Oldrich J. Kolar

Multiple sclerosis: magnetic resonance imaging, evoked responses, and spinal fluid electrophoresis.

Magnetic resonance images (MRI), evoked responses (ER), and CSF findings were compared in 39 patients with possible, probable, or definite MS. MRI disclosed multiple lesions (72%) more often than ERs (55%) in the total group of patients. In possible MS, MRI showed multiple lesions in 71%, and ER abnormalities were found in 41%. MRI is the preferred test for patients with suspected MS, but ERs are useful when MRI is normal and in the evaluation of optic nerve or spinal cord lesions.

Reflections on the etiology and pathogenesis of subacute sclerosing pan encephalitis

THE ELECTRON MICROSCOPIC demonstration of pseudomyxovirus in the brain tissue of a patient with subacute sclerosing panencephalitis (SSPE) and the subsequent observation of rising measles antibody titers during the course of the disease2 seem to have firmly established the etiology of this puzzling malady of the central nervous system. Before the implications of these findings are discussed in more detail, I will dwell briefly on some historical developments which have led to the delineation of SSPE and draw a sketch of its clinical manifestations. An excursion into the historical development of the concept of SSPE provides an arresting glimpse into what may be called the autistic thinking of pathologists, for the disease was described under at least five and possibly six different headings, each of which implied a separate nosological entity. I t was suggested by Lumsdem that Schilder was one of the first to put a pertinent case on record in 1924.3 Preoccupied as he was with his efforts to delineate a diffuse primary demyelinating disease from the heterogeneous group of diffuse sclerosis, Schilder identified his case as ‘‘encephalitis periaxialis diffusa,” unaware of the fact that his two previous observations493 represented two entirely different nosological entities. Bodechtel and GuttmannG reported a case under the title “Diffuse encephalitis with sclerosing inflammation of the hemisphere white matter,” certainly the most inclusive but also the clumsiest terms yet devised. Dawson7VR described two more cases, termed “epidemic” and “lethargic encephalitis,” but subsequently called “inclusion body encephalitis.” Whereas his neuro-pathologic predecessors had based their histopathologic examination on celloidin embedded hemisphere sections, Dawson, a general pathologist, relied on small H&E stained paraffin sections. Using these to the best advantage by high-powered light microscopy, he discovered the intranuclear inclusion bodies but did not mention the typical demyelination and gliosis of the white matter. Pette and DGring studied five cases of encephalitis. They were impressed by the generalized involvement of the brain tissue with inflammatory lesions and introduced the term “panencephalitis”; however, only their cases 3 and 5 seem to have been instances of SSPE. Van BogaertloJl stressed the discrepancy between the enormous astrocytic proliferation and the lesser degree of demyelination in the white matter by the designation ‘hbacute sclerosing leukoencephalitis.” Though this term neglects the usually marked and often pathognomonic lesions in the gray matter, it enjoys worldwide usage. From 1948 on, various investigators adduced piecemeal evidence that all the conditions mentioned above represented actually one entityl2-I4 and re-examination of van Bogaert’s 21 cases revealed intranuclear inclusion bodies in five.15 Thus, it appears that Dawson’s inclusion body encephalitis, van Bogaert’s subacute sclerosing leukoencephalitis, and the panencephalitis of Pette and Doring, those terms being most frequently fnund in present texts as representing different entities,

The diagnosis and classification of multiple sclerosis Evoked responses and spinal fluid electrophoresis

Mu1timodality evoked responses (including visual, brainstem auditory, and somatosensory) and CSF analysis were evaluated in 123 patients grouped into definite, probable, and possible MS according to the McAlpine criteria. The evoked responses (ERs) were very sensitive in detecting asymptomatic lesions and can therefore be used in conjunction with clinical data to provide evidence of multiple lesions. The CSF abnormalities also have high sensitivity and specificity in MS. ER and CSF findings, therefore, should be considered in addition to the clinical data in any classification of MS.

Differences in the Occurrence of Carotid Transient Ischemic Attacks Associated With Antiplatelet Aggregation Therapy

Twenty-six of 117 consecutive patients with a provisional diagnosis of transient ischemic attacks answered the following criteria: (1) transient hypofunction of an area supplied by a branch of an internal carotid artery, (2) no evidence of infarction, (3) carotid and vertebral arterial systems visualized angiographically, (4) cerebral blood flow and metabolism studies performed, (5) followed a minimum of three months, (6) other causes of transient dysfunction had been ruled out, and (7) no carotid arterial system surgery. Only six (23%) had occlusion greater than 50% and 21 (81%) had evidence of irregularity or ulceration of an atherosclerotic plaque in the appropriate internal carotid artery. It was noted in retrospect that 15 of the patients were treated with aspirin (300 mg b.i.d.) and 11 were not. No difference in ultimate infarction or death was noted, but only two (13%) of those treated with aspirin had an additional attack compared to nine (82%) of those who had no aspirin. These findings suggest that fibrin-platelet emboli may be a major contributor to transient ischemic attacks in the carotid circulation. The authors stress that this is a retrospective study and its importance is to further support the need for prospective studies before antiplatelet aggregating drugs are used indiscriminately.

Immunopathologic observations in subacute sclerosing panencephalitis

In view of the limited time, we present our observations in tabular form. For didactic purposes we have broken down our observations into several categories which are, to some extent, arbitrarily chosen. The abnormalities listed should be understood to have been present only during certain phases of the disease. It should be mentioned also that not all tests were done on all patients. We have therefore included observations on a few of the patients only if they appear to be of significance or if they elaborate on an important aspect of the pathogenesis. Table 1 represents epidemiological studies in our cases of SSPE. The most frequent infectious disease in the histories of our cases was measles. However, it remains to be determined, how often clinically manifest measles appeared in the normal population. No epidemiologic relationship between any of the 79 observed cases of SSPE could be established. Table 2 summarizes the immunopathologic data in our SSPE patients. Methodical details can be found in the references. The hypersensitivity reaction produced in guinea pigs with standardized water soluble extract from SSPE brain tissue1 (Table 2A-11-2 and Table 2B-11-4) was studied as follows: One tenth ml. of a standardized brain tissue antigen was injected intradermally into the skin of a guinea pig shaved 24 hours previously. At the same time heparinized blood (.2 ml.) or a spinal fluid (1.5 to 2 ml.) was injected intraperitoneally into the same animal. In 24 to 48 hours an induration greater than 5 mm. in diameter, at the site of intradermally a p plied standardized brain extract, accompanied with erythema, was considered as positive reaction. From the immunological point of view the mechanisms of this reaction are not well known. It should be pointed out that application of spinal fluid containing lower cell and total protein amount than blood, showed a higher number of positive results under the same experimental conditions. The standardized brain tissue antigen used also for complement fixation reaction is not absolutely specific for SSPE and reacts also with the spinal fluid in other subacute inflammatory and/or demyelinating central nervous system diseases. Table 2B presents observations related to immunopathologic events in the central nervous system. As mentioned before the tables do not reflect the fluctuations of clinical, immunological and biochemical symptomatology in SSPE patients during the course of the disease. The extent of this quantitative and qualitative manifestation is variable in different cases of SSPE. Relative stabilization of the pathologic process can last from a few months to years. In some patients with SSPE a chronic progressive course of the disease can be ob-

Serum and cerebrospinal fluid immunoglobulins in multiple sclerosis

SUMMARYThirty-seven aspects related to the pathophysiology of serum and CSF immunoglobulins, including electrophoresis, immunoelectron-phoresis, CSF cytomorphology, and determination of the concentration of serum and CSF immunoglobulins, were studied in 64 patients with multiple sclerosis. The studies support the assumption that in addition to the immunopathological manifestations carried by immunocompetent cells in the CNS structures of patients with multiple sclerosis, the extraneural lymphoreticular system exhibits an abnormal activity, at least during certain phases of the disease. From our experiences in electrophoretic, immunochemical, and cytomorphological examinations of over 900 patients with different neurological diseases, no specific manifestations were observed which might allow, per se, the diagnosis of MS.

Magnetic resonance imaging in multiple sclerosis Analysis of correlations to peripheral blood and spinal fluid abnormalities

MRI of the brain, peripheral blood (PB) T cell subsets and B cells, CSF T cell subsets, CSF IgG concentration and incidence of CSF oligoclonal bands (OB), and plasma cells were studied in 32 clinically suspected MS patients. The CSF in MS patients with MRI lesions showed increased IgG concentration and higher incidence of plasma cells and OB compared with those without MRI lesions. In PB, the percentage of kappa light-chain positive B cells was significantly increased in patients with abnormal MRI as compared with controls. The correlation of MRI of the head and immunologic studies in MS will be helpful in better understanding the pathogenesis and dynamics of the disease.

Cerebrospinal fluid and serum light polypeptide chains in 160 patients with various nervous system disorders.

SummaryIn 160 patients with various neurological diseases, the cerebrospinal fluid and serum kappa/lambda light polypeptide chains ratios were determined. In addition, immunoelectrophoretic studies of the CSF and serum kappa and lambda polypeptide chains were performed. Quantitative changes in the cerebrospinal fluid light polypeptide chains and/or immunoelectrophoretic abnormalities in their precipitation arcs were predominantly found in patients with multiple sclerosis, in other subacute and chronic inflammatory and/or demyelinating central nervous system diseases and in lymphoproliferative disorders with neurological symptomatology.ZusammenfassungIn einem Beobachtungsgut von 160 Patienten mit verschiedenen neurologischen Erkrankungen wurde das Verhältnis der Kappa/Lambdaleichten Polypeptidketten in der Cerebrospinalflüssigkeit und im Serum bestimmt. Daneben wurden die leichten Polypeptidketten im Liquor immunoelektrophoretisch untersucht. In der Cerebrospinalflüssigkeit wurden vorwiegend die quantitativen Änderungen der leichten Polypeptidketten und/oder deren immunoelektrophoretischen Präcipitate bei Patienten mit multipler Sklerose, anderen subakuten oder chronischen entzündlichen oder demyelinisierenden Erkrankungen des Zentralnervensystems und bei lymphoproliferativen Prozessen mit neurologischer Symptomatologie erfaßt.

Serum IgG, IgA and IgM concentration in 1,038 patients with various neurological disorders

SummaryConcentration of serum IgG, IgA and IgM in 1,038 unselected patients with various neurological diseases was determined. In 521 instances, the levels of CSF IgG, IgA and IgM were also established. In serum, the most frequent selective quantitative abnormality was found in the IgA concentration. In CSF, an increased level of IgG with normal IgA concentration and undetectable IgM was established about 8 times more frequently than isolated increase of CSF IgA. Selective quantitative abnormalities in serum IgG were observed in 35% of patients with subacute sclerosing panencephalitis as compared to 5% in instances in the “definite” MS group. Abnormal bands in the serum gamma-globulin field were most frequently seen in electropherograms from patients with subacute sclerosing panencephalitis, in cases of malignant lymphoproliferative disorders and in patients with “definite” MS. No correlation between the concentration of serum and CSF immunoglobulins could be established. Most frequent quantitative abnormalities in serum IgG, IgA and/or IgM were established in malignant lymphoproliferative disorders, in patients with myopathies including myositides and in subacute or chronic inflammatory CNS disorders. Highest incidence of increased CSF IgG, IgA and/or IgM concentration was detected in patients with inflammatory CNS disease, in instances of “definite” MS and in malignant lymphoproliferative disorders with CNS symptomatology. Increased CSF IgG and IgA concentration with detectable levels of IgM in patients with elevated CSF total proteins indicated alterations in the blood/CNS barrier structures.ZusammenfassungBei 1038 unausgewählten Patienten mit verschiedenen neurologischen Erkrankungen wurde die Konzentration von IgG, IgA and IgM im Serum bestimmt. In 521 Fällen wurde gleichzeitig der IgG-, IgA- und IgM-Spiegel im Liquor cerebrospinalis gemessen. Die häufigste selektive quantitative Abweichung im Serum fand sich in der IgA-Konzentration. Erhöhte IgG-Werte im Liquor verbunden mit normaler IgA-Konzentration und fehlendem IgM waren etwa 8mal häufiger als bloßer Anstieg des Liquor-IgA. 35% der Kranken mit subakuter sklerosierender Panencephalitis zeigten selektive quantitative Veränderungen im Serum-IgG, während die Zahl bei Fällen von „definitiven“ Multiplen Sklerosen nur 5% betrug. Pathologische Banden im Bereich des Serum-gamma-Globulin traten am häufigsten bei der subakuten sklerosierenden Panencephalitis, bei bösartigen Erkrankungen des lymphoreticulären Systems und bei „definitiven“ Multiplen Sklerosen auf. Es bestand keine Korrelation zwischen der Konzentration der Serumund Liquor-Immunglobulinen.Die häufigsten quantitativen Abweichungen der Serum-IgG, -IgA und/oder -IgM wurden bei malignen lymphoreticulären Erkrankungen, bei Myopathien (einschließlich Myositiden) sowie bei subakuten oder chronischen Entzündungsprozessen des ZNS beobachtet. IgG, IgA und/oder IgM waren im Liquor bei Patienten mit entzündlichen Krankheiten des ZNS, bei Fällen von „definitiven„ Multiplen Sklerosen und bei den malignen lymphoreticulären Erkrankungen, die mit neurologischen Symptomen einhergingen, am häufigsten vermehrt. Erhöhte IgG- und IgA-Werte im Liquor sowie nachweisbares IgM bei Patienten mit Zunahme der Gesamt-Liquorproteine zeigten Änderungen der Bluthirnschranken-Strukturen an.

Thrombosis During the Healing Phase

Twenty dogs were treated with either acetylsalicylic acid or a lactose placebo for 5.5 ± 2.3 days before surgical or chemical injury to the carotid and femoral arteries and for the following 34.5 days. Only the laboratory diener had knowledge of the random table used to select type of treatment until after all determinations had been completed. Following sacrifice the arteries were classified for the presence of intimal proliferation, defects in the internal elastica, presence of organized thrombi and the percentage of recanalization, and the presence of fresh thrombi and the percentage of occlusion. Thrombi were present in 8% of the arteries of dogs treated with acetylsalicylic acid and in 36% of those treated with placebo. This difference is significant (P<0.01). The degree of intimal proliferation and defects in the internal elastica were not significantly different between the two groups. We conclude that in dogs acetylsalicylic acid therapy during the healing phase following arterial injury protects against thrombosis and does not retard the healing process.