COVID-19-associated myoclonus in a series of five critically ill patients.

BACKGROUND: In addition to respiratory symptoms, many patients with coronavirus disease 2019 (COVID-19) present with neurological complications. Several case reports and small case series described myoclonus in five patients suffering from the disease. The purpose of this article is to report on five critically ill patients with COVID-19-associated myoclonus. MATERIAL AND METHODS: The clinical courses and test results of patients treated in the study center ICU and those of partner hospitals are described. Imaging, laboratory tests and electrophysiological test results are reviewed and discussed. RESULTS: In severe cases of COVID-19 myoclonus can manifest about 3 weeks after initial onset of symptoms. Sedation is sometimes effective for symptom control but impedes respiratory weaning. No viral particles or structural lesions explaining this phenomenon were found in this cohort. CONCLUSION: Myoclonus in patients with severe COVID-19 may be due to an inflammatory process, hypoxia or GABAergic impairment. Most patients received treatment with antiepileptic or anti-inflammatory agents and improved clinically.

The relation between inflammation and neurodegeneration in multiple sclerosis brains.

Some recent studies suggest that in progressive multiple sclerosis, neurodegeneration may occur independently from inflammation. The aim of our study was to analyse the interdependence of inflammation, neurodegeneration and disease progression in various multiple sclerosis stages in relation to lesional activity and clinical course, with a particular focus on progressive multiple sclerosis. The study is based on detailed quantification of different inflammatory cells in relation to axonal injury in 67 multiple sclerosis autopsies from different disease stages and 28 controls without neurological disease or brain lesions. We found that pronounced inflammation in the brain is not only present in acute and relapsing multiple sclerosis but also in the secondary and primary progressive disease. T- and B-cell infiltrates correlated with the activity of demyelinating lesions, while plasma cell infiltrates were most pronounced in patients with secondary progressive multiple sclerosis (SPMS) and primary progressive multiple sclerosis (PPMS) and even persisted, when T- and B-cell infiltrates declined to levels seen in age matched controls. A highly significant association between inflammation and axonal injury was seen in the global multiple sclerosis population as well as in progressive multiple sclerosis alone. In older patients (median 76 years) with long-disease duration (median 372 months), inflammatory infiltrates declined to levels similar to those found in age-matched controls and the extent of axonal injury, too, was comparable with that in age-matched controls. Ongoing neurodegeneration in these patients, which exceeded the extent found in normal controls, could be attributed to confounding pathologies such as Alzheimer's or vascular disease. Our study suggests a close association between inflammation and neurodegeneration in all lesions and disease stages of multiple sclerosis. It further indicates that the disease processes of multiple sclerosis may die out in aged patients with long-standing disease.

Widespread demyelination in the cerebellar cortex in multiple sclerosis.

Neocortical demyelination in the forebrain has recently been identified as an important pathological feature of multiple sclerosis (MS). Here we describe that the cerebellar cortex is a major predilection site for demyelination, in particular in patients with primary and secondary progressive MS. In these patients, on average, 38.7% of cerebellar cortical area is affected, reaching in extreme examples up to 92%. Cerebellar cortical demyelination occurs mainly in a band-like manner, affecting multiple folia. The lesions are characterized by primary demyelination with relative axonal and neuronal preservation, although some axonal spheroids and a moderate reduction of Purkinje cells are present. Although cortical demyelination sometimes occurs together with demyelination in the adjacent white matter (leukocortical lesions), in most instances, the cortex was affected independently from white matter lesions. We found no correlation between demyelination in the cortex and the white matter, and in some cases, extensive cortical demyelination was present in the near absence of white matter lesions. Our data identify cortical demyelination as a potential substrate of cerebellar dysfunction in MS.

Acute cerebral white matter damage in lethal salicylate intoxication.

A 34-year-old oligophrenic woman was admitted in comatose state with marked tachypnea. History revealed the oral ingestion of a large amount of acetylsalicylate to attenuate ear pain within the preceding 3 days. Laboratory investigations showed a toxic concentration of serum salicylate (668 mg/l, toxic range above 200 mg/l) and metabolic acidosis. Oxygenation, blood pressure, electrocardiography, echocardiography and CT of thorax and brain were normal. The patient was intubated, fluid and bicarbonate was given intravenously. Six hours after admission asystolia refractory to resuscitation led to death. Autopsy showed venous congestion of the brain, cardiac dilatation and pulmonary edema. Brain histopathology showed myelin disintegration and caspase-3 activation in glial cells, whereas, grey matter changes were sparse. Acute white matter damage is suggested to be the substrate of cerebral dysfunction in salicylate intoxication and possible mechanisms are discussed.

Remyelination is extensive in a subset of multiple sclerosis patients.

Although spontaneous remyelination does occur in multiple sclerosis lesions, its extent within the global population with this disease is presently unknown. We have systematically analysed the incidence and distribution of completely remyelinated lesions (so-called shadow plaques) or partially remyelinated lesions (shadow plaque areas) in 51 autopsies of patients with different clinical courses and disease durations. The extent of remyelination was variable between cases. In 20% of the patients, the extent of remyelination was extensive with 60-96% of the global lesion area remyelinated. Extensive remyelination was found not only in patients with relapsing multiple sclerosis, but also in a subset of patients with progressive disease. Older age at death and longer disease duration were associated with significantly more remyelinated lesions or lesion areas. No correlation was found between the extent of remyelination and either gender or age at disease onset. These results suggest that the variable and patient-dependent extent of remyelination must be considered in the design of future clinical trials aimed at promoting CNS repair.

Cortical demyelination and diffuse white matter injury in multiple sclerosis.

Focal demyelinated plaques in white matter, which are the hallmark of multiple sclerosis pathology, only partially explain the patient's clinical deficits. We thus analysed global brain pathology in multiple sclerosis, focusing on the normal-appearing white matter (NAWM) and the cortex. Autopsy tissue from 52 multiple sclerosis patients (acute, relapsing-remitting, primary and secondary progressive multiple sclerosis) and from 30 controls was analysed using quantitative morphological techniques. New and active focal inflammatory demyelinating lesions in the white matter were mainly present in patients with acute and relapsing multiple sclerosis, while diffuse injury of the NAWM and cortical demyelination were characteristic hallmarks of primary and secondary progressive multiple sclerosis. Cortical demyelination and injury of the NAWM, reflected by diffuse axonal injury with profound microglia activation, occurred on the background of a global inflammatory response in the whole brain and meninges. There was only a marginal correlation between focal lesion load in the white matter and diffuse white matter injury, or cortical pathology, respectively. Our data suggest that multiple sclerosis starts as a focal inflammatory disease of the CNS, which gives rise to circumscribed demyelinated plaques in the white matter. With chronicity, diffuse inflammation accumulates throughout the whole brain, and is associated with slowly progressive axonal injury in the NAWM and cortical demyelination.

Low cerebrovascular reserve capacity in long-term follow-up after subarachnoid hemorrhage.

BACKGROUND: Intradural arteries formerly in vasospasm after subarachnoid hemorrhage (SAH) show structural changes that result in arterial wall thickening and luminal narrowing. To evaluate if these changes lead to maldistribution of cerebral perfusion and reduced cerebrovascular reserve capacity (CVRC) in surviving patients, a long-term follow-up study of 18 adult patients after SAH was performed. METHODS: Eighteen patients were selected for the study, all had shown vasospasm after an early operation on a ruptured aneurysm, were in good neurological condition (GOS [Glasgow Outcome Score] 4 or 5 ), and had no residual infarcts. A technetium-99m-hexamethyl-propylenamine oxime (HMPAO) single-photon emission computed tomography was performed 15 to 73 months after SAH. To study CVRC, a second investigation after application of acetazolamide was performed 1 week later. RESULTS: Single-photon emission computed tomography showed areas of focally reduced HMPAO uptake predominantly in the hemisphere ipsilateral to the vessels more affected by posthemorrhagic vasospasm. The thalamus and the basal ganglia, the frontal lobe, and the temporal lobe were the regions most frequently showing reduced uptake. The individual change of HMPAO uptake after acetazolamide application ranged from -7% to 44% (mean, 17% +/- 15%). CONCLUSIONS: These results show a remarkable reduction of CVRC compared with findings in healthy individuals. Based on these new findings, further investigations focusing on CVRC in routine SAH follow-up are worth being considered.

Preferential loss of myelin-associated glycoprotein reflects hypoxia-like white matter damage in stroke and inflammatory brain diseases.

Destruction of myelin and oligodendrocytes leading to the formation of large demyelinated plaques is the hallmark of multiple sclerosis (MS) pathology. In a subset of MS patients termed pattern III, actively demyelinating lesions show preferential loss of myelin-associated glycoprotein (MAG) and apoptotic-like oligodendrocyte destruction, whereas other myelin proteins remain well preserved. MAG is located in the most distal periaxonal oligodendrocyte processes and primary "dying back" oligodendrogliopathy may be the initial step of myelin degeneration in pattern III lesions. In the present study, various human white matter pathologies, including acute and chronic white matter stroke, virus encephalitis, metabolic encephalopathy, and MS were studied. In addition to a subset of MS cases, a similar pattern of demyelination was found in some cases of virus encephalitis as well as in all lesions of acute white matter stroke. Brain white matter lesions presenting with MAG loss and apoptotic-like oligodendrocyte destruction, irrespective of their primary disease cause, revealed a prominent nuclear expression of hypoxia inducible factor-1alpha in various cell types, including oligodendrocytes. Our data suggest that a hypoxia-like tissue injury may play a pathogenetic role in a subset of inflammatory demyelinating brain lesions.

Subacute brainstem angioencephalopathy: a case report and review of the literature.

A previously healthy 69-year-old man developed a progressive neurological illness with bulbar signs and ataxic paraparesis. Repeated MRI examinations revealed a large space occupying lesion in the lower brain stem with patchy contrast enhancement. MRI angiography was unremarkable and CSF had normal cell count but raised protein content. A brainstem tumor was suspected and a course of intravenous glucocorticosteroids was started. No improvement occurred and the patient died of pneumonia 11 weeks after onset. Neuropathology revealed confluent areas of complete or incomplete necrosis with marked edema in the lower brainstem. Predominantly venous meningeal vessels of the brainstem showed extensive fibromuscular thickening of all layers with luminal narrowing. In addition, intramural mononuclear infiltration was found. With the exception of localisation, this case exhibits all pathologic features of subacute diencephalic angioencephalopathy (SDAE), a rare fatal disease of unknown aetiology. In addition, the clinical features of typical age, male sex, disease duration and raised CSF proteins are shared. A common disease entity is suggested and the pathogenetic relevance of inflammation and venous outflow obstruction is discussed.

A new paraclinical CSF marker for hypoxia-like tissue damage in multiple sclerosis lesions.

Recent studies on the immunopathology of multiple sclerosis revealed a heterogeneity in the patterns of demyelination, suggesting interindividual differences in the mechanism responsible for myelin destruction. One of these patterns of demyelination, characterized by oligodendrocyte dystrophy and apoptosis, closely mimics myelin destruction in acute white matter ischaemia. In the course of a systematic screening for virus antigen expression in multiple sclerosis brains, we identified a monoclonal antibody against canine distemper virus, which detects a cross-reactive endogenous brain epitope, highly expressed in this specific subtype of actively demyelinating multiple sclerosis lesions with little or no immunoreactivity in other active multiple sclerosis cases. The respective epitope, which is a phosphorylation-dependent sequence of one or more proteins of 50, 70 and 115 kDa, is also expressed in a subset of active lesions of different virus-induced inflammatory brain diseases, but is present most prominently and consistently in acute lesions of white matter ischaemia. Its presence is significantly associated with nuclear expression of hypoxia-inducible factor-1 alpha within the lesions of both inflammatory and ischaemic brain diseases. The respective epitope is liberated into the CSF and, thus, may become a useful diagnostic tool to identify clinically a defined multiple sclerosis subtype.