Crossed cerebellar diaschisis in acute stroke patients: case analysis and report

Background. Stroke represents a high-risk condition for long-term disability and death. The role of diaschisis in the severity of acute neurological deficit and spontaneous stroke recovery is significant. However, currently there are not enough published prospective, hospital-based, cohort studies that report and analyze clinical characteristics of crossed cerebellar diaschisis in acute stroke patients. Moreover, modern stroke treatment may change clinical representation of diaschisis. The purpose of this study is to determine the features of the clinical manifestations of crossed cerebellar diaschisis after acute cerebral stroke and to improve the efficiency of its diagnosis by comparing the obtained data with the results of the magnetic resonance imaging findings. Materials and methods. We prospectively recruited 124 acute stroke patients, who were admitted to a single department of the academic tertiary care hospital in Kyiv, Ukraine. The primary outcome was the combined incidence of stroke and diaschisis. In the secondary analyses, we studied pathophysiological, anatomical, and clinical features specific to crossed cerebellar diaschisis in a cohort of acute stroke patients with diaschisis. Results. Among 124 selected acute stroke patients admitted to the department, 42 (33.9 %) persons were diagnosed with different forms of diaschisis: cerebrospinal (n = 22), commissural (n = 4), crossed cerebellar (n = 5), crossed cerebellar-hemispheric (n = 6), crossed and ponto-cerebellar diaschisis (n = 5). We have conducted a detailed pathophysiological and clinical analysis of crossed cerebellar diaschisis in acute ischemic stroke patients, described clinical manifestations of crossed cerebellar diaschisis. Utilizing the von Monakow theory of diaschisis, we found a scientific explanation for the pathophysiology of clinical manifestations of that remote form of diaschisis. Conclusions. Results of this study showed that cerebellar infarction is associated not only with typical symptoms of cerebellar lesion, but also with paresis, disturbances of sensitivity, and higher mental functions. Further study of the issues addressed in this article will help to improve the diagnosis and management of patients with acute cerebellar stroke.

For decades, the concept of diaschisis coined by von Monakow in 1914 to describe the neurophysiologi-cal changes that occur distant to a focal brain lesion was placed at the center of the understanding of brain function [23][24][25][26][27][28][29]. Until the late 1970s, this concept triggered widespread clinical interest to describe symptoms and signs which primary stroke lesion could not fully explain [30]. However, after the first imaging studies that only partially confirmed the clinical significance of diaschisis, the concept of diaschisis became neglected and subsequently disappeared from mainstream research in clinical neuroscience [31].

ОРИГІНАЛЬНІ ДОСЛІДЖЕННЯ /ORIGINAL RESEARCHES/
The development of new imaging techniques allows a clear visualization and deeper understanding of structural and functional connectivity between brain areas which are distant to the primary lesion. These techniques have consequently revitalized the concept of diaschisis. Presently, one of the most promising techniques is neuromodulation utilizing transcranial magnetic stimulation. Once this last technique becomes successful, the concept of diaschisis will regain all the clinical respectability that was unobtainable during decades of research.
Remote diaschisis focusing on specific networks seems to relate more consistently to the clinical findings, especially after stroke in the motor and attentional networks. Normalization of remote connectivity changes in these networks is associated with better recovery [26]. Therefore, neurophysiological changes distant to the lesion should be the target of therapeutic strategies, and specific clinical characteristics of diaschisis should be well understood and promptly recognized by clinicians.
The purpose was to conduct a prospective hospital-based cohort study in acute stroke patients in order to analyze clinical features of all forms of distant diaschisis in modern treatment.

Materials and methods
The materials and methods of this study have been reported in detail previously [32,33]. We have conducted a prospective, hospital-based, cohort study of patients with newly diagnosed acute ischemic stroke (n = 124) who were admitted to the department of cerebrovascular diseases of the University hospital (Oleksandrivska Clinical Hospital, Kyiv, Ukraine) within the first 24 hours after the stroke occurred. All cases were reviewed by at least two board-certified neurologists trained in cerebrovascular diseases.
All participants underwent standardized examination to obtain: clinical history, 12-lead electrocardiogram, blood testing (blood chemistry, thyroid, renal, and hepatic function, complete blood count, serum glucose, coagulation studies), carotid Doppler ultrasound (carotid duplex (Multigon 500M, USA) or carotid triplex (Aloka SSD-4000, Japan)), computed tomography of the head (Toshiba Activion 16 Multislice CT system, Nasu, Japan) and 1.5T brain magnetic resonance imaging (MRI), magnetic resonance angiography (Vantage MRI System, Japan) within 24-72 hours after the onset of symptoms and in dynamics during the period of maximum severity of symptoms. A chest radiograph was done if pulmonary disease or heart failure was suspected.
Stroke was defined according to criteria of the World Health Organization, American Heart Association/American Stroke Association guidelines for adult stroke and was confirmed by neuroimaging [34,35]. The etiology of stroke was classified according to the TOAST (trial of ORG 10172 in acute stroke treatment) criteria [36]. The National Institutes of Health Stroke Scale, modified Rankin scale, Barthel index were used in all participants based on the data available upon admission and in their respective medical records. Secondary stroke prevention was prescribed according to the American Heart Association/American Stroke Association and the European Stroke Organisation guidelines, immediately after the stroke diagnosis was made [36][37][38][39][40][41][42][43][44].
Parametric and non-parametric univariate analyses were performed with χ 2 , Fisher's exact, Mann-Whitney U, and Student t tests, as appropriate. The log-rank test was used for univariate comparisons of event-free survival between groups. A two-sided p < 0.05 was considered significant for all analyses. All statistical analyses were performed using IBM SPSS Statistics Version 22 (IBM, Armonk, NY).

Results and discussion
In total, 124 patients aged 28 to 84 years with acute ischemic stroke were screened. The localization of primary stroke lesion confirmed by neuroimaging was as follows: cerebral hemispheres (n = 68), brainstem (n = 11), cerebellum (n = 45).
Among the 124 patients, 42 persons (22 men and 20 women) were diagnosed with remote diaschisis. These 42 patients had a mean age of 60.8 ± 12.5 years (from 32 to 84 years). The localization of primary brain lesion in the study group was as follows: brain hemisphere (n = 31), pons Varolii (n = 5), cerebellar hemisphere (n = 6).
Based on the localization of primary brain lesion and considering secondary dysfunction of brain neighboring structures, we have analyzed and described clinical manifestations and characteristics of the following forms of remote diaschisis: cerebrospinal (n = 22), commissural (n = 4), crossed cerebellar (n = 5), crossed cerebellar-hemispheric (n = 6), and ponto-cerebellar diaschisis (n = 5). Clinical features of cerebrospinal and commissural diaschisis were analyzed in detail in our previous publications [33]. This article deals with the analysis of clinical manifestation and course of crossed cerebellar diaschisis.
Crossed cerebellar diaschisis was detected in 5 patients. It arose with an acute hemispheric territorial infarction. The localization of the primary stroke lesion was as follows: cortex of frontoparietal lobe (n = 4), inner capsule and basal ganglia (n = 1). The clinical manifestation of stroke was determined not only by the localization of primary stroke lesion and its size, but also by the MRIproved ischemic focus (diaschisis) in the contralateral cerebellar hemisphere.
Synchronous or sequential diaschisis (acute ischemic injury of structures that are anatomically and functionally connected, but remote to the primary brain lesion) caused more severe neurological deficit compared to that expected from the primary brain lesion. Clinically, patients were diagnosed with hemiparesis and hemihypesthesia on the side opposite to the primary brain lesion. Diaschisis was manifested clinically with the symptoms of hemiataxia in these patients. For illustration, we present a clinical case of patient E., who has developed regional ischemic stroke with hemorrhagic transformation (Fig. 1).
Neurological deficit in crossed cerebellar diaschisis composed a syndrome of motor and ataxic hemiparesis -hemiparesis-hemiataxia. The main mechanism of its occurrence is damage at the level of the first corticopontine neuron of www.mif-ua.com, http://inj.zaslavsky.com.ua

Figure 2. Scheme of afferent connections of the cerebellum and the mechanism of crossed cerebellar diaschisis development in patients with hemispheric stroke and lesion located in the frontal or parietal lobe
the cortico-cerebellar path, which causes the dissociation of its parts and dissolution. This results in deactivation of the afferent impulses from the brain lesion in the cerebral hemisphere to the cross-pontine-cerebellar path in the pons. Because of this deactivation, the function of the pathway returns to the phylogenetically lower level (Fig. 2). Damage of the corticopontine neuron (i.e., ischemic damage (diaschisis)) at the level of different parts of the cerebral cortex (mainly, in frontal or parietal lobe of brain hemisphere) led to the deactivation of afferent impulses to the cross-pontine-cerebellar pathway in the pons. This deactivation causes a decrease in blood flow and metabolic depression in cerebellar hemisphere opposite to the stroke brain lesion (i.e., opposite to the brain hemisphere with the primary damage). Contralateral hypoperfusion in the cerebellum was detected in 58 % of patients with hemispheric stroke [26].

Conclusions
Isolated cerebellar infarctions often cause crossed cerebellar-hemispheric diaschisis in the contralateral cortex of the frontal or frontoparietal lobe of the brain accompanied by structural and morphological findings on MRI in 87.5 % of observations. Neurologists should know that cerebellar stroke can manifest not only in typical symptoms of cerebellar dysfunction (dizziness, disorders of static and coordination, dysmetria, intentional tremor, nystagmus, dysarthria), but also in the remote symptoms such as paresis of limbs, impaired sensitivity and mental functions caused by a crosshemispheric diaschisis.
Conflicts of interests. Authors declare no conflicts of interests that might be construed to influence the results or interpretation of their manuscript.