Therapy for paraneoplastic neurologic syndromes in six patients with protein A column immunoadsorption

BACKGROUND: Paraneoplastic neurologic syndromes, although rare, cause significant morbidity and mortality. They are thought to be immunologically mediated, but to date those involving the central nervous system (CNS) have not been particularly responsive to immunologic therapy. The use of the novel immunomodulator, protein A immunoadsorption, was explored to address this question. METHODS: Six patients with neurologic paraneoplastic syndromes were treated with this technique, using the "off line" method. Two hundred fifty ml of plasma was perfused through a column containing protein A covalently attached to a silica matrix. The plasma was then returned to the patient. RESULTS: Five of the patients responded to the therapy, with complete and durable responses in three patients with opsoclonus-myoclonus, objective, though transient, improvement in one patient with paraneoplastic brainstem encephalitis associated with a Merkel cell tumor, and stabilization and partial improvement in one patient with paraneoplastic limbic encephalitis. The patient without response developed a cutaneous vasculitis after the second treatment, and therapy was discontinued. CONCLUSIONS: This therapy appears beneficial for a number of paraneoplastic syndromes, most dramatically in the opsoclonus/myoclonus syndrome.     

Clinical and epidemiologic aspects of paraneoplastic dermatoses in hospitalized patients treated at the Clinic for Dermatologic and Venereal Diseases in Novi Sad over a 10-year period (1980-1990)

Authors report results of a retrospective investigation on frequency of paraneoplastic dermatoses, their clinical characteristics, time of onset and course regarding 10 - year material on hospitalized patients at the Clinic for Infectious and Dermatovenerous Diseases in Novi Sad. Out of 9086 hospitalized patients in 14 patients (0.16%) paraneoplastic dermatisis was diagnosed. Out of 14 patients in 5 patients (35.71%) Herpes zoster was diagnosed; in 4 patients (28.57%) bullous dermatosis; in 2 patients (14.29%) paraneoplastic acrokeratosis; in 1 patient (7.14%) exudative multiform erythema in 1 patient (7.14%) erythema figuratum and in one more patient necrotic Herpes labialis was diagnosed. Concerning malignant neoplasms of internal organs together with paraneoplastic dermatosis in most cases (4 - 28.57%) chronic lymphocyte leucosis was found, and in remaining 10 (71.43%) carcinomas were diagnosed at different internal organs. In 7 cases (50%) malignancy proceeded paraneoplastic dermatosis, in 4 cases (28.57%) the malignancy was diagnosed at the same time as paraneoplastic dermatosis and in 3 cases (28.43%) malignancy was established after the onset of paraneoplastic dermatosis. Authors point to the fact that usual skin changes, characteristic for the dermatologic diseases mentioned, in cases when they are associated with visceral malignomas, are characterized by a more serious clinical picture, a longer course of the disease and resistance concerning usual therapy.     

Paraneoplastic pemphigus with tracheobronchial involvement

BACKGROUND: Paraneoplastic pemphigus is a bullous skin disease with characteristic polymorphous clinical presentation and precise histological and immunological features. We report a case of paraneoplastic pemphigus associated with chronic lymphoid leukemia involving the tracheobronchial epithelium. CASE REPORT: A patient with chronic lymphoid leukemia developed pluriorificial lesions. There were several conjunctival, buccal and genital erosions associated with erosive plaques on the trunk, Nikolski's sign and bullous lesions suggestive of paraneoplastic pemphigus. Histology examination of a bulla showed intraepidermal blistering and suprabasal acantholysis. Direct immunofluorescence evidenced intercellular IgG and C3 deposits. Search for anti-intercellular substance antibodies was positive with fluorescence on specific paraneoplastic pemphigus substrates. At immunotransfer, the serum recognized several bands corresponding to 250, 230, 210 and 190 kD antigens, confirming the diagnosis of paraneoplastic pemphigus. Several days later, the patient's general condition deteriorated with bronchorrhea. Bronchial endoscopy visualized ulceronecrotic plaques. Tracheal biopsy evidenced acantholytic cells and intraepithelial cleavage. General corticosteroid therapy was initiated and led to improvement of the skin lesions but the patient died rapidly from pneumonia. Autopsy confirmed the presence of epithelial cleavage and acantholysis involving the trachea and bronchi. DISCUSSION: This case illustrates the difficulty of diagnosing paraneoplastic pemphigus in the early stages. The pluriorificial lesions were suggestive of a Stevens-Johnson syndrome. Besides the genital, conjunctival and buccal mucosa, other mucosa can be involved. In our case, despite the absence of an immunological element, histology was highly suggestive of specific tracheobronchial localizations. The presence of such lesions, which should be searched for in all cases with bronchopulmonary manifestations, worsens the prognosis.     

Psychiatrist and nonphysician mental health provider staffing levels in health maintenance organizations

OBJECTIVE: To describe a patient with a paraneoplastic cerebellar syndrome and optic neuritis with circulating anti-CV2 antibodies and clinical improvement after excision of a small cell lung carcinoma. DESIGN: Report of a case. SETTING: A 62-year-old man simultaneously developed a severe cerebellar syndrome and a bilateral optic neuritis predominantly in the left eye (visual acuity, 20/25 in the right eye; < 20/400 in the left eye; and bilateral swelling of the optic discs). MAIN OUTCOME AND RESULTS: Anti-CV2 antibodies, recently described as associated with paraneoplastic neurological syndrome, were detected in the patient's serum sample. These antibodies were demonstrated to react with the cytoplasm of a subpopulation of oligodendrocytes in the white matter of rat brain in the cerebellum, brainstem, spinal cord, and optic chiasm. The patient was found to have a small cell lung carcinoma, which was removed. After excision of the tumor, the cerebellar syndrome improved dramatically and the papilledema disappeared despite aftereffects of the optic neuritis. CONCLUSIONS: These findings were consistent with the diagnosis of a paraneoplastic neurological syndrome, although both optic neuritis and remission of the cerebellar syndrome are uncommon patterns of paraneoplastic syndromes. CV2 antigen expression by the oligodendrocytes of the cerebellum, brainstem, spinal cord, and optic chiasm correlated with the clinical syndrome observed in our patient. However, the precise pathophysiological role of anti-CV2 antibodies is still unknown.     

A paraneoplastic mixed bullous skin disease associated with anti-skin antibodies and a B-cell lymphoma

BACKGROUND: The full spectrum of bullous diseases associated with underlying cancers remains to be fully defined. OBSERVATION: We describe a patient with a mixed bullous disease exhibiting combined features of cicatricial pemphigoid and pemphigus and associated with a B-cell lymphoma producing an IgM paraprotein to intercellular antigens in human skin. The patient had the clinical features of cicatricial pemphigoid and the histologic and immunofluorescence abnormalities of both cicatricial pemphigoid and pemphigus. These included oral and cutaneous erosions; ocular scarring; subbasal and acantholytic intraepidermal bullae; and circulating and tissue-fixed basement membrane zone and intercellular antibodies. The antibodies were directed to a 140-kd antigen in dermal extracts of skin split with 1 mol/L of sodium chloride and to antigens with approximate molecular weights of 150, 180, 230, and 285 kd in the dermal extract. In contrast to paraneoplastic pemphigus, the intercellular antibodies did not react to mammalian bladder. The intercellular antibodies were of the IgM class and were associated with the paraprotein produced by the malignant B cells. CONCLUSIONS: We believe that this condition represents a novel bullous disease, which we refer to as paraneoplastic mixed bullous disease. This condition illustrates that distinct bullous diseases are associated with paraneoplastic syndromes and that at least one possible mechanism for such eruptions is the production of anti-skin antibodies by malignant B cells.     

The anti-Hu syndrome: a clinical and immunological study of 7 cases

The authors describe the clinical and biological data of seven patients with anti-Hu antibodies. Six of them displayed a small cell lung carcinoma (SCLC), but no cancer was detected in the 7th patient in spite of an extensive workup. The clinical heterogeneity of the anti-Hu syndrome is emphasized. The major symptoms were linked to a severe sensory neuropathy in three cases, to cerebellitis in two cases, to dysautonomia in one case, and to gastro-intestinal pseudo-obstruction in one case. One patient also displayed EMG abnormalities characteristic of the Lambert-Eaton myasthenic syndrome. Two patients developed opsoclonus or ocular flutter associated with severe confusion in the late stage of their disease. In four patients, the neurological signs and symptoms preceded the discovery of the SCLC, and in two cases the initial detection of anti-Hu antibodies prompted the successful search for this tumor. Immunopathological events injuring the peripheral and central nervous system are briefly discussed.     

Paraneoplastic encephalomyelitis and seminoma: importance of testicular ultrasonography

We report two patients with paraneoplastic limbic and brainstem encephalitis associated with occult nonmetastatic testicular seminoma. In each patient, the neoplasm was detectable only by testicular ultrasonography. Male patients with this syndrome in whom lung cancer is not found should undergo testicular ultrasonography as part of the search for an extrapulmonary neoplasm. A normal clinical testicular examination is insufficient to exclude an occult seminoma.     

Intravenous immunoglobulin treatment in paraneoplastic neurological syndromes with antineuronal autoantibodies

OBJECTIVE: To evaluate the effect of intravenous high dose human immunoglobulin (IVIg) therapy on the clinical course and autoantibody titres of patients with neurological paraneoplastic syndromes. METHODS: Twenty two patients with paraneoplastic encephalomyelitis and sensory neuronopathy syndrome associated with anti-Hu antibodies (18) or paraneoplastic cerebellar degeneration (PCD) with anti-Yo antibodies (four), were treated with 1-26 (mean 5.8) cycles of IVIg. The Rankin scale was used to evaluate the response. RESULTS: The only serious toxicity was one case of haemolytic anaemia. Twenty one patients were evaluable for therapeutic response. One patient, with subacute sensory neuronopathy (SSN), improved for at least 15 months, 10 remained stable (eight with anti-Hu and two with anti-Yo antibodies), and 10 deteriorated (eight with anti-Hu and two with anti-Yo antibodies). In seven of the 10 patients who stabilised, the syndrome had already made a plateau when the treatment was started but three patients (one with anti-Hu and two with anti-Yo antibodies) who had still been progressing stabilised for six, eight, and more than 48 months, including one patient with SSN who achieved stabilisation when the neurological dysfunction was only moderate (Rankin scale = 3). Another patient with SSN and initial stable response worsened when IVIg was reduced and improved when it was increased. No significant predictive factors of outcome could be identified but improvement or stabilisation was more frequent in patients with isolated involvement of the peripheral nervous system (62%) than in patients with evidence of CNS damage (37%) at the onset of treatment. Stabilisation in patients with CNS involvement was only achieved when the neurological dysfunction was already severe (Rankin scale > 3). The titres of autoantibodies did not change significantly. CONCLUSION: Treatment with IVIg at the doses given in the present protocol was not effective in paraneoplastic CNS syndromes associated with antineuronal antibodies. The role of this regime in the treatment of SSN should be further evaluated.     

Immune surveillance: paraneoplastic or environmental triggers of autoimmunity

Autoimmunity associated with tumor cell development seems an important mechanism by which to prevent progression to clinical cancer. In this brief review, tumor autoantigens associated with paraneoplastic syndrome, non-HLA-associated organ-specific autoimmune diseases, and the highly cell-specific autoimmune eradication of the islet beta cells in type 1 diabetes are compared and discussed. It is suggested that autoreactivity is important in preventing tumor formation; however, it may be at the expense of the development of autoimmune disease. Although the cytotoxic T lymphocytes (CTL) induction by HLA class I has been studied and used in clinical trials, little is understood about the initiation and HLA class II mediated induction of an immune response to neoplastic cells. This induction apparently takes place because paraneoplastic disorders are often due to an immune response to the tumor cell resulting in a cross-reactivity with a normally expressed autoantigen on a remote nontumor-associated target cell. The problem of immune surveillance to eradicate neoplasm or downregulate pathological autoimmunity are therefore closely related phenomena. An improved understanding of immune mediated tumor suppression should therefore greatly benefit immunotherapy of type 1 diabetes, and the two areas of research would benefit from an interdisciplinary endeavor.     

Effects of doxycycline on cancer cells in vitro and in vivo

We present the case of a 71-year-old white male with paraneoplastic pemphigus associated with a B-cell non-Hodgkin's lymphoma. Diagnosis of paraneoplastic pemphigus was made by the characteristic findings on immunoprecipitation performed on a serum specimen. Paraneoplastic pemphigus is a severe autoimmune disease comprised of polymorphous mucocutaneous lesions, characteristic laboratory findings, association with one of several types of neoplasms, and a very poor prognosis.     

Paraneoplastic syndromes affecting the nervous system

Paraneoplastic syndromes can affect virtually any portion of the nervous system. Most paraneoplastic syndromes are believed to be caused by an autoimmune reaction to an "onconeural" antigen shared by the cancer and the nervous system. The immune reaction may retard growth of the cancer, but it also damages the nervous system. Specific autoantibodies found in some individual paraneoplastic syndromes are usually associated with specific tumors. Neurological disorders, clinically and pathologically identical to paraneoplastic syndromes, may occur in some patients without cancer, but paraneoplastic antibodies are not found in these patients. The diagnosis of a paraneoplastic syndrome is based on its increased incidence in patients with cancer, the occasional response of the neurological syndrome to treatment of the underlying cancer, or the presence of specific autoantibodies. Some paraneoplastic syndromes respond to treatment of the underlying cancer or to immunosuppression but, for most syndromes, no effective treatment exists.     

Sarcoid-like hepatic granulomas, associated with gastric neoplasia. Description of a case

Giant cell granulomas in liver biopsies is a relative common finding. Among the many causes of granulomatous lesions of the liver primary biliary cirrhosis and sarcoidosis are the most frequently diagnosed. On the other hand sarcoid-like granulomatous reaction can be encountered associated to malignant tumours. Purpose of the present paper is to describe a case of a sarcoid-like reaction of the liver associated to gastric adenocarcinoma. The patient was a 66 yr old man who underwent gastrectomy for a signet-ring cell adenocarcinoma. Pathological anamnesis was unremarkable. Liver function tests were within normal limits. Chest x ray was normal. A liver biopsy was performed during surgery as the liver presented an irregular surface. On histology giant cell granulomas with sarcoid-like features were seen in the hepatic parenchyma. Same reaction was present in the perigastric lymph nodes. The patient died immediately after surgery due to massive pulmonary embolism. No autopsy was performed. Among the possible diagnoses primary biliary cirrhosis, sarcoidosis and paraneoplastic sarcoid-like granulomatous reaction were considered. Primary biliary cirrhosis and sarcoidosis were excluded on the basis of the past clinical history of the patient, that was unremarkable; furthermore liver function tests performed preoperatively were within normal ranges. Thus paraneoplastic sarcoid-like reaction involving the liver was regarded as the most likely diagnosis.     

Response of melanocortin-4 receptor-deficient mice to anorectic and orexigenic peptides

Whether P/Q-type voltage-gated calcium channel (VGCC) antibodies are present in the serum of patients with paraneoplastic syndromes other than the Lambert-Eaton myasthenic syndrome (LEMS) and tumors other than small-cell lung cancer (SCLC) is controversial. Using a commercially available radioimmunoprecipitation assay kit, we examined the sera of 93 patients with paraneoplastic syndromes of the central nervous system (CNS), including 27 patients with paraneoplastic cerebellar degeneration (PCD) associated with tumors other than SCLC and 66 SCLC patients with paraneoplastic encephalomyelitis and sensory neuronopathy (PEM/SN). All PCD sera from patients with tumors other than SCLC were negative for P/Q-type VGCC antibodies. Eight of 66 (12%) SCLC patients with PEM/SN had P/Q-type VGCC antibodies; 4 had LEMS and the other 4 had no symptoms of LEMS or they were overlooked and, therefore, not examined electrophysiologically. In patients with paraneoplastic syndromes of the CNS, the detection of P/Q-type VGCC antibodies supports the diagnosis of LEMS; in our series, only 6% of patients with SCLC and PEM/SN may have had a false positive antibody result, or undiagnosed LEMS.     

Kinsbourne syndrome: review of our cases

INTRODUCTION: The childhood opsoclonus-myoclonus or Kinsbourne syndrome, is a uncommon process, of acute or subacute beginning, which affects infant and children. It's course is characterized by opsoclonus, polimyoclonias and cerebellar ataxia. The disease is frequently associated to neuroblastoma (46%). MATERIAL AND METHODS: We present a retrospective study on 9 patients, emphasizing the clinical presentation and the evolution aspects. RESULTS AND CONCLUSIONS: We found changes in the EEG in three cases. Most surprising is the scarce incidence of neuroblastoma, which has been found only in a one out of nine patients. We found three cases with relapse during the treatment or on withdrawal and one of them relapsed twice again. The evolution has been variable, since 5/9 patient have presented some type of mild or moderate neuro-psychological sequelae. Out of three patient with relapses, two presented permanent neurological sequelae. A patient which suffered three relapses, is also the one which presents more serious sequelae.     

Paraneoplastic syndromes in patients with ovarian neoplasia

The prevalence of several paraneoplastic syndromes associated with ovarian cancer was determined from a clinicopathological study of 908 patients with primary ovarian malignancy in the North East Thames Region. The diversity and rarity of these manifestations are great and the explanation for them is difficult. Circumstantial evidence suggests that in some cases an autoimmune phenomenon is the most plausible cause.     

Epilepsia partialis continua: a new manifestation of anti-Hu-associated paraneoplastic encephalomyelitis

We report on 3 anti-Hu-positive patients who presented with clinical and electroencephalographic (EEG) features of epilepsia partialis continua (EPC). Two of the patients had an associated small cell carcinoma. Magnetic resonance imaging (MRI) disclosed a hyperintense nonenhancing focal lesion in T2-weighted images in the sensorimotor area in 2 patients. Histopathological analysis of the lesion revealed inflammatory infiltrates and neuronal cell loss. In the patient who had a postmortem study, these neuropathological changes were not observed in other areas of the nervous system. This study emphasizes that the possibility of an anti-Hu-associated paraneoplastic disorder must be considered in patients with cortical encephalitis presenting with EPC when a brain tumor can be excluded.     

Factors predictive of bile duct stones in patients with acute calculous cholecystitis

A 13-month-old girl developed opsoclonus-myoclonus syndrome in association with neuroblastoma. She showed irritability, hyperhidrosis and a bad temper. Serum and urinary vanilmandelic acid, homovanilic acid and catecholamines were elevated at the same time. Chest CT demonstrated the presence of neuroblastoma in the paravertebral region. Cranial CT and MRI revealed no abnormal findings. Brainstem auditory-evoked potentials and short latency somatosensory evoked potentials were normal, whereas blink reflex showed long duration and high amplitude of late components (R2 and R2') indicating hyperexcitability of the interneurons in the lower brainstem. These findings improved gradually as opsoclonus disappeared. Her neurologic symptoms resolved completely within 2 years after the resection of the tumor. The hyperexcitability of the blink reflex may indicate the hyperactivity of the neurons in the brainstem reticular formation responsible for the abnormal saccadic eye movements (opsoclonus), which could be caused by the oversecretion of dopamine or by the supersensitivity of dopaminergic receptors.     

Severe algoneurodystrophy of the right foot associated with prostatic cancer

The authors report 1 case of particularly severe reflex neurovascular dystrophy whose clinical course was marked by the discovery of a carcinoma of the prostate. There was improvement in the reflex neurovascular dystrophy despite hormonal therapy of the cancer. Reflex neurovascular dystrophy cannot be considered as a form of a paraneoplastic syndrome.     

Paraneoplastic elevation of serum alkaline phosphatase in renal cell carcinoma: incidence and implication on prognosis

PURPOSE: We investigated the incidence and prognostic significance of paraneoplastic elevation of serum alkaline phosphatase in patients with renal cell carcinoma. MATERIALS AND METHODS: Clinical data of 365 pathologically proved renal cell carcinoma cases were reviewed. Serum alkaline phosphatase level greater than 100 units per 1., but without obvious conditions that may cause phosphatase elevation, including metastasis to or disease of liver or bone and pregnancy, was regarded as paraneoplastic serum alkaline phosphatase elevation. Survival was evaluated using the Kaplan-Meier method. RESULTS: Of 365 patients 77 (21.1%) had paraneoplastic serum alkaline phosphatase elevation. The respective incidence from stage I to IV cases was 9.9% (16 of 161), 31.9% (15 of 47), 34.3% (23 of 67) and 25.6% (23 of 90). Patients with stage I disease had the lowest incidence but there were no statistically significant differences among stages II, III and IV disease. Of 77 patients with elevated serum alkaline phosphatase 48 had additional paraneoplastic manifestations. The disease specific 5-year survival rate in patients with normal serum alkaline phosphatase was significantly better than in patients with isolated phosphatase elevation, which in turn was better than in patients with multiple paraneoplastic syndromes (70.7 versus 50.5 versus 30.8%). Patients with persistent or recurrent elevation of serum alkaline phosphatase after radical nephrectomy had metastatic lesion or local recurrence. In some patients serum alkaline phosphatase returned to normal after nephrectomy but metastasis developed later without recurrent phosphatase elevation. CONCLUSIONS: Paraneoplastic serum alkaline phosphatase elevation in renal cell carcinoma patients implies an unfavorable prognosis, and additional paraneoplastic syndromes further worsen the prognosis. Recurrent or persistent serum alkaline phosphatase elevation after radical nephrectomy suggests distant metastasis or residual tumor. However, the return of serum alkaline phosphatase to normal does not guarantee cure of the disease. Identification of paraneoplastic serum alkaline phosphatase elevation is valuable in the prediction of outcome and postoperative followup of renal cell carcinoma patients.     

Scleredema, acanthosis nigricans and IgA/Kappa multiple myeloma

BACKGROUND: Scleredema is an uncommon disease of unknown origin. Characteristic thick skin with symmetrical diffuse induration develops. The infiltration begins on the face and neck then extends to the root of the upper limbs and trunk. There are three clinical types of scleredema. The first is preceded by an upper airway infection and progresses rapidly before regressing spontaneously within a few months. The second type is associated with chronic diabetes. The third type is associated with monoclonal gammapathy, rarely of myelomatous type, and develops insidiously. Acanthosis nigricans can be a paraneoplastic syndrome, often associated with a gastrointestinal cancer. Few cases associating scleredema and acanathosis nigricans have been reported. CASE REPORT: A 56-year old woman had developed scleredema over the last 6 years when acanthosis nigricans appeared together with IgA kappa multiple myeloma. Treatment with melphalan and prednisolone was effective against the myeloma as well as the scleredema and acanthosis nigricans. DISCUSSION: Only five cases of associated scleredema and multiple myeloma have been reported, four with kappa IgG myeloma and one with IgA myeloma. An association between acanthosis nigricans and sclerederma could be coincidental although the fact that the different manifestations regressed together after the myeloma treatment would suggest some relationship between these three diseases.