A progressive neurologic disorder with supranuclear vertical gaze paresis and distinctive bone marrow cells.

Nine patients with a progressive neurologic disorder that was characterized by mental deterioration, supranuclear vertical gaze paresis, and foam cells or sea-blue histiocytes in the bone marrow are described and compared with patients who were previously described as having " neurovisceral storage disease with vertical supranuclear ophthalmoplegia" and "dystonic lipidosis." The clinical manifestations of our patients and those described by others and the pathologic findings and profiles of lipid analysis reported by others are similar to those in patients with Niemann-Pick disease, type C. Sphingomyelinase activities in leukocytes and skin fibroblasts were normal in our patients and in more than half of the reported cases; these findings are also compatible with those in patients with Niemann-Pick disease, type C. Until the biochemical and genetic abnormalities of Niemann-Pick disease, type C are clearly defined, it is justifiable to classify the disorder under discussion as a subgroup of Niemann-Pick disease, type C because it seems to be a heterogeneous group. From the clinical point of view, the diagnosis is difficult to establish in the absence of abnormalities in the bone marrow in patients who are older than 20 years; repeat examinations of the bone marrow are necessary in such patients. Clinicians should be aware of this disorder not only in patients in the first and second decades of life, when this disorder usually becomes symptomatic, but also in patients in the fourth and fifth decades.

Chlorambucil in the treatment of uveitis and meningoencephalitis of Behçet's disease.

Among 21 patients with Behçet's disease, the results of various treatments were assessed. Treatment with chlorambucil, 0.1 mg/kg daily, compared favorably with corticosteroids. Uveitis and visual acuities improved in five of seven eyes when the patients were treated with chlorambucil, whereas improvement was observed in only four of 13 eyes when treatment consisted of corticosteroids. In 19 treatment courses among 14 patients with meningoencephalitis or recurrent meningitis, eight of nine patients treated with chlorambucil had remission of their disease; eight of 10 treatment courses with other agents--generally, corticosteroids--failed to induce remission in any of eight patients. Elevated cerebrospinal fluid cell counts returned to normal in five of nine patients treated with chlorambucil but remained elevated in five of six patients treated with corticosteroids. Two patients died, one who was taking prednisone plus cyclophosphamide and the other after prednisone plus multiple immunosuppressive treatments. Toxicity from chlorambucil included leukopenia (two patients), thrombocytopenia (one), bronchopneumonia (one), and amenorrhea (two). The duration of chlorambucil therapy averaged 1.8 years both for patients with uveitis and for those with meningoencephalitis.

Cauda equina syndrome secondary to long-standing ankylosing spondylitis.

Fourteen patients with cauda equina syndrome secondary to long-standing ankylosing spondylitis are described. The roughly symmetrical neurological deficits were very slowly progressive and began long after the onset of the spondylitis, usually well after the rheumatological symptoms had stopped. Eventually every patient had cutaneous sensory loss in the fifth lumbar and sacral dermatomes. All patients developed urinary sphincter disturbances of a lower motor neuron type. There was prominent loss of rectal sphincter tone, and all but 2 patients had bowel complaints, including incontinence and severe constipation. Seven patients had mild to moderate weakness in the lumbosacral myotomes. Seven patients had pain in the rectum or lower limbs. Electromyographic abnormalities were consistent with multiple lumbosacral radiculopathies. Myelography and computed tomographic scanning of the lumbosacral spine showed characteristic enlargement of the caudal sac and dorsal arachnoid diverticula that had eroded the laminae and spinous processes. Recognition of this syndrome, coupled with computed tomographic scanning of the lower spinal canal, allows one to omit myelography, a procedure that is difficult because of the associated spine abnormalities. Surgical intervention should be avoided.

Renal stones in Wilson's disease.

Fifty-four patients with Wilson's disease were studied with regard to renal stones. Seven of the 45 patients (16 per cent) who underwent roentgenographic procedures of the urinary tract had unequivocal evidence of renal stones. In four of the seven patients with Wilson's disease who had renal stones, the stones were discovered at the time or before the diagnosis of Wilson's disease was made. Of the several possible factors that may predispose patients with Wilson's disease to renal stone formation, the renal tubular acidosis pattern of abnormality in acid-base excretion is probably the most significant. In general, patients with renal stones and unexplained neurologic, bony or hepatic abnormalities should be screened for Wilson's disease by slit-lamp examination, determination of serum copper and ceruloplasmin concentrations, and urinary excretion of copper, particularly if they have relatively alkaline urine.

Clinical spectrum of Wilson's disease (hepatolenticular degeneration).

Fifty-eight patients with Wilson's disease are reviewed, of whom 25 symptomatic patients experienced liver disease first and 28, brain disease. Ten of these patients presented with liver disease alone, 19 with brain disease alone, and 24 with evidence of both liver and brain disease. The remaining five were discovered as asymptomatic siblings of known patients. Three of the patients with hepatic presentation and one with neurologic presentation later experienced the other type of symptomatology, bringing the total number of patients with mixed disease to 28. Of the 44 patients with brain disease, 12 presented primarily with extrapyramidal findings, 6 with cerebellar findings, and 17 with both; pseudobulbar findings were noted in 9 patients, all of whom had other symptoms of severe nervous system disease. In addition to these presentations, in an appreciable number of patients the first symptoms were of a mental or emotional disorder. Disease of other organ systems, such as the joints and kidneys, also occurred but infrequently. Where adequate family information was available, 13 of 65 siblings (20%) were known to have had or were suspected of having had Wilson's disease. This is consistent with the autosomal-recessive pattern of inheritance.

Hematologic (cytopenic) manifestations of Wilson's disease (hepatolenticular degeneration).

The records of 54 consecutive patients with Wilson's disease seen at the Mayo Clinic from 1952 through early 1977 were reviewed to determine the frequency fo hematologic abnormalaties in their evaluation. Leukopenia and thrombocytopenia sometimes have been ascribed to treatment with D-penicillamine and its toxicity; however, we have found cytopenia to be a frequent finding in the presenting laboratory data of patients with Wilson's disease. Twenty-eight patients (52%) had thrombocytopenia and 16 of these patients (30% of the total) also had leukopenia. Severe, acute, intermittent hemolytic episodes were the initial and only presenting complaint of one patient. Six of the patients with significant cytopenias had splenectomy, and in all cases the peripheral blood counts returned to normal values. Long-term treatment with D-penicillamine improved the hepatic and neurologic dysfunction in most patients; however, the cytopenias remained unchanged except in three patients (treated 2, 5, and 10 years).

The ophthalmologic manifestations of Wilson's disease.

Fifty-three patients with Wilson's disease were studied with regard to ophthalmologic abnormalities. Of the 35 symptomatic patients initially seen and treated at the Mayo Clinic, 34 (97%) had Kayser-Fleischer rings and 6 (17%) had sunflower cataracts at the time of diagnosis. In patients followed for a year or more, penicillamine therapy resulted in improvement of the Kayser-Fleischer rings in 18 of 20 (90%) patients and total clearing of the sunflower cataracts in 4 of 5 patients. The specific pattern of copper deposition in Kayser-Fleischer rings and the improvement with treatment occurred along four reproducible stages. None of five asymptomatic siblings of patients with known Wilson's disease had Kayer-Fleischer rings at the time of initial study. In one (untreated) of the five, Kayser-Fleischer rings developed 20 months after the initial normal slit-lamp examination. The presence of Kayser-Fleischer rings, and the absence of other ophthalmologic signs (such as nystagmus, cranial nerve palsies, and other movement disorders), can be of great assistance in the diagnosis of Wilson's disease. Once the condition has been diagnosed, specific medical therapy with penicillamine and low-copper diet dramatically improves what would otherwise be an inevitably fatal course.

Neurologic involvement in seven patients with Behçet's disease.

Of 25 patients with Behçet's disease seen in five years at the Mayo Clinic, seven had central nervous system involvement. The mean interval from onset of Behçet's disease to central nervous system involvement was 1.3 years, and the mean period of observation thereafter was 3.8 years. All patients had headache and fever during or preceding exacerbations of the central nervous system disease, and all had cerebrospinal fluid pleocytosis (white cell counts ranged from 6 to 490/mm3) with predominant lymphocytosis. The mean cerebrospinal fluid protein level was 55 mg/dl, and gamma globulin was less than 15 per cent in six patients. Results of cerebrospinal fluid, lesional and serologic studies for bacterial, fungal and viral agents were negative. Clinical findings included corticospinal tract disease (five patients), cerebellar ataxia (four patients), pseudobulbar palsy (three patients) and transient ocular palsies (three patients). All these occurred in concert with the systemic phases, especially aphthosis. Corticosteroid therapy was used in six patients, cyclophosphamide therapy in two and azathioprine therapy in two. The neurologic manifestations tended to recur when dosages of the drugs were lowered and established central nervous system damage could not be reversed. The case histories suggest that steroids, when used promptly and in sufficient dosage (up to 60 mg prednisone), are effective in reducing or preventing progression of central nervous system disease. Three patients died, one from Pneumocystis carinii infection, one from neurologic disease and another from presumed myocardial infarction. The central nervous system involvement in Behçet's disease should be diagnosed earlier, and it can be if attention is given to other systemic criteria, that is, aphthous stomatitis, aphthous genital lesions, cutaneous vasculitis, uveitis and synovitis.

Platelet function and coagulation in patients with Wilson disease.

Sixteen patients with Wilson disease (hepatolenticular degeneration) were studied from the hemostatic point of view, particularly with regard to platelet function. Five of the patients had a mild bleeding tendency that was characterized by easy bruising. Moderate thrombocytopenia was observed in three of the five bleeders and in two of the others. One bleeder was thrombocytotic and hyperfibrinogenemic. Bleeding times, platelet retention and prothrombin consumption were abnormal rarely. However, 15 of the 16 patients had some abnormality of platelet aggregation: one when adenosine diphosphate was added to platelet rich plasma, three when epinephrine was added, and the remainder when collagen was added. The collagen abnormalities were delayed or absent aggregation (five patients, four of whom were bleeders) and absence of a change of shape (12 of the 16 patients). Platelet aggregation was completely normal in only one patient.

Wilson's disease (hepatolenticular degeneration) of late adult onset: report of case.

Wilson's disease usually has its onset in childhood, adolescence, or early adulthood. The clinical picture of hepatic dysfunction without dysfunction of the central nervous system is more typical of the disease in the child or the adolescent than in the adult. We are presenting the case of a man whose age at onset of the disease was 55 years and who had the hepatic complications of Wilson's disease without clinical evidence of disease of the central nervous system. All patients with chronic hepatitis (chronic active liver disease) or cirrhosis of unknown etiology should be screened for the possibility of Wilson's disease. This screening should include slit-lamp biomicroscopy for Kayser-Fleischer rings, determination of serum ceruloplasmin concentration, and measurement of 24-hour urinary excretion of copper. If doubt exists concerning the diagnosis, either a radiocopper kinetic study, using 64Cu or 67Cu, or, if the patient's condition permits, a liver biopsy with measurement of hepatic copper concentration should be done. The rubeanic stain of hepatic tissue for copper is unreliable in making or excluding the diagnosis of Wilson's disease.

Pigmented corneal rings in a patient with primary biliary cirrhosis.

A patient with primary biliary cirrhosis who had high hepatic, serum, and urine copper levels was found by slit-lamp biomicroscopy to have pigmented corneal rings similar to Kayser-Fleischer rings. Wilson's disease was excluded on the basis of the elevated serum ceruloplasmin and copper levels, the lack of neurological disease despite advanced liver disease, a negative family history, and the typical clinical features of primary biliary cirrhosis. Although the exact chemical nature of the corneal rings is unknown, the cornea may be another tissue associated with elevated tissue copper levels in primary biliary cirrhosis.

Biliary bile acid composition in Wilson's disease.

Biliary bile acid composition and pattern of bile acid conjugation with glycine or taurine were found to be within normal limits in six patients with documented Wilson's disease. Four patients had previous biopsy evidence of cirrhosis (three with active hepatitis), but most conventional liver function tests gave normal results at the time of the study. Serum levels of conjugates of cholic acid, measured by radioimmunoassay, were not increased. However, plasma disappearance if intravenously injected glycine conjugate of cholic acid was significantly delayed in all subjects, suggesting that this is a more sensitive test of hepatic excretory function and may be of value for assessing hepatic function in patients with this rare genetic disorder. No evidence of a primary disturbance in bile acid metabolism was found in these patients.

Effect of dietary D-penicillamine on metabolism of copper in the rat.

When normal rats were put on a diet containing d-penicillamine equivalent to a dosage of about 1.75 g/day in a 70-kg man, there was a prompt, marked decrease in biliary excretion of copper and of radiocopper after its intravenous administration. Urinary copper increased as tissue copper levels decreased; this decrease was most pronounced in bone marrow, kidney, lung, and spleen. Plasma copper increased and p-phenylendiamine oxidase activity increased. Fecal copper decreased modestly, which was probably attributable to decreases in food intake and biliary copper. Copper-toxic rats, already hypercupriuric, excreted more urinary copper when given d-penicillamine.