Mar 1, 1987 - I11 seroconversion during acute neuropathy with CSF pleocytosis and ... Peripheral neuropathy is increasingly recognized as a complica-.
letters to the editor Steroid-responsivepainful ophthalmoplegia is not always Tolosa-Hunt To t h e Editor: Spector and Fiandaca’ described four patients with steroid-responsive painful ophthalmoplegia that was not TolosaHunt syndrome. I recently observed two patients with similar syndromes, one with an aneurysm of the posterior cerebral artery and one with pituitary apoplexy. Case 1. A 67-year-old hypertensive man noted right forehead pain, drooping of the right eyelid, and diplopia on right gaze. General examination was normal. Mental state was normal. Visual acuity was 20/60 0s and 20/70 OD. There was a monocular right superior temporal scotoma. The right pupil was 1mm larger than the left and reacted less briskly to light. Fundi were normal. Medial and downward movements of the right eye were limited, and there was complete loss of abduction. Ocular movements on the left were normal. Sensation on the face was normal a t first, but 24 hours later there was numbness in the first division of the right trigeminal nerve. Except for mild sensorineural hearing loss bilaterally, the remainder of the neurologic examination was normal. Two days later, the periorbital pain and ptosis were worse, and there was complete ophthalmoplegia. Intravenous dexamethasone, 30 mg, eliminated the pain. CSF was normal. CT demonstrated an enhancing mass that invaded the right cavernous sinus, with posterior erosion of the sella turcica. Surgery was performed using a transsphenoidal approach, and postoperatively there was almost complete recovery of oculomotor function. Pathologic examination of the specimen revealed a pituitary adenoma with an organized hematoma and necrosis. A published CPC2 case described a 19-year-oldman with pituitary apoplexy whose course was similar. Case 2. A 50-year-old nurse was admitted with severe pain above the left eye. Within 24 hours, she developed ptosis, with paralysis of the inferior and superior recti and weakness of the medial rectus. The left pupil reacted sluggishly to light. The remainder of the examination was normal. Dexamethasone suppressed the pain but had no other effect. Cerebral angiography demonstrated an 8-mm aneurysm of the left posterior cerebral artery. There was no vasospasm. At surgery, there was a small amount of local hemorrhage. The aneurysm was clipped successfully, and the patient recovered completely. I agree with Spector and Fiandaca that response of painful ophthalmoplegia to corticosteroids should not, by itself, be used diagnostically to confirm a clinical impression of Tolosa-Hunt syndrome. Other conditions, including those that require surgical treatment, must be excluded. Barbara S. Koppel, M D New York, NY
References 1. Spector RH, Fiandaca MS. The “sinister” Tolosa-Hunt syndrome. Neurology 198636198-203. 2. CPC Case 3-1986. N Engl J Med 1986;314:229-238.
Guillain-Barre syndrome associated with seroconversion for anti-HTLV-I11 To t h e Editor: Primary AIDS retrovirus infection defined by seroconversion for anti-HTLV-111 is associated with lymphocytic meningitis.’ Recently, Piette et a12 reported two patients with HTLVI11 seroconversionduring acute neuropathy with CSF pleocytosis and facialpalsy, respectively.We report a patient in whom seroconvenion was associated with acute Guillain-Barrh syndrome (GBS). A 42-year-oldhomosexual man had a 3-day episode of malaise and fever without diarrhea, skin rash, or respiratory symptoms. Ten days later, he complained of progressive weakness in the four extremities. By the sixth day, neurologic examination was remarkable for severe bilateral facial weakness and complete quadriplegia. All reflexes were absent. Mild hypoalgesia was found below the knees. He became hypoxic and was intubated. Initial CSF examination was normal, but 544 NEUROLOGY 37 March 1987
CSF protein level increased to 72.5 mg/dl in successive lumbar punctures. CSF proteinogram was normal. T4:T8 T-cell ratio was decreased. Neurophysiologic studies showed slowing of nerve conduction velocities (median, 32.9 m/sec, ulnar 27.7 m/sec) with prolonged distal latencies (median, 7.8 msec, ulnar 9.6 msec). EMG needle examination disclosed severe acute denervation in all musclesstudied. Serologic evidence for recent infection by CMV, Epstein-Barr virus, toxoplasmosis, or hepatitis B virus was negative. Antibodies to HTLV-111 were detected by enzyme immunoassay (Diagnostics, Pasteur). Serum samples from the time of admission and 2 months later were negative, but serum and CSF samples obtained 5 months after admission were positive. Anti-HTLV-111 was positive up to serum dilution of 1:16, but no further dilutions were tested. Results were confirmed by the Abbott HTLV-111 Confirmatory EIA kit (Abbott Laboratories) that detects antibodies directed against envelope and core proteins of the virus. Treatment with steroids and plasmapheresis was ineffective. By the fourth month, motor weakness began to improve, and 2 months later, he remains with a moderate quadriparesia. Peripheral neuropathy is increasingly recognized as a complication of otherwise asymptomatic HTLV-111-positivepatients or with AIDS-related complex.:’ The etiology of the neuropathy is unknown. The neuropathy of our patient met all the established criteria for acute GBS.4 GBS is considered an immunologically mediated disorder usually associated with acute viral infections.” The documentation of HTLV-111 seroconversion during GBS suggests that immunopathologicprocessesplay an important role in the pathogenesis of some of the neurologic syndromes associated with primary HTLV-I11 infection.
J . Vendrell, MD C. Heredia, M D M. Pujol, M D J . Vidal, M D R. Blesa, MD F.Gram, M D Barcelona, Spain
References 1. Ho DD, Sarngadharan MG, Resnick L, Di Marzo-Veronese F, Rota TR, Hirscli MS. Primary human T-lymphotropic virus type 111 infection. Ann Intern Med 1985;103:880-883. 2. Piette AM, Tusseau F, Vignon D, et al. Acute neuropathy coincident with seroconversion for anti-LAV/HTLV-111. Lancet 1985;1:852. 3. Lipkin I, Parry G, Kiprov D, Abrams D. Inflammatory neuropathy in homosexual men with lymphadenopathy. Neurology 1985;351479-1483, 4. Asbury AK. Diagnostic considerations in Guillain-Barre syndrome. Ann Neurol 1981;9(suppl):1-5. 5. Dowling PC, Cook SD. Role of infection in Guillain-Bar+ syndrome: laboratory c o n f i r m a t i o n of herpesviruses in 41 cases. Ann Neurol 1981;(suppl):44-55.
Don’t throw out the baby with the bathwater To the Editor: Amyotrophic lateral sclerosis (ALS) is a fatal degenerative disease of unknown cause. Over the years, scores of therapeutic trials have been carried out in an attempt either to provide symptomatic relief or to alter the rate of motor neuron loss. No properly controlled and blinded study has ever demonstrated therapeutic efficacy, subjective or objective. The February 1986 issue of Neurology contains three placebocontrolled reports examining whether thyrotropin-releasing hormone (TRH) is beneficial in the symptomatic treatment of ALS. These reports include two single-dose pilot studies‘.?and two multiple-dose studies over 8 weeks” and 12 weeks.2 It is useful to analyze these studies, in terms of both the data presented and the authors’ interpretations of these data. They were carried out by clinical research groups with broad experience. Although the experimental design in each case has certain weaknesses, as in any clinical study,
the authors are to be congratulated for their efforts. The reports by Caroscio et a1 and Brooke et a1 do, in fact, suggest an acute beneficial effect of T R H in ALS. In the acute studies-of Caroscio et al,’ significant muscle strength increases were recorded at 1 hour after subcutaneous administration; in addition, there was a trend (p = 0.07) for the spinal score to increase. The analysis used would have a 90% power to detect a difference of one standard deviation in neurologic ratings at a p < 0.05 (two-tailed ttest), but wouldbe less likely to pick up smaller differences in favor of or against TRH. Moreover, 11 of 12 patients noted subjective improvement, and this may relate to the change in the spinal score a t 8 hours. In the study of Brooke e t a1,3multiple doses were used and patients showed benefit, according to the authors’ analysis at 1week of therapy. This benefit did not persist, except on some occasions in one subgroup of proximal muscles. The authors did not specify when the patients were tested relative to TRH administration. Since the beneficial effects of TRH may have a narrow time window, it is crucial to time-link the evaluations. EMG compound muscle action potentials in the first dorsal interosseous muscles were studied in both TRHtreated and placebo-treated patients. The absolute value of the pooled compound action potentials increased more in the TRH-treated group compared with the decrease in the control group at visit 3 0,= 0.02),but we were told that the decreases in both groups over time did not differ significantly. In addition, cessation of TRH was associated with a more rapid decline in patients treated with TRH compared with placebo. The authors rightly point out that theirutudy was designed to have a 95% chance of finding a total arrest of the disease process and an 84% chance of finding an 80%reduction in the rate of deterioration of ALS. Unfortunately, such strict criteria may preclude recognition of a less dramatic effect. It is now established that ALS is not associated with a primary defect of TRH in spinal cord.‘ It is thus not surprising, in view of the reduced number of alpha motoneurons available for response and a major problem with the drug’s crossing the blood-brain barrier, that the observed improvement was modest in degree and distribution. This lack of dramatic improvement should not detract from the potential importance of these observations. One only need be reminded of the early days of L-dopa evaluation in Parkinson’s disease and of steroid therapy in myasthenia gravis as two illustrations of drugs in common use which were initially judged to be ineffective. We would caution investigators and patients not to be overly enthusiastic about potential therapies in ALS. Nevertheless, as clinical investigators, we must be aware that the first step in treating this disease may be small. If, however, progress is established on the firm foundation of careful clinical observations, time-linked to the administration of a drug, we can proceed to a better understanding of the pathogenetic mechanisms involved. If we construct too rigid criteria for the initial evaluation of a drug, we will have the selffulfillingprophecy of finding no treatment for this disease. We would do well to learn from our oncology colleagues in trying to generate a strategy to develop a treatment for ALS. Small steps placed in sequence may provide the way to effective therapy. To neglect the positive findings from these two investigations, as modest as they are, might be “throwing out the baby with the bathwater.”
our studies, one of the Cybex dynamometer results showed a statistically significant improvement in patients on chronic subcutaneous TRH treatment only in one period. All the other variables in the dynamometer testing, however, were statistically negative. It is difficult to determine whether such improvement represents a “subtle improvement” or a mere statistical chance. We certainly would like to see more of these improvements. We also would like to point out that some patients on the placebo had a so-calledplacebo effect during the trials. Therefore, there is no doubt that we are facing many difficult problems. This may be the time we all put our efforts together to improve the current methods of clinical trials in ALS patients.
Theodore L. Munsat, MD
1. Caroscio JT, Cohen JA, Zawodniak J, et al. A double-blindplacebo-controlled
Boston, M A
Benjamin R. Brooks, MD Madison, WI Reply f r o m the Authors: Drs. Munsat and Brooks expressed their concern about the possibility that we might have missed a subtle improvement in ALS patients in our control studies with TRH.2 We indeed worried about such possibilities during and after our trials. In
Hiroshi Mitsumoto, MD Maurice R. Hanson, MD Virgilio D. Salanga, MD Cleueland, OH
Bathwater disposal service Reply f r o m the Author: The points in the letter from Drs. Munsat and Brooks are well taken. Our study showed a small beneficial effect of TRH which occurred immediately, was statistically measurable, was not accounted for by the fact that we were measuring a large number of variables, and which was documented in our paper. Equally, studies showed that TRH, as we administered it, did not provide the patients with any effect that they believed beneficial, nor did it alter the course of the illness. The study had a greater than 80% chance of detecting an 80% reduction in the rate of the illness. The reader should be careful not to misinterpret this. These numbers do not mean that a 50%slowingin the rate of the illness would have been missed by the study but that the chances of detecting this effect would have been less. Furthermore, the sensitivity to detect acute changes in strength (as opposed to a change in the rate of progression) was quite high. During the days during which these studies were designed, some fairly enthusiastic statements were being made about the efficacy of TRH. Our study and those of others were designed to test whether this enthusiasm was warranted. We have no wish to throw out the baby with the bathwater. On the other hand, somebody had to deal with this particular effluvium, which seemed to be accumulating in large amounts. If you allow us to get rid of the bathwater, we will return the baby back to you safe and sound.
Michael H. Brooke, MD St. Louis,MO
References trial of T R H in amyotrophic lateral sclerosis. Neurology 1986;36:141-145. 2. Mitsumoto H,Salgado ED, Negroski D, et al. Amyotrophic lateral sclerosis: effects of acute intravenous and chronic subcutaneous administration of thyrotropin-releasing hormone in controlled trials. Neurology 1986,36152-159. 3. Brooke MH, Florence JM, Heller SL,et al. Controlled trial of thyrotropinreleasing hormone in amyotrophic lateral sclerosis. Neurology 1986,36146-151. 4. Jackson IMD,Adelman LS,Munsat TL,et al. Amyotrophic lateral sclerosis: thyrotropin-releasinghormone and histidyl proline diketopiperazine in the w spinal cord and cerebrospinal fluid. Neurology 19W36:1218-1223.
March 1987 NEUROLOGY 37 645
Guillain−Barre syndrome associated with seroconversion for anti−HTLV−I11 J. Vendrell, C. Heredia, M. Pujol, et al. Neurology 1987;37;544-544-a DOI 10.1212/WNL.37.3.544-a This information is current as of March 1, 1987 Updated Information & Services
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Neurology ® is the official journal of the American Academy of Neurology. Published continuously since 1951, it is now a weekly with 48 issues per year. Copyright © 1987 by the American Academy of Neurology. All rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.
