issue was complicated by the fact that all investigators assumed that these zones were arranged parallel to the midline. The stage was set for a comparatively novel experimental approach, a fresh hypothesis, and encouragement to investigate the proposal. In the first sentence of his publication Voogd [1] states “...we will be concerned with the significance of fiber connections in the search for a ‘Bauplan’ a fundamental pattern in the morphology of the mammalian cerebellum.” Rather than approach this problem from the cortical side, as had been the experimental plan in studies spanning the period 1899–1969, Voogd approached it from the subcortical side. He studied the myeloarchitecture of the ferret cerebellum using the Häggqvist method which allowed him to determine the pattern of fibers in the white matter by fiber diameter. This approach turned out to be key. Voogd made several seminal observations that were absolutely essential to future investigations. First, he noted that the subcortical white matter was organized into “compartments” containing fibers of a larger diameter separated from each other by “raphes” made up of areas D. E. Haines Department of Anatomy, University of Mississippi Medical center, 2500 North State Street, Jackson, MS 39216, USA e-mail: dhaines@umc.edu

Discrepancy between Dysmetric Centrifugal Movements and Normometric Centripetal Movements in Psychogenic Ataxia

A method to unravel an aberrant motor behaviour in psychogenic ataxia is reported. The kinematic features of fast reaching movements in the vertical plane are described in a patient presenting a psychogenic ataxia. The procedure compared centrifugal and centripetal movements. Path ratios were computed for each phase, as well as the ratios of the paths for centrifugal and centripetal directions. Trajectories of centrifugal phases were erratic but centripetal movements were very regular, whereas both centripetal and centrifugal movements were irregular in patients presenting an organic cerebellar syndrome. A similar incongruity between movements in opposite directions is also shown for a second patient exhibiting psychogenic ataxia. Discrepancies between the centrifugal phase and the centripetal phase of multi-joint reaching movements support the diagnosis of a psychogenic movement disorder.