Challenges in multiple sclerosis; how to define occurence of progression.

The challenges in MS are related to number of controversies in various aspects of disease but the relationship between relapses and disability progression, or aspects of MS as an inflammatory and/or neurodegenerative disease are extremely important because of its implications on prognosis and therapy of MS. MS was classically regarded as white matter inflammatory disease, while disability progression, brain and spinal cord atrophy were regarded as a consequence of global inflammation of NAWM and secondary involvement of grey matter. More recent histopathology studies, but also new, modern MRI techniques changed this view in MS as a prominent grey and white matter disease. Inflammatory demyelination of grey matter occurs early in MS sometimes even before occurrence of white matter lesions. Inspite of early therapy of MS with immunomodulatory drugs disability progression and neurodegeneration are still important and common part of MS pathogenesis. This indicate that treatment is not adequate to the predicted severity of MS, or perhaps to the basic pathogenetic mechanisms in MS. Beside acute clinical symptoms, conclusions about the severity of the disease are reflection of MRI sensitivity to detect focal WM lesions and insensitivity to detect grey matter lesions which correlate better with clinical symptoms. All presented studies and evaluations point to the necessity of changing the established diagnostic evaluation and treatment in MS. At the earliest stage of MS as well as in follow up of disease it would be necessary to apply a new MRI techniques more available for clinical practice such as DIR brain MR imaging at 3T because of their sensitivity to detect grey matter lesions. In patient with present cortical lesions even in earliest stages of MS depending on severity of grey matter involvement more efficacious therapy like second or even third line therapy should start.

Alemtuzumab more effective than interferon ß-1a at 5-year follow-up of CAMMS223 clinical trial.

OBJECTIVE: To report the long-term safety and efficacy results from CAMMS223 comparing alemtuzumab with interferon ß-1a in early, active relapsing-remitting multiple sclerosis (RRMS). What are the long-term effects of alemtuzumab treatment, received 36 to 48 months previously, on relapse and disability in early, active RRMS? This study provides evidence of the effectiveness of alemtuzumab in reducing the relapse rate and accumulation of disability compared with interferon ß-1a (IFNß-1a) through extended follow-up (up to 60 months from baseline). METHODS: Of 334 patients originally randomized, 198 participated in the extension phase (151 [68%] alemtuzumab and 47 [42%] IFNß-1a). Disability, relapses, and safety were assessed as in the original study period. Efficacy outcomes were analyzed from baseline of the original trial period to 60 months. Safety data extended beyond 60 months. RESULTS: Over 5 years, alemtuzumab lowered the risk of sustained accumulation of disability by 72% and the rate of relapse by 69% compared with IFNß-1a (both p < 0.0001). The annualized relapse rate from baseline to month 60 was 0.11 for alemtuzumab and 0.35 for IFNß-1a. Complete safety follow-up reflected 988 and 376 person-years for alemtuzumab and IFNß-1a patients, respectively. Serious infections were seen in 7% of alemtuzumab patients and 3% of IFNß-1a patients, and thyroid disorders were seen in 30% of alemtuzumab patients vs 4% of IFNß-1a patients. Immune thrombocytopenia occurred in 3% of alemtuzumab patients and 0.9% of IFNß-1a patients during the initial study period; no additional events were reported during the extension phase. One alemtuzumab patient developed Goodpasture disease 39 months after the second annual cycle of alemtuzumab. CONCLUSIONS: Through extended follow-up, alemtuzumab remained significantly more efficacious than IFNß-1a, with a safety profile consistent with previous reports. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that alemtuzumab is more effective than interferon ß-1a in reducing relapses and disability in patients with RRMS in a long-term follow-up of a rater-blinded, randomized clinical trial with 59.5% of patients participating in the extended follow-up period.

A case of lichen ruber planus in a patient with familial multiple sclerosis.

Multiple sclerosis and lichen ruber planus are clinically and histologically distinct complex disorders of putative autoimmune aetiology that are fairly commonly observed in isolation but rarely found in combination. Only two previous reports have described lichen skin disorders in association with multiple sclerosis. The present report describes the case of a 51-year-old Caucasian woman exhibiting both familial multiple sclerosis and lichen ruber planus. This combination may have occurred by chance or it might imply that these disorders share common mechanisms in their pathogenesis.

Disseminated encephalomyelitis and multiple sclerosis: two different diseases - a critical review.

The practice of initiating immunomodulatory treatment immediately after a clinically isolated syndrome (CIS) suggestive of multiple sclerosis (MS) emphasizes the need to distinguish between disseminated encephalomyelitis (DEM) and MS. Their clinical, genetic, imaging, and histopathological characteristics establish that they are distinct disease entities. Acute and recurrent DEM are more common in children, but also occur in adults. DEM is polysymptomatic and includes signs and symptoms rarely encountered in MS, such as fever, alterations of the state of consciousness, cognitive and aphasic symptoms, and meningism. Cerebrospinal oligoclonal bands are rare. Magnetic resonance imaging (MRI) is the best means of distinguishing between DEM and MS. In the former, the lesion load is heavy, thalamus or basal ganglia are often affected, and early in the disease most of the lesions are usually larger than those of MS and enhance with gadolinium. The MRI spinal cord lesions are longer than three vertebral segments, and define neuromyelitis optica (NMO). Antibodies against aquaporin-4 are present in some NMO, but are also found in cases of MS and DEM. Most NMO are forms of DEM, not MS, and are identical with the 'Oriental' or 'optico-spinal' form of MS.

Avellis syndrome due to borreliosis.

Avellis syndrome is a rare form of alternating hemiparesis that is usually because of atherosclerosis. We report a 67-year-old man who developed paresthesiae of the left arm, dysphagia and dysphonia. The clinical picture, magnetic resonance imaging and cerebrospinal fluid findings were consistent with Avellis syndrome caused by brain stem arteritis because of late stage Borrelia burgdorferi infection, an extremely unusual aetiology for Avellis syndrome; this may well be the first such instance. It may be unrecognized in elderly patients with other risk factors for cerebrovascular disease.

Recurrent optic neuromyelitis with endocrinopathies: a new syndrome or just a coincidence?

The spectrum of optic neuromyelitis (ONM) ranges from monophasic or recurrent idiopathic forms of the disease, to ONM associated with autoimmune disorders. A distinct form of the disease, called recurrent ONM with endocrinopathies, characterized by spinal cord involvement (cavitations with syringomyeloid sensory disturbance), rapid evolution to blindness and paraplegia, characteristic cerebrospinal fluid (CSF) findings, and association with hypothalamus-pituitary dysfunction, has recently been described. The first case of ONM with endocrinopathies in a female Caucasian from Europe is presented, supporting the existence of this syndrome as a separate entity.

[The laboratory diagnosis of multiple sclerosis]. / Laboratornye metody v diagnostike rasseiannogo skleroza.

The importance of laboratory methods for multiple sclerosis (MS) diagnosis and differential diagnosis is often overestimated now. The role of several methods including MRI, evoked potentials, examination of the cerebrospinal fluid and some others methods are discussed in this review. Several conditions may in some patients mimick the appearance of MS and it is easy to understand why there is a tendency among many clinicians to embark on extensive- and expensive-laboratory investigations to establish the correct diagnosis at early stages of the disease. Disorders like cerebrovascular diseases, vasculitis, Lyme disease, neurosarcoidosis, acute disseminated encephalomyelitis, progressive multifocal leukoencephalopathy, HIV-associated encephalitis may cause very close changes of the results of these examinations. A detailed, exhaustive history and the neurological examination, along with a careful scrutiny of the actual MRI films by the neurologist experienced in the diagnosis of MS, will obviate the need for additional tests in the overwhelming majority of cases. So, the MS diagnosis and differential diagnosis is still based mainly of the data of clinical observation.

Diagnostic criteria for multiple sclerosis.

Over a hundred years ago, Charcot set down what he considered to be some of the clinical characteristics of multiple sclerosis (MS). His triad was not specific but it was the first attempt to separate this disease from the many others affecting the nervous system. The history of clinical diagnostic criteria demonstrates the evolution from rather tentative classifications of restricted value to the more elaborate 1983 scheme which incorporates some laboratory procedures under the rubric paraclinical tests, considered to be extensions of the neurological examination, as well as a new category based on the presence of specific abnormalities of the cerebrospinal fluid (CSF). It is curious that until then the term definite MS had been avoided except for autopsy-proven cases, perhaps a wise move, since exact diagnosis may require long term observation. All the proposed schemes have been based on the twin principles of dissemination in both time and space. The diagnosis of MS must remain a clinical one, supported but not supplanted by the increasingly popular magnetic resonance imaging, which is non-specific and is frequently overinterpreted by radiologists lacking appropriate clinical information. Reliance on the MRI as the principal if not exclusive basis for the diagnosis leads to error in as many as one third of cases. This assumes a great deal of importance considering that such non-MS patients may be counted in epidemiological surveys and included in therapeutic trials for disease-modifying drugs, or eventually treated with these very expensive drugs with still controversial long term efficacy. Not surprisingly, attempts to develop reliable criteria for the MRI diagnosis of MS have been unsuccessful in view of the lack of specificity of that procedure. Great care should be taken to exclude the presence of extrinsic cervical spine lesions which might impinge on the cord, leading to the formation of plaques, or mimic the course of MS. An MRI of the cervical spine is recommended in all patients suspected of having MS who have symptoms suggestive of spinal cord involvement. The diagnosis of MS is, and will remain, based on clinical criteria which codify the characteristic dissemination in time and space of MS.

Changes in short-term memory processes in patients with multiple sclerosis.

In this study we compared the performance of 39 multiple sclerosis (MS) patients with 28 age-, sex- and education-matched controls on both the Mini-Mental State Examination, a global cognitive assessment tool, and the Sternberg Short-Term memory scanning task, a standardized test of short-term memory (STM) processes. While the STM span of our MS patients did not differ from that of our controls, STM scanning time of the MS group was reliably slower than that of the controls and a significant correlation was observed between STM scanning time and duration but not severity of illness. Our results suggest that processing stages other than the manipulation of data within the STM buffer are also affected by MS.

Creutzfeldt-Jakob disease in a patient with a lyophilized dura mater graft.

A 37-year-old patient with Creutzfeldt-Jakob disease (CJD) is presented, who had received a cadaveric dura matter graft 12 year before the onset of neurologic symptoms. Initial clinical presentation included cerebellar symptoms, with dementia and myoclonus developing in later stages of the disease. EEG showed diffuse slowing with sporadic triphasic periodic activity. CT was normal in the early stage but pronounced cerebral and cerebellar atrophy with widened sulci were seen on MRI in the late stage of the disease. The prion protein (PrP) gene was homozygous for valin at the polymorphic codon 129. Cerebrospinal fluid analysis for 14-3-3 protein was positive. We believe that this patient is the first Croatian to acquire CJD by dural implant. Based on this case and a review of 66 cases from the literature, it is manifest that the awareness of iatrogenic transmission of CJD and adoption of preventive measures are the only effective way to stop the spread of CJD among surgically treated patients.

Severe progression of ALS/MND after intervertebral discectomy.

We observed seven patients who developed their first signs and symptoms of motor neuron disease together with signs of protrusion/prolapse of intervertebral disc. The age of the patients was between 55 and 67, of which one female and six male patients. All of them suffered from cervical spine pain or low back pain. The female patient and one male patient developed weakness in the small feet muscles as initial symptom and they complained of paresthesia along dermatomes L5S1 and of severe pain. The other five patients developed wasting of the hands muscles. They had a rather mild pain in the cervical spine and early morning paresthesia as well as severe causalgia along dermatomes C5C6 or C6C7. After the diagnosis of compressive radiculopathy in all patients, they underwent surgical treatment and very soon developed very severe progression of muscle wasting which included muscles of limbs, trunk and bulbar innervated muscles with signs and symptoms of lower and upper motor neuron lesion. Five patients died from 12 to 15 months after surgical treatment and two patients are still living.

Cerebrospinal fluid complement activation in neurological diseases.

Laser nephelometry (LN) is a rapid and very sensitive method for simultaneous determination of albumin, immunoglobulins, C3c and C4 in diluted serum and paired cerebrospinal fluid (CSF) samples. It is very useful in routine analyses. Determination of C3c and C4 covers classical as well as alternative pathways of complement activation. In CSF, they are mostly derived from and related to serum values. Under physiological conditions, the addition of intrathecal C4 synthesis is likely. The incidence of complement activation within CSF is also influenced by the method of choice (native molecules, activation products and complexes, inhibitors) and the mode of interpretation of results according to the functional state of the blood-brain barrier (BBB). Calculation of indexes and the modified Reiber's graph method are valid means of detection of complement activation within CSF. Complement activation within CSF was confirmed in 36% (111/302) of neurological patients examined; in 55% (48/87) of patients with inflammatory and demyelinating diseases, in 40% (37/94) of patients with CNS infections and complications, in 33% (4/12) of patients with motor neuron diseases, in 27% (11/40) of patients with spinal cord compression and sequelae, in 25% (8/32) of patients with neoplastic disease, and in 17% (6/37) of patients with cerebrovascular accidents.

Autonomic dysfunction in patients with multiple sclerosis.

The disturbances of autonomic cardiovascular reflexes have already been described in patients with multiple sclerosis (MS). It seems that this disturbances are the result of reflex pathways impairment in the central nervous system. We have tested 28 patients with MS and control group of 21 healthy volunteers using a set of autonomic cardiovascular reflexes tests. In all of patients zones of demyelinization have been discovered with magnetic resonance imaging (MRI). The biggest number of abnormal results was found in respiratory sinus arrhythmia (RSA) test (60.7%) and cortical activation test (35.7%). In 11 patients we found abnormal results in 2 or more tests. Patients with abnormal results in 4 or more tests had clinical impairment of other autonomic functions (urinary bladder regulation). The results of autonomic dysfunction tests show positive correlation to the MRI findings.

[Disorders of consciousness as a manifestation of neurologic disease]. / Poremecaj svijesti kao manifestacija neuroloskih bolesti.

Seventy-nine patients admitted in the neurological Intensive care unit because of severe disturbances of consciousness has been evaluated. Protocol based on previous experiences in evaluation of unconsciousness patients was used. Forty-four patients died and thirty-five survived. In 46 patients cause of illness was intracerebral hemorrhage. In 44 of them the cause of hemorrhage was arterial hypertension and in two of them rupture of a-v malformation. The majority of patients actually 41 of them showed hemispheral localization of intracerebral hematoma and five subtentorial. Pontien hemorrhages was found in three and cerebellar in two patients. In majority of 24 patients with hemispheral localization of intracerebral hematoma who showed progressive deterioration of consciousness the signs of descendent transtentorial herniation were found. The symptoms of uncal herniation were rare. In three patients with subtentorial localization of intracerebral hematoma who died signs of upward transtentorial herniation were observed. In 16 patients with ischemic cerebrovascular accident who showed disturbances of the consciousness at the admittance or soon after, nine patients died and seven survived. The cause of their condition were great hemispheral, smaller brain stem ischemic lesion, or deterioration of consciousness was related to the somatic illness. Patients with great ischemic lesions showed similar course of consciousness deterioration as it was observed in patients with hemispherical intracerebral hematomas with difference that biphasic course of illness characterized with temporary stagnation or even slight improvement of patients condition and than secondary progression of deterioration was seen only in patients with intracerebral hematoma, probably because of secondary ischemic complications. Ten patients were admitted because of subarachnoidal and two of them because of intraventricular hemorrhage. Six of them died and four survived. These patients has rupture of great sacular aneurysm with fast development of high intracranial pressure. In two of them the cause of death was rerupture of aneurysm. Stuporous patient with hemispheral neoplasm showed development of descendent transtentorial herniation which was stopped by anti oedematous and corticosteroid therapy. Comatose patient with brisk response on oculocephalic stimulation and normal papillary light reflexes was suspected on intoxication rather than structural brain lesion. He recovered by diuretics and forced rehydratation. After becoming conscious barbiturate intoxication was confirmed. Three patients were admitted in coma because of poisoning with CO, two patients died. Two patients admitted in epileptic status showed late diencephalic state of coma and they survived after anti epileptics and antioedematous treatment.

Diagnostic significance of methemoglobin determination in colorless cerebrospinal fluid.

The presence of various heme derivatives can be demonstrated spectrophotometrically in colorless cerebrospinal fluid (CSF). Because of the high sensitivity of the method, it may detect compounds that reflect a "traumatic tap" rather than a disease process. However, the presence of methemoglobin excludes the possibility of a hemorrhagic CSF being caused by traumatic lumbar puncture. Here we describe a highly sensitive spectrophotometric method involving measurement at the Soret band (400-420 nm) to detect methemoglobin (greater than or equal to 15%) in trace amounts of hemoglobin mixture (less than 0.3 mumol/L). We demonstrated methemoglobin in colorless CSF samples in 9% of 454 patients with cerebrovascular pathology and in 4% of 449 patients with other neurological diseases (n = 449). In a group of 21 patients with verified acute cerebral hematomas, methemoglobin was confirmed in 66% of colorless CSF samples after ultrafiltration. We conclude that routine spectrophotometric analysis of all CSF samples is very useful, allowing detection of xanthochromic compounds in patients with small cerebral and subdural hematomas as well as in those with minimal subarachnoid hemorrhages, hemorrhagic infarctions, or bleedings from aneurysms and neoplasms.

Epileptic seizures as a symptom of various neurological diseases.

The authors evaluate the most frequent causes of seizures in 562 patients admitted at the emergency out-patient ward because of fits. 194 patients were admitted because of the first occurrence of seizures, in 12 of them the first manifestation was status epilepticus of the generalized (8), or focal type (4). The commonest causes of seizures were alcoholism (82), disturbances of the brain blood flow (74), posttraumatic states (20), brain tumor (4), or encephalopathies. In 11 patients the cause of seizures was not found. Besides the causes, the authors stressed the most frequent type of seizures, as well as therapeutic measures. They pointed out that in alcoholism generalized seizures, and grand mal status were the commonest expression of seizures. The same was found in patients with posttraumatic seizures, but they mostly suffered single attacks, and the same in encephalopathies. In patients with vascular lesions focal seizures were not rare. The antiepileptic therapy is not applied in the first occurrence of convulsions, therapy is causal, linked primarily to basic etiopathogenic mechanism responsible for triggering seizures.

Hereditary antigen characteristics of blood in ischemic cerebrovascular accident.

In order to determine genetic differences between 50 examinees with ischemic cerebrovascular accident (iCVA) and those of comparative group, we have chosen 1883 persons from phenotypic healthy population divided into 5 different subgroups. The purpose of our investigation was exploring hereditary characteristics of antigenes linked to erythrocyte membrane. The highest discriminating value in genetic distance had MN and ABO genetic loci. The frequency of M antigen in stroke patients was 70% (in the comparative group 55%), N antigen had frequency 30% in patients with iCVA and 45% in the comparative group. The frequency of the blood group A in the patients with iCV was 32.68% and 27.16% in the comparative group. Blood group B had frequency in the patients 10.69% and in the comparative group 6.72%. O blood group had frequency in the patients 56.73% and in the comparative group 66.12%. Genetic distance between patients with iCVA and the comparative group were determined with gene frequencies, that was shown on the dendrogram. The dendrogram clearly shows that patients with iCVA are separated from all other comparative subgroups. The results of our investigation presented the highest discriminating value of MN and ABO genetic loci. The possibility of linkage between genetic loci for these erithrocyte antigenes (on the 4th and 9th chromosome) and genetic loci which determine iCVA cannot be excluded. Finally we consider that this method can support earlier identification of persons who belong to "high risk group for cerebrovascular disease".