Cranial Neuropathy Associated with Sarcoidosis

Cranial Neuropathy Associated with Sarcoidosis Case Report* MANOHAR D. SINGH, M.D.** AND MARTIN J. FITZPATRICK, M.D., F.C.C.P.t Kansas City, Kansas ARCOIDOSIS, A DISEASE OF UNDETERmined etiology involving many organ S systems, has been reported with increasing frequency in the medical literature during the past decade. The clinical entity has expanded considerably since Boeck's classic description of the dermatologic manifestation of this disease in 1899. 2 Winkler's report in 1905 quoted by Salvesen,t5 demonstrated that sarcoidosis could involve the central nervous system. In 1909, Heerfordt 5 added the description of uveo-parotid fever with facial nerve palsy. Schaumann u1 then followed with the postulation that sarcoidosis is a primary systemic disease of the lympho-hemopoietic system and that the dermatologic manifestations are merely accidental and of little consequence. Since then, little has been added to our knowledge concerning the pathogenesis of the disease. Sarcoid granulomas are found most frequently in skin, lymph nodes, lungs, eyes, liver, spleen, and the central nervous system. Histologically, these lesions are characterized by the formation of nodules of epithelioid cells, without central caseation, and a minimal inflammatory reaction. These histologic features, however, are also common to a broad group of granulomatous infectious diseases including tuberculosis, leprosy, brucellosis, syphilis, histoplasmosis and leishmaniasis. Beryllium, parif- *Presented at the Kansas Chapter meeting, American College of Chest Physicians, Kansas City, Kansas, March, 1962. **Resident, Pulmonary Disease Service, Kansas University Medical Center. Present address: Scripps Clinic and Research Foundation, La Jolla, California. tchief, Pulmonary Disease Service and Associate Professor of Medicine, Kansas University School of Medicine. Present address: Director, Will Rogers-O'Donnell Memorial Research tories, Saranac Lake, New York. Labora INTRODUCTION 431 fin, and other lipids, morphine, iron, arsenic, glass and stone particles are also capable of eliciting a histologic lesion that closely mimics that of sarcoidosis. ll NEUROLOGIC OF MANIFESTATIONS SARCOIDOSIS Winkler (cited by Salvesen U ) is credited with first reporting the central nervous system manifestations of sarcoidosis in 1905. Since then, reports have demonstrated that sarcoidosis can involve cranial and peripheral nerves, the cerebral hemisphere, basal ganglia, hypothalamus, pituitary gland, cerebellum, brain stem, spinal cord, and meninges, either singly or in combination. It has been estimated that the central nervous system is involved in 1 to 5 per cent of all patients with sarcoidosis. 14 In 1948, Colover 3 reviewed the literature and found 118 cases of central nervous system involvement, the majority of which also exhibited involvement of the peripheral nerves. In general, cranial or peripheral nerve palsies or paralyses are transient, and recovery, either partial or complete, is seen within a few weeks. Remissions and exacerbations may occur affecting the same extremity or the opposite limb. Unlike the peripheral neuropathies, however, signs of central involvement tend to progress or to remain stationary for longer periods of time, and regression is rare. 8 By 1953, only 25 cases with intracranial or meningeal involvement had been substantiated by necropsy or surgical biopsy, and most of them proved fatal. 3.14 The present report describes a patient with cranial neuropathy associated with sarcoidosis manifested by dysphagia and aphonia. She later showed a complete re-

43 2 SINGH AND FITZ PATRICK Diseases of the Chest covery of neurologic function following the use of adrenal corticosteroid. CASE REPORT A 39-year-old colored woman was admitted to the University of Kansas Medical Center for the second time in December, 1961 complaining of difficulty in swallowing and hoarseness of recent onset. She had previously been evaluated in May, 1961 because of an abnormal routine chest roentgenogram (Fig. I). Past history was not remarkable except for the surgical excision of a cystic mass from the limbus of the left cornea in 1959. This was thought to be a local lymphoma at that time. She had previously had two chalazia removed from her upper eyelids prior to 1958. She denied any previous lympadenopathy, arthropathy, dermatitis, exposure to silica or beryllium, and was completely free of symptoms. Biopsies of a palpable prescalene lymph node and of the liver disclosed non-caseating granulomata characteristic of sarcoidosis. She was discharged with that diagnosis to the Out Patient Clinic without treatment. In the next six months, she was well and free of symptoms. Chest roentgenogram showed no significant change in comparison to x-ray film taken in May, 1961 (Fig. 2). Approximately eight days prior to her second admission, she noted the rather abrupt onset of difficulty in swallowing solid foods accompanied by hoarseness. Two days prior to admission she could only swallow liquids and was unable to speak. She was admitted with a presumptive diagnosis of the tenth cranial nerve palsy with bilateral adductor paralysis of the vocal cords. Physical Examination. Physical examination revealed a well-developed, well-nourished colored woman in no acute distress. Blood pressure was 110/70 mm.hg, pulse 92 per minute, and respiration 20 per minute. There were several palpable pea-sized posterior cervical, and supraclavicular lymph nodes noted. The liver was palpable two to three fingerbreadths below the right costal margin. Neurologic examination revealed severe dysplagia, failure to elevate the palate, and dysphonia, but was otherwise normal. Laboratory and X-ray Findings. Hematogram revealed hemoglobin 13.7 gm., white blood cells 8,830 per cmm., with a normal differential. Serum albumin 4.12 gm., globulin 2.50 gm., serum calcium 5.0 meq./l.; serum phosphorus 2.0 meq./l., second strength PPD negative, histoplasmin skin test negative. Cerebrospinal fluid examination revealed 21 lymphocytes, normal pressure, sugar 70 mg. per cent, (blood sugar 96 mg. per cent), protein 35 mg. per cent, and a negative Wassermann complement fixation test. Sputum smears for acid fast bacilli and H. capsulatum were negative. Sputum cultures were also negative for tubercle bacilli and H. capsulatum. A bone marrow aspiration revealed no abnormality. Urine Sulkowitch's test was positive. Hospital Course. A barium swallow revealed apparent obstruction at the level of the inferior pharyngeal constrictor muscle (Fig. 3). Fortyeight hours after admission, she was unable to swallow liquids without aspiration into the tracheobronchial tree. Findings on bronchoscopy and esophagoscopy at that time were normal. A presumptive diagnosis of sarcoid infiltration of 5-26-61 Admission: 12-13-61 FlO. I FIG. 2 FIGURE I: This x-ray picture was taken during a routine gynecologic examination before admission. A previous x-ray film taken in August, 1959 was normal. FIGURE 2: This x-ray film was taken on admission.

Volume 4~. April 1964 No.4 CRANIAL NEUROPATHY ASSOCIATED WITH SARCOIDOSIS 433 FIGURE 3: A cinefluorography revealed considerable paresis of the hypopharynx and atonic strictures of the upper esophagus. Repeat examination nine days after prednisone was started was normal. This barium swallow revealed apparent obstruction at the level of the inferior pharyngeal constrictor muscle. the brain stem with the tenth cranial neuropathy was made. She was started on prednisone. 40 mg. daily. After 48 hours of treatment, she was able to swallow and to speak in a normal manner. Visualization of the vocal cords at that time was normal. Subsequently, prednisone was gradually reduced to 5 mg. daily over a period of eight weeks with no recurrence of symptoms (Fig. 4). X-ray examination of the chest revealed marked regression of hilar lymphadenopathy (Fig. 5). Repeated cerebrospinal fluid examina- tions some three and nine months later were normal. At the present time, the patient is not receiving any medication and remains asymptomatic. Chest x-ray findings have remained stable (Fig. 6). This case history represents one of the true medical emergencies encountered in patients with sarcoidosis involving the central nervous system requiring energetic treatment. Women manifesting symptoms of dysphagia or dysphonia are frequently considered to be functional problems of conversion hysteria. This actually was the initial impression recorded on the present patient when first seen in the emergency room. COMMENT Hypersensitivity of some of the tissues of the host to agents as yet undefined has been suggested as a pathogenic factor in sarcoidosis. Certain features of the disease, among which are tuberculin anergy, eosinophilia, erythema nodosum and hyperglobulinemia, suggest that hypersensitivity may play a role in the development of this disease. Teilum" has postulated an allergic basis for the hyalinization of sarcoid lesions. He feels that the reticuloendothelial system elaborates excessive gamma globulin which is then precipitated in tissues and trans- 1-17-62 4-12-62 FIG. 4 FIG. 5 FIGURE 4: Prednisone was started December 18, 1961, then subsequently reduced to 5 mg. daily without recurrence of symptoms. X-ray film shows regressing hilar adenopathy. FIGURE 5: X-ray film continues to show marked regression of hilar adenopathy. Prednisone was still maintained at 5 mg.

434 SINGH AND FITZ PATRICK Diseases of the Chest 3-8-63 FIGURE 6: Prednisone discontinued. X-ray finding remains stable. No withdrawal effect of Prednisone was observed. formed either within or outside the granuloma into hyaline or para-amyloid substances. Similar histologic findings have been observed in the hyperglobulemic states such as Letterer-Siwe's disease, disseminated lupus erythematous, lymphogranuloma inguinale, etc. Substances capable of neutralizing tuberculin skin sensitivity (anticutins) have been demonstrated in the serum of some sarcoid patients who failed to react to tuberculoprotein or Bacillus Calmette Guerin. Pinner, Weiss and Cohen" studied these substances in a small number of normal, TEMP ~ 100 1 986~_ PR~~rSO~Day---- tuberculous, and sarcoid patients. They found that a neutralizing substance (anticutin) was present in 36 per cent of the patients with sarcoid, 18 per cent of tuberculous subjects and in 3 to 9 per cent of normal individuals. They felt that the anticutin 2~LL. L,'-- SYMPTOMS Ice C,hips SotI diet IlIbf..-lli! ~ljows lio~ Reg. diel Aphaglc -I I I Normal t Aphonic Hoarse- Normal played no significant immunologic role in the pathogenesis of sarcoidosis. It has been observed that most patients with sarcoidosis are anergic to tuberculin. Hoyle, Dawson, and Walters' in 1954, however, demonstrated that this anergy to tuberculin is not always present. In their series of 90 patients with sarcoidosis (62 confirmed histologically) they found that only 28 per cent of the individuals were insensitive to a.t. 1: 1,000 and 48 per cent were insensitive to I: 100. From these and other observations, the consensus has evolved that all negative tuberculin reactors with sarcoidosis should be followed with skin tests quarterly. When conversion to a positive tuberculin skin test does occur, the possibility that the patient has developed active tuberculosis should strongly be considered, and appropriate diagnostic and therapeutic measures instituted. In recent years, considerable interest has been shown in the abnormal calcium metabolism noted in some patients with sarcoidosis. Anderson et al.' and Henneman and his associates have postulated that the hypercalcemia of some patients results from J J SPINAL FLUID II I I Cells 21 20 Lymph 4 Lymph Sugar 70 Mg % 56 Mg 52 Mg Total proi 35 Mg 36 M? ~ O::---~...ul IL.<I...LI_...~~...,...L~...L.I ~-...L4~f J----t-f~ f--7s WEEKS FIGURE 7: Graph illustrating the effect of prednisone on temperature. spinal fluid findings, and symptoms of dysphagia and aphonia.

Volume 4~. April 1964 No.4 CRANIAL NEUROPATHY ASSOCIATED WITH SARCOIDOSIS 435 increased calcium absorption secondary to an increased sensitivity to Vitamin D or to hypervitaminosis D. Studies to date indicate that sarcoidosis patients exhibiting hypercalciuria, have an abnormally low level of fecal calcium. The administration of prednisone increases the fecal excretion of calcium with a resultant reduction in the serum and urinary calcium levels to normal ranges. The administration of vitamin D produces the opposite effect. The adrenal corticosteroid hormones have been found to exert a beneficial influence on many of the diseases characterized by hypersensitivity to either host or foreign substances. They have been used extensively in patients with sarcoidosis, but their exact contribution to regression of a disease that is known to wax and wane spontaneously has always been difficult to assess. Cortisone has been used to treat neurologic complications of sarcoidosis with equivocal results. Matthews 8 reported three patients in whom he was unable to evaluate any drug effect. Others 4 have observed a dramatic clearing of neurologic lesions with cortisone. A third group of studies 17 suggests that in some individuals cortisone exerted a deleterious effect on the course of the disease. The prompt and dramatic improvement noted in this patient following the administration of prednisone suggests that its use in sarcoidosis patients with cranial neuropathy can be life-saving. Other accepted indications for steroid treatment in sarcoidosis include: 1. Active ocular disease. 2. Progressive pulmonary involvement, that is symptomatic. 3. Persistent hypercalciuria and hypercalcemia. 4. Central nervous system involvement with concomitant functional impairment. 5: Disfiguring dermatologic lesions. 6. Myocardial involvement with a conduction defect. The desired goal in using corticosteroids in sarcoidosis is to control the clinical manifestations of the disease with as minimal a dose of drug as possible. REFERENCES ANDERSON, J., DENT, C. E., HARPER, C. AND PHILPOT, G. R.: "Effect of Cortisone on Calcium Metabolism in Sarcoidosis with Hypercalceamia: Possible Antagonistic Actions of Cortisone and Vitamin D," Lancet, 2: 720, 1954. 2 BOECK, C.: "Multipelt Benignt hud-sarkoid," Norsk. Mag. f. Laegevigensk, 60: 1321, 1899. 3 COLOVER, J.: "Sarcoidosis with Involvement of the Nervous System," Brain, 71 :451, 1948. 4 FITZPATRICK, D. P. AND EWART, G. E.: "Central Nervous Treated with System Sarcoidosis Prednisone," Arch. Successfully Int. M ed., 100: 139, 1957. 5 HEERFORDT, C. F.: "Uber eine Febric U veoparotidae Subchronica," Arch. Ophthal., 70: 254, 1909. 6 HOOK, 0.: "Sarcoidosis with Involvement of the Nervous System," A.M.A. and Psychiat., 71: 554, 1954. Arch. Neurol. 7 HOYLE, C., DAWSON, J. AND MATHER, H. G.: "Skin Sensitivity in Sarcoidosis," Lancet, 2: 164, 1954. 8 ISRAEL, H. L., SONES, M. AND HARRELL, D.: "Cortisone Treatment of Sarcoidosis," I AMA, 156 :461, 1954. 9 MATTHEWS, W. B.: "Sarcoidosis of the Nervous System," Brit. Med. I., 1: 267, 1959. 10 PENNELL, W. H.: "Boeck's Sarcoid with Involvement of the Central Nervous System," A.M.A. Arch. Neurol. and Psychiat., 66: 728, 1951. 11 PINNER, M.: "On the Etiology of Sarcoidosis," Amer. Rev. Tuberc., 54: 582, 1946. 12 PINNER, M., WEISS, M. AND COHEN, A. C.: "Procutins" and "Anticutins," Y ale I. Bioi. and Med., 15 :459, 1943. 13 RICH, A. R. AND MCCORDOCK, H. A.: "Enquiry Concerning Role of Allergy, Immunity and Other Factors of Importance in the Pathogenesis of Human Tuberculosis," Bull. lohns Hopkins Hosp., 44: 273, 1929. 14 RICKER, W. AND CLARK, M.: "Sarcoidosis: A Clinicopathologic Review of 300 Cases, Including 22 Autopsies," Amer. I. Clin. Path., 19: 725, 1949. 15 SALVESEN, H. A.: "The Sarcoid of Boeck, A Disease of Importance to Internal Medicine," Acta Med. Scand., 86: 127, 1935. 16 SCHAUMANN, J.: "Benign Lymphogranuloma and. Its Cutaneous Manifestations," Brit. /. Dermatol., 36: 515, 1924. 17 STONE, D. J., SCHWARTZ, A., FELTMAN, J. A. AND LOVELOCK, F. J.: "Pulmonary Function in Sarcoidosis," Amer. I. Med., 15:468, 1953. 18 TEILUM, G.: "Allergic Hyperglobulinosis and Hyalinosis ( Paramyloidosis) in Reticulo-endothelial System in Boeck's Sarcoid and Other Conditions; Morphologic Immunity Reaction," Amer. ]. Path., 24: 389, 1948. For reprints, please write Dr. Singh, Scripps Clinic and Research Foundation, La Jolla, California.