Central Nervous
System Involvement in the
Eosinophilia-Myalgia Syndrome
Joanne Lynn, MD; Kottil W. Rammohan, MD; Robert A. Bornstein, PhD; John T. Kissel, MD
patient with eosinophilia-myalgia syndrome developed progressive central nervous system involvement that did not improve despite discontinuation of L-tryptophan therapy. Neurologic impairment was manifested initially by spastic monoparesis, which was improved by treatment with methylprednisolone and hydroxyurea. Recurrence of weakness was accompanied by gait ataxia, dysphagia, and complaints \s=b\ A
gradual decline in memory and concentration. Neuropsychological testing identified a broad pattern of cognitive deficits suggestive of a subcortical dementia, and magnetic resonance imaging demonstrated multiple high-signal lesions in the white matter. Cognitive deficits appear to be underrecognized in patients with the eosinophilia-myalgia syndrome. The response of our patient's initial symptoms to corticosteroid therapy suggests a possible role for autoimmune mechanisms in the pathogenesis of central nervous system involvement in the eosinophilia-myalgia syndrome. Neuropsychological evaluation should be performed in patients with cognitive complaints to delineate the full spectrum of central nervous system impairment associated with the eosinophilia-myalgia syndrome. of
a
(Arch Neurol. 1992;49:1082-1085)
multi¬ eosinophilia-myalgia syndrome (EMS) after The disease that first the system recognized break of nationwide The Centers for is
a
epidemic in
a
out¬
was
1989.
Disease Control's initial surveillance definition
required generalized debilitating myalgias, peripheral eosinophilia of at least l.OXlO9 cells per liter, and the absence of any in¬ fection or neoplasm.1 The symptom complex includes my¬
algias, arthralgias, rash, cough or dyspnea, fever, fatigue, and peripheral edema. Although the condition is associ¬ ated with ingestion of L-tryptophan-containing products, the pathogenesis of EMS remain unknown. Reported nervous system involvement in EMS was pri¬ marily limited to peripheral neuropathy until the recent description by Tolander et al2 of a 46-year-old woman with a strokelike presentation and multiple white matter lesions who stabilized after withdrawal of L-tryptophan. We deAccepted for publication April 29, 1992. From the Departments of Neurology (Drs Lynn, Rammohan, and Kissel) and Psychiatry (Dr Bornstein), Ohio State University College of
Medicine, Columbus. Reprint requests to Department of Neurology, Ohio State University College of Medicine, 1654 Upham Dr, Columbus, OH 43210 (Dr Lynn).
scribe
a
patient
with EMS and central
nervous
system
(CNS) involvement in whom the CNS disorder
was
progressive even after the discontinuation of L-tryptophan
therapy.
REPORT OF A CASE
48-year-old woman was admitted to a community hospital lanuary 27, 1989, for left upper extremity numbness and weak¬ ness, dysarthria, and ataxia that had developed over several days. A few days earlier she had experienced transient disorientation and diplopia. She also complained of diffuse muscle and joint aches, leg rash, edema, and headaches. Her medical history was significant for chronic depression, borderline personality disor¬ der, and mild chronic obstructive pulmonary disease secondary to a 70-pack-year history of tobacco abuse. She had been treated with lithium and 6 g/d of oral L-tryptophan for depression for approximately 11 months. On initial examination, the patient's vital signs were normal. The general examination was notable for an erythematous rash in both lower extremities below the knees and 1 + pitting edema at both ankles. Neurologic examination revealed a normal mental status, including mood and affect, by bedside testing. The results of an examination of the cranial nerves, including eye movements, were unremarkable. Strength was graded 2 to 3 (Medical Research Council scale) in the left upper extremity. Reflexes were 2+ on the right and 3+ on the left. Plantar responses were flexor. Sensory examination demonstrated decreased perception of pinprick in the left upper extremity. Rapid alternating movements were moderately slowed in both upper extremities. Admission laboratory investigations were notable for a white A
blood cell count of 14.6X107L (reference range, 4 to 10X109/L) with 55% eosinophils. The absolute eosinophil count was 8.0X10YL (reference range, 0.1 to 0.3X107L). The patient's he¬ moglobin level, platelet count, and liver function test results were normal. A magnetic resonance imaging (MRI) scan of the brain demon¬ strated several small foci of abnormal high-signal intensity in the white matter of the right temporal lobe and periventricular regions (Figure). A lumbar puncture was traumatic, with the fol¬ lowing results: red blood cells, 34X10VL; white blood cells, 0.140X107L (reference range, 0 to 0.005X107D; and protein, 2.46 g/L (reference range, 0.15 to 0.45 g/L). Oligoclonal IgG bands were absent. The antinuclear antibody titer, erythrocyte sedimen¬ tation rate, rheumatoid factor, and vitamin B12 level were all nor¬ mal. Stool samples were negative for ova and parasites. A bone marrow biopsy specimen and aspirate were significant only for increased eosinophil precursors. An electroencephalogram, vi¬ sual evoked potentials, and a two-dimensional echocardiogram were normal. Electromyographic examination of the left upper
Downloaded From: http://archneur.jamanetwork.com/ by a University of Pittsburgh User on 06/19/2015
Magnetic resonance imaging, axial planes. Top row, Initial presentation.
Bottom row,
Follow-up 22 months later. Top left, T-weighted image (rep¬
[TRI, 2000 milliseconds [ms]; echo time ¡TEj, 80 ms) at the level of the pons shows one or two small high-signal lesions within the pons. Top center, Subsequent study shows large confluent areas of abnormal signal in the central pons without mass effect. Top right, Proton density (TR, 2000 ms; TE, 30 ms) image at the level of lateral ventricles shows several punctate areas of increased signal within the white matter. Bottom left, etition time
Subsequent study shows enlarged confluent areas of abnormal signal within the periventricular white matter with right parieto-occipital extension. Bottom center, Proton density (TR, 2000 ms; TE, 30 ms) image at level of centrum semiovale shows several small areas of abnormal signal that in¬ crease on subsequent examination (bottom right).
extremity showed decreased firing rates and recruitment fre¬ quencies suggestive of an upper motor neuron lesion. A diagnosis of possible idiopathic hypereosinophilic syndrome was made. The patient was treated with intravenous methylprednisolone (1 g/d for 5 days), with prompt resolution of eosinophilia and gradual resolution of neurologic symptoms. Be¬ cause the patient exhibited manic symptoms during oral pred¬ nisone therapy, eosinophilia was subsequently suppressed with oral hydroxyurea therapy (1.5 g/d). The patient continued to re¬ ceive L-tryptophan because EMS was not yet recognized. In May 1989, the patient discontinued the hydroxyurea therapy
for 3 weeks. Her white blood cell count rose to 22.9X10YL with 50% eosinophils, and she developed recurrent left upper extrem¬ ity weakness, incoordination in both upper extremities, gait im¬ balance, and dysphagia. On physical examination, left upper ex¬ tremity strength was graded 3 to 4, and moderate incoordination of finger movements was present bilaterally. The patient was treated with intravenous vincristine (1.4 mg/m2 weekly for four doses), followed by reinstitution of oral hydroxyurea therapy (1.5 mg/d), with little improvement. Over the following 6 months, the patient reported a gradual decline in memory and concentration, as well as worsening of her rash and myalgias. Treatment with L-tryptophan was discontin¬ ued in July 1989 because of the development of dysphagia. When reports of the association between L-tryptophan and the EMS be-
gan to appear, a skin and right gastrocnemius biopsy was performed, which demonstrated several perivascular lymphocytic infiltrates with occasional eosinophils in subcutaneous tis¬ sue, fascia, and muscle. The patient presented to the Department of Neurology, Ohio State University College of Medicine, Columbus, in October 1991 for further evaluation of fatigue and memory loss. The general examination was significant for brawny induration of the skin of all limbs, mild sclerodermatous changes of the face and hands, and diffuse tenderness of all muscle groups. The motor examina¬ tion was significant for grade 4 left upper extremity weakness. Reflexes were diffusely brisk with clonus at both ankles. The plantar response was extensor on the left and flexor on the right. Sensory examination demonstrated decreased vibration in both lower extremities to the ankles and patchy diffuse hypoesthesia. Her gait was hesitant and broad based.
EVALUATION The patient underwent detailed neuropsychological test¬ ing for further evaluation of her complaints of memory and concentration difficulties. The examination included the Wechsler Adult Intelligence Scale-Revised, subtests of the Wechsler Memory Scale-Revised, the California Verbal Learning Test, the Continuous Visual Memory Test, the Wis-
Downloaded From: http://archneur.jamanetwork.com/ by a University of Pittsburgh User on 06/19/2015
Results of
Neuropsychological
WAIS-R
Verbal IQ Performance IQ
98 79t
Memory, percentile memory
Immediate
Delayed
21 26
Delayed recall Recognition
System Involvement in the
Eosinophilia-Myalgia Syndrome
Joanne Lynn, MD; Kottil W. Rammohan, MD; Robert A. Bornstein, PhD; John T. Kissel, MD
patient with eosinophilia-myalgia syndrome developed progressive central nervous system involvement that did not improve despite discontinuation of L-tryptophan therapy. Neurologic impairment was manifested initially by spastic monoparesis, which was improved by treatment with methylprednisolone and hydroxyurea. Recurrence of weakness was accompanied by gait ataxia, dysphagia, and complaints \s=b\ A
gradual decline in memory and concentration. Neuropsychological testing identified a broad pattern of cognitive deficits suggestive of a subcortical dementia, and magnetic resonance imaging demonstrated multiple high-signal lesions in the white matter. Cognitive deficits appear to be underrecognized in patients with the eosinophilia-myalgia syndrome. The response of our patient's initial symptoms to corticosteroid therapy suggests a possible role for autoimmune mechanisms in the pathogenesis of central nervous system involvement in the eosinophilia-myalgia syndrome. Neuropsychological evaluation should be performed in patients with cognitive complaints to delineate the full spectrum of central nervous system impairment associated with the eosinophilia-myalgia syndrome. of
a
(Arch Neurol. 1992;49:1082-1085)
multi¬ eosinophilia-myalgia syndrome (EMS) after The disease that first the system recognized break of nationwide The Centers for is
a
epidemic in
a
out¬
was
1989.
Disease Control's initial surveillance definition
required generalized debilitating myalgias, peripheral eosinophilia of at least l.OXlO9 cells per liter, and the absence of any in¬ fection or neoplasm.1 The symptom complex includes my¬
algias, arthralgias, rash, cough or dyspnea, fever, fatigue, and peripheral edema. Although the condition is associ¬ ated with ingestion of L-tryptophan-containing products, the pathogenesis of EMS remain unknown. Reported nervous system involvement in EMS was pri¬ marily limited to peripheral neuropathy until the recent description by Tolander et al2 of a 46-year-old woman with a strokelike presentation and multiple white matter lesions who stabilized after withdrawal of L-tryptophan. We deAccepted for publication April 29, 1992. From the Departments of Neurology (Drs Lynn, Rammohan, and Kissel) and Psychiatry (Dr Bornstein), Ohio State University College of
Medicine, Columbus. Reprint requests to Department of Neurology, Ohio State University College of Medicine, 1654 Upham Dr, Columbus, OH 43210 (Dr Lynn).
scribe
a
patient
with EMS and central
nervous
system
(CNS) involvement in whom the CNS disorder
was
progressive even after the discontinuation of L-tryptophan
therapy.
REPORT OF A CASE
48-year-old woman was admitted to a community hospital lanuary 27, 1989, for left upper extremity numbness and weak¬ ness, dysarthria, and ataxia that had developed over several days. A few days earlier she had experienced transient disorientation and diplopia. She also complained of diffuse muscle and joint aches, leg rash, edema, and headaches. Her medical history was significant for chronic depression, borderline personality disor¬ der, and mild chronic obstructive pulmonary disease secondary to a 70-pack-year history of tobacco abuse. She had been treated with lithium and 6 g/d of oral L-tryptophan for depression for approximately 11 months. On initial examination, the patient's vital signs were normal. The general examination was notable for an erythematous rash in both lower extremities below the knees and 1 + pitting edema at both ankles. Neurologic examination revealed a normal mental status, including mood and affect, by bedside testing. The results of an examination of the cranial nerves, including eye movements, were unremarkable. Strength was graded 2 to 3 (Medical Research Council scale) in the left upper extremity. Reflexes were 2+ on the right and 3+ on the left. Plantar responses were flexor. Sensory examination demonstrated decreased perception of pinprick in the left upper extremity. Rapid alternating movements were moderately slowed in both upper extremities. Admission laboratory investigations were notable for a white A
blood cell count of 14.6X107L (reference range, 4 to 10X109/L) with 55% eosinophils. The absolute eosinophil count was 8.0X10YL (reference range, 0.1 to 0.3X107L). The patient's he¬ moglobin level, platelet count, and liver function test results were normal. A magnetic resonance imaging (MRI) scan of the brain demon¬ strated several small foci of abnormal high-signal intensity in the white matter of the right temporal lobe and periventricular regions (Figure). A lumbar puncture was traumatic, with the fol¬ lowing results: red blood cells, 34X10VL; white blood cells, 0.140X107L (reference range, 0 to 0.005X107D; and protein, 2.46 g/L (reference range, 0.15 to 0.45 g/L). Oligoclonal IgG bands were absent. The antinuclear antibody titer, erythrocyte sedimen¬ tation rate, rheumatoid factor, and vitamin B12 level were all nor¬ mal. Stool samples were negative for ova and parasites. A bone marrow biopsy specimen and aspirate were significant only for increased eosinophil precursors. An electroencephalogram, vi¬ sual evoked potentials, and a two-dimensional echocardiogram were normal. Electromyographic examination of the left upper
Downloaded From: http://archneur.jamanetwork.com/ by a University of Pittsburgh User on 06/19/2015
Magnetic resonance imaging, axial planes. Top row, Initial presentation.
Bottom row,
Follow-up 22 months later. Top left, T-weighted image (rep¬
[TRI, 2000 milliseconds [ms]; echo time ¡TEj, 80 ms) at the level of the pons shows one or two small high-signal lesions within the pons. Top center, Subsequent study shows large confluent areas of abnormal signal in the central pons without mass effect. Top right, Proton density (TR, 2000 ms; TE, 30 ms) image at the level of lateral ventricles shows several punctate areas of increased signal within the white matter. Bottom left, etition time
Subsequent study shows enlarged confluent areas of abnormal signal within the periventricular white matter with right parieto-occipital extension. Bottom center, Proton density (TR, 2000 ms; TE, 30 ms) image at level of centrum semiovale shows several small areas of abnormal signal that in¬ crease on subsequent examination (bottom right).
extremity showed decreased firing rates and recruitment fre¬ quencies suggestive of an upper motor neuron lesion. A diagnosis of possible idiopathic hypereosinophilic syndrome was made. The patient was treated with intravenous methylprednisolone (1 g/d for 5 days), with prompt resolution of eosinophilia and gradual resolution of neurologic symptoms. Be¬ cause the patient exhibited manic symptoms during oral pred¬ nisone therapy, eosinophilia was subsequently suppressed with oral hydroxyurea therapy (1.5 g/d). The patient continued to re¬ ceive L-tryptophan because EMS was not yet recognized. In May 1989, the patient discontinued the hydroxyurea therapy
for 3 weeks. Her white blood cell count rose to 22.9X10YL with 50% eosinophils, and she developed recurrent left upper extrem¬ ity weakness, incoordination in both upper extremities, gait im¬ balance, and dysphagia. On physical examination, left upper ex¬ tremity strength was graded 3 to 4, and moderate incoordination of finger movements was present bilaterally. The patient was treated with intravenous vincristine (1.4 mg/m2 weekly for four doses), followed by reinstitution of oral hydroxyurea therapy (1.5 mg/d), with little improvement. Over the following 6 months, the patient reported a gradual decline in memory and concentration, as well as worsening of her rash and myalgias. Treatment with L-tryptophan was discontin¬ ued in July 1989 because of the development of dysphagia. When reports of the association between L-tryptophan and the EMS be-
gan to appear, a skin and right gastrocnemius biopsy was performed, which demonstrated several perivascular lymphocytic infiltrates with occasional eosinophils in subcutaneous tis¬ sue, fascia, and muscle. The patient presented to the Department of Neurology, Ohio State University College of Medicine, Columbus, in October 1991 for further evaluation of fatigue and memory loss. The general examination was significant for brawny induration of the skin of all limbs, mild sclerodermatous changes of the face and hands, and diffuse tenderness of all muscle groups. The motor examina¬ tion was significant for grade 4 left upper extremity weakness. Reflexes were diffusely brisk with clonus at both ankles. The plantar response was extensor on the left and flexor on the right. Sensory examination demonstrated decreased vibration in both lower extremities to the ankles and patchy diffuse hypoesthesia. Her gait was hesitant and broad based.
EVALUATION The patient underwent detailed neuropsychological test¬ ing for further evaluation of her complaints of memory and concentration difficulties. The examination included the Wechsler Adult Intelligence Scale-Revised, subtests of the Wechsler Memory Scale-Revised, the California Verbal Learning Test, the Continuous Visual Memory Test, the Wis-
Downloaded From: http://archneur.jamanetwork.com/ by a University of Pittsburgh User on 06/19/2015
Results of
Neuropsychological
WAIS-R
Verbal IQ Performance IQ
98 79t
Memory, percentile memory
Immediate
Delayed
21 26
Delayed recall Recognition
