Nonprogressive Course Research Articles

Idiopathic biliary ductopenia in adults without symptoms of liver disease.

Idiopathic adulthood ductopenia is a severe cholestatic liver disease of unknown cause characterized by loss of the interlobular bile ducts in more than 50 percent of the portal tracts. In most reported cases, cirrhosis and liver failure develop. We studied 24 adults with abnormal results on liver-function tests but no symptoms of liver disease. All had liver biopsies that showed a lack of bile ducts in many of the portal tracts. The 17 women and 7 men had a mean age of 41 years (range, 27 to 57). All were asymptomatic and had high serum gamma-glutamyltransferase concentrations (mean [+/-SD], 179 +/- 84 U per liter); 75 percent also had abnormal serum alanine aminotransferase concentrations. The proportion of portal tracts that had bile ducts was 62 +/- 7 percent (range, 55 to 78 percent). Three patients had a second liver biopsy three to nine years after the first; there were no changes over time. In four of the five patients treated with 600 to 900 mg of ursodiol two to three times daily, results of liver-function tests returned to normal. Idiopathic biliary ductopenia, with an apparently nonprogressive clinical course, can occur in adults who have no symptoms of biliary disease.

“Benign erythrocytosis” and other familial and congenital polycythemias

The term familial and congenital polycythemia encompasses a heterogeneous group of disorders with the common characteristic of an absolute increased red cell mass since birth and/or similar phenotype also present in relatives. In the last 2 decades the differential diagnosis between primary and secondary familial polycythemias became more physiologically relevant as new sensitive techniques, such as accurate measurements of serum erythropoietin (S-EPO) concentration by radioimmunoassay (RIA) or ELISA, and assessment of growth of erythroid progenitor cells in vitro became available. Consequently, correct classification of many older previous reports of familial polycythemias is difficult. While familial secondary polycythemias due to high oxygen affinity hemoglobin mutants are not infrequent and have been well delineated in terms of molecular pathophysiology and phenotype during the last 3 decades, those secondary familial polycythemias due to 2,3 DPG deficiency are very rare. Familial and congenital polycythemias with increased EPO concentration and normal arterial oxygen saturation and oxygen dissociation kinetics represent an intriguing group of disorders wherein the molecular lesions remain obscure; however, in some instances a possibility of abnormal oxygen sensing pathway involving hypoxia inducible factor-1 (HIF-1) open an intriguing yet unexplored area of hematology and biology. In contrast the primary familial and congenital polycythemia (PFCP) has been only recently recognized (the first report published in 1977). Various designations have been used in the past to describe PFCP, a rare clinical syndrome, including: benign familial erythrocytosis, polycythemia vera of childhood, primary polycythemia, pure erythrocytosis, etc. Some of these terms stressed the relatively benign, non-progressive course of the disease with a normal lifespan of affected subjects; however, the apparent benignity of some of these disorders has been questioned. These disorders are familial and/or congenital, and the clinical and laboratory evidence of secondary polycythemias must be excluded. Only about 2 dozen familial and sporadic cases with PFCP have been reported. However, the mutations of erythropoietin receptor (EPOR) found in some of families with PFCP represent the only defined molecular defect of primary polycythemic phenotypes. All reported PFCP associated EPOR mutations result in truncation of its intracytoplasmic C-terminal domain which negatively regulates the EPO/EPOR signal transduction pathway. Subjects with these mutations have decreased or normal S-EPO and increased sensitivity of erythroid progenitor cells to low EPO concentrations in in vitro assays. Mutations of other genes involved in post EPOR signaling pathway such as JAK-2, HCP and STAT 5 may also play a causative role in pathogenesis of some of PFCP families where mutation of EPOR was not found.

Familial Creutzfeldt-Jakob disease with a five-repeat octapeptide insert mutation

We report a familial form of Creutzfeldt-Jakob disease, associated with a unique insert mutation of the PRNP gene in an American family of Ukrainian origin. Ten family members exhibited early age at onset and longduration illnesses characterized primarily by personality changes, cognitive impairment, and spasticity. The proband, presenting at age 42 years, exhibited a fairly stable, nonprogressive course over 7 years, followed by precipitous decline and death in the eighth year. Other affected family members exhibited marked clinical heterogeneity. Each tested affected member had an insert mutation consisting of five extra octapeptide repeats between codons 51 and 91 of the PRNP gene on chromosome 20. Examination of two autopsy cases showed classic spongiform change, neuronal loss and astrocytosis in one case, and minimal pathologic abnormality in the other case. This report documents a new insert mutation of the PRNP gene, and confirms the early age of onset, characteristically prolonged clinical course, and clinical and pathologic heterogeneity seen in such mutations.NEUROLOGY 1996;47: 727-733

Konzo, an Epidemic Spastic Paraparesis in Africa, Is Not Associated with Antibodies to HTLV-I, HIV, or HIV gag-Encoded Proteins

To the Editor: Geographical foci of two kinds of spastic paraparesis have been described in Zaire in the last few years: HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) (1-3) and konzo (4-7). The HTLV-I-associated myelopathy is characterized by gradual onset and progressive course, whereas konzo is clinically different with a sudden onset and a nonprogressive course. Konzo mainly affects women of child-bearing age and children. Epidemiological studies in four African countries show an association to exclusive consumption of insufficiently processed cassava. This leads to a high dietary cyanide intake combined with low intake of sulfur amino acids that provide the sulfur substrate necessary for detoxification of cyanide to thiocyanate (7). An etiological role of retroviral infection in konzo has also been suggested (4), and one report suggests that cyanide exposure may trigger the myelopathic effects of HTLV-I infection (3). We have investigated possible associations between konzo and retroviral infection in two previously described konzo foci in Zaire, situated 300- and 400 km east of the capital Kinshasa in the Bandundu region (5,6). The diagnostic criteria for konzo were (a) a visible symmetric spastic abnormality of gait while walking or running, (b) a history of onset in <1 week followed by a nonprogressive course in a formerly healthy person, and (c) bilaterally exaggerated knee or ankle jerks without signs of disease of the spine (5). Lathyrism (8) was excluded because grass pea (Lathyrus sativus) was not consumed in the areas. With informed consent, blood was obtained from 30 of 35 konzo cases in one village and from 93 eligible healthy controls from 39 randomly selected households in two villages in the first area, and from 3 of 7 konzo cases and 16 eligible healthy controls from 8 randomly selected households in one village in the second area. In total, 13 male and 20 female patients aged 10 to 56 years (median 19) and 109 healthy controls (53 males and 56 females) aged 4 to 68 years (median 30) were included in the study. Serum samples were tested for the presence of HIV-1 antibodies with two different ELISA kits: Wellcozyme HIV-1 (Wellcome Diagnostics, Dartford, England) and Abbott anti-HIV-1 (North Chicago, IL, U.S.A.) (first area) or Enzygnost anti-HIV-1 + 2 (Behring, Marburg, Germany) (second area). All samples were further tested by HIV-1 Western blot kit (Dupont, Wilmington, DE, U.S.A.). We used the WHO criteria for HIV-1 Western blot seropositivity requiring reactivity with at least two envelope bands (9). Screening for antibodies to HTLV-I was performed with Abbott/Anti-HTLV-I ELISA, and reactive sera were further tested by an HTLV-I Western blot assay including recombinant glycoproteins, rgp46, and rgp21 (Diagnostics Biotechnology, Singapore). Reactivity with one envelope protein and one gag-encoded protein was required for HTLV-I Western blot seropositivity. All 142 sera tested were negative for HIV-1 antibodies on ELISA. None of the sera fulfilled the criteria for a positive HIV-1 Western blot reaction because there was no reactivity with the HIV-1 envelope glycoproteins. However, reactivity against the HIV-1 gag-encoded proteins p17 and p24 was seen in 41 of the 142 tested subjects, but there was no difference in frequency between konzo patients and controls (Table 1). None of the subjects had antibodies to HTLV, but three sera from subjects in the control group showed indeterminate reactions on HTLV-I Western blot. Of the 3,700 konzo cases reported from Africa in the literature (10), 128 patients from five foci have been tested to date (4,11-13), and all were found negative for retroviral antibodies (110 were tested for HTLV-I, 13 for HTLV-II, 128 for HIV-1, and 77 for HIV-2). In addition, we found no relation between konzo and gag-encoded protein reactivity. It is therefore unlikely that any human retrovirus should be important in the etiology of konzo. We conclude that human retroviruses are not involved in the causation of konzo. T. Tylleskär; *M. Banea; †B. Böttiger; †R. Thorstensson; †G. Biberfeld; H. Rosling Unit for International Child Health; Department of Pediatrics; Uppsala University; Uppsala, Sweden *CEPLANUT (Centre National de Planification de Nutrition Humaine); Ministry of Health; Kinshasa, Zaire †Department of Immunology; Swedish Institute for Infectious Disease Control; Stockholm, Sweden

Congenital hypomyelination neuropathy: decreased expression of the P2 protein in peripheral nerve with normal DNA sequence of the coding region

Congenital hypomyelination neuropathy (Lyon type) is characterized by a non-progressive clinical course and a histopathological formation of atypical onion-bulb. We have studied the immunohistochemical expression of the major peripheral myelin proteins including P0 protein, myelin basic protein (MBP) and P2 protein in three such patients. No significant difference was observed between the patients and the controls, as to the P0 and MBP staining. In contrast, P2 protein antiserum scarcely stained the patients' nerve fibers except for a few scattered adequately myelinated fibers. Assuming the pathogenetic contribution of the extremely decreased P2 protein to the disease, we investigated P2 protein gene by sequencing all coding regions but failed to detect any change in the nucleotide sequence. Further investigation including the analysis of promoter region of P2 protein gene is needed to elucidate the mechanism of congenital hypomyelination neuropathy.

Can immunosuppressive drugs slow the progression of IgA nephropathy?

The role of immunosuppressive drugs in the treatment of IgA nephropathy (IgAN) remains controversial. The effect of treatment with prednisolone and azathioprine on the clinical course of patients with IgA nephropathy is described in this retrospective study. One hundred and fourteen patients, 66 treated (age 13-77 years) and 48 untreated (age 15-64 years), were evaluated. The two groups of patients differed significantly with respect to heavier proteinuria (median 3.6 g/day, range 0.2-18 g/day), lower serum albumin level (< 40 g/l) and more severe renal histopathological involvement in the treated group (P < 0.01). Oral prednisolone 40 mg/day and azathioprine 2 mg/kg BW/day was commenced initially and after gradual tapering was continued at low dose (5 mg/day) for a median duration of 24 months (range 12-98). The median duration of follow-up was 46 months (range 12-180). The clinical course was defined as progressive or non-progressive on the basis of serial serum creatinine (Scr). Of the patients who presented with renal impairment (Scr > 110 mumol/l), a non-progressive course was observed in 79.5% patients of the treated group (n = 39), while only in 36% of the untreated group (n = 22), the difference was statistically significant (P < 0.001). Slopes of reciprocal of Scr versus time were also calculated by linear regression analysis to represent the trend of renal function for patients who had had 3 or more years follow-up (n = 101). An analysis of variance of these trends in patients with renal impairment at presentation (n = 51) showed significant recovery of renal function in the treated group (n = 33) and a decline of renal function in the untreated group (n = 18, P = 0.004). There was no significant effect of the treatment on proteinuria. The histopathological features that favoured response to the treatment were mesangial proliferation, capsular adhesions and interstitial infiltration on light-microscopy, C3 and fibrin deposits on immunofluorescence (P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Ataxia-oculomotor apraxia syndrome.

Ataxia-oculomotor apraxia is a distinct entity first comprehensively described in 1988. The features include early childhood onset of ataxia and oculomotor apraxia, mimicking ataxia telangiectasia but without the extraneurologic findings of ataxia telangiectasia. We add to the clinical description of the ataxia-oculomotor apraxia syndrome by reporting eight patients, ages 2 to 15 years, from four families, suggesting autosomal recessive inheritance, with the longest follow-up over 6 years. After initial gait deterioration, all had a nonprogressive course. We have postulated that ataxia-oculomotor apraxia should be established as a separate disease from ataxia telangiectasia or its variants not only by clinical history, examination findings, and course, but primarily by the biologic markers of normal chromosome breakage and radiation sensitivity studies. We found no increased chromosome breakage in the four patients studied and intermediate sensitivity to chronic ionizing radiation of cultured skin fibroblasts on the three patients studied. Family studies revealed an intermediate radiosensitivity from two patients, their asymptomatic parents, and a sister. The lack of chromosome breakage strongly separates ataxia-oculomotor apraxia from ataxia telangiectasia. The radiation sensitivity studies are compatible with two possibilities: (1) symptomatic ataxia telangiectasia heterozygotes, but this would be highly unusual because the degree of clinical involvement in the ataxia-oculomotor apraxia patients is not mild, as would be expected if they were heterozygotes and (2) a separable disease entity, which is the interpretation we favor.

Hyaline body myopathy

Muscle biopsy from two unrelated patients, a male aged 40 and a female aged 3, with relatively non-progressive limb weakness since infancy, revealed numerous subsarcolemmal glassy, hyaline appearing bodies present in 20–30% of the fibres. Type 1 fibre predominance was present, and the hyaline bodies were exclusive to type 1 fibres. The hyaline bodies were negative with oxidative enzyme and periodic acid-Schiff stains. Electron microscopy showed the hyaline bodies to contain amorphous granular material of unknown composition. No membrane separated the hyaline bodies from the surrounding sarcoplasm. Hyaline body myopathy most likely represents a distinct congenital myopathy because of its childhoot-onset, non-progressive course, and distinct morphological features.

Konzo in the Central African Republic.

We identified a new focus of konzo, an upper motor neuron disease, in a part of western Central African Republic. Interviews and high serum levels of thiocyanate indicate that cyanide exposure from insufficiently processed cassava may cause konzo. Abrupt onset, nonprogressive course, and seronegativity to HTLV-I clearly differentiate konzo from HTLV-I-associated myelopathy in tropical countries.

Clinical analysis of cases with acute exacerbation of chronic renal failure

We analyzed the total number of 42 events of acute exacerbation of chronic renal failure (CRF) in 35 patients who were admitted to the Matsuyama Red Cross Hospital Kidney Center between 1985 and 1990. These patients consisted of 16 males and 19 females with a mean age of 59.8 +/- 12.7 years. The most frequent original renal diseases were diabetic nephropathy (DM) and arteriosclerotic nephrosclerosis (NS). The most frequent acute exacerbation factors were dehydration and infection. Four cases died and one case transferred to chronic hemodialysis, but the other 37 events (88%) in 31 cases recovered to normal renal functioning. Tentative dialysis therapy was performed for 12 events, in which the cases with DM as the original disease and infection as the exacerbation factor were responsive to this therapy. In the analysis of long-term prognosis, 7 out of 26 cases died of non-renal diseases, 15 transferred to chronic dialysis therapy and only 4 remained in a CRF state. The intervals between the date of discharge and that of the start of dialysis therapy was shorter in the cases with DM (mean of 5 months) or chronic glomerulonephritis (mean of 7.6 months) than in cases with chronic interstitial nephritis, polycystic kidney disease and NS (mean of 17.7 months). We concluded that even though many of the cases eventually transferred to chronic dialysis therapy, appropriate therapy during the acute exacerbation period could allow recovery to a natural progressive or nonprogressive course in each case.

Natural history of aortoarteritis: An angiographic study in 26 survivors

The natural history of aortoarteritis was angiographically studied in 26 surviving patients (19 female; 7 male). The interval between the initial and current angiographic study was 38-228 months (mean -84.46 months). All patients underwent panaortography during both studies and one patient also underwent pulmonary angiography. The lesions were extensive involving the ascending, arch and the descending thoracic and/or the abdominal aorta (Type III) in 15 patients; localized to the arch alone (Type I) in five patients and to the descending thoracic and/or abdominal aorta in five patients (Type II). Pulmonary angiography in the solitary patient with clinical features of pulmonary hypertension showed occlusion of the lower lobe branch of the right pulmonary artery. The lesions were occlusive in 19 patients, aneurysmal in one patient and mixed in six patients. While four patients developed fresh lesions in the follow-up period, two showed progression of existing lesions and one revealed partial thrombosis of an aneurysm. Persistently elevated erythrocytic sedimentation rate (> 40 mm) was identified as a reliable indicator for activity of inflammatory process and disease progression. The stable nature of the lesions in 20 out of 26 patients in this study indicates a non-progressive course in the healed stage of aortoarteritis and suggests a conservative approach to the management of this disease in all patients except those with severe, life-threatening manifestations.

Dominantly inherited early-onset non-progressive cerebellar ataxia syndrome

A mother and daughter with suspected dominantly inherited, early-onset, non-progressive cerebellar ataxia syndrome have been reported. A review of the literature and the clinical features of the present cases revealed the nosologic features of this rare disorder, possibly dominant inheritance, floppiness and delayed milestones preceding early-onset mild cerebellar ataxia, non-progressive clinical course, retained or even brisk tendon reflexes without pyramidal tract involvement, normal or slightly delayed intelligence, and occasional nystagmus. Neuroimaging reveals selective involvement of the cerebellum, which is prominent in the vermis and the anterior part of the hemispheres.

Clinical course and prognosis of the lymphoproliferative disease of granular lymphocytes. A multicenter study

Lymphoproliferative disease of granular lymphocytes (LDGL) is a recently recognized, relatively rare atypical lymphocytosis characterized by the presence of over 2000 lymphocytes with cytoplasmic azurophilic granules/mm3 in the peripheral blood. The clinical course is heterogeneous, varying from spontaneous regression to progressive, malignant disease. As a consequence, clinical intervention is not standardized. In a worldwide multicenter study, the authors observed 151 patients with LDGL for a mean follow-up time of 29 months. Forty-three patients were asymptomatic at the time of diagnosis. In the remaining cases, clinical symptoms included fever (41 cases), infections (58), neutropenia (47), anemia (17), and thrombocytopenia (12). In 69 cases, LDGL coexisted with an associated disease. Most patients had a nonprogressive clinical course despite the presence of severe symptoms. In 19 patients, death related to LDGL occurred within 48 months. The authors investigated which features at diagnosis were significantly associated with increased mortality. In the univariate analysis, lymph node and liver enlargement, fever at presentation, skin infiltration, a low (less than or equal to 5000/mm3) or high (greater than 20,000/mm3) peripheral leukocyte count, relatively low (less than or equal to 3000) or high (greater than 7000/mm3) absolute peripheral granular lymphocyte (GL) count, and a low (less than or equal to 15%) percentage of HNK-1-positive cells were found to be predictors of increased mortality. In the multivariate analysis, significant independent predictors were fever at diagnosis, a low (less than or equal to 15%) percentage of HNK-1-positive peripheral blood mononuclear cells (PBMC) and a relatively low (less than or equal to 3000) GL count. These results showed that about 25% of the patients with LDGL were diagnosed after a routine blood count and had no clinical symptoms. The remaining patients were symptomatic, with some experiencing a fatal clinical course. The author's analysis of the significant prognostic features of LDGL may help in understanding the heterogeneous nature of this syndrome.

CONGENITAL MYASTHENIA ASSOCIATED WITH FACIAL MALFORMATIONS IN IRAQI AND IRANIAN JEWS

Fourteen Jewish patients from 10 families of either Iraqi or Iranian origin with congenital myasthenia had associated facial malformations which included an elongated face, mandibular prognathism with class III malocclusion and a high-arched palate. Other common features were muscle weakness restricted predominantly to ptosis, weakness of facial and masticatory muscles, and fatigable speech; mild and nonprogressive course; response to cholinesterase inhibitors; absence of antibodies to acetylcholine receptor; decremental response on repetitive stimulation at 3 Hz but no repetitive compound muscle action potential in response to a single nerve stimulus. This newly recognized form of congenital myasthenia with distinctive ethnic clustering and associated facial malformations is transmitted as an autosomal recessive disorder. The facial abnormalities may be secondary to the neuromuscular defect or may be primary and unrelated. Further studies are needed to elucidate the defect in neuromuscular transmission responsible for the pathogenesis of this syndrome.

Hypotonia, congenital nystagmus, and abnormal auditory brainstem response

A Taiwanese boy, 1 year, 8 months of age, is reported with poor weight gain, hypotonia, trunk ataxia, motor developmental retardation, and horizontal pendular nystagmus with only wave I on auditory brainstem responses. Our patient clinically resembled 9 patients reported in the Japanese literature. Because of its male predominance, occurrence in siblings, early onset, non-progressive course, and characteristic auditory brainstem response findings, the syndrome may be of genetic origin and attributable to a dysgenetic brainstem lesion.

Benign Familial Hematuria

Fifty children had benign familial hematuria. They were from 43 families showing neither deafness, heavy proteinuria, nor chronic renal failure and had a nonprogressive course. Light microscopy of renal biopsy specimens showed little or no glomerular changes. Immunofluorescence showed no significant glomerular deposits of immunoglobulins or complement components, but deposition of C3 in the arteriolar walls was observed in 21 of the 39 patients examined. Electron microscopy demonstrated widespread attenuation of the glomerular basement membrane (GBM) in 19 patients, focal attenuation in 22, and normal GBM in nine. These observations suggest that patients with benign familial hematuria are heterogeneous and that the thin GBM may be related to hematuria.

The rigid spine syndrome and Emery-Dreifuss muscular dystrophy

We present five patients, three of whom suffered from a rigid spine syndrome and two from Emery-Dreifuss muscular dystrophy. One patient with rigid spine syndrome showed a nonprogressive course, normal cardiac rhythm and mild myopathic changes in muscle histology, while in the other two patients there was a rapidly progressive course, sinus tachycardia without cardiac conduction defects and marked fiber necrosis in muscle histology. The two patients suffering from Emery-Dreifuss muscular dystrophy showed a very mildly progressing course, myopathic changes in muscle histology, cardiac conduction defects and deviations in electrocardiograms. These findings show that rigid spine syndrome can be distinguished from Emery-Dreifuss muscular dystrophy.

Chronic hepatitis with nonspecific histological changes. Is it a distinct variant of chronic hepatitis?

A longitudinal follow-up study has been undertaken in 62 patients with clinicopathologically verified chronic hepatitis with non-specific reactive histological changes (NSRH) in comparison with 28 patients with chronic persistent hepatitis (CPH), the clinical features of which are quite similar to NSRH. In contrast to the stationary and non-progressive course of CPH, 45.2% of patients with NSRH, either HBsAg positive or negative, ran a fluctuating course with moderate to marked elevation of SGPT (greater than 200 IU/l) In HBsAg-positive patients, only those positive for HBeAg and a few negative for both HBeAg and anti-HBe had fluctuating courses. In addition, patients with apparent clinical and biochemical changes could show histological features of chronic lobular hepatitis (CLH). A few developed chronic active hepatitis and/or cirrhosis on follow-up biopsy. It is concluded that NSRH is a form of chronic hepatitis different from CPH, but similar to or representing a phase of CLH. It is suggested that NSRH should be categorized as CLH in the classification of chronic hepatitis.

Nonprogressive course of non-A, non-B chronic hepatitis in multitransfused hemophiliacs

Eleven hemophiliacs with chronic liver disease were studied prospectively for 6 yr, with liver function tests and liver biopsies carried out at intervals of 3 yr. The second series of biopsies, compared with the first series, showed continuation of chronic persistent hepatitis in four patients, change to chronic lobular hepatitis in two, and spontaneous improvement of the disease in the four cases who had had chronic active hepatitis characterized by moderate piecemeal necrosis. One patient with active cirrhosis died of liver failure during the follow-up period. Study of the serum and intrahepatic markers for hepatitis B and delta viruses suggests that chronic liver disease is nonprogressive in hemophiliacs who have no intrahepatic viral marker.

Nonprogressive Course of Non-A, Non-B Chronic Hepatitis in Multitransfused Hemophiliacs

Eleven hemophiliacs with chronic liver disease were studied prospectively for 6 yr, with liver function tests and liver biopsies carried out at intervals of 3 yr. The second series of biopsies, compared with the first series, showed continuation of chronic persistent hepatitis in four patients, change to chronic lobular hepatitis in two, and spontaneous improvement of the disease in the four cases who had had chronic active hepatitis characterized by moderate piecemeal necrosis. One patient with active cirrhosis died of liver failure during the follow-up period. Study of the serum and intrahepatic markers for hepatitis B and delta viruses suggests that chronic liver disease is nonprogressive in hemophiliacs who have no intrahepatic viral marker.