Enfermedad por priones, encefalopatía espongiforme humana y enfermedad de Creutzfeldt-Jakob / Prion induced spongiform encephalopathy of Creutzfeldt-Jakob disease

The infectious protein or prion (PrPSC) is a transmissible and replicable polypeptide, which arises from an abnormal folding of the PrP protein, by unknown mechanisms and without changes in the primary sequence of its amino acids. Its new spatial disposition arises from the substitution of its alpha helices by beta bands, which increase its structural stability, avoiding its complete proteolysis, resulting in a residual accumulation of prions. These prions induce the misfolding of normal PrP protein, generating their exponential increase, leading to a disturbance of neuronal homeostasis which results in the development of the fatal spongiform encephalopathy of the Creutzfeldt-Jakob disease (CJD). This is the most prevalent human prion disease, and 90% of cases are sporadic, suggesting the endogenous genesis of prions. There are different types of prions, identified based on the genetic variance of codon 129 amino acids of the prion protein. Meteonin (M) and Valine (V)), associated with the result of their enzymatic proteolysis, define prions type 1 (21 kDa) and type 2 (19 kDa). The Classical form of CJD produced by MM1 prion occurs in 70% of the cases. The Cerebellar form originated by the VV2 prion occurs in 15% of cases, the form with Kuru plates, associated with the prion MV2 occurs in 5%, and the Vacuolar, related to the MM2 prion occurs in 4%. CJD is always characterized by behavioral, motor, cognitive, and vision alterations and by findings in magnetic resonance imaging, electroencephalogram and cerebrospinal fluid that define each clinical and neuropathological form.

[Prion induced spongiform encephalopathy of Creutzfeldt-Jakob disease]. / Enfermedad por priones, encefalopatía espongiforme humana y enfermedad de Creutzfeldt-Jakob.

The infectious protein or prion (PrPSC) is a transmissible and replicable polypeptide, which arises from an abnormal folding of the PrP protein, by unknown mechanisms and without changes in the primary sequence of its amino acids. Its new spatial disposition arises from the substitution of its alpha helices by beta bands, which increase its structural stability, avoiding its complete proteolysis, resulting in a residual accumulation of prions. These prions induce the misfolding of normal PrP protein, generating their exponential increase, leading to a disturbance of neuronal homeostasis which results in the development of the fatal spongiform encephalopathy of the Creutzfeldt-Jakob disease (CJD). This is the most prevalent human prion disease, and 90% of cases are sporadic, suggesting the endogenous genesis of prions. There are different types of prions, identified based on the genetic variance of codon 129 amino acids of the prion protein. Meteonin (M) and Valine (V)), associated with the result of their enzymatic proteolysis, define prions type 1 (21 kDa) and type 2 (19 kDa). The Classical form of CJD produced by MM1 prion occurs in 70% of the cases. The Cerebellar form originated by the VV2 prion occurs in 15% of cases, the form with Kuru plates, associated with the prion MV2 occurs in 5%, and the Vacuolar, related to the MM2 prion occurs in 4%. CJD is always characterized by behavioral, motor, cognitive, and vision alterations and by findings in magnetic resonance imaging, electroencephalogram and cerebrospinal fluid that define each clinical and neuropathological form.

Caídas y alteraciones de la marcha en los adultos mayores / Falls and gait disorders in the elderly

There is a higher frequency of falls in the elderly than in young people, due to age related physiological changes in gait. There is a lower amplitude of pelvic movements that affects gait efficiency. Equilibrium is also disturbed since the trunk assumes the leadership of gait, displacing the pelvis. Many diseases of elderly individuals, such as Parkinson disease, spastic paraparesis, cerebrovascular accidents or neuropathies, further impair the gait. Therefore, after the age of 65, all falls must be considered symptomatic

Paraparesia espástica progresiva idiopática HTLV-I seronegativa: estudio clínico y neurofisiológico de las manifestaciones sensitivas / HTLV-I seronegative idiopathic progressive spastic paraparesis: clinical and neurophysiological study of the sensory features

Background: HTLV-I associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a defined entity. However, there are many patients not well characterized with a similar clinical picture who are HTLV-I seronegative. Objective: Clinical and neurophysiological description of patients with HTLV-I seronegative idiopathic paraparesia. Patients and Methods: Seventeen patients (4 women and 13 men aged 24-67 years, average 52.3) were evaluated including clinical assessment, vibratory sensory analysis, quantitative somatosensory thermotest (QST), somatosensory evoked potentials (SSEPs), electromyography (EMG) and motor and sensory nerve conductions. Results: In addition to the spastic paraparesis, 3 (17.6 percent) patients had pseudobulbar symptoms. Ten (58.8 percent) patients had a spastic gait but could walk unaided, 6 (35.2 percent) needed support and 1 patient could not walk. Bladder dysfunction was found in 10 (58.8) patients and sensory symptoms in 7 (41.1 percent). There was mild distal impairment of vibration and position sense, distal tactile and pinprick hypoesthesia in 4 (23.4 percent) patients. Tibial SSEPs were abnormal in 11 (64.7 percent). Nerve conduction studies and EMG were normal. QST showed cold hypoesthesia in 14 (82.4 percent) patients. Warm sensation and heat pain appeared unimpaired. Conclusions: All sensory abnormalities found were restricted to sensations carried by myelinated (A beta and A delta) channels. Sensory and motor abnormalities are similar to HAM/TSP patients suggesting a common pathogenesis

Incremento de la actividad metaloproteinásica y de sus inhibidores en el líquido cefalorraquídeo, en pacientes con paraparesia espástica tropical / Increased activity of matrix metalloproteinases and their tissue inhibitors in cerebrospinal fluid of patients with HTLV-1 associated tropical spastic paraparesis

Background: Proteolytic modifications of neuronal surfaces and the surrounding extracellular matrix are very important in neuronal development and regeneration. Increased activity of matrix metalloproteinases (MMPs) and their tissue inhibitors, due to secretion by macrophages and lymphocytes, occur in inflammatory processes that disrupt the blood brain barrier. However, neurons and microglia can also secrete these enzymes. Aim: To identify the type of MMP present in the cerebrospinal fluid (CSF) and changes in the expression of tissue inhibitors of metalloproteinases (TIMPs) in patients with HTLV-1 associated tropical spastic paraparesis. Patients and methods: CSF samples from 12 patients with HTLV-1 associated tropical spastic paraparesis and 12 healthy controls were obtained by an atraumatic lumbar puncture. The presence of MMPs was measured by zymography and the relative amounts of TIMPs were measured by immunowestern blot. Results: In the CSF of both controls and patients, a similar gelatinolytic band corresponding to proMMP-2 (latent form) was observed. In 83.3 percent of patients with HTLV 1 associated tropical spastic paraparesis, the MMP-9 was also present. TIMP-1, TIMP-2 and TIMP-3 were elevated 2.24 ñ 0.72, 3.85 ñ 1.38 and 5.89 ñ 3.4 fold, respectively, in the CSF of patients as compared to controls. Conclusions: Patients with HTLV-1 associated tropical spastic paraparesis have elevated activity of MMP-9 and levels of TIMPs in the CSF, when compared to healthy controls

Leucemia linfoma T del adulto en Chile: estudio clínico patológico y molecular de 26 pacientes / Adult T cell leukemia lymphoma in Chile: a clinical-pathological and molecular study of 26 patients

Background: Adult T cell leukemia lymphoma is a lymphoproliferative syndrome etiologically associated to human T cell lymphotropic virus type I. Aim: To describe the clinical and laboratory features of 26 caucasian chilean patients, with HTLV-I positive adult T-cell leukemia lymphoma (ATLL). Material and methods: Diagnostic criteria included clinical features, cell morphology, immunophenotype, HTLV-I serology and/or DNA analysis by southern blot or PCR. Results: According to the clinical presentation, 12 cases had the acute ATLL form, 6 had a lymphoma, 4 the chronic form and 4 had smoldering ATLL. The median presentation age was 50 years, younger than the Japanese patients, but significantly older than patients from other south american countries (eg Brasil, Jamaica, Colombia). The main clinical features: lymphadenopathy, skin lesions and hepatosplenomegaly, were similar in frequency to those of patients from other countries, except for the high incidence of associated neurological disease. Tropical spastic paraparesis (TSP) in our series of ATLL, was seen in one third of the patients (8/26). A T-cell immunophenotype was shown in all 26 cases and HTLV-I serology was positive in 25/26 patients. Molecular analysis on the seronegative patient showed clonal integration of proviral HTLV-I DNA into the lymphocytes DNA, and thus he may have been a poor responder to the retroviral infection. Proviral DNA integration was also demonstrated in 15/16 patients being clonal in 10, polyclonal in 3 (all smoldering cases) and oligoclonal in one. Conclusions: ATLL in Chile has similar clinical and laboratory features than the disease in other parts of the world, except for a younger age than japanese patients but older than those from other latin american countries and a high incidence of patients with associated TSP. Detailed morphological and immunophenotypic analysis of the abnormal circulating lymphocytes, together with the documentation of HTLV-I by serology and/or DNA analysis are key tests for the identification of this disease

El gen tax del virus linfotrópico humano tipo I en la identificación etiológica de la paraparesia espástica tropical: estudio clínico, serológico y de polimerasa en cadena en 72 pacientes / HTLV-I tax gene on the etiological identification of tropical spastic paraparesis: a clinical, serological and polymerase chain reaction study in 72 patients

Background: Tropical spastic paraparesis (TSP) is an endemic disease in Chile. In most countries, only 50 percent of patients are seropositive to HTLV-I. However, new studies suggest that seronegative TSP is also associated with HTLV-I. Aim: To describe clinical and virological features of seronegative patients with TSP. Patients and methods: seventy two chilean patients with TSP, studied by clinical, radiological and laboratory methods during 1998, are reported. The determination of antibodies to HTLV-I was accomplished by ELISA, immunofluorescence and western-blot analysis. Polymerase chain reaction for tax and 5'Ltr genes was made using primers SK 43-44, LTR1 and LTR6. Results: Thirty one patients were HTLV-I positive and 41 were negative. No clinical, radiological or laboratory differences were observed between both groups. In seropositive patients, tax and 5'ltr viral gene sequences of the HTLV-I provirus were detected in DNA of peripheral blood mononuclear cells. In seronegative cases, sequences of tax gene were detected, exclusively, in 18 of 41 patients. Conclusions: These results confirm an association with HTLV-I infection in 43,9 percent of the TSP seronegative patients. These findings support the hypothesis that a defective provirus infects peripheral blood mononuclear cells in seronegative cases of TSP. The importance tax gene in the diagnosis of the TSP is also emphasized

Demencia subcortical en paraparesia espástica tropical asociada a HTLV-I: estudio de 43 casos / Subcortical dementia in HTLV-I tropical spastic paraparesis: study of 43 cases

Background: Central nervous system damage associated to HTLV-I does not limit itself to the spinal cord, but also involves subcortical structures, producing cognitive impairment and behavioral changes which eventually could conform a new form of subcortical dementia. Aim: To study cognitive changes in patients with HTLV-I associated myelopathy. Patients and methods: Forty three patients (31 female) with Tropical Spastic Paraparesis, aged 52 years old as a mean and with a disease lasting a mean of 7.5 years, were studied. The diagnosis was based on clinical, radiological and neurophysiological changes. The virus was identified with ELISA, indirect immunofluorecence, Western Blot or proviral DNA identification. Cognitive assessment was done using the Wechler Adult Intelligence Scale (WAIS) and Benton Visual Retention Test (form D). Patients were grouped according to their motor disability in; 23 patients with independent spastic gait, 11 patients that needed support to walk and 9 patients unable to walk. Results: WAIS test demonstrated cognitive impairment with special deficit in some subtests such as Digit Span, Digit Symbol, Picture Arrangement and Object Assembly. Benton Test also disclosed cognitive impairment. There was a positive relationship between cognitive and motor performance. Conclusions: At least 50 percent of patients with Tropical Spastic Paraparesis have certain degree of intellectual and affective impairment

Hemorragias cerebrales y angiopatía amiloidea / Cerebral amyloid angiopathy in brains of patients dying of non traumatic cerebral hemorrhages

Background: Cerebral amyloid angiopathy is considered pathogenic in non traumatic cerebral lobar hemorrhages. Aim: To study the frequency of cerebral amyloid angiopathy in brains of patients dying of non traumatic cerebral hemorrhages. Material and methods: Thirty seven brains from patients, 25 men and aged 65ñ10 years old, with cerebral hemorrhages (14 lobar, 18 in basal ganglia and 5 in cerebellum or brainstem) were studied. As controls, the brains of 30 subjects, 14 men and aged 64ñ16 years old, dying of non neurological causes were studied. Deep and cortical vessels were stained with hematoxylin eosin, Gomori, Thioflavin T and Bodian. Definitive cerebral amyloid angiopathy was diagnosed when amyloid deposition was observed in the media of vessels. Results: Twenty six out of 32 patients dying of cerebral hemorrhage and 3 of 21 controls had chronic hypertension. Cerebral amyloid angiopathy was present in 19 of 37 brains of patients with cerebral hemorrhage and 13 of 30 control brains. In patients with hypertension, vascular changes independent of the location and volume of amyloid deposition, were observed. Such changes were dilatation, tortuousness, thickening of walls specially in muscular and adventitia and hyaline degeneration. Thirteen brains with hemorrhage had fibrinoid necrosis and 10 had microaneurysms. Conclusions: In this series of patients, cerebral amyloid deposition was unspecific and its role in the pathogenesis of cerebral hemorrhages was not confirmed. Hypertension was associated with vascular degenerative changes that can lead to cerebral hemorrhages

Mononeuropatía múltiple y vasculitis / Multiple mononeuropathy and vasculitis

Background: Seventy percent of vasculitis are neurologically expressed as multiple mononeuropathy (MM) or asymmetrical neuropathy (AN). Concurrent nerve and muscle biopsy increases the diagnostic accuracy of the disease. Aim: To define the pathological features of vascular damage in nerve and muscle in patients with MM or AN. Patients and methods: Between 1980 and 1997, 50 patients with a MM or AN diagnosis, based on neurological and neurophysiological findings, were studied at the Neurology Department of Hospital del Salvador. All underwent nerve and muscle biopsy (of the superficial peroneal nerve and the short peroneal muscle). Slices were stained with hematoxylin eosin, luxol fast blue and Gomori staining. Results: Forty two patients, aged 52 ñ 15 years old (29 female) had a vasculitis. These subjects with MM or AN associated to vasculitis, corresponded to 22 percent of neuropathies subjected to nerve biopsy at the Department in the study period. Thirty two cases (76 percent) had necrotizing arteritis, characterized by wall fibrinoid necrosis and lumen occlusion in large vessels (>100 microns), with Iymphoplasmocytic and macrophage infiltration. Ten cases showed an inflammatory reaction and endothelial proliferation without wall necrosis, specially in small epineural arteries. Vascular recanalization was found in 33 percent of cases. Diagnostic vascular changes were found in 87 percent of nerve biopsies and 53 percent of muscle biopsies. No definitive relationship between the intensity of vascular and nerve lesions was found. All muscle biopsies showed some degree of neurogenic atrophy and 5 had micro infarcts. Conclusions: Superficial peroneal nerve biopsy is diagnostic in most patients with MM or AN associated with vasculitis. Nerve and muscle biopsies are complementary in the diagnostic work up

Neuromielitis óptica: una enfermedad necrotizante del sistema nervioso central / Optic neuromyelitis: a necrotizing disease of the central nervous system

Optic neuromyelitis is characterized by simultaneous or successive necrotizing lesions involving the optic nerves and the spinal cord. We report two females with the disease, aged 30 and 34 years old. In the latter, a neuropathological study was done. Both patients had clinical, neuroradiological and pathological features that differed from those of primary demyelinating syndromes such as multiple sclerosis. These patients illustrate the selectivity of optic nerve and spinal cord lesions. The latter involve mainly pyramidal and Goll tracts while, within the necrotizing lesions of the optic chiasma, the fibers of the unaffected optic nerve are spared. This pattern suggests a selective injury to some population of axons. Blood vessels were not affected in the necrotizing areas and the lesions did not follow a vascular territory, therefore a vascular mechanism causing the disease is unlikely. The clinical and neuropathological features of neuromyelitis optic suggest a selective involvement of some axons

Forma familiar de la paraparesia espástica tropical: estudio de cuatro familias / Familial form of tropical spastic paraparesis: report of four families

We report eight patients with familial tropical spastic paraparesis belonging to four families. The diagnosis was reached by clinical, radiological and electrophysiological studies. Human lymphotropic virus type I infection was confirmed by ELISA, immunofluorescence essays, Western blot and polymerase chain reaction in DNA of peripheral blood mononuclear cells, using primers for tax and 5'ltr genes. In all these families there was a vertical transmission of the disease from the first to the second generation. All patients improved their spastic gait after prednisone treatment. Among patients of the second generation, all had dacrysialoadenitis, three had leukemia like lymphocytes in the blood smear, two had mycosis fungoides and one had hepatic cirrhosis

Sindrome desmielinizante aislado del sistema nervioso central como expresión de una esclerosis múltiple tardía: estudio anatomoclínico de un caso / Isolated central nervous system cemyelinating syndrome as the clinical expression of a late multiple sclerosis: report of one case

We report a 56 years old male developed a transverse myelopathy with cuadriparesis,neurogenic bladder and a sensitive level at C4. Cerebral and spinal cord magnetic resonance imaging showed only one demyelinative lesion at the cervical level. Post morten neuropathological study showed segmental myelin loss without anatomical limits and with axonal preservation in the involved spinal cord segment. This lesion had the classical features of multiple sclerosis.The isolated lesion, the pathological findings and the delayed age of onset allow the definition of this case as an isolated nervous system demyelinative syndrome

Nueva forma de demencia subcortical: encefalopatía por infección del virus linfotrópico T humano (HTLV-I): caso clínico / New kind of subcortical demencia: encephalopathy by human T lymphotropic virus (HTLV-I): clinical case

We report a 45 years old female with HTLV-I associated myelopathy, followed up for 10 years who, 5 years ago, developed personality changes and intellectual deterioration, assessed with the Wais-Benton test. She also had alterations in the electroencephalogram and a nuclear magnetic resonance imaging of the brain showed hypodensity in T1 and hyperdensity in T2 subcortical regions. The progression of intellectual impairement was related to an increase in proviral DNA, assessed with polymerase chain reaction

Efecto del núcleo CMP forte en 46 pacientes con paraparesia espástica progresiva: estudio randomizado y ciego / Effect of CMP forte nucleus in 46 patients with progressive spastic paraparesis: randomized and blind study

Idiopatic or HTLV-1 associated progressive spastic paraparesis does not have a clear etiology or treatment. To assess the effects of a medication containing cytidinmonophosphate, uridintriphosphate and vitamin B 12 in the treatment of progressive spastic. Patients with the disease were randomly assigned to receive the Nucleus CMP forte (containing dysodic cytidinmonophosphate 5 mg,trisodic uridintriphosphate 3 mg and hydroxicobalamin 2 mg) tid or placebo during 6 months. Gait, spasticity, degree of neurogenic bladder and somatosensitive evoked potentials were assessed during treatment. Forty six patients aged 25 to 79 years old were studied, 24 were female and 29 HTLV-1 positive. Twenty two were treated with the drug and the rest with placebo. Gait and spasticity improved in 7 of 22 patients receiving the drug and 1 of 24 receiving placebo (p<0.05). Neurogenic bladder improved in 10 of 22 receiving the drug and 4 patients treated with the drug and in two of seven treated with placebo. The medication caused a modest improvement in patients with progressive spastic paraparesis and was free of side effects

Polimiositis primaria asociada a HTLV-I / Primary polymyositis associated to HTLV-I

We report a 68 years old male with a polymyositis associated to HTLV-I. Diagnosis was based on clinical picture, an increased creatin-phosphokinase levels, electromyography and muscle biopsy. The patient had positive HTVL-I antibodies, measured by particle agglutination test, indirect immunofluorescence and polymerase chain reaction in lymphocytes. Skin biopsy showed a mycosis fungoides. Schirmer test and minor salivary gland biopsy showed a dacryosialoadenitis. There was no central nervous system involvement. This patient is the only with positive HTLV-I antibodies, among 18 patients with polymiositis in whom these antibodies were measured

Miopatía centro nuclear tardía: forma autosómica dominante / Later centronuclear myopathy: autosomal dominant form

We report a family with three generation affected by an autosomal dominant centronuclear palsy. This gene is characterized by ptosis that begins in childhood and a slowly progressive weakness that starts in the second decade of life, involving face, neck and limbs. In this stage, muscle pan associated to exercise or cold muscle sparms may apprear. The gene is expressed with differing intensity in each individual. Myopathic electro myographic alterations are only found in fuctionally impaired subjects. Muscle biopsy shows type I fiber atrophy and central nuclei in a high percentage of fibers, specially in type I fibers

Enfermedad de Creutzfeldt-Jakob en dos médicos pertenecientes a una familia de la mutación en el codon 200 del cromosoma 20 / Creutzfeldt-Jakob disease in 2 physicians belonged to a family affected by codon 200 mutation in the chromosome 20

Se presentan dos casos de enfermedad de Creutzfeldt-Jakob (ECJ) ocurridos en un médico patólogo y en un biólogo molecular de 62 y 70 años de edad respectivamente. El patólogo realizó alrededor de 10.000 autopsias, 10 de ellas en casos definitivos de ECJ. Ambos médicos eran miembros de una familia afectada por la ECJ, con otros 2 casos probables y 1 definitivo en 2 generaciones sucesivas. En este último caso, fallecido en Italia, se demostró la presencia de una mutación en el codon 200 del cromosoma 20, hecho que ha sido también demostrado en otras 6 familias chilenas afectadas por la ECJ. Se concluye en que si bien el contacto físico con material orgánico proveniente de casos de ECJ es un potencial factor de riesgo para contraer la enfermedad, en los 2 casos presentados hay un mecanismo genético determinante que es de primordial importancia para explicar su manifestación clínica

Miopatía por déficit de maltasa ácida en el adulto / Myopathy due to acid maltase deficiency in an adult patient

We report a 46 years old male presenting with tetraparesis and severe respiratory involvement. He had moderately elevated serum creatine phosphokinase values and the electromyography showed myopathic alterations and irritative signs. In the muscle biopsy a vacuolar myopathy with increased collagen deposits was found. Circulating lymphocytes presented abnormal PAS positive granules in their cytoplasm