A case of Crow-Fukase syndrome associated with idiopathic thrombocytopenic purpura

A 40-year-old man was admitted to our hospital because of paresthesia and weakness of the limbs. At the age of 38, he was diagnosed as having an idiopathic thrombocytopenic purpura (ITP) which have been refractory to oral administration of prednisolone and splenectomy. Platelet-associated IgG was elevated markedly at that time. It was, however, only mildly elevated on this admission. He showed polyneuritis, generalized pigmentation, hirsutism, and marked edema on the legs. The bone X-ray disclosed a lytic lesion in the left iliac bone, which was confirmed as a plasmacytoma by bone biopsy. Axonal degeneration with marked loss of myelinated figure was seen on sural nerve biopsy. Serum immunoelectrophoresis revealed his monoclonal IgG was lambda type. Then, he was diagnosed as having a Crow-Fukase syndrome associated with ITP. Plasma exchange, pulse therapy, and irradiation to plasmacytoma resulted in a slight improvement of the polyneuritis and the skin symptoms, and a disappearance of edema. However, ITP has not responded to these therapies. Although the same autoimmune mechanism is suggested in these conditions, we could not clarify how this monoclonal IgG produce both polyneuritis and ITP.     

A case of Crow-Fukase syndrome with extramedullary plasmacytoma: marked clinical deterioration following a biopsy to plasmacytoma]

A 66-year-old man developed paresthesia of the distal parts of the bilateral lower limbs a week after his upper respiratory infection, followed by the weakness with the legs and paresthesia with the lip area, tongue and finger tips. Those symptoms gradually became worse to the point that he was unable to walk 10 days later. Although skin pigmentation, edema, and lymph node swelling were not found, we made a diagnosis of Crow-Fukase syndrome (CFS) because of clinical features of polyneuropathy, IgG-lambda type M proteinemia, endocrinological abnormality, elevated plasma level of vascular endothelial growth factor (VEGF) and extramedullary plasmacytoma in his abdomen. Following intravenous immunoglobulin therapy (IVIg), he showed marked improvement. However, his neurologic symptoms deteriorated acutely just after open biopsy together with the elevation of VEGF level, and a few days later he was in the state of flaccid quadriparesis. We tried IVIg therapy again and his neurologic symptoms were markedly improved. We speculated that an elevated VEGF, released from plasma cells induced by the bioprocedure, might have caused an increase in microvascular permeability and affected the blood-nerve-barrier, thereby his neurologic symptoms deteriorated. It is thought that this case may support the hypothesis that a significant role is played by VEGF in the pathomechanism of the development of CFS. Additionally we experienced that IVIg was very effective to the neurologic symptoms, and we think that IVIg will be able to be one of the future therapy of the CFS. To our knowledge, there has been no report of CFS which manifested acute deterioration of his neurologic symptoms just after open biopsy with acute onset with Guillain-Barré syndrome like symptoms.     

A patient with Crow-Fukase syndrome associated with pulmonary plasmacytoma]

We here reported a 54-year-old female patient with Crow-Fukase syndrome associated with pulmonary plasmacytoma. She was found to have scattered tumor in 1990. Although the tumor had slowly grown for the last 10 years, she showed no clinical symptoms. Numbness and weakness of lower extremities began in June 1999, and she was referred to Kyoto University Hospital on Oct. 21 1999 for evaluation of progressive symptoms. She had skin pigmentation, edema of the lower extremities, lymphadenopathy, muscle weakness and sensory disturbance in a glove-and-stocking distribution. Serological examination showed monoclonal IgG-lambda gammopathy. Serum vascular endothelial growth factor (VEGF) was markedly elevated. Microscopic studies on biopsied sural nerve demonstrated mild decrease of myelinated fibers. Immunohistochemically, the pulmonary tumor was defined as an IgG (lambda type) plasmacytoma. After treatment with melphalan-prednisolone therapy, the neurological symptoms improved along with decrease of serum VEGF levels as well as the size of pulmonary plasmacytoma. This is the first report of a patient with Crow-Fukase syndrome associated with pulmonary plasmacytoma. This case suggests that growth of pulmonary plasmacytoma might have played an important role in the overproduction of VEGF and thus development of Crow-Fukase syndrome.     

Crow-Fukase syndrome

In Japan, Crow-Fukase syndrome is a target of active research because of many cases reported. Therefore, the following three topics regarding this syndrome were discussed. 1) Etiology of Crow-Fukase syndrome. Even in reported cases of Crow-Fukase syndrome with monoclonal protein or polyclonal immunoglobulins and no apparent multiple myeloma, there were plasmacytomas in the lymph node or other tissues, and symptoms became improved after removal of these tumors. Therefore, plasma cells seem to be involved. According to recent studies, impairment of the pituitary function may play some role. 2) New pathological findings in the lymph node histology. In the lymph node of patients with this syndrome, we found in its germinal center a peculiar abnormality called angiosclerosis, in which branching tortuous capillaries with thickened wall including many cells were prominent, which may be different from those of Castleman's disease. 3) Nerve conduction studies using a new collision technique. Crow-Fukase syndrome is associated with marked slowing of even the maximal motor and sensory conduction velocities. Therefore, in order to understand its pathophysiology better, submaximal conduction velocities should be measured using the new collision technique because this technique is different from Hopf's method that is affected by the refractory period of nerve fibers.     

A case of Crow-Fukase syndrome with increased serum interleukin-6]

We experienced a 47-year-old Japanese female with polyneuropathy, edema, hypertrichosis, hyperpigmentation, and white nail, which were diagnostic as having Crow-Fukase syndrome. Laboratory and radiological evaluation showed neither plasma cell dyscrasia nor monoclonal gammopathy. Increased factor VIII activity and thrombocytosis, which suggested thrombotic tendency, were observed at the exacerbation of clinical symptoms. In her third exacerbation, she presented marked cyanosis in her right foot, and angiography confirmed narrowing of arteries at the ankle. Increased serum interleukin-6 was also observed, and the production of interleukin-6 by endothelial cells of cutaneous angioma was shown. Possible role of interleukin-6 in Crow-Fukase syndrome was discussed.     

A patient with lambda type light-chain disease associated with Crow-Fukase syndrome and autoimmune thrombocytopenia]

A 67-year-old woman, who presented polyneuropathy, pleural effusion, ascites and sclerosing changes in the ribs, was admitted to our hospital on June 17, 1987. On admission, cerebrospinal examination showed a marked protein-cell dissociation and a delay in nerve conduction velocity. Bence-Jones protein was detected in urine, and the immunohistochemical study of biopsied bone marrow of the rib revealed lambda-chain positive plasmacytoma. Serum immunoelectrophoresis, however, showed no monoclonal gamma-globulinemia. From the findings described above, she was diagnosed as having Crow-Fukase syndrome associated with lambda-type light chain disease. Even with a therapy by prednisolone, platelet counts progressively declined to 10,000/ml3. Bone marrow aspiration showed normal number of megakaryocytes. Since platelet-associated IgG was increased to 452 ng/1.0 x 10(8) plt, a diagnosis of autoimmune thrombocytopenia was considered. Melphalan and cyclophosphamide to plasmacytoma resulted in a marked improvement of platelets. In addition, the level of platelet-associated IgG returned to normal range. Polyneuropathy, however, didn't respond to those therapies. It was suggested that both Crow-Fukase syndrome and thrombocytopenia were closely concerned with plasmacytoma but developed in a different manner.     

A case of Crow-Fukase syndrome with respiratory failure due to bilateral diaphragmatic paralysis]

A 62-year-old man with well-controlled diabetes mellitus developed numbness of the bilateral feet and hands, followed by subacutely progressive weakness and amyotrophy of extremities. He became bed-ridden state, and dyspnea also appeared, so he was referred to our hospital. Physical examination revealed a lean man, with dark-reddish skin pigmentation, crabbed fingers, bilateral pretibial pitting edema, and bristles in extremities. Thoracoabdominal paradoxical respiration was observed and pulmonary vesicular sounds was decreased markedly in the both lungs. Laboratory data revealed hypoproteinemia, abnormalities of endocrine system, but M-protein was not detected. Serum vascular endothelial growth factor level was quite high. Chest radiography revealed elevation of the bilateral diaphragm, the % vital capacity (%VC) was 24%, and arterial blood gas analysis showed marked hypoxia with hypercapnia. These findings suggested that his respiratory failure was induced by bilateral diaphragmatic paralysis caused by bilateral phrenic nerve palsy due to Crow-Fukase syndrome. He became somnolent because of hypercapnic narcosis, so non-invasive positive pressure ventilation (NIPPV) was started. We treated him with intravenous immunoglobulin and oral corticosteroids therapies, and after these therapies, his symptoms were remarkably recovered and NIPPV became unnecessary soon. The most frequent causes of respiratory failure in Crow-Fukase syndrome are pleural effusion and pulmonary hypertension, and only two cases of this syndrome with respiratory failure caused by bilateral diaphragmatic paralysis were reported until now. When the patients with Crow-Fukase syndrome complain of dyspnea, we should take the diaphragmatic paralysis into consideration, which may be improved by appropriate therapies.     

POEMS syndrome (or Crow-Fukase syndrome)

POEMS is an acronym for polyneuropathy, organomegaly, endocrinopathy, M-protein and skin changes. POEMS syndrome is also called Crow-Fukase syndrome, chiefly in Japan. The 5 above mentioned features are not always present at the first examination. The minimal criteria to establish the diagnosis are the presence of a demyelinating and axonal polyneuropathy associated with an IgA or IgG monoclonal gammopathy, the light chain being almost always lambda, and at least 2 of the 8 other features: sclerosing plasmocytoma, endocrinopathy, skin changes, organomegaly, Castleman's disease, anasarca, papillary edema or thrombocytosis. Among these features, only cutaneous glomeruloid angioma are specific. Ultrastructural identification of uncompacted myelin lamellae on the peripheral nerve biopsy is also a strong argument in favor of the diagnosis. An associated "osteosclerotic" bone lesion must be carefully searched, because its treatment may improve the other features of the syndrome, especially the neuropathy. Cytokines and the vascular growth endothelial factor might play a role in the pathogenesis of this rare multisystemic disorder.     

An autopsy case of Prader-Labhart-Willi syndrome

An autopsy case of 23-years-old man with Prader-Labhart-Willi syndrome (P-L-W syndrome), who had died by acute renal failure due to burn injury, was reported. P-L-W syndrome was constituted by hypotonia, hypogonadism, hypomentia, obesity and other minor anomalies, however, CNS anomaly had not been reported. The patient sat at 3 years of age, walked at 4 years old, began to utter single words at 3-4 years, and he began to obese at 4 years of age. He fulfilled the condition of P-L-W syndrome mentioned above. On his age 15, laboratory findings on admission revealed remarkable diabetic pattern by oral glucose tolerance test and intelligence quotient was 28, and the other laboratory findings were within normal limit. During his clinical history, complications of diabetes mellitus, such as diabetic retinopathy and neuropathy, were aggrevated, and upstanding and gait were impossible at 20 years of age. On his age 23, he suffered from burn injury at left lower extremity and he fell in acute renal insufficiency. Five autopsy cases of P-L-W syndrome have been reported so far, however, CNS anomaly has not been observed. Following anomalies in our case was recognized, such as shortness of the frontal lobe, partial micropolygyria of the dentate nucleus, heterotopia of the inferior olivary nucleus, ectopia of Purkinje cell in the molecular layer, heterotopia of middle sized neuron in the deep white matter of the cerebellum and large number of residual nerve cells in the cerebral subcortical white matter.(ABSTRACT TRUNCATED AT 250 WORDS)     

Intracranial extramedullary hematopoiesis associated with pilocytic astrocytoma: a case report

Intracranial EMH is only occasionally found in primary brain tumors (mostly hemangioblastomas) and, to our knowledge, this is the first case of EMH associated with an astrocytoma. Intracranial extramedullary hematopoiesis (EMH) is described in a 29-year-old man with a recurrent pilocytic astrocytoma in the tectal region. Special stains confirmed the identities of erythroid, myeloid and megakaryocytic cells. The patient had no evidence of a predisposing bone marrow disorder or systemic EMH. Although the presence of multinucleated and blastic cells associated with a low-grade brain neoplasm is unusual, recognition of hematopoietic lineages allows EMH to be readily identified. Another tumor resection after a year of follow-up confirmed the absence of malignant progression in this recurrent astrocytoma. The small number of cases describing intracranial EMH in the absence of systemic hematologic abnormalities are correlated with the findings in this case. The low incidence of intracranial EMH indicates that cells with hematopoietic potential are seldom exposed to a supportive microenvironment within the central nervous system. However, intracranial EMH should be included as a potential, ancillary diagnosis when considering brain lesions. This may be particularly true if medical therapies involving growth factors or stem cells are found to promote hematopoiesis.     

The role of interleukin-6 in Crow-Fukase syndrome]

We measured serum interleukin-6 (IL-6) levels in 14 patients with Crow-Fukase syndrome. Five out of 14 patients with Crow-Fukase syndrome showed high serum IL-6 levels above 10 pg/ml, which was statistically significant in comparison with control subjects with other neurological diseases. Serial studies of serum IL-6 levels in two patients revealed the increase before the exacerbation of clinical symptoms of edema, and pleural or cardiac effusion, and the fall after the treatment by high dose pulsed methylprednisolone. We suggest that serum IL-6 level appears to be a useful marker to predict its exacerbation. Also we performed immunohistochemical study on cutaneous angioma from three Crow-Fukase syndrome patients using anti-IL-6 antibody. The cytoplasm of endothelial cells of cutaneous angioma from two patients was positively stained, which might imply the abnormality of endothelial cells in Crow-Fukase syndrome.     

An autopsy case of catastrophic antiphospholipid syndrome presenting with recurrent multiple cerebral infarction associated with lung cancer]

We reported an autopsy case of cerebral infarction with primary lung cancer. The patient was a 50-year-old man. Despite having been treated with warfarin potassium and ticlopidine hydrochloride, he relapsed cerebral infarction. His laboratory data on admission showed that lupus anticoagulant was positive, together with a high value of beta-thromboglobulin, thrombin-antithrombin III complex, markers of platelet and coagulation activation, CEA and CA 19-9. The autopsy finding revealed a primary papillary adenocarcinoma in the right lower lung, multiple cerebral infarction, renal infarction, pulmonary infarction and splenic infarction. The atherosclerotic changes were mild in the whole tissues and findings of vasculitis were not observed. Recurrence of cerebral infarction was effectively suppressed with the addition of steroid therapy to antithrombotic therapy. This case was considered as catastrophic antiphospholipid syndrome. It is necessary to differentiate antiphospholipid syndrome in case of the abnormal coagulation and fibrinolytic factors with recurrent cerebral infarction. Moreover, systemic examinations are important, because malignant tumor may exist on the background of the case.     

An autopsied case of the Crow-Fukase syndrome: a neuropathological study with emphasis on spinal roots

Summary An autopsied case of the Crow-Fukase syndrome is reported. Neuropathological findings were as follows: (1) in the sural nerve, there was marked decrease of large and small myelinated fibers. Myelinated fibers showing axonal degeneration and segmental demyelination and remyelination were moderately increased. (2) In the lumbar spinal roots, myelinated fibers showing segmental demyelination and remyelination were frequently observed. The density of myelinated fibers of the ventral root was less at the dural site than the spinal site, while that of the dorsal roots was less at the spinal site than the dural site. (3) In the dorsal root ganglion, there were Nageotte's residual nodules and satellitosis; (4) in the lumbar and thoracic spinal cord, there was pallor of the dorsal column; and (5) nerve cells showing central chromatolysis were frequently observed in the spinal anterior horn cells. Segmental demyelination and remyelination in the spinal roots and loss of myelinated fibers with axonal degeneration in the sural nerve are fibers with axonal degeneration in the sural nerve are main neuropathological features of this syndrome.     

Crow-Fukase syndrome associated with Castleman disease showing hypertrophic cranial pachymeningitis and bilateral internal carotid artery occlusion]

A 51-year-old woman was diagnosed as Crow-Fukase syndrome on July 1997, presenting with lymph node swelling, polyneuropathy, hepatomegaly, hypothyroidism, renal dysfunction, edema and skin change. Lymph node swelling and polyneuropathy improved in some degree after chemotherapy. She was admitted to our hospital on march 6, 1998 because of consciousness disturbance, right hemiparesis and non-fluent aphasia after fever and hypotension. The next day of admission, consciousness disturbance, right hemiparesis and non-fluent aphasia disappeared. MR images of the brain revealed low intensity on a T1-weighted image and high intensity on a T2-weighted image in the left parietal lobe. Furthermore, MR images also revealed diffuse hypertrophic dura matter with enhancement by Gd-DTPA, which made the diagnosis of chronic cranial pachymeningitis. The cerebral angiographies showed bilateral internal carotid artery occlusion. The cerebrospinal fluid showed normal cell count, total protein level of 82 mg/dl, and IgG level of 18 mg/dl. Since there has been very few case reports describing intimate relationship between Crow-Fukase syndrome and pachymeningitis, and between carotid occlusion and pachymeningitis, we speculated that the pachymeningitis might be associated with Crow-Fukase syndrome. Furthermore, pachymeningitis might be a cause of her bilateral carotid occlusion. The number of cases of Crow-Fukase syndrome associated with cerebrovascular disease was very rare. This is the first case which had bilateral internal carotid artery occlusion probably caused by chronic cranial pachymeningitis. Therefore, it is necessary to pay attention to cerebrovascular disease when the patient of Crow-Fukase syndrome is associated with pachymeningitis.     

An autopsy case of neurocutaneous melanosis associated with intracerebral malignant melanoma

The authors reported the clinical course and the postmortem examination of a unique case of neurocutaneous melanosis with numerous anomalies and complications, which included congenital dislocation of lenses, hypogonadism, ectopia of prostatic duct, genuine phimose, retentio testis, psina bifida and neurogenic bladder. This 13-year-old boy with a large hairy nevus in a bathing trunk configulation and multiple small nevi over the whole body since his birth was admitted to our hospital for evaluation of headache and vomiting. Neurological examination showed bilateral papilledema and slight left hemiparesis. A CT scan revealed a large right frontal mass and craniotomy was performed with subtotal removal of this tumor which was confirmed as a malignant leptomeningeal melanoma. He initially made uneventful postoperative recovery, and two courses of chemotherapy with DTIC, ACNU and VCR were given; however, the currence of brain tumor ensued shortly thereafter, and he died in approximately six months after the onset of intracranial symptoms despite of the third course of chemotherapy. Thirty five cases of neurocutaneous melanosis associated with or without malignant melanoma have been reported in Japan. Twenty-eight cases were male and 7 female. Two cases showed the evidence of primary malignant melanoma outside of the central nervous system, whereas twenty eight leptomeningeal melanoma, in which 22 were solid and 6 diffuse, were shown intracranially. Other 5 cases had epileptic seizure and/or hydrocephalus caused by wide spreaded leptmeningeal melanosis. This high incidence of intracranial malignant melanoma in this disorder was remarkable compaired with the previous reports in other countries. Mean duration between deaths and the onset of symptoms of intracranial hypertension or focal neurological signs was 7 months, ranging from 1 to 24 months, showing the rapidly deteriorating course in this disorder.(ABSTRACT TRUNCATED AT 250 WORDS)     

An autopsy case of amyotrophic lateral sclerosis associated with cervical syringomyelia

An autopsied case of amyotrophic lateral sclerosis complicated by cervical syringomyelia was reported. The case was a 59-year-old man, who first noticed weakness of both lower extremities at 54-year-old. The weakness spread to both upper extremities within 2 years. Cervical myelography revealed multi-level cervical spondylosis and anterior fusion of C5-C7 was done. But the weakness and atrophy of proximal muscle, diminished deep tendon reflex on upper extremities, hyperreflexia and pathological reflexes on both legs, tongue fasciculation and respiratory muscle weakness developed successively, and the patient died of respiratory distress at 59-year-old. Autopsy revealed multiple independent four syrinxes located at the level between C2-C7. One of these syrinxes had ependymal cell lining and thought to be idiopathic syringomyelia. The other three syrinxes were considered to be the cavitation in association with cervical spondylotic myelopathy. Degeneration and decreasing of spinal anterior horn cells, atrophy of medullary pyramis and Bunina bodies were observed as features of typical amyotrophic lateral sclerosis. Cervical spondylosis as causative lesion of multiple syrinxes was discussed, and relationship between ALS and the syrinxes was not indicated clearly.