Biomedical subjects
M Kremenchutzky
Publications and source records attributed to M Kremenchutzky.
The natural history of multiple sclerosis: a geographically based study: 8: familial multiple sclerosis.
We have examined the demographics and long-term outcome of 1044 patients with sporadic and familial multiple sclerosis in a population-based cohort from London, Ontario. The mean follow-up was 25 years in duration, and by this time most patients had reached the unambiguous endpoint scores of the Kurtzke disability status scale (DSS), DSS 6, 8 or 10. An affected family member was identified in 19.8% of the total population, and this subgroup was further divided arbitrarily into the following three groups by the type and number of relatives affected: (i) first degree only; (ii) first degree plus others; (iii) second or third degree. The outcome in these groups was compared with that for those patients who, at a mean 25 year follow-up, had no relatives known to be affected. Familial cases closely resembled those remaining sporadic in both demographics and outcome, although onset in the most heavily loaded families was earlier and male/female ratio was greater. The times to DSS 6, 8 and 10 did not differ significantly when sporadic, familial and familial subgroups were compared. These results provide no clinical support for viewing familial multiple sclerosis as distinct from the sporadic form. The observed recurrence rate for siblings in a strictly defined epidemiological sample was 3.5%, much as projected. These results validate the recurrence risks which have previously been derived from age-corrected data for these first-degree relatives.
Diagnostic brain MRI findings in primary progressive multiple sclerosis.
The clinical course of multiple sclerosis can be classified as relapsing from onset (relapsing-remitting), or progressive from onset (primary progressive - PPMS). These clinical phenotypes have been based on historical and clinical observations. It has been reported that PPMS patients tend to have quantitatively less MRI activity and disease burden. We evaluated the sensitivity and diagnostic value of conventional brain MRI scan in 143 PPMS patients. Brain MRIs were blindly evaluated to determine if they satisfied Paty and/or Fazekas diagnostic criteria. Patients were divided into those with typical, atypical or normal scans. They satisfied brain MRI criteria in 92% cases. Findings included: 131 typical, four atypical, and eight normal scans. All 12 non-typical scans' subjects had spinal onset; spinal MRI scans were positive in four of seven cases. Sex, age of onset, site and number of symptoms involved at onset among those groups were not significantly different but accumulation of disability had a tendency to be slower in these few individuals with normal or atypical head MRI's. Although there may be quantitative differences in lesion activity/burden, MRI scanning in PPMS unexpectedly has diagnostic sensitivity very similar to that seen in RRMS. A normal brain MRI is unusual in PPMS patients.
The natural history of multiple sclerosis: a geographically based study. 7. Progressive-relapsing and relapsing-progressive multiple sclerosis: a re-evaluation.
Classifications of multiple sclerosis subtypes have been largely based on clinical phenomenology. Nevertheless, definitions of relapse, remission and progression have been imprecise. Recently an international consensus group, as part of a reclassification of disease subtypes, recommended dropping the term 'relapsing-progressive' (RP) and retaining the term 'progressive-relapsing' (PR) multiple sclerosis. The term 'RP' multiple sclerosis had been applied when the early course combined both relapses and progression and was believed to identify some patients with a worse than average outcome. The PR group consisted of patients with primary progressive disease who later in their course developed relapses. Since the terminology has been largely arbitrary, we have evaluated the validity of the terms 'RP' and 'PR' multiple sclerosis in the context of long-term outcome within a large population-based cohort of progressive multiple sclerosis patients seen at the London Multiple Sclerosis Clinic (Canada) between 1972 and 1984. Mean follow-up of the entire cohort was 25 years. Designation of RP multiple sclerosis did identify a more rapidly progressive subgroup. To realign these natural history data with consensus recommendations, these patients were reassigned to secondary progressive (SP) or to primary progressive (PP) multiple sclerosis, with progression defined as at least 1 year of progressive deterioration. PP multiple sclerosis patients with relapses after a year were designated as having PR multiple sclerosis. Relapses in primary progressive multiple sclerosis occurred in 27.8% of patients at some point even two to three decades after onset. In general these relapses were mild and remitting, but served to blur the distinction between progressive and relapsing-remitting disease. The long-term outcomes of time to Kurtzke disability scores (DSS) of 3, 6, 8 and 10 were compared among the progressive subtypes. Times to these disability end-points and to death were not different between PR and PP multiple sclerosis. Survival curves for progressive patients have been amended to incorporate the reassignment of PR multiple sclerosis patients into the PP group and the RP multiple sclerosis patients into the PP and SP subgroups. The time to reach DDS 3, 6, 8 and 10 for a population-based cohort of primary and secondary progressive patients resulting from the elimination of the categories of RP multiple sclerosis and PR multiple sclerosis has been established. These results provide justification for retaining only PP and SP multiple sclerosis as the subgroups of progressive disease.
The natural history of multiple sclerosis: a geographically based study. 5. The clinical features and natural history of primary progressive multiple sclerosis.
We report a natural history study of 216 patients with primary progressive (PP)- multiple sclerosis defined by at least 1 year of exacerbation-free progression at onset. This represents 19.8% of a largely population-based patient cohort having a mean longitudinal follow-up of 23 years. This subgroup of PP-multiple sclerosis patients had a mean age of onset of 38.5 years, with females predominating by a ratio of 1.3:1.0. The rate of deterioration from disease onset was substantially more rapid than for relapsing-remitting multiple sclerosis, with a median time to disability status score (DSS) 6 and DSS 8 of 8 and 18 years, respectively. Forty-nine percent of patients were followed through to death. Examination of the early disease course revealed two groups with adverse prognostic profiles. Firstly, a shorter time to reach DSS 3 from onset of PP-multiple sclerosis significantly adversely influenced time to DSS 8. Second, involvement of three or more neurological systems at onset resulted in a median time to DSS 10 of 13.5 years in contrast to PP-multiple sclerosis patients with one system involved at onset where median time to death from multiple sclerosis was 33.2 years. However, age, gender and type of neurological system involved at onset appeared to have little influence on prognosis. Life expectancy, cause of mortality and familial history profile were similar in PP-multiple sclerosis and non-PP-multiple sclerosis (all other multiple sclerosis patients from the total population). From clinical onset, rate of progression was faster in the PP-multiple sclerosis group than in the secondary progressive (SP)-multiple sclerosis group. When the rates of progression from onset of the progressive phase to DSS 6, 8 and 10 were compared, SP-multiple sclerosis had a more rapid progressive phase. A substantial minority (28%) of the PP-multiple sclerosis cohort had a distinct relapse even decades after onset of progressive deterioration. These studies establish natural history outcomes for the subgroup of multiple sclerosis patients with primary progressive disease.
The natural history of multiple sclerosis: a geographically based study. 6. Applications to planning and interpretation of clinical therapeutic trials in primary progressive multiple sclerosis.
The natural history of primary progressive multiple sclerosis (PP-multiple sclerosis) recently has been defined in a geographically based multiple sclerosis population. For a series of prognostically defined hypothetical entry criteria based upon current trends in presentation to the London Multiple Sclerosis Clinic, we determined the number of patients who would have been trial eligible. Using 23 year mean longitudinal natural history data, we identified the observed rate of deterioration for frequently used trial endpoints. Hypothetical entry criteria were based on the practical considerations which would attend the execution of clinical trials in progressive multiple sclerosis. We then developed a series of sample size tables giving the number of patients with PP-multiple sclerosis and the length of observation that would be required to detect a significant result (P = 0.05) for a 25, 50 and 75% decrease in the median time to progression with 80 or 90% power, with treatment efficacy based upon the ability to slow progression on the disability status score. It is expected that the considerations outlined here will prove useful for both trial design and interpretation of trials in PP-multiple sclerosis which will require multi-centre collaborative efforts.
Further studies on HTLV-I associated myelopathy in Argentina.
We report 10 HTLV-I virus seropositive subjects, eight of them with HTLV-I associated myelopathy (HAM), two of them also infected with HIV as well as two asymptomatic HTLV-I+ relatives of two unrelated patients. HTLV-I is endemic in several tropical areas, where it causes different neurological diseases. Only few patients have been reported in our country since 1994. We studied 8 patients, who fulfilled the clinical criteria for chronic spastic paraplegia, and 2 other non-symptomatic HTLV-I seropositive relatives, with electromyography (EMG), motor and sensory conduction velocities (NCV), somatosensory, visual and brainstem auditory evoked potentials (SSEP, VEP and BAEP), Magnetic Resonance Images (MRI) and cerobrospinal fluid (CSF) analysis. The latter was carried out only in seven symptomatic patients. In every case positive ELISA tests for HTLV-I/II were confirmed by Western Blot. The two asymptomatic persons were clinically and electromyographically assessed, one of them was also submitted to SSEPs studies. Three patients were males. Patient's ages ranged from 5 to 65 years old. All symptomatic patients showed muscular weakness, spasticity with pyramidal signs and sphincter disturbances. Five of them had paresthesias and 2 had burning pain on their feet. The EMGs and the NCVs were normal in 7 patients and in the 2 asymptomatic ones. SSEPs, obtained by stimulating the posterior tibial nerves, were impaired in 7 patients and in the asymptomatic person who received the procedure. The 7 symptomatic patients who underwent lumbar puncture had positive tests for HTLV-I in CSF, 3 out of these 7 patients had also high protein levels and 4 had increased number of lymphocytes. In 2 patients intrathecal IgG production could also be demonstrated. MRI were normal in 7 patients and in the 2 asymptomatics, the exception being a female who had bilateral hyperintense lesions in cerebral white matter in T2. In conclusion, tropical spastic paraparesis is apparently a rare disorder in Argentina. However, some cases have been reported recently. Most probably, its prevalence is currently underestimated. Its diagnosis should be considered in every patient with progressive spastic paraplegia.
[Hemichorea associated with cerebral toxoplasmosis and AIDS].
Only 12 AIDS cases with hemichorea were reported in the literature. We report the first case of hemichorea associated with AIDS and cerebral toxoplasmosis in our country. A 26-year-old man had 3 episodes of focal seizures on the left side with subsequent loss of consciousness. A few weeks later, he noticed progressive left-sided weakness. Examination revealed a left hemiparesis. MRI of the head showed a round mass in the right frontal lobe and a smaller lesion in the left temporo-occipital area. Laboratory showed positive serum ELISA and Western Blot analysis for HIV antibodies. Serum tests for Toxoplasma showed elevated titers. He was treated with pyrimethamine and sulfadiazine. His weakness improved and he had no further seizures. Two weeks later, choreic movements appeared in the left foot, finally involving the entire left hemibody. A second MRI showed a new small lesion in the right cerebral peduncle. The patient completed 6 weeks of treatment, with further reduction in the size of the lesions. Nevertheless, the left hemichorea persisted. We believe that the hemichorea our patient had was caused by the contralateral peduncular lesion. Lesions involving the subthalamic nucleus or its connections may cause contralateral hemiballismus or hemichorea. In spite of the favorable response to antitoxoplasmic therapy, the hemichorea persisted. The present report illustrates an uncommon neurological complication in AIDS. We believe that a combination of a focal cerebral lesion and the HIV infection caused the movement disorder presented by the patient.
[The natural history of multiple sclerosis].
INTRODUCTION: Multiple sclerosis is one of the commonest idiopathic inflammatory diseases of the central nervous system in young adults. The study of the natural history of multiple sclerosis implies in the first place, establishing precise limits for the diagnosis of the disease, which is still of unknown origin. It is also necessary to analyze the wide range of varieties, which as different categories or subgroups and with different degrees of severity, make up the clinical spectrum of this entity. DEVELOPMENT AND CONCLUSIONS: Throughout this review benign and malignant multiple sclerosis, remitting and progressive forms, are studied from epidemiological and clinical points of view in the context of large populations of patients with multiple sclerosis on long-term follow up at a specialized centre, with the objective of finding, if possible, the patterns of the natural history of the disease.
[A statistical analysis of 1300 patients with dizziness-vertigo. Its most frequent causes].
PATIENTS AND METHODS: We analysed the records of the individuals who were attended because of dizziness or vertigo in the vestibular sector, with the aim of describing the epidemiological clinical profile of a group of patients with such symptoms. 1300 patients were systematically evaluated according to our neuro otological examination protocol. Diagnoses were ordered, according to the international classification reported by Drachman and later modified by Bahlo, in four categories: 1. Vertigo, 2. Instability, 3. Pre syncope and 4. Miscellaneous. Each of these classes was organised according to the topography of the lesion and these were in turn grouped by aetiologies (viral, vascular, tumoural, demyelinating, post traumatic, idiopathic, autoimmune, etc.). The data were stored and analysed in a computer database, Epi info 6.02 (OMS 1994), which was especially adapted by the researchers for the purpose. RESULTS: 63.1% were women. The average age was 55.5 years old (SD: 17.5, interval: 4 93). Vertigo was diagnosed in 68.9%, instability was found in 12.4%, 1.8% presented syncope and miscellaneous disorders occurred in 16.9% (of these, 64.1% had disorders of the central integrator and 16.4% were of a psychogenic origin). Of the 1300 patients, 896 presented vertigo; the positional type was seen in 54%, sustained in 6.5%, recurrent in 27.7% and 11.8% were found to have the otolithic type. CONCLUSIONS: The relevance of the epidemiological work based on clinical evaluation and the thorough neuro otological examination in our medium must be highlighted. These findings were similar to those reported in the international literature in more delimited series.
[Data base for patients with balance disorders].
INTRODUCTION: With the aim of integrating clinical thinking and obtaining epidemiological and biostatistical results in long series of patients who present balance disorders, we have developed a neuro otological protocol and its corresponding database. This offers answers to the questions of how to assess the patient, how to conduct a clinical interview correctly, and which complementary studies should be requested and how. RESULTS: The information from the protocol is stored and analysed in our database, which was designed in the Epi Info software application, produced by CDC (NIH, USA), in collaboration with the WHO Global Program on AIDS. The application, which we call ENO LK, has already been used to store data concerning 1,100 patients whose average age is 54.5 years old and 62.8% of which were females (SD 18, range 4 93). 69.1% were diagnosed as suffering from vertigo, 12.7% displayed instability, 1.9% syncope and 16.3% had other causes (37% psychogenic and 28% disorders affecting the central integrator). Of the 760 patients with vertigo, in 55% it was positional (60% of these were idiopathic benign), 6.3% were sustained (peripheral causes accounted for 74% and a vascular aetiology was predominant in the central causes), 26.6% were recurring and 12.1% otolithic (in this series the vertigos all had a central aetiology). CONCLUSIONS: With this application the user has the possibility of obtaining epidemiological and diagnostic conclusions efficiently and effectively, as well as aiding to follow up all patients who present balance disorders.