Peripheral Neuropathy Associated with Eosinophha-Myalgia Syndrome T. D. Heiman-Patterson, MD,' S. J. Bird, MD,S G. J. Parry,§ J. Varga, MD,t M. E. Shy, MD,* N. W. Culligan, MD," L. Edelsohn, MD,"' G. T. Tatarian, MD," M. P. Heyes, MD,tl 6 . A. Garcia!' and A. J. Tahmoush, MD+ _.
In 1989, the Centers for Disease Control recognized the existence of an epidemic illness characterized by myalgia and eosinophilia in individuals taking preparations containing L-tryptophan. We evaluated 3 patients with eosinophiliamyalgia syndrome who presented with subacute progressive neuropathies. The neuropathies were predominantly motor and maximal in the lower extremities. Two patients were confined to a wheelchair and one was ventilatordependent and bedridden. Sensory loss predominantly involved small fiber modalities. Electrophysiological studies showed multifocal marked conduction slowing and conduction block indicating segmental demyelination, with associated axonal degeneration that was accentuated distally. Examination of sural nerve biopsy specimens demonstrated axonal degeneration in all 3 patients and perivascular infiltrates in 2. Levels of quinolinic acid, a neurotoxic metabolite of t-tryptophan, were elevated in the cerebrospinal fluid in the 2 patients in whom it was measured. The cause of the neuropathy is unknown but may include immune mechanisms or toxicity of eosinophils, L-tryptophan, its metabolic products, or contaminants within L-tryptophan preparations. Heiman-Patterson TD, Bird SJ, Parry GJ, Varga J, Shy ME, Culligan NW, Edelsohn L, Tatarian GT, Heyes MP, Garcia CA, Tahmoush AJ. Peripheral neuropathy associated with eosinophilia-myalgia syndrome. Ann Neurol 1990;28:522- 52 8 In November 1989, the Centers for Disease Control (CDC) recognized the existence of an epidemic illness characterized by myalgia and eosinophilia in individuals taking preparations containing L-tryptophan El5 } . We studied 3 patients who presented with subacute progressive neuropathies of variable severity which developed during chronic ingestion of L-tryptophan, associated with a systemic illness and eosinophilia. We report the clinical, electrophysiological, and pathological features of the neuropathy in these patients. In addition, we provide evidence for elevated levels of quinolinic acid, a neurotoxic metabolite of L-tryptophan in the cerebrospinal fluid (CSF). This presentation of the eosinophilia-myalgia syndrome (EMS) can be life-threatening and has not been described to date. It is important for the neurologist to recognize this association so that the appropriate diagnostic and therapeutic steps can be promptly initiated.
Case Reports Patient 1 A 57-year-old woman was admitted to Thomas Jefferson University Hospital in December 1989 for progressive
From the Departments of "Neurology and tfieumatology, Jefferson Medical College, and the Department of $Neurology, [Jniversity Of Philacielphia, PA; Departments Of and 'Pathology, Louisiana State Universiv, New Orleans, LA; Department of **Neurology, Christiana Hospital, Wilmington, DE; and ??National Institute of Mental Health, Laboratory of Clinical Science, Rethesda, MD.
522
weakness. In August 1989, she developed a diffuse erythematous rash, low-grade fevers, productive cough, diarrhea, severe diffuse myalgia, and malaise. She gained 9.1 kg (20 Ib) over a 2-week period. She had been taking lithium, amitriptyline, diphenhydramine, and diazepam for an affective disorder, as well as r-tryptophan, 8,000 mg daily, for the treatment of insomnia for 4 months prior to the onset of symptoms. In September 1989, she underwent evaluation for edema and low-grade fevers. Laboratory evaluation revealed a pleural effusion, ascites, and hypoalbuminemia (2.4 gmidl). Leukocyte count was 15,000 cells/mm3 with 71%) segmented cells, 4% rnonocytes, and 15% eosinophils. The absolute eosinophil count was 2,250 cells/mm3. The serum creatine kinase (CK) level was normal but aldolase activity was elevated (12 unitdliter; normal 5 7 unitsiliter). Alkaline phosphatase (390 unitsiliter) and lactate dehydrogenase (LDH)(404 unitsiliter) levels were elevated. She was treated with diuretics without improvement. Her condition continued to deteriorate until November, when she was hospitalized with progressive dyspnea and weakness. On physical examination, there was anasarca and generalized muscle weakness. The peripheral blood eosinophi1 count was intermittently elevated (as high as 1,700 cells/ mrn3).Her hospital course was complicated by a hemothorax
Received Feb 23, 1990, and in revised form Apr 19. Accepted for publication Apr 23, 1990. Address correspondence to Dr Heiman-Patterson, Associate professor of ~ ~Jefferson Medical ~ College, ~ 1025 lWalnut Street, ~ Suite 1, Philadelphia, PA 19107-5083.
Copyright 0 1990 by the American Neurological Association
~
Nerve Conduction Studies" Patient 1 Amplitudeb
(msec)
Velocity (misec)
5.7 2.7 18.4
4.3
33
7.9 6.4
47
8.1
3.3 2.1 2.0
4.7
30
10.6 7.2 5.3
NO NO
0.6 0.3
6.7
NO NO NO
2.6 NO
6.0
Amplitudeb Median motor Distal Proximal Median sensory Ulnar motor Distal Proximal Ulnar sensory Peroneal Distal Proximal Posterior tibial Distal Proximal Surd nerve
Latency' (msec)
Patient 3
Patient 2 Velocity (misec)
1.3 6 24.3 0.3 Could not be done due to technical difficulties 1.0
4.1
32
0.9 Could not be done due to technical difficulties
Latency'
41 21
Amplitudeb
0.59 0.39
10.9 8.8 7.0
NO
Latency' (msec)
Velocity (m/sec)
4.8
44 52
3.2
42
50 7.5
21
4.6
35 38
"Normal values are those reported by the Mayo Clinic 1217. bAmplitudes are measured in mV for motor conductions and pV for sensory conductions %tency is measured to onset in motor conduction velocities. NO = not obtainable
during thoracentesis, necessitating utilization of a chest tube and mechanical ventilatory support. She remained ventilatordependent and was transferred to Thomas Jefferson University Hospital because of progressive wasting and weakness. General examination showed symmetrical, tender induration of the forearms, arms, abdomen, legs, and feet. There were no digital ulcerations, joint abnormalities, or tendon friction rubs. Neurological examination demonstrated an intact sensorium and mild facial diplegia. The rest of the cranial nerve examination was normal. Motor examination showed diffuse wasting that was more prominent distally. There was bilateral deltoid weakness (115)with symmetrical weakness in the distal upper extremities ( 2 to 3/5). Proximal leg strength was 0/5, while distal strength was 1 to 215. Deep tendon reflexes were absent. The sensory examination demonstrated mild to moderate hypesthesia to pain and temperature in the distal areas of the extremities. Vibration was mildly diminished in the lower extremities. Electrophysiological findings were consistent with a demyelinating neuropathy with severe axonal loss (Table). Needle electromyography (EMG) demonstrated fibrillations in all muscles throughout, accentuated distally. The CSF protein level was initially 16 mgidl, but 2 weeks later it was 54 mg!dl with normal glucose levels and no cells. The aldolase was 7.6 unitslliter and CK, 9 unitsiliter. Antinuclear antibody (ANA) became positive (1 :160, homogeneous immunofluorescence pattern) during her hospitalization, but anti-DNA and anti-smooth muscle antibodies were negative. Thyroid function tests showed mild hypothyroidism. Eosinophils remained elevated at 2,340 cells/mm'. A bone marrow biopsy specimen showed increased eosinophil and erythroid precur-
sors. Westergren erythrocyte sedimentation rate (ESR) was 124 mmihr. Lyme serologies were negative. Polyclonal elevation of IgG was noted on serum protein electrophoresis (2,580 mg/dl). A full-thickness skin biopsy specimen from the dorsal aspect of the left forearm revealed a superficial perivascular infiltrate consisting of lymphocytes and eosinophils with moderate dermal sclerosis and markedly thickened fascia. Bronchoalveolar lavage fluid contained an increased number of neutrophils with 294 eosinophils. Muscle and sural nerve biopsies were done. The sural nerve showed severe, acute panfascicular axonal degeneration affecting all fascicles equally (Fig 1).All myelinated axons were at the same stage of degeneration. There was some evidence of early axonal regeneration. No inflammatory cells were seen in the endoneurium or epineurium and there was no evidence of vasculitis. The perineurium was notably thickened. The biopsy specimen of the vastus lateralis demonsuated marked atrophy of muscle fibers with the presence of pyknotic nuclear clumps and small fibers staining darkly with NADH and nonspecific esterase. Some muscle fibers were degenerating and a marked amount of acid-phosphatase activity could be seen within fibers and phagocytic cells. Other fibers appeared 10 be regenerating. There was an increase in both endomysial and perimysial connective tissue associated with scattered phagocytes in the endomysium and perimysium. Quinolinic acid levels were determined in the CSF E61 and were markedly elevated (299.0 nm; normal controls, 10 to 30 nm). A 20-liter plasma exchange followed by prednisone, 80 mg/day, produced no improvement in strength. Eosinophil
Heiman-Patterson et al: Neuropathy and EMS 5 2 3
Fag 1. Sural nerve specimen from Patient 1 at (a) low ( X 130 before 21 % redgction) and (b) high ( x 320 before 21 redgction) magnification. There is severe, panfascicular acute axonal degeneration,with all myelinated axons at appvo.rirnately the same stage of degeneration. There are a few small, thinb myelinated regenerating axons.
counts dropped to zero. Five months after the onset of symptoms, generalized and mildly tender induration, profound muscle weakness, persistent tachycardia, and intermittent ileus persisted. At the time of writing, the patient remained ventilator dependent.
Patient 2 In July 1989, a 34-year-old woman was noted to have myalgias and arthralgias followed by the onset of diffuse muscle weakness, fatigue, productive cough dyspnea, and low-grade fevers. An erythematous, pruritic, blotchy rash was noted on her stomach, back, face, and fingers. The cough and dyspnea resolved with antibiotic treatment, but all other symptoms persisted. She had been taking L-tryptophan, 1,500 mg daily (four different brands), since March 1989 for premenstrual syndrome. She also had a history of depression, infectious mononucleosis, and hepatitis at age 24. An eosinophil count of 56% was noted. In November 1989, the patient developed progressive proximal muscle weakness, ascending numbness, and pain to the umbilicus and elbows. L-Tryptophan was discontinued, but she was hospitalized 1 month later for progressive symptoms. Findings on general examination were unremarkable, with no skin rash present. Neu-
524 Annals of Neurology Vol 2 8 N o 4
October 1990
rological examination demonstrated mild weakness throughout, marked muscle tenderness, patchy sensory deficit involving small fiber function in the arms and legs, and diffuse hyporeflexia. Blood eosinophil count was 4,600/mm3. CSF was normal. A muscle biopsy specimen showed inflammation with interstitial and perimysial infiltrates composed of plasma cells, lymphocytes, and eosinophils. Scattered muscle fibers were undergoing necrosis. A full-thickness skin biopsy specimen showed nonspecific pathological alterations, with occasional eosinophils present. She was treated with prednisone, 60 mg daily, with prompt normalization of the eosinophil count and some relief of myalgias. However, the numbness, weakness, and sensory loss progressed, and she was admitted to Thomas Jefferson University Hospital in January 1990 for additional workup and treatment with plasmapheresis. Her general physical examination was unremarkable. She had normal mental status and cranial nerves. Her arms demonstrated full strength proximally, with 4 + / 5 strength in her hands. Her proximal leg strength was 4-15 with 3/5 distal motor strength. There was significant atrophy in the distal parts of the extremities. She was hyporeflexic in the arms but was areflexic in her legs. Sensory examination demonstrated hypesthesia to pain and temperature distally. Laboratory evaluation demonstrated mild leukocytosis with 32% eosinophils. The aldolase level was elevated (11 units/liter) but results of liver function tests, ESR, and serum protein electrophoresis were normal. Tests for ANA were negative. Electrodiagnostic studies demonstrated a moderately severe sensorimotor neuropathy (motor > sensory), with both patchy demyelination and associated severe axonal degeneration (see Table). Motor conduction velocities were markedly reduced, with conduction block and dispersion in median, ulnar, and peroneal nerves. Needle EMG demonstrated fibrillations and chronic partial denervation in all muscles, accentuated distally. The sural nerve specimen showed moderately severe loss of myelinated axons with some myelin debris, indicating recent axonal degeneration, and prominent regeneration (Figs 2 and 3). The severity of the changes differed markedly between fascicles and even within individual fascicles, indicating a multifocal process. These were occasional large, thinly myelinated axons. There was focal perivascular lymphocytic infiltration around epineural blood vessels but no evidence of vasonecrosis, medial fibrosis, or blood vessel occlusion. Quinolinic acid levels were measured in the CSF [GI and found to be moderately elevated (68.4 nm; normal controls, 10 to 30 nM). The patient was maintained on prcdnisone while plasmapheresis was initiated. The patient noted improvement after 6 liters of exchange. Examination showed that objective strength increased by one grade in all muscles tested; however, sensory examination demonstrated no change. Reflexes remained diminished.
Patient 3 In June 1988, a 44-year-old woman had an exacerbation of depression, which she had had intermittently since adoles-
~~~
Fig 2. Sural nerve specimen frovn Patient 2 ( x 130 before 27% reduction). (u) and (bj are from dijjjrent fuscicles. I n fuxicle (a), the myelinatedfiber density is mildly reduced. mainly iri the subperineurial region. In fascicle (b), the rnyelinatedjbw density is much more severely reduced. However, part of the fascicle (upper right) is relatively spured. In both fuscicles the perineurium is substantially thickened.
cence. She was treated with doxepin and L-tryptophan (666 mg of L-tryptophan four times daily), and coritinued to take these medications throughout the surniner. Findings on physical examination at that time were normal. In October 1988, she was evaluated for severe myalgias and an eosinophilia of 27%. Liver function studies showed mildly elevated levels of serum transaminases. ESR, ANA, rheumatoid factor, serum protein electrophoresis, and Lyrne titer were normal or negative. She discontinued all medications. By November the myalgia had increased in severity and she noted numbness and tingling paresthesias in her feet and hands, accompanied by slowly progressive muscle weakness. She was admitted to the Hospital of the University of Pennsylvania. General physical findings were unremarkable. She had normal mental status and cranial nerves. Hcr arms demonstrated normal strength proxiinally with 415 intrinsic hand weakness. In her legs, proximal strength was 415 and distal strength was 3 -15. She was unable to get out of a chair without using her arms. She was areflexic with the exception of a 1 biceps reflex. She had moderate hypcsthesia to pain and temperature distally. The CSF was normal. Chest roentgenogram, radionuclide bone scan, and skeletal survey were normal. The complete
+
Fig 3. Sural nerve specimens from Patient 2 (a) and Patient 3 (b) demonstrating perivascular mononucleur injiltrutes ( x 1 30 before 26% reduction). The injltrata can Be seen iri the endoneurium,perineurium, and elineurium.
blood cell count showed 7% eosinophils. Liver function studies, ESR, and creatine kinase, serum cryoglobulin, and complement levels were normal. Antibodies to SSA, SSB, RPR, MHA-TP, hepatitis surface antigen, and human immunodeficiency virus (HIV) were not detected. Results of serum and urine immunoelectrophoresis were normal. An electrodiagnostic study was consistent with a moderately severe polyneuropathy with demyelinating features (see Table). Conduction block was seen in the ulnar motor response on one side. EMG demonstrared fibrillations and chronic partial denervation that was most severe distally. Examination of a sural nerve biopsy specimen demonstrated a mild, active, axonal neuropathy with inflammatory features. There was a mild reduction in numbers of myelinated fibers. Thinly myelinated, regenerating fibers and myelin debris were seen. Several prominent perivascular mononuclear cell infihates were seen around epineural and endoneurial blood vessels (see Fig 3). No vasonecrosis, neutrophils, or eosinophils were noted. Teased fiber preparations showed occasional fibers undergoing degeneration without segmental demyelination or remyelination. The patient was treated for 5 days with intravenous methylprednisolone (2 50 mgiday) for possible inflammatory neuropathy and was discharged on 60 mg of prednisone daily. Peripheral blood eosinophilia resolved. After 3 weeks the corticosteroids were stopped because of acute depression,
HeimamPatterson et al: Neuropathy and EMS 525
but the 8-week course of deterioration had been halted. A brief course of plasma exchange (six plasma volumes over 5 days) was ineffective. Azathioprine was initiated but had to be stopped because of elevated levels of serum transaminases. Three weeks later, sclerodermalike skin changes were noted over the distal regions of the legs and hands. Leukocyte count was 30,000 cells/mm3with 53% eosinophils. A full-thickness skin biopsy specimen showed marked eosinophilic infiltration of cutaneous fat, dermis, and fascia, as well as dermal and fascial sclerosis. A bone marrow biopsy specimen was unremarkable. Results on repeat tests of CK, ESR, and ANA were normal. She was started on prednisone, 40 mg daily, with rapid resolution of the skin changes, but over the subsequent 2 months steady deterioration in neurological function occurred. On examination, she had developed new weakness of jaw opening, as well as mild dysphagia and dyspnea. She had increased weakness in the extremities with 415 proximal arm strength and 315 in the proximal legs. Her distal strength was 115 in the upper and 015 in the lower extremities, with severe muscle atrophy. She was areflexic and had a moderately severe distal impairment of all sensory modalities. She was unable to stand or ambulate, even with assistance. She continued to have severe myalgia with a normal CK level. Eosinophilia resolved slowly after 1 month of prednisone therapy. Her condition remained unchanged over the subsequent 4 months while she took prednisone, 40 mg daily.
Discussion L-Tryptophan ingestion has been associated with the development of EMS, and is characterized by myalgia and fatigue associated with swelling of the extremities, skin rash, and elevation of blood eosinophil count {I51. Frequently, dyspnea and respiratory involvement are observed in the early phase of the illness. Skin biopsies of involved areas have demonstrated thickening of the fascia, deep dermal fibrosis, and accumulation of mononuclear cells and abundant eosinophils { 5 ] . CDC reports have included information supplied by reporting physicians regarding muscle biopsies. Muscle biopsy specimens reportedly demonstrate perivascular inflammatory infiltrates that are typically composed of eosinophils and round cells. Vasculitis has also been reported to the CDC C41. Surd nerve biopsy findings have not been previously described. The CDC has suggested the following criteria for the diagnosis of EMS: (1) the presence of generalized myalgia, (2) eosinophil counts of 1,000 cells/mm3 or more, and (3) the absence of any infection or neoplasia that could account for either of the first two criteria [1-5}. In this report we document the presence of moderate to severe neuropathy in 3 patients who fit the clinical criteria recommended by the CDC for the diagnosis of EMS. A recent editorial pointed out that a progressive and sometimes fatal ascending neuropathy can occur in EMS 141. Although it was noted that electrophysiological studies demonstrating axonal loss with a mononeuritis multiplex pattern can be seen, 526 Annals of Neurology Vnl 2 8 No 4 October 1990
clinical, physiological, and pathological features of EMS neuropathy have not been reported to date. In our patients, the neuropathy was predominantly motor, involving both proximal and distal muscles, suggesting demyelination. Sensory loss was more severe distally and primarily involved small fiber modahties, although reflexes were absent in involved areas. A complete evaluation excluded other causes of progressive acute-subacute demyelinating and axonal neuropathies. The neuropathy of these patients progressed in spite of stopping ingestion of L-tryptophan and treatment of EMS with prednisone, which was associated with resolution of the eosinophilia Immunosuppressive therapy with azathioprine did not result in improvement in 1 patient (Patient 3). The patient with the least severe neuropathy (Patient 2) improved during plasmapheresis while no beneficial effect was seen in the most severely affected patient (Patient I). The weight of electrophysiological evidence favors an initial and early demyelinating process with severe secondary axonal degeneration. While distally accentuated axonal denervation was present, there was evidence of conduction block and significant slowing of motor conduction velocity that cannot be explained by the axonal loss itself (see Table). Although conduction block has been described with ischemia and vasculitis {7, 81, it is more characteristic of demyelination C91. Pathological features in the sural nerve have not previously been reported in EMS. All 3 of our patients had axonal degeneration, without segmental demyelination, that was associated with perivascular mononuclear cell infiltration in 2 patients (Patients 2 and 3). The pattern of pathological changes was suggestive of nerve infarction in 2 patients (Patients 1 and 2). Perineurial thickening was noted in both of these patients and may represent fibrosis. In one, there was panfascicular wallerian degeneration with all myelin at the same stage of degeneration and very little regeneration. Such an acute monophasic event is most commonly ischemic in origin. In another, there was differential interfascicular and intrafascicular axonal degeneration without evidence of significant demyelination, changes most consistent with nerve ischemia. However, the changes in the sural nerve distally might also be due to downstream axonal degeneration resulting from a proximal, primarily demyelinating lesion with severe associaxed axonal injury 110, 111. This explanation would be more consistent with the electrophysiological findings. Muscle pathological study was done in 2 patients (Patients 1 and 2) and demonstrated perivascular and interstitial inflammatory infiltrates along with myopathic changes in both patients and severe changes of muscle fiber atrophy and endomysial fibrosis in Patient 1. These atrophic fibers were denervated by histochemical stains. Rare eosinophils were observed in
Patient 2. These changes are similar to those described in anecdotal reports 14). The inflammatory nature of the nerve specimens in 2 patients suggests that immune mechanisms may play a role in this neuropathic process. The lack of eosinophils in these nerve specimens may be related to the timing of the biopsies, which were performed while patients were receiving treatment with prednisone, at which time blood eosinophil counts had dropped to zero. Additional evidence for the role of immune mechanisms includes the demyelinating features that resembled acquired demyelinating neuropathies on electrophysiological studies and the response of 1 patient to plasmapheresis. However, in general our patients did not respond well to immunosuppressive therapy with prednisone or azathioprine, perhaps due to the extensive axonal damage. Since these patients have not been followed for long periods subsequent to treatment, we cannot be certain whether the neuropathic process was halted and whether slow recovery with axonal regeneration will occur. Alternatively, even though toxic neuropathies are characteristically distal axonopathies and not the pattern seen in these patients, the neuropathy of EMS may, in part, be due to direct toxicity caused by eosinophilic infiltration of nerves, by L-tryptophan, by its breakdown products, or by unknown contaminants within L-tryptophan preparations. Patients with idiopathic hypereosinophilic syndromes demonstrate neuropathies 112-141 in association with pulmonary, cardiovascular, renal, hepatic, and/or skin involvement. Eosinophils need not be present within nerve specimens, and both the serum and the eosinophils from such patients demonstrate in vitro toxicity to dorsal root ganglion neurons { 151. Furthermore, eosinophils have been shown to contain eosinophil-derived neurotoxin, which can cause ataxia and paralysis in experimental animals as well as damage to myelinated nerve fibers 116). Rather than a direct toxicity of eosinophils, L-tryptophan or its metabolites may play a role in development of the neuropathy. CSF levels of quinolinic acid were measured in 2 patients and found to be elevated in both, with higher levels in the more severely affected patient (Patient 1).These results are provocative, since L-tryptophan is metabolized by one of two pathways, either through 5-OH tryptophan to serotonin, or via the kynurenine pathway to quinolinic acid I17). Quinolinic acid has been shown to be neurotoxic [lS], and elevated CSF levels have been associated with some neurological disorders including HIV encephalitis E191. It is of note that the first enzyme of the kynurenine pathway of tryptophan metabolism, indoleamine-2,3-dioxygenase(IDO), is activated in infections and that resultant elevations in quinolinic acid concentrations have been found in the CSF and brain
during infectious states 120). Thus the increased CSF concentration of quinolinic acid may reflect locd inflammatory responses in the patients with EMS. Our report is the first to demonstrate elevation of CSF quinolinic acid levels in patients with severe neuropathy in the setting of L-tryptophan-associated EMS. Finally, there may be contaminants within L-tryptophan preparations that act as neurotoxins, as well as promoting the development of eosinophilia and a systemic illness that have yet to be identified. In summary, we presented the cases of 3 patients who had a predominantly demyelinating neuropathy with associated severe axonal degeneration in the setting of a systemic eosinophilic illness, developing during chronic ingestion of L-tryptophan-containingpreparations. The mechanism may be immune-mediated or due to direct nerve toxicity of either eosinophik, L-tryptophan, the metabolites of t-tryptophan, or a contaminant within L-tryptophan preparations. Dr J. Varga is the recipient of a Clinical Investigator Award (KO8 AR 01817) from the National Institutes of Health (NIH). Dr. M. Shy is a recipient of a Clinical Investigator Development Award (1 KO8 NS01261-01) from the NIH.
References 1. Centers for Disease Control. Eosinophilia-myakia . - svndrome. New Mexico. MMWR 1989;38:7651767 2. Centers for Disease Control. Eosinophilia-myalgia syndrome and L-tryptophan-containing products-New Mexico, Minnesota, Oregon, and New York, 1989. MMWR 1989;38:785788 3. Centers for Disease Control. Update: eosinophilia-myalgiasyndrome associated with ingestion of L-tryptophan in the United States as of January 9, 1990. MMWR 1990;39:14-15 4.Kdbourne EM, Swygert LA, Philen RM,et al. Interim guidance on the eosinophilia-myalgia syndrome. Ann Intern Med 1990;112:85-87 5. Varga J, Peltonen J, Uirto J, Jimenez SA. Development of diffuse fascitis with eosinophilia during L-rryptophan treatment: a ctinicopathoiogical study of four cases and demonstration of elevated type 1 collagen gene expression in affected tissues. Ann Intern Med 1990;112:344-351 6. Heyes MP, Markey SP. Effects of pyrazinamide and tryptophan on cortical quinolinic acid content in rats: an animal model of glutaric aciduria type 1. SOCNeurosci Abstr 1987;13:453-459 7. Parry GJ, Linn DJ. Conduction block without demyelination following acute nerve infarction. J Neurol Sci 1988;84:265-273 8. Ropert A, Metrao S. Conduction block in neuropathies with necrorizing vasculitis. Muscle Nerve 1990;13: 102-105 9. Thomas PK, Holdorff B. Neuropathy due to physical agents. In: Dyck PJ, Thomas PK, Lamben EH, Bunge R, eds. Peripheral neuropathy. Philadelphia: W.B. Saunders, 1984:1479-1511 10. Arnason BGW. Acute inflammatory demyelinating peripheral neuropathies. In: Dyck PJ, Thomas PK, Lambert EH, Bunge R, eds. Peripheral neuropathy. Philadelphia: W.B. Saunders, 1984:2059 11. Dyck PJ. Chronic inflammatory demyelinating polyradiculoneuropathy. In: Dyck PJ, Thomas PK, Lambert EH, Bunge R, eds. Peripheral neuropathy. Philadelphia: W.B. Saunders, 1984~2 101-2 114
Heiman-Patterson et al: Neuropathy and EMS 527
12. Dorfman LJ, Ransom BR, Forno LS, Kelts A. Neuropathy in the hypereosinophilic syndrome. Muscle Nerve 1983;6:291298 13. Durack DT, Sum SM, Klebanoff SJ. Neurotoxicity of human eosinophils. Proc Natl Acad Sci USA 1979;76:1443-1447 14. Wichman A,Buchtal F, Pezeshkpour GH, Fauci AS. Peripheral neuropathy in hypereosinophilic syndrome. Neurology 1985; 35:1140- 1145 15. Sunohara N, Furukawa S, Nishio T, et al. Neurotoxicity of human eosinophils towards peripheral nerves. J Neurosci 1989;92:1-7 16. Dwack DT, Ackerman SJ, Leogering DA, Gleich GJ. Purification of human eosinophil-derived neurotoxin. Proc Natl Acad Sci USA 1981;78:5165-5169
528 Annals of Neurology Vol 28 No 4 October 1990
17. During MJ, Freese A, Heyes M, et al. Neuroactive metabolites of L-tryptophan, serotonin, and quinolinic acid in striatal extracellular fluid. FEBS Lett 1989;2:438-444 18. Schwarcz R, Whetsell WO, Mangano RM. Quinolinic acid: an endogenous metabolite can produce axon-sparing lesions in rat brain. Science 1983;219:316-318 19. Heyes MP, Rubinow D, Lane C, et al. Cerebrospinal fluid quinolinic acid concentrations are increased in acquired immune deficiency syndrome. Ann Neurol 1989;26:275-277 20. Takikowa 0,Yoshida R, Kid0 R, et al. Tryptophan degradation J Biol Chem in mice initiated by indoleamine-2,3-dioxygenase. 1986;261:3648-3653 21. A manual of techniques in clinical EMG. Rochester, MN: Electromyography Laboratory, Mayo Clinic, 1983:2-12, 2-19
In 1989, the Centers for Disease Control recognized the existence of an epidemic illness characterized by myalgia and eosinophilia in individuals taking preparations containing L-tryptophan. We evaluated 3 patients with eosinophiliamyalgia syndrome who presented with subacute progressive neuropathies. The neuropathies were predominantly motor and maximal in the lower extremities. Two patients were confined to a wheelchair and one was ventilatordependent and bedridden. Sensory loss predominantly involved small fiber modalities. Electrophysiological studies showed multifocal marked conduction slowing and conduction block indicating segmental demyelination, with associated axonal degeneration that was accentuated distally. Examination of sural nerve biopsy specimens demonstrated axonal degeneration in all 3 patients and perivascular infiltrates in 2. Levels of quinolinic acid, a neurotoxic metabolite of t-tryptophan, were elevated in the cerebrospinal fluid in the 2 patients in whom it was measured. The cause of the neuropathy is unknown but may include immune mechanisms or toxicity of eosinophils, L-tryptophan, its metabolic products, or contaminants within L-tryptophan preparations. Heiman-Patterson TD, Bird SJ, Parry GJ, Varga J, Shy ME, Culligan NW, Edelsohn L, Tatarian GT, Heyes MP, Garcia CA, Tahmoush AJ. Peripheral neuropathy associated with eosinophilia-myalgia syndrome. Ann Neurol 1990;28:522- 52 8 In November 1989, the Centers for Disease Control (CDC) recognized the existence of an epidemic illness characterized by myalgia and eosinophilia in individuals taking preparations containing L-tryptophan El5 } . We studied 3 patients who presented with subacute progressive neuropathies of variable severity which developed during chronic ingestion of L-tryptophan, associated with a systemic illness and eosinophilia. We report the clinical, electrophysiological, and pathological features of the neuropathy in these patients. In addition, we provide evidence for elevated levels of quinolinic acid, a neurotoxic metabolite of L-tryptophan in the cerebrospinal fluid (CSF). This presentation of the eosinophilia-myalgia syndrome (EMS) can be life-threatening and has not been described to date. It is important for the neurologist to recognize this association so that the appropriate diagnostic and therapeutic steps can be promptly initiated.
Case Reports Patient 1 A 57-year-old woman was admitted to Thomas Jefferson University Hospital in December 1989 for progressive
From the Departments of "Neurology and tfieumatology, Jefferson Medical College, and the Department of $Neurology, [Jniversity Of Philacielphia, PA; Departments Of and 'Pathology, Louisiana State Universiv, New Orleans, LA; Department of **Neurology, Christiana Hospital, Wilmington, DE; and ??National Institute of Mental Health, Laboratory of Clinical Science, Rethesda, MD.
522
weakness. In August 1989, she developed a diffuse erythematous rash, low-grade fevers, productive cough, diarrhea, severe diffuse myalgia, and malaise. She gained 9.1 kg (20 Ib) over a 2-week period. She had been taking lithium, amitriptyline, diphenhydramine, and diazepam for an affective disorder, as well as r-tryptophan, 8,000 mg daily, for the treatment of insomnia for 4 months prior to the onset of symptoms. In September 1989, she underwent evaluation for edema and low-grade fevers. Laboratory evaluation revealed a pleural effusion, ascites, and hypoalbuminemia (2.4 gmidl). Leukocyte count was 15,000 cells/mm3 with 71%) segmented cells, 4% rnonocytes, and 15% eosinophils. The absolute eosinophil count was 2,250 cells/mm3. The serum creatine kinase (CK) level was normal but aldolase activity was elevated (12 unitdliter; normal 5 7 unitsiliter). Alkaline phosphatase (390 unitsiliter) and lactate dehydrogenase (LDH)(404 unitsiliter) levels were elevated. She was treated with diuretics without improvement. Her condition continued to deteriorate until November, when she was hospitalized with progressive dyspnea and weakness. On physical examination, there was anasarca and generalized muscle weakness. The peripheral blood eosinophi1 count was intermittently elevated (as high as 1,700 cells/ mrn3).Her hospital course was complicated by a hemothorax
Received Feb 23, 1990, and in revised form Apr 19. Accepted for publication Apr 23, 1990. Address correspondence to Dr Heiman-Patterson, Associate professor of ~ ~Jefferson Medical ~ College, ~ 1025 lWalnut Street, ~ Suite 1, Philadelphia, PA 19107-5083.
Copyright 0 1990 by the American Neurological Association
~
Nerve Conduction Studies" Patient 1 Amplitudeb
(msec)
Velocity (misec)
5.7 2.7 18.4
4.3
33
7.9 6.4
47
8.1
3.3 2.1 2.0
4.7
30
10.6 7.2 5.3
NO NO
0.6 0.3
6.7
NO NO NO
2.6 NO
6.0
Amplitudeb Median motor Distal Proximal Median sensory Ulnar motor Distal Proximal Ulnar sensory Peroneal Distal Proximal Posterior tibial Distal Proximal Surd nerve
Latency' (msec)
Patient 3
Patient 2 Velocity (misec)
1.3 6 24.3 0.3 Could not be done due to technical difficulties 1.0
4.1
32
0.9 Could not be done due to technical difficulties
Latency'
41 21
Amplitudeb
0.59 0.39
10.9 8.8 7.0
NO
Latency' (msec)
Velocity (m/sec)
4.8
44 52
3.2
42
50 7.5
21
4.6
35 38
"Normal values are those reported by the Mayo Clinic 1217. bAmplitudes are measured in mV for motor conductions and pV for sensory conductions %tency is measured to onset in motor conduction velocities. NO = not obtainable
during thoracentesis, necessitating utilization of a chest tube and mechanical ventilatory support. She remained ventilatordependent and was transferred to Thomas Jefferson University Hospital because of progressive wasting and weakness. General examination showed symmetrical, tender induration of the forearms, arms, abdomen, legs, and feet. There were no digital ulcerations, joint abnormalities, or tendon friction rubs. Neurological examination demonstrated an intact sensorium and mild facial diplegia. The rest of the cranial nerve examination was normal. Motor examination showed diffuse wasting that was more prominent distally. There was bilateral deltoid weakness (115)with symmetrical weakness in the distal upper extremities ( 2 to 3/5). Proximal leg strength was 0/5, while distal strength was 1 to 215. Deep tendon reflexes were absent. The sensory examination demonstrated mild to moderate hypesthesia to pain and temperature in the distal areas of the extremities. Vibration was mildly diminished in the lower extremities. Electrophysiological findings were consistent with a demyelinating neuropathy with severe axonal loss (Table). Needle electromyography (EMG) demonstrated fibrillations in all muscles throughout, accentuated distally. The CSF protein level was initially 16 mgidl, but 2 weeks later it was 54 mg!dl with normal glucose levels and no cells. The aldolase was 7.6 unitslliter and CK, 9 unitsiliter. Antinuclear antibody (ANA) became positive (1 :160, homogeneous immunofluorescence pattern) during her hospitalization, but anti-DNA and anti-smooth muscle antibodies were negative. Thyroid function tests showed mild hypothyroidism. Eosinophils remained elevated at 2,340 cells/mm'. A bone marrow biopsy specimen showed increased eosinophil and erythroid precur-
sors. Westergren erythrocyte sedimentation rate (ESR) was 124 mmihr. Lyme serologies were negative. Polyclonal elevation of IgG was noted on serum protein electrophoresis (2,580 mg/dl). A full-thickness skin biopsy specimen from the dorsal aspect of the left forearm revealed a superficial perivascular infiltrate consisting of lymphocytes and eosinophils with moderate dermal sclerosis and markedly thickened fascia. Bronchoalveolar lavage fluid contained an increased number of neutrophils with 294 eosinophils. Muscle and sural nerve biopsies were done. The sural nerve showed severe, acute panfascicular axonal degeneration affecting all fascicles equally (Fig 1).All myelinated axons were at the same stage of degeneration. There was some evidence of early axonal regeneration. No inflammatory cells were seen in the endoneurium or epineurium and there was no evidence of vasculitis. The perineurium was notably thickened. The biopsy specimen of the vastus lateralis demonsuated marked atrophy of muscle fibers with the presence of pyknotic nuclear clumps and small fibers staining darkly with NADH and nonspecific esterase. Some muscle fibers were degenerating and a marked amount of acid-phosphatase activity could be seen within fibers and phagocytic cells. Other fibers appeared 10 be regenerating. There was an increase in both endomysial and perimysial connective tissue associated with scattered phagocytes in the endomysium and perimysium. Quinolinic acid levels were determined in the CSF E61 and were markedly elevated (299.0 nm; normal controls, 10 to 30 nm). A 20-liter plasma exchange followed by prednisone, 80 mg/day, produced no improvement in strength. Eosinophil
Heiman-Patterson et al: Neuropathy and EMS 5 2 3
Fag 1. Sural nerve specimen from Patient 1 at (a) low ( X 130 before 21 % redgction) and (b) high ( x 320 before 21 redgction) magnification. There is severe, panfascicular acute axonal degeneration,with all myelinated axons at appvo.rirnately the same stage of degeneration. There are a few small, thinb myelinated regenerating axons.
counts dropped to zero. Five months after the onset of symptoms, generalized and mildly tender induration, profound muscle weakness, persistent tachycardia, and intermittent ileus persisted. At the time of writing, the patient remained ventilator dependent.
Patient 2 In July 1989, a 34-year-old woman was noted to have myalgias and arthralgias followed by the onset of diffuse muscle weakness, fatigue, productive cough dyspnea, and low-grade fevers. An erythematous, pruritic, blotchy rash was noted on her stomach, back, face, and fingers. The cough and dyspnea resolved with antibiotic treatment, but all other symptoms persisted. She had been taking L-tryptophan, 1,500 mg daily (four different brands), since March 1989 for premenstrual syndrome. She also had a history of depression, infectious mononucleosis, and hepatitis at age 24. An eosinophil count of 56% was noted. In November 1989, the patient developed progressive proximal muscle weakness, ascending numbness, and pain to the umbilicus and elbows. L-Tryptophan was discontinued, but she was hospitalized 1 month later for progressive symptoms. Findings on general examination were unremarkable, with no skin rash present. Neu-
524 Annals of Neurology Vol 2 8 N o 4
October 1990
rological examination demonstrated mild weakness throughout, marked muscle tenderness, patchy sensory deficit involving small fiber function in the arms and legs, and diffuse hyporeflexia. Blood eosinophil count was 4,600/mm3. CSF was normal. A muscle biopsy specimen showed inflammation with interstitial and perimysial infiltrates composed of plasma cells, lymphocytes, and eosinophils. Scattered muscle fibers were undergoing necrosis. A full-thickness skin biopsy specimen showed nonspecific pathological alterations, with occasional eosinophils present. She was treated with prednisone, 60 mg daily, with prompt normalization of the eosinophil count and some relief of myalgias. However, the numbness, weakness, and sensory loss progressed, and she was admitted to Thomas Jefferson University Hospital in January 1990 for additional workup and treatment with plasmapheresis. Her general physical examination was unremarkable. She had normal mental status and cranial nerves. Her arms demonstrated full strength proximally, with 4 + / 5 strength in her hands. Her proximal leg strength was 4-15 with 3/5 distal motor strength. There was significant atrophy in the distal parts of the extremities. She was hyporeflexic in the arms but was areflexic in her legs. Sensory examination demonstrated hypesthesia to pain and temperature distally. Laboratory evaluation demonstrated mild leukocytosis with 32% eosinophils. The aldolase level was elevated (11 units/liter) but results of liver function tests, ESR, and serum protein electrophoresis were normal. Tests for ANA were negative. Electrodiagnostic studies demonstrated a moderately severe sensorimotor neuropathy (motor > sensory), with both patchy demyelination and associated severe axonal degeneration (see Table). Motor conduction velocities were markedly reduced, with conduction block and dispersion in median, ulnar, and peroneal nerves. Needle EMG demonstrated fibrillations and chronic partial denervation in all muscles, accentuated distally. The sural nerve specimen showed moderately severe loss of myelinated axons with some myelin debris, indicating recent axonal degeneration, and prominent regeneration (Figs 2 and 3). The severity of the changes differed markedly between fascicles and even within individual fascicles, indicating a multifocal process. These were occasional large, thinly myelinated axons. There was focal perivascular lymphocytic infiltration around epineural blood vessels but no evidence of vasonecrosis, medial fibrosis, or blood vessel occlusion. Quinolinic acid levels were measured in the CSF [GI and found to be moderately elevated (68.4 nm; normal controls, 10 to 30 nM). The patient was maintained on prcdnisone while plasmapheresis was initiated. The patient noted improvement after 6 liters of exchange. Examination showed that objective strength increased by one grade in all muscles tested; however, sensory examination demonstrated no change. Reflexes remained diminished.
Patient 3 In June 1988, a 44-year-old woman had an exacerbation of depression, which she had had intermittently since adoles-
~~~
Fig 2. Sural nerve specimen frovn Patient 2 ( x 130 before 27% reduction). (u) and (bj are from dijjjrent fuscicles. I n fuxicle (a), the myelinatedfiber density is mildly reduced. mainly iri the subperineurial region. In fascicle (b), the rnyelinatedjbw density is much more severely reduced. However, part of the fascicle (upper right) is relatively spured. In both fuscicles the perineurium is substantially thickened.
cence. She was treated with doxepin and L-tryptophan (666 mg of L-tryptophan four times daily), and coritinued to take these medications throughout the surniner. Findings on physical examination at that time were normal. In October 1988, she was evaluated for severe myalgias and an eosinophilia of 27%. Liver function studies showed mildly elevated levels of serum transaminases. ESR, ANA, rheumatoid factor, serum protein electrophoresis, and Lyrne titer were normal or negative. She discontinued all medications. By November the myalgia had increased in severity and she noted numbness and tingling paresthesias in her feet and hands, accompanied by slowly progressive muscle weakness. She was admitted to the Hospital of the University of Pennsylvania. General physical findings were unremarkable. She had normal mental status and cranial nerves. Hcr arms demonstrated normal strength proxiinally with 415 intrinsic hand weakness. In her legs, proximal strength was 415 and distal strength was 3 -15. She was unable to get out of a chair without using her arms. She was areflexic with the exception of a 1 biceps reflex. She had moderate hypcsthesia to pain and temperature distally. The CSF was normal. Chest roentgenogram, radionuclide bone scan, and skeletal survey were normal. The complete
+
Fig 3. Sural nerve specimens from Patient 2 (a) and Patient 3 (b) demonstrating perivascular mononucleur injiltrutes ( x 1 30 before 26% reduction). The injltrata can Be seen iri the endoneurium,perineurium, and elineurium.
blood cell count showed 7% eosinophils. Liver function studies, ESR, and creatine kinase, serum cryoglobulin, and complement levels were normal. Antibodies to SSA, SSB, RPR, MHA-TP, hepatitis surface antigen, and human immunodeficiency virus (HIV) were not detected. Results of serum and urine immunoelectrophoresis were normal. An electrodiagnostic study was consistent with a moderately severe polyneuropathy with demyelinating features (see Table). Conduction block was seen in the ulnar motor response on one side. EMG demonstrared fibrillations and chronic partial denervation that was most severe distally. Examination of a sural nerve biopsy specimen demonstrated a mild, active, axonal neuropathy with inflammatory features. There was a mild reduction in numbers of myelinated fibers. Thinly myelinated, regenerating fibers and myelin debris were seen. Several prominent perivascular mononuclear cell infihates were seen around epineural and endoneurial blood vessels (see Fig 3). No vasonecrosis, neutrophils, or eosinophils were noted. Teased fiber preparations showed occasional fibers undergoing degeneration without segmental demyelination or remyelination. The patient was treated for 5 days with intravenous methylprednisolone (2 50 mgiday) for possible inflammatory neuropathy and was discharged on 60 mg of prednisone daily. Peripheral blood eosinophilia resolved. After 3 weeks the corticosteroids were stopped because of acute depression,
HeimamPatterson et al: Neuropathy and EMS 525
but the 8-week course of deterioration had been halted. A brief course of plasma exchange (six plasma volumes over 5 days) was ineffective. Azathioprine was initiated but had to be stopped because of elevated levels of serum transaminases. Three weeks later, sclerodermalike skin changes were noted over the distal regions of the legs and hands. Leukocyte count was 30,000 cells/mm3with 53% eosinophils. A full-thickness skin biopsy specimen showed marked eosinophilic infiltration of cutaneous fat, dermis, and fascia, as well as dermal and fascial sclerosis. A bone marrow biopsy specimen was unremarkable. Results on repeat tests of CK, ESR, and ANA were normal. She was started on prednisone, 40 mg daily, with rapid resolution of the skin changes, but over the subsequent 2 months steady deterioration in neurological function occurred. On examination, she had developed new weakness of jaw opening, as well as mild dysphagia and dyspnea. She had increased weakness in the extremities with 415 proximal arm strength and 315 in the proximal legs. Her distal strength was 115 in the upper and 015 in the lower extremities, with severe muscle atrophy. She was areflexic and had a moderately severe distal impairment of all sensory modalities. She was unable to stand or ambulate, even with assistance. She continued to have severe myalgia with a normal CK level. Eosinophilia resolved slowly after 1 month of prednisone therapy. Her condition remained unchanged over the subsequent 4 months while she took prednisone, 40 mg daily.
Discussion L-Tryptophan ingestion has been associated with the development of EMS, and is characterized by myalgia and fatigue associated with swelling of the extremities, skin rash, and elevation of blood eosinophil count {I51. Frequently, dyspnea and respiratory involvement are observed in the early phase of the illness. Skin biopsies of involved areas have demonstrated thickening of the fascia, deep dermal fibrosis, and accumulation of mononuclear cells and abundant eosinophils { 5 ] . CDC reports have included information supplied by reporting physicians regarding muscle biopsies. Muscle biopsy specimens reportedly demonstrate perivascular inflammatory infiltrates that are typically composed of eosinophils and round cells. Vasculitis has also been reported to the CDC C41. Surd nerve biopsy findings have not been previously described. The CDC has suggested the following criteria for the diagnosis of EMS: (1) the presence of generalized myalgia, (2) eosinophil counts of 1,000 cells/mm3 or more, and (3) the absence of any infection or neoplasia that could account for either of the first two criteria [1-5}. In this report we document the presence of moderate to severe neuropathy in 3 patients who fit the clinical criteria recommended by the CDC for the diagnosis of EMS. A recent editorial pointed out that a progressive and sometimes fatal ascending neuropathy can occur in EMS 141. Although it was noted that electrophysiological studies demonstrating axonal loss with a mononeuritis multiplex pattern can be seen, 526 Annals of Neurology Vnl 2 8 No 4 October 1990
clinical, physiological, and pathological features of EMS neuropathy have not been reported to date. In our patients, the neuropathy was predominantly motor, involving both proximal and distal muscles, suggesting demyelination. Sensory loss was more severe distally and primarily involved small fiber modahties, although reflexes were absent in involved areas. A complete evaluation excluded other causes of progressive acute-subacute demyelinating and axonal neuropathies. The neuropathy of these patients progressed in spite of stopping ingestion of L-tryptophan and treatment of EMS with prednisone, which was associated with resolution of the eosinophilia Immunosuppressive therapy with azathioprine did not result in improvement in 1 patient (Patient 3). The patient with the least severe neuropathy (Patient 2) improved during plasmapheresis while no beneficial effect was seen in the most severely affected patient (Patient I). The weight of electrophysiological evidence favors an initial and early demyelinating process with severe secondary axonal degeneration. While distally accentuated axonal denervation was present, there was evidence of conduction block and significant slowing of motor conduction velocity that cannot be explained by the axonal loss itself (see Table). Although conduction block has been described with ischemia and vasculitis {7, 81, it is more characteristic of demyelination C91. Pathological features in the sural nerve have not previously been reported in EMS. All 3 of our patients had axonal degeneration, without segmental demyelination, that was associated with perivascular mononuclear cell infiltration in 2 patients (Patients 2 and 3). The pattern of pathological changes was suggestive of nerve infarction in 2 patients (Patients 1 and 2). Perineurial thickening was noted in both of these patients and may represent fibrosis. In one, there was panfascicular wallerian degeneration with all myelin at the same stage of degeneration and very little regeneration. Such an acute monophasic event is most commonly ischemic in origin. In another, there was differential interfascicular and intrafascicular axonal degeneration without evidence of significant demyelination, changes most consistent with nerve ischemia. However, the changes in the sural nerve distally might also be due to downstream axonal degeneration resulting from a proximal, primarily demyelinating lesion with severe associaxed axonal injury 110, 111. This explanation would be more consistent with the electrophysiological findings. Muscle pathological study was done in 2 patients (Patients 1 and 2) and demonstrated perivascular and interstitial inflammatory infiltrates along with myopathic changes in both patients and severe changes of muscle fiber atrophy and endomysial fibrosis in Patient 1. These atrophic fibers were denervated by histochemical stains. Rare eosinophils were observed in
Patient 2. These changes are similar to those described in anecdotal reports 14). The inflammatory nature of the nerve specimens in 2 patients suggests that immune mechanisms may play a role in this neuropathic process. The lack of eosinophils in these nerve specimens may be related to the timing of the biopsies, which were performed while patients were receiving treatment with prednisone, at which time blood eosinophil counts had dropped to zero. Additional evidence for the role of immune mechanisms includes the demyelinating features that resembled acquired demyelinating neuropathies on electrophysiological studies and the response of 1 patient to plasmapheresis. However, in general our patients did not respond well to immunosuppressive therapy with prednisone or azathioprine, perhaps due to the extensive axonal damage. Since these patients have not been followed for long periods subsequent to treatment, we cannot be certain whether the neuropathic process was halted and whether slow recovery with axonal regeneration will occur. Alternatively, even though toxic neuropathies are characteristically distal axonopathies and not the pattern seen in these patients, the neuropathy of EMS may, in part, be due to direct toxicity caused by eosinophilic infiltration of nerves, by L-tryptophan, by its breakdown products, or by unknown contaminants within L-tryptophan preparations. Patients with idiopathic hypereosinophilic syndromes demonstrate neuropathies 112-141 in association with pulmonary, cardiovascular, renal, hepatic, and/or skin involvement. Eosinophils need not be present within nerve specimens, and both the serum and the eosinophils from such patients demonstrate in vitro toxicity to dorsal root ganglion neurons { 151. Furthermore, eosinophils have been shown to contain eosinophil-derived neurotoxin, which can cause ataxia and paralysis in experimental animals as well as damage to myelinated nerve fibers 116). Rather than a direct toxicity of eosinophils, L-tryptophan or its metabolites may play a role in development of the neuropathy. CSF levels of quinolinic acid were measured in 2 patients and found to be elevated in both, with higher levels in the more severely affected patient (Patient 1).These results are provocative, since L-tryptophan is metabolized by one of two pathways, either through 5-OH tryptophan to serotonin, or via the kynurenine pathway to quinolinic acid I17). Quinolinic acid has been shown to be neurotoxic [lS], and elevated CSF levels have been associated with some neurological disorders including HIV encephalitis E191. It is of note that the first enzyme of the kynurenine pathway of tryptophan metabolism, indoleamine-2,3-dioxygenase(IDO), is activated in infections and that resultant elevations in quinolinic acid concentrations have been found in the CSF and brain
during infectious states 120). Thus the increased CSF concentration of quinolinic acid may reflect locd inflammatory responses in the patients with EMS. Our report is the first to demonstrate elevation of CSF quinolinic acid levels in patients with severe neuropathy in the setting of L-tryptophan-associated EMS. Finally, there may be contaminants within L-tryptophan preparations that act as neurotoxins, as well as promoting the development of eosinophilia and a systemic illness that have yet to be identified. In summary, we presented the cases of 3 patients who had a predominantly demyelinating neuropathy with associated severe axonal degeneration in the setting of a systemic eosinophilic illness, developing during chronic ingestion of L-tryptophan-containingpreparations. The mechanism may be immune-mediated or due to direct nerve toxicity of either eosinophik, L-tryptophan, the metabolites of t-tryptophan, or a contaminant within L-tryptophan preparations. Dr J. Varga is the recipient of a Clinical Investigator Award (KO8 AR 01817) from the National Institutes of Health (NIH). Dr. M. Shy is a recipient of a Clinical Investigator Development Award (1 KO8 NS01261-01) from the NIH.
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12. Dorfman LJ, Ransom BR, Forno LS, Kelts A. Neuropathy in the hypereosinophilic syndrome. Muscle Nerve 1983;6:291298 13. Durack DT, Sum SM, Klebanoff SJ. Neurotoxicity of human eosinophils. Proc Natl Acad Sci USA 1979;76:1443-1447 14. Wichman A,Buchtal F, Pezeshkpour GH, Fauci AS. Peripheral neuropathy in hypereosinophilic syndrome. Neurology 1985; 35:1140- 1145 15. Sunohara N, Furukawa S, Nishio T, et al. Neurotoxicity of human eosinophils towards peripheral nerves. J Neurosci 1989;92:1-7 16. Dwack DT, Ackerman SJ, Leogering DA, Gleich GJ. Purification of human eosinophil-derived neurotoxin. Proc Natl Acad Sci USA 1981;78:5165-5169
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17. During MJ, Freese A, Heyes M, et al. Neuroactive metabolites of L-tryptophan, serotonin, and quinolinic acid in striatal extracellular fluid. FEBS Lett 1989;2:438-444 18. Schwarcz R, Whetsell WO, Mangano RM. Quinolinic acid: an endogenous metabolite can produce axon-sparing lesions in rat brain. Science 1983;219:316-318 19. Heyes MP, Rubinow D, Lane C, et al. Cerebrospinal fluid quinolinic acid concentrations are increased in acquired immune deficiency syndrome. Ann Neurol 1989;26:275-277 20. Takikowa 0,Yoshida R, Kid0 R, et al. Tryptophan degradation J Biol Chem in mice initiated by indoleamine-2,3-dioxygenase. 1986;261:3648-3653 21. A manual of techniques in clinical EMG. Rochester, MN: Electromyography Laboratory, Mayo Clinic, 1983:2-12, 2-19
