Significance of Purkinje cell density in seizure suppresion by chronic cerebellar stimulation.

Cerebellar biopsy specimens were obtained at the time of cerebellar electrode installation in three epileptic patients. Cerebellar autopsy specimens also were examined from four epileptic patients and from five patients without epilepsy or neurologic disease. All specimens from seizure patients showed isomorphic gliosis of the cerebellar cortices. Significantly lower Purkinje cell densities were found in epileptic patients as compared with nonepileptic control patients. Our two epileptic patients showing marked Purkinje cell loss before cerebellar stimualtaion appeared to have better seizure control during stimulation than the patient who had only mild reduction in Purkinje cell density. These data suggest that augmentation of Purkinje cell inhibitory discharges in not the dominant mechanism for seizure suppression during cerebellar stimulation. Comparison of cerebellar specimens obtained during electrode installation with those obtained later during electrode revisions may have been prognostic significance.     

Degeneration of the cerebellar system in X-chromosome-linked copper malabsorption.

Examination of the cerebellar system of 5 autopsied patients with X-chromosome-linked copper malabsorption led to the discovery that among cerebellar afferent systems, only the dorsal spinocerebellar tract showed consistent degenerative changes. Cerebellar cortical lesions comprised granule cell loss and Purkinje cell abnormalities that included nuclear and cytoplasmic degenerative changes with cell loss and deficient dendritic arborization as well as the presence of somatic sprouts. Perisomatic baskets were often absent in the area of sprouting Purkinje cells. Cerebellar cortical topographical analysis revealed relative sparing of the caudal portion of the cerebellum. The nodulus was intact in all patients. The dentate nucleus and the superior cerebellar peduncle were preserved. The red nucleus was consistently degenerated.     

Cerebellar Atrophy in Patients with Subcortical-Type Vascular Cognitive Impairment

Recent studies suggest that the role of the cerebellum extends into cognitive regulation and that subcortical vascular dementia (SVaD) can result in cerebellar atrophy. However, there has been no evaluation of the cerebellar volume in the preclinical stage of SVaD. We aimed to compare cerebellar volume among patients with amnestic mild cognitive impairment (aMCI) and subcortical vascular mild cognitive impairment (svMCI) and evaluate which factors could have contributed to the cerebellar volume. Participants were composed of 355 patients with aMCI, svMCI, Alzheimer's disease (AD), and SVaD. Cerebellar volumes were measured using automated methods. A direct comparison of the cerebellar volume in SVaD and AD groups showed that the SVaD group had a statistically smaller cerebellar volume than the AD group. Additionally, the svMCI group had a smaller cerebellar volume than the aMCI group, with the number of lacunes (especially in the supratentorial regions) being associated with cerebellar volume. Cerebellar volumes were associated with some neuropsychological tests, digit span backward and ideomotor apraxia. These findings suggest that cerebellar atrophy may be useful in differentiating subtypes of dementia and the cerebellum plays a potential role in cognition.     

Cerebellar infarction in the territory of the medial branch of the superior cerebellar artery

The authors studied 14 patients with an isolated cerebellar infarct in the territory of the medial branch of the superior cerebellar artery (MSCA). The most common clinical finding was severe gait ataxia with sudden falling (n = 9) or severe veering (n = 2). Cerebellar dysarthria was found in 8 patients. Eight patients had a mild unilateral limb ataxia. These findings emphasize that MSCA territory cerebellar infarction presented with the prominent gait ataxia and cerebellar dysarthria.     

Unilateral cerebellar hypoplasia with different clinical features

Unilateral cerebellar hypoplasia (UCH) is a rare pathological condition characterized by the loss of volume in cerebellar hemispheres ranging from mild asymptomatic to severe symptomatic cases. As the designation of UCH remains problematic, the underlying etiopathogenesis also lacks explanation. We investigated the patients admitted to Departments of Child Neurology, Neurology, and Genetics between the years 1992 and 2010 and detected 12 patients with unilateral cerebellar volume loss, with the exclusion of all other cerebellar pathologies. The ages of patients ranged between 6 months to 55 years. Five patients had a delay in developmental milestones, and one of these was diagnosed with neurofibromatosis type 1. Two patients had epileptic seizures, one patient had peripheral facial paralysis as a component of Moebius syndrome, and four patients were incidentally diagnosed during etiological work-up for headache. The clinical outcomes of patients varied from healthy subjects to marked developmental impairment. Radiologically, five patients had severe disproportionate UCH, six had moderate disproportionate, and one had mild proportionate UCH. Cerebellar peduncles were affected in all, and vermis was partly hypoplastic in eight patients. Brainstem was involved in four patients, and seven patients showed involvement of white matter and/or corpus callosum. Imaging features supported that patients with severe disproportionate UCH also displayed additional cerebral and commissural changes, which were related to ischemic or vascular injuries, implying a prenatally acquired disruption. In the presence of such a wide spectrum of clinical and radiological features, a prenatally acquired lesion and, thus, a disruption seem to be more explanatory rather than a primary developmental process or malformation in the etiopathogenesis of unilateral cerebellar hypoplasia.     

Secondary changes in cerebellar perfusion (diaschisis) in hemiplegia during childhood: SPECT study of 55 children

Diaschisis is a functional impairment at a site in the brain remote from the lesion causing it. An investigation of cerebellar diaschisis in childhood was undertaken to better understand the functional maturation of the corticopontocerebellar tract in developing brain. A retrospective study of cerebellar diaschisis in 55 hemiplegic children was conducted using singlephoton emission computed tomography (SPECT) with ¹²³I-IMP. Cerebellar diaschisis was evaluated by 2 authors. Crossed cerebellar diaschisis (CCD) was found in 6 of 55 patients. SPECT findings of patients who presented with CCD disclosed supratentorial hypoperfusion of varying degrees, from focally to the whole hemisphere; however, patients had frontal and/or parietal hypoperfusion in common. A second type of cerebellar diaschisis also was demonstrated. Cerebellar hypoperfusion ipsilateral to supratentorial lesions, ipsilateral cerebellar diaschisis (ICD), was observed in 10 of 55 patients. CCD occurred in the patients who suffered from brain injuries after 7 years, 5 months of age, while ICD manifested in patients whose brain injuries occurred before 3 years, 1 month of age. The production of remote effects, such as CCD and ICD, could be closely related to maturation of the corticopontocerebellar tract in the developing brain during childhood.     

Patterns of cerebellar atrophy in patients with chronic epilepsy: a quantitative neuropathological study

Cerebellar atrophy occurring in patients with chronic epilepsy is considered either to be a sequel of cumulative seizure-mediated cell loss or a side effect of phenytoin treatment but there is little neuropathological data regarding the distribution of this cerebellar damage. We aimed to address if there is any relationship between the localisation of the cortical pathology in symptomatic epilepsy and the pattern of neocerebellar atrophy. A quantitative neuropathological post mortem analysis of the lobular distribution of hemispheric cerebellar atrophy in 16 patients with chronic epilepsy and four controls was carried out. Cerebellar atrophy, as measured by significant reductions in hemispheric linear Purkinje cell densities was confirmed in the epilepsy patients (P = 0.015) and even where the cerebellum appeared macroscopically normal, Purkinje cell loss was evident (P = 0.062). Two distinct patterns of atrophy were observed, predominantly involving either the anterior or posterior cerebellar lobes. Posterior lobe atrophy was more often associated with old fronto-temporal contusions and may be post traumatic in aetiology rather than a result of excitotoxic damage mediated via cerebro cerebellar pathways. As the majority of patients showing either pattern of atrophy had received phenytoin treatment, we concluded that it is unlikely that this drug acts alone in inducing the Purkinje cell loss.     

Dystonia and calcification of the basal ganglia

We studied a family with dominantly inherited dystonia and intracranial calcification. Thirty-seven members were examined; 13 were affected by dystonia that was segmental in most patients, affecting especially the voice, face, neck, and limbs. Intracranial calcification involved the putamen, pallidum, cerebral white matter and cortex, and cerebellar nuclei. Several patients had both dystonia and calcification, but others had either dystonia or calcification alone.     

Abnormal eye movements in Creutzfeldt–Jakob disease

We report 3 patients with autopsy-proven Creutzfeldt–Jakob disease who, early in their course, developed abnormal eye movements that included periodic alternating nystagmus and slow vertical saccades. These findings suggested involvement of the cerebellar nodulus and uvula, and the brainstem reticular formation, respectively. Cerebellar ataxia was also an early manifestation and, in 1 patient, a frontal lobe brain biopsy was normal at a time when ocular motor and cerebellar signs were conspicuous. As the disease progressed, all saccades and quick phases of nystagmus were lost, but periodic alternating gaze deviation persisted. At autopsy, 2 of the 3 patients had pronounced involvement of the cerebellum, especially of the midline structures. Creutzfeldt-Jakob disease should be considered in patients with subacute progressive neurological disease when cognitive changes are overshadowed by ocular motor findings or ataxia.     

Comparison of cerebellar intention tremor under isotonic and isometric conditions

The characteristics of cerebellar intention tremor were investigated by comparing the properties of tremor following movements about the elbow with that following isometric contractions of biceps and triceps brachii. Cerebellar dysfunction was produced by local, reversible cooling of the dentate and interposed nuclei in three Cebus monkeys. Cerebellar nuclear cooling disrupted isometric contractions to the aimed target and produced oscillations in torque. Whereas the cerebellar tremor that followed movements was regular and had a frequency of 3-5 Hz, the oscillations in the isometric task were irregular and were often of a lower frequency. In addition, cycles of tremor following movements were in phase from trial to trial, while the oscillations that occurred following isometric contractions did not show this phase-relationship. It is concluded that a cerebellar tremor can occur in an isometric situation but that movement about a joint is required for development of a rhythmic 3-5-Hz cerebellar intention tremor.     

Preserved verb generation in patients with cerebellar atrophy

A role of the right cerebellar hemisphere has been suggested in linguistic functions. Nevertheless, studies of verb generation in cerebellar patients provide inconsistent results. The aim of the present study was to examine verb generation in a larger group of cerebellar patients with well-defined lesions. Ten subjects with degenerative cerebellar disorders and ten healthy matched controls participated. Subjects had to generate verbs to the blocked presentation of photographs of objects (i.e. four blocks of sixteen objects). As control condition, the objects had to be named. Furthermore, dysarthria was quantified by means of a sentence production and syllable repetition task. Volumetric analysis of individual 3D-MR scans was performed to quantify cerebellar atrophy. Cerebellar patients were slower in the sentence production and syllable repetition tasks, and cerebellar volume was decreased compared to controls. Despite cerebellar atrophy and dysarthria, the answers produced did not differ between patients and controls. In addition, both groups revealed the same amount of decrease in verbal reaction time over blocks (i.e. learning). The results suggest that the role of the cerebellum in verb generation is less pronounced than previously suggested.     

Cerebellar blood volume in bipolar patients correlates with medication.

BACKGROUND: Cerebellar abnormalities, including decreased tissue volume, have been implicated in the pathophysiology of bipolar disorder. Relatively little research has focused on blood flow in the cerebellum of patients with bipolar disorder. Furthermore, the significance of metabolic changes in the brains of psychiatric patients may be confounded by the effects of various pharmacotherapies. Having previously found differences in cerebellar blood volume in patients with bipolar disorder compared to healthy control subjects, this study examined whether some variability in the patient population may be an effect of medication. METHODS: In this study, we have examined the association between medication status and cerebellar blood volume. Thirteen healthy comparison subjects and 21 bipolar patients underwent dynamic susceptibility contrast magnetic resonance imaging. Nine cerebellar regions were identified, and the absolute cerebellar blood volume data from each was compared to medication status measures. RESULTS: Patients on conventional antipsychotics had the lowest mean absolute blood volume measures for all cerebellar regions, whereas those on atypical antipsychotics had the highest blood volume measures. Comparison subjects had cerebellar blood volume measures in the middle, with results closer to subjects in the atypical group. CONCLUSIONS: This evidence suggests that antipsychotic treatment may influence cerebellar blood volume. This effect will be important in considering imaging studies on medicated patients with bipolar disorder and may suggest novel pathways by which these medications affect their changes.     

Cerebellar degeneration due to chronic phenytoin therapy

Five patients developed cerebellar degeneration while being treated with phenytoin. All had high plasma levels of the drug, and none was having seizures of a type that could have caused systemic hypoxia at the time the cerebellar syndrome appeared. Cerebellar degeneration was confirmed by the finding of atrophy on CT scan and by persistence of cerebellar signs when plasma phenytoin levels were decreased. We suggest that chronic phenytoin therapy can cause cerebellar degeneration. The question of whether phenytoin or the cumulative effect of hypoxia from repeated convulsions causes cerebellar degeneration should not be posed as one of exclusive alternatives, since hypoxia is a well-known cause of cerebellar atrophy. Instead, the question should be whether or not phenytoin can also be responsible. The cases reported here suggest that it can.     

Interval timing disruptions in subjects with cerebellar lesions

The cerebellum has long been implicated in time perception, particularly in the subsecond range. The current set of studies examines the role of the cerebellum in suprasecond timing, using analysis of behavioral data in subjects with cerebellar lesions. Eleven cerebellar lesion subjects and 17 controls were tested on temporal estimation, reproduction and production, for times ranging from 2 to 12 s. Cerebellar patients overproduced times on both the reproduction and production tasks; the effect was greatest at the shortest duration. A subset of patients also underestimated intervals. Cerebellar patients were significantly more variable on the estimation and reproduction tasks. No significant differences between normal and cerebellar patients were found on temporal discrimination tasks with either sub- or suprasecond times. Patients with damage to the lateral superior hemispheres or the dentate nuclei showed more significant impairments than those with damage elsewhere in the cerebellum, and patients with damage to the left cerebellum had more significant differences from controls than those with damage to the right. These data suggest that damage to the middle-to-superior lobules or the left hemisphere is especially detrimental to timing suprasecond intervals. We suggest that this region be considered part of a network of brain structures including the DLPFC that is crucial for interval timing.     

Reduced Cerebellar Inhibition in Migraine with Aura: A TMS Study

Subtle clinical cerebellar alterations have been found in migraine. Moreover, abnormalities in visual and motor cortex excitability consistent with a lack of inhibitory efficiency have been described in migraine, and it is known that cerebellum exerts an inhibitory control on cerebral cortex. Here, we investigated if impairment of cerebellar activity on motor cortex, i.e. reduced inhibitory control, can be found in migraine. Ten migraineurs with aura and seven healthy controls underwent a transcranial magnetic stimulation (TMS) protocol to investigate the cerebellar inhibitory drive on motor cortex: a conditioning pulse on right cerebellar cortex was delivered 5, 7, 10, 15 ms before a test stimulus (TS) on contralateral motor cortex. The cerebellar conditioning stimulus inhibits the size of the motor-evoked potential (MEP) produced by the TS alone by approximately 30–50%. Amplitude of MEP to TS alone showed no significant difference between patients and controls. Cerebellar conditioning TMS showed a significant deficit of cerebellar inhibition in migraine patients as compared to controls at all interstimulus intervals (5–15 ms) tested. Cerebellar inhibition is reduced in migraineurs. This could account, at least in part, for the reduced inhibitory efficiency previously showed in cerebral cortex of these patients.     

Causative factors and epidemiology of bilateral vestibulopathy in 255 patients

OBJECTIVE: To determine the causative factors and epidemiology of bilateral vestibulopathy (BV). METHODS: This is a retrospective review of 255 patients (mean age, 62 +/- 16 years) with BV diagnosed in our dizziness unit between 1988 and 2005. All patients had undergone a standardized neurophthalmological and neurootological examination, electronystagmography with caloric irrigation, cranial magnetic resonance imaging or computed tomography (n = 214), and laboratory tests. RESULTS: Sixty-two percent of the study population were male subjects. Previous vertigo attacks had occurred in 36%, indicating a sequential manifestation. The definite cause of BV was determined in 24% and the probable cause in 25%: The most common causes were ototoxic aminoglycosides (13%), Menière's disease (7%), and meningitis (5%). Strikingly, 25% exhibited cerebellar signs. Cerebellar dysfunction was associated with peripheral polyneuropathy in 32% compared with 18% in BV patients without cerebellar signs. Hypoacusis occurred bilaterally in 25% and unilaterally in 6% of all patients. It appeared most often in patients with BV caused by Cogan's syndrome, meningitis, or Menière's disease. INTERPRETATION: The cause of BV remains unclear in about half of all patients despite intensive examinations. A large subgroup of these patients have associated cerebellar dysfunction and peripheral polyneuropathy. This suggests a new syndrome that may be caused by neurodegenerative or autoimmune processes.     

Contribution of alcohol abuse to cerebellar volume deficits in men with schizophrenia

BACKGROUND: It is controversial whether cerebellar tissue volume deficits occur in schizophrenia and, if so, what regions and tissue types are affected. Complicating such investigations is the high incidence of alcoholism comorbidity in patients with schizophrenia that itself can contribute to cerebellar abnormalities. METHOD: We studied 61 healthy men (control subjects), 25 men with alcoholism, 27 men with schizophrenia, and 19 men comorbid for schizophrenia and alcoholism with the use of magnetic resonance imaging. Cerebellar structures were outlined manually, tissue classification was determined statistically, and regional volumes were corrected for normal variation in head size and age. RESULTS: Patients with schizophrenia alone had enlarged fourth ventricles (1.5 SD relative to controls) but showed no cerebellar tissue volume deficits. The alcoholic group had gray and white matter vermian deficits (-0.5 SD), most prominent in anterior superior lobules, and gray matter hemisphere deficits (-0.8 SD), but not fourth ventricle enlargement. The comorbid group had cerebellar hemisphere (-1.3 SD) and vermian gray matter volume deficits (-0.7 SD) and fourth ventricular enlargement (1.6 SD); these abnormalities were greater than in either single-diagnosis group, despite significantly lower levels of alcohol consumption compared with the alcoholic group. Gray matter volume in the anterior superior vermis correlated with lifetime alcohol consumption in the schizophrenic and comorbid groups when combined. CONCLUSIONS: Cerebellar tissue volume deficits were detected in schizophrenia only when accompanied by alcoholism. By contrast, fourth ventricular enlargement occurred in schizophrenia even without alcoholism, although it was exacerbated by alcoholism. These findings support a model of cerebellar supersensitivity to alcohol-related tissue volume deficits in schizophrenia.     

Some neurophysiological effects of cerebellar stimulation in man.

This paper presents the results of neurophysiological studies of the effects of cerebellar stimulation on H reflexes, late reflexes, blink reflexes, evoked potentials and EEG patterns in 18 human subjects (Male 13, Female 5, Age 25.8+/-10.0, Epileptic 9, Cerebral Palsy 9). In addition to the effects of cerebellar stimulation on the H reflex studies on soleus we assessed V1 and V2, "late" responses (Upton et al., 1971), cortical somatosensory evoked potentials (SSEP) after median nerve stimulation, and visual evoked responses (VER) after flash stimulation. Experiments were extended to assess recovery curves of all the potentials and we examined the effects of changes on the rate or voltage of cerebellar stimulation. Cerebellar stimulation was inhibitory to all the responses except the visual evoked potentials. Serial studies in five patients produced consistent results. Preoperative and postoperative results were compared in two patients with no significant difference in the results in the absence of cerebellar stimulation. Ipsilateral cerebellar stimulation (CS) had the greatest inhibitory effects on H, V1 and V2 responses in the arm and leg whereas contralateral CS produced the greatest effects on cortical SSEPs. There was a greater bilateral effect on SSEPs and reflex responses after right CS than left CS and this may be the first indication of "dominance" in the cerebellar hemispheres. Cerebellar stimulation in patients on diphenylhydantoin produced minimal effects on SSEP's and this observation has led to further studies in patients taking diphenylhydantoin. Recovery of amplitude of the reflex and cortical responses took eight to 30 minutes after one minute of cerebellar stimulation. Serial CS of one minute on and one minute off produced increasing inhibition of SSEP's and reflexes for up to five stimulations. Recovery after cessation of cerebellar stimultion was associated with rebound excitation in six patients, the rebound being noted in the amplitude of H reflexes and SSEP's as well as in the frequency of paroxysmal spike and wave discharges in the EEG. The correlation of the results of such quantitative neurophysiological tests with clinical improvement may allow prediction of clinical improvement may allow prediction of clinical results after cerebellar stimulation. These techniques have already been used to measure the threshold of stimulation and may allow optimal stimulation characteristics to be assessed. The prolonged neurophysiological effects of stimulation may allow the use of maximum effective intervals between optimal epochs of stimulation so that any cerebellar damage can be minimized.