Crow-Fukase syndrome

Case Report and Literature Review

Phrenic nerve paresis is an unusual complication of POEMS (polyneuropathy, organomegaly, endocrinopathy, M-protein spike and skin changes) syndrome. In this report, we describe a case of POEMS syndrome in which a 56-year-old woman presented with dyspnea and ventilatory failure due to bilateral phrenic nerve paralysis. To our knowledge, only one other case of phrenic neuropathy in POEMS syndrome has been reported.

(CHEST 1999; 115:1740-1742)

Key words: diaphragm; multiple myeloma; neuropathy; paralysis; phrenic; POEMS syndrome; pulmonary; respiratory failure

Abbreviations: POEMS--polyneuropathy, organomegaly, endocrinopathy, M-protein spike, and skin changes

POEMS (polyneuropathy, organomegaly, endocrinopathy, M-protein spike, and skin changes) syndrome, also known as Takatsuki-Crow-Fukase syndrome, was first described in 1956.[1,2] Although there is no established definition of this syndrome, classic common features are considered to be secondary to the plasma cell dyscrasia.[3] Respiratory manifestations of POEMS syndrome include pulmonary hypertension,[4,5] pleural effusion,[6] phrenic neuropathy,[7] and pulmonary tumorlets.[8]

CASE REPORT

A 56-year-old woman with a history of multiple myeloma and POEMS syndrome was hospitalized with progressive dyspnea on exertion, orthopnea, and peripheral edema that had occurred over 1 month. She denied the presence of a cough, excess mucus, fever, chest pain, or weight loss.

A diagnosis of osteoclastic multiple myeloma had been made 8 years before, and the disease was treated with prednisone and melphalan. Remission occurred and continued for several years. The patient had no history of smoking or occupational exposure to smoke.

Two years before the present admission, diabetes mellitus type II had developed in the patient. One year ago, axillary lymphadenopathy had developed. A biopsy specimen revealed that multiple myeloma had recurred. A peripheral neuropathy had also developed in the lower extremities. The patient was given a high dosage of dexamethasone, 40 mg/d, 4 d/wk. The treatment was continued until the present admission.

Examination showed the patient to be in mild respiratory distress. Vital signs were normal except for a respiratory rate of 22 breaths/min. Air entry at the bases of the lungs was decreased and wheezes or crackles were absent. The heart examination revealed regular rate and rhythm without [S.sub.3], split [S.sub.2], or murmurs. The liver span was enlarged, with a palpable liver edge 10 em below the costal margin. The patient had axillary and inguinal lymphadenopathy, hyperpigmented skin, and bilateral lower extremity edema. In addition, her proximal muscle strength, sensation to touch, and deep tendon reflexes were diminished in the lower extremities.

Initial laboratory findings included a normal CBC and normal levels of electrolytes, BUN, creatinine, glucose, and liver function tests. Albumin was low at 2.5 g/dL. Arterial blood gas analysis revealed a pH of 7.40, Pa[CO.sub.2] of 37 mm Hg, and Pa[CO.sub.2] of 6 mm Hg while the patient received 2 L/min supplemental oxygen. The chest roentgenogram showed small bilateral pleural effusions and an elevated left hemidiaphragm that were consistent with a left upper lobectomy that had been performed 35 years ago for pulmonary tuberculosis. There was no evidence of mediastinal lymphadenopathy. The pleural effusions had been present for 2 years.

Despite the administration of empiric therapy for congestive heart failure, progressive dyspnea and ventilatory failure developed in the patient. These conditions were aggravated while the patient was in the supine position. The Pa[CO.sub.2] rose to 62 mm Hg, and the pH fell to 7.18. There was no change in her alveolararterial gradient. The chest radiograph had not changed, and echocardiography showed no abnormalities. A fluoroscopic examination revealed minimal movement of both diaphragms, which was consistent with bilateral paralysis. Electromyographic and nerve conduction velocities demonstrated severe sensorimotor, mixed axonal, and demyelinating polyneuropathy of the upper and the lower extremities. Transcutaneous phrenic nerve stimulation revealed an extremely prolonged phrenic nerve motor latency that was consistent with phrenic neuropathy[9,10] (Table 1). There was no evidence of myopathy. The results of an abdominal fat-pad biopsy were negative for amyloidosis. Pulmonary function tests were performed with the patient sitting, because she could not tolerate a supine position. The tests revealed a severe restrictive defect, with total lung capacity at 1.77 L (35% of predicted), vital capacity at 0.95 L (30% of predicted), and FE[V.sub.1] at 0.82 L (31% of predicted). Maximum inspiratory pressure was -33 cm [H.sub.2]O (44% of predicted),[11] maximum expiratory pressure was 53 cm [H.sub.2]O (49% of predicted), and maximum voluntary ventilation was 49 L/min (52% of predicted).

Table 1--Comparison of Nerve Conduction Study Results Measured in July 1997 and October 1998(*)

(*) NR = no response; NA = not applicable; mV = millivolts; [micro]V = microvolts; ms = milliseconds.

The patient was given continuous noninvasive bilevel positive pressure ventilation with success. Her myeloma was treated with a new regimen of cyclophosphamide, melphalan, prednisone, and vincristine. There was gradual improvement in her neuropathy and a reduction in breathlessness, allowing discontinuation of daytime noninvasive positive pressure ventilation after 10 days and complete discontinuation in 21 days. In view of the clinical improvement, the nerve conduction studies and the fluoroscopic examination of the diaphragms were not repeated. Sixteen months after discharge, the patient was still not requiring noninvasive positive pressure ventilation. She was fully ambulatory and showed dramatic improvement in the motor strength of her upper and lower extremities. Repeat nerve conduction studies demonstrated significant improvement in distal latency and amplitude of the phrenic nerve (Table 1). Maximum inspiratory pressure and maximum expiratory pressure had risen to -63 cm [H.sub.2]O (85% of predicted) and 139 cm [H.sub.2]O (100% of predicted), respectively.

DISCUSSION

The incidence of respiratory involvement in POEMS syndrome is not known. Based on single reports, the incidence of pleural effusions may exceed 40%[3] and pulmonary hypertension is nearly 25%.[12] Less common respiratory manifestations include pulmonary tumorlets and, as this case illustrates, phrenic neuropathy. Amyloidosis can cause infiltration of the diaphragms and has been reviewed.[13-17] Diabetes mellitus has been associated with bilateral phrenic neuropathy,[18] but this combination is very rare. Our patient's condition improved with chemotherapy, which supports POEMS as the cause of neuropathy.

Polyneuropathy is common in POEMS syndrome. Eighty-five percent of patients present with slowly progressive polyneuropathy and features of demyelination. Antinerve antibodies, included in the M-spike paraproteins, have been detected in 90% of patients with POEMS. These antibodies have been identified in the endoneurium by indirect immunofluorescent staining and are linked to the neural damage.[19] The phrenic nerves are rarely involved, as they are in the present case. Bilateral phrenic nerve involvement may not lead to major reductions in maximum inspiratory pressure or maximum expiratory pressure[20] but should be suspected when dyspnea and a restrictive process complicate POEMS syndrome. Our case demonstrates that this condition is reversible if the underlying process is successfully treated.

REFERENCES

[1] Nakanishi T, Sobue I, Toyokura Y, et al. The Crow-Fukase syndrome: a study of 102 cases in Japan. Neurology 1984; 34:712-720

[2] Viard JP, Lesavre P, Boitard C, et al. POEMS syndrome presenting as systemic sclerosis: clinical and pathologic study of case with microangiopathic glomerular lesions. Am J Med 1988; 84:524-528

[3] Soubrier MJ, Dubost JJ, Sauvezie JM, et al. POEMS syndrome: a study of 25 cases and a review of the literature; French Study Group on POEMS Syndrome. Am J Med 1994; 97:543-553

[4] Ribadeau-Dumas S, Tillie-Leblond I, Rose C, et al. Pulmonary hypertension associated with POEMS syndrome. Eur Respir J 1996; 9:1760-1762

[5] Iwasaki H, Ogawa K, Yoshida H, et al. Crow-Fukase syndrome associated with pulmonary hypertension. Intern Med 1993; 32:556-560

[6] Loeb JM, Hanger PH, Carney JD. Refractory ascites due to POEMS syndrome. Gastroenterology 1989; 96:247-249

[7] de la Pena A, Subtil JC, Rodriguez-Rosado R. Sindrome POEMS: a proposito de dos casos y revision de la literatura. An Med Interna 1996; 13:291-294

[8] Gomez Rodriguez F, Iriarte Garcia-Baquero LM, Grilo Reina A, et al. Tumorlets pulmonares en el sindrome POEMS. An Med Interna 1991; 8:555-558

[9] MacLean IC, Mattioni TA. Phrenic nerve conduction studies: a new technique and its application in quadriplegic patients. Arch Phys Med Rehabil 1981; 62:70-73

[10] Markand ON, Kincaid JC, Pourmand RA, et al. Electrophysiologic evaluation of diaphragms by transcutaneous phrenic nerve stimulation. Neurology 1984; 34:604-614

[11] Black LF, Hyatt RE. Maximal respiratory pressures: normal values and relationship to age and sex. Am Rev Respir Dis 1969; 99:696-702

[12] Lesprit P, Bertrand G, Authier FJ, et al. Pulmonary hypertension in POEMS syndrome: a new feature mediated by cytokines. Am J Respir Crit Care Med 1998; 157:907-911

[13] Santiago RM, Scharnhorst D, Ratkin G, et al. Respiratory muscle weakness and ventilatory failure in AL amyloidosis with muscular pseudohypertrophy. Am J Med 1987; 83:175-178

[14] Streeten EA, de la Monte SM, Kennedy TP. Amyloid infiltration of the diaphragm as a cause of respiratory failure. Chest 1986; 89:760-762

[15] Cordier JF. Les amyloidoses et les depots amyloides: amyloidoses du bas appareil respiratoire. Rev Mal Respir 1989; 6:5-14

[16] Olofsson BO. Pulmonary function in familial amyloidosis with polyneuropathy. Acta Med Scand 1981; 209:379-384

[17] Ashe J, Borel CO, Hart G, et al. Amyloid myopathy presenting with respiratory failure. J Neurol Neurosurg Psychiatry 1992; 55:162-165

[18] Chan CK, Loke J, Virgulto JA, et al. Bilateral diaphragmatic paralysis: clinical spectrum, prognosis, and diagnostic approach. Arch Phys Med Rehabil 1988; 69:976-979

[19] Ropper AH, Gorson KC. Neuropathies associated with paraproteinemia. N Engl J Med 1998; 338:1601-1607

[20] Mulvey DA, Aquilina RJ, Elliot MW. Diaphragmatic dysfunction in neuralgic amyotrophy: an electrophysiologic evaluation of 16 patients presenting with dyspnea. Am Rev Respir Dis 1993; 147:66-71

(*) From the Division of Pulmonary and Critical Care, Department of Medicine, Northwestern University Medical School, Chicago, IL.

Manuscript received July 30, 1998; revision accepted January 12, 1999.

Correspondence to: Manu Jain, MD, Division of Pulmonary and Critical Care, Department of Medicine, Northwestern University Medical School, 345 E Superior St, 358C, Chicago, IL 60611; e-mail: m-jain@nwu.edu

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