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Peripheral Neuropathy Associated With Protriptyline
CASE STUDY Peripheral Neuropathy Associated With Protriptyline MICHAEL E. STEPT, M.D.,
AND
S.H. SUBRAMONY, M.D.
Abstract. A case is reported of a 14-year-old boy with a hypothalamic disorder whodeveloped a peripheral neuropathy while being treated with protriptyline for depressive symptoms. Electromyographic studies and sural nerve biopsy support the clinical evidence that the etiology of the polyneuropathy was a toxic effect of the protriptyline, A possible mechanism forthis isdiscussed. J. Am. Acad. Child Adolesc. Psychiatry, 1988,27,3:377380. Key Words: peripheral neuropathy, protriptyline, As childhood depression has been more closely studied and defined in recent years, some clinical investigators are recommending the use of tricyclic antidepressants (Puig-Antich, 1982; Weiner, 1984). These medications have their side effects. One rare side effect, reported mainly with amitriptyline, is peripheral neuropathy. This has occurred after both acute overdose and regular long-term administration (Casarino, 1977; Isaacs and Carlish, 1963; Lewitt and Forrno, 1985; Meadows et aI., 1982; Nimmo Smith and Grieve, 1963). Ophthalmoplegia has been reported with tricyclic antidepressant overdose (LeWitt, 1981; Spector and Schnapper, 1981). In his report, LeWitt states that the gaze paresis might have a peripheral basis but does not suggest a mechanism for this. In the following case, a 14-year-old boy who had a hypothalamic disorder developed a severe peripheral neuropathy after taking protriptyline for 3 months for depressive symptoms. This boy had had a hypothalamic disorder since the age of 8. One could not distinguish whether the psychiatric symptoms and signs were of an organic-neurologic basis, were caused by a primary affective disorder whose manifestations were influenced by the physiologic and metabolic effects of the hypothalamic disorder, or were caused by the emotional and social stresses of his chronic illness. This is the first reported case of peripheral neuropathy associated with the tricyclic antidepressant protriptyline where electromyographic studies and sural nerve biopsy have confirmed a severe axonal degeneration compatible with a toxic mechanism.
age, he began to gain about 2 pounds a month. Several months later, he gradually became apathetic and lethargic. He began sleeping more at night, going to bed earlier and awakening later, and he began falling asleep in class or in the middle of activities at home. He was started on methylphenidate with some decrease of the lethargy. He was initially hospitalized in Mississippi in the fall of 1980 with severe dehydration and electrolyte abnormalities. He had a sodium of 179 mliq/L, which was partially attributed to a dysfunctional thirst mechanism. He responded to hydration. During that time, his temperature fluctuated from 96° to 103° F with no source of infection found. Subsequent neurologic and endocrinologic evaluations have not revealed an etiology for the hypothalamic disorder. Several CT scans of the head have been unremarkable. S.T. has had difficulties in the regulation of food and water intake, wakefulness, and temperature as well as hyperprolactinemia. He has hypothalamic hypopituitarism with deficiencies of ACTH, FSH, LH, TSH, ADH, and HGH. His lethargy has continued as has the hypersomnolence. The methylphenidate was discontinued in 1983. The family moved to Pennsylvania in 1981, and S. T. was hospitalized several times with hypothermia and/or electrolyte imbalance. In 1983, at the age of 12, he was begun on levothyroxine sodium and hydrocortisone and Iypressin nasal spray. The family returned to Mississippi in November, 1983, and S. T. was followed at the University Medical Center Pediatric Endocrine Clinic. At the time of his admission in April 1985, his medications were levothyroxine sodium 0.1 mg per day and hydrocortisone 20 mg per day. Several months before his admission in April 1985, S. T. 's parents noted changes in his behavior. In school, he began to sleep more during class but could stay awake during recess. He was sleeping more at home and he was either not doing his chores or did them quite slowly. Both his teachers and his mother thought that S. T. was not trying and that this might not be just a manifestation of his difficulty maintaining an alert state. He had begun having temper tantrums, which was unusual for this exceptionally placid boy. He began scavenging food in the middle of the night and refusing to cooperate with the restricted diet he had been placed on because of his lack of normal control of his appetite. About I month before admission, S. T. began talking about "the Devil trying to take over his body because he has special powers." He told his father that he was hearing three voices: the Devil, his old self (before the onset of his illness), and his new self. A few days before admission, his mother was hospitalized for a respiratory
Case Report The patient (S. T.) is a 14-year-old boy who first came to the attention of the Child Psychiatry Department in April 1985. He was hospitalized at that time because of auditory hallucinations, deteriorating school performance, increasing daytime sleeping, and an aggressive change in his behavior. Since the age of 8, the patient had a hypothalamic disorder of undetermined etiology. Before that, he was described by his parents as being an active, lean, and robust boy who had a normal development with normal milestones. At 8 years of Accepted January 25. 1988. Dr. Stept is Assistant Professor. Department ofPsychiatry. and Dr. Subramony is Associate Professor. Department ofNeurology. University ofMississippi Medical Center. 2500 North State St .. Jackson. M1 39216. Reprint requests to Dr. Stept.
0890-8567/88/2703-O377$02.00/0© 1988 by the American Academy of Childand Adolescent Psychiatry. 377
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STEPT AND SUBRAMONY
illness. The morning of admission, he approached his father and said that the Devil was inside him telling him to do things and that his father had better get him to the hospital. His father was frightened by S. T.'s forcefulness of expression and demeanor. On admission, S. T. was noted to have slow mentation and to be lethargic. His height was 61 112 inches and his weight 205 lb. His temperature was 97° F, pulse 88 per min, respirations 19 per minute. Physical examination was remarkable for an obese body habitus, somewhat masked facies, and small genitalia. Except for the slow mentation, auditory hallucinations, and lethargy, mental status and neurologic examinations were unremarkable. He was oriented to person, place, time, and situation. Laboratory studies were essentially unremarkable, except for mild liver enzyme elevation: Na 143 mliq/L, K 4.6 mEq/L, CI 107 mEq/L, CO2 29 mEq/L, BUN 14 mg/dl, creatinine 0.6 mg/dl, glucose 85 mg/dl, Ca lOA mg/dl, P04 5.5 mg/dl, GGT 20 ru/t, GPT 77 tun, GOT 64 ru/t, LDH 221 lUlL, alkaline phosphate 272 iu/t, bilirubin (total) 0.3 mg/dl, thyroxine (T4) 9.2 ~g/dl, Hgb 12.0 g/iOO ml, Hct 35.6%, WBC, 5,IOO/cmm, platelets 102,OOO/cmm; urinalysis: pH 4.5, specific gravity 1.012, negative for protein, glucose, and blood. A CT scan of the head did not reveal any abnormalities. On psychiatric interview, S. T. was an obese young man with a sad childlike face. He moved little and quite slowly when he did. He spoke slowly, clearly, coherently, and in a dull monotone. He was alert and oriented; he showed no difficulties with either attention or memory. He appeared to be of average intelligence and he could abstract well. His mood was sad and his affect restricted. S. T. described hearing voices as if in a dream. The voices were his self, his "old" self, and the Devil. The voices came from inside of him; the Devil's voice was similar to his own and told him to do whatever he wanted to do and not to stick to his diet. He talked about struggling with this Devil for control of his actions. These hallucinations occurred mainly at night while he was falling asleep and occasionally during the day. S. T. talked about what it was like when he was "skinny." He mentioned with sadness the anticipated departure of an older sister who was about to graduate from high school. He had a particularly close relationship with her. His family had limited financial resources, and he felt guilty that he needed special low calorie food and yet argued with his mother about his diet and sneaked food at night. He remarked that entering school (he had been in a Home Bound program in Pennsylvania) was a difficult adjustment for him. He was concerned about his mother's recent illness, the fact that she worked, and his father's absences (he is a long-distance truck driver). The auditory hallucinations appeared congruent with his mood and expressed his conflicts and feeling of anger and grief about his chronic illness, his body image, and his dependency upon his family and upon medical care. He showed adequate insight. After a few days of hospitalization and supportive interviewing, the hallucinations receded and his mood brightened. Studies of S. T. in the Sleep Disorders Center showed a diffuse delta pattern, absent K complexes, almost no REM sleep, and absent sleep spindles. Neither narcolepsy nor ob-
structive apnea were found. It was thought that the patient's hypersomnolence was caused by posterior hypothalamic damage with possible involvement of the brainstem and thalamus. It was thought that there was a significant affective component to this boy's depressed mood, poor school performance, auditory hallucinations, filching of food, and increased daytime sleepiness. Because he lived 100 miles away and his family could not bring him for regular psychotherapy, it was elected to attempt a therapeutic trial of a stimulating antidepressant to treat the affective symptoms and to see if his alertness could be improved. He was started on protriptyline on May 3, 1985, at 5 mg b.i.d. He was discharged on May II on hydrocortisone 25 mg, levothyroxine sodium 0.1 mg, and protriptyline 5 mg t.i.d. (15 mg total dose). He was seen I month later in the Child Psychiatry Clinic and was noted to have improved sleep and a better ability to stay awake. His family thought he was more outgoing. He had no further hallucinations. There were no side effects from the protriptyline. Two months after beginning the protriptyline the patient seemed somewhat lessdepressed and lethargic. Again, no side effects were noted. In mid-July 1985, he had an episode of dozing and auditory hallucinations that occurred during the visit of an older sister. These symptoms receded after his sister departed. He was seen in clinic 3 weeks later and he had no hallucinations. The protriptyline was increased to 10 mg t.i.d. (30 mg total dose). Three and one half months after the protriptyline was begun, S. T. was seen in clinic and noted to be walking differently. He stated this was because he had new shoes and they did not fit properly. His sleep, alertness, and mood were unchanged. On August 30, methylphenidate 5 mg b.i.d. was started because of continued hypersomnolence. The protriptyline was changed to 20 mg in the morning and 20 mg h.s. (40 mg total dose). Three weeks later, he was sent home from school because he appeared disoriented, was sleeping in class, and could not walk from one class to another. The protriptyline was decreased to 20 mg h.s. and the methylphenidate increased to 10 mg t.i.d. Four and one half months after the protriptyline was started, S. T. was examined and found to have a shuffling gait, decreased coordination, decreased strength in his lower extremities, and flat plantar reflexes. His mother stated that this had begun before the methylphenidate was started and that he was more alert since then. The protriptyline was discontinued. Two weeks after the protriptyline was stopped, the patient was admitted to UMC because he was unable to walk without assistance. He had no hallucinations and was cooperative and alert. Neurologic examination showed intact cranial nerves, pronounced weakness of both lower extremities with bilateral foot drop, and decreased vibratory and proprioceptive sensation over his toes. The Achilles tendon reflex was trace and other deep tendon reflexes were 2+ and symmetrical. The plantar reflex could not be elicited. Cerebellar function was normal. Laboratory studies on admission were unremarkable, except for a low sodium: Glu 79 mg/dl, NA 129 mliq/L, K 4.2 mEq/L, CI 94 mEq/L, CO2 28 mEq/L, Mg 1.6 mEq/L, BUN 8 mg/dl, Ca 9.2 mg/dl, creatinine 0.5 mg/dl, uric acid 2.9 mg/dl, Hgb 12.0 g/iOO ml, Hct 34.6%, WBC 4,OOO/cmm, folate 2.9 ng/rnl, BI2 868.0 pg/rnl, T4 11.8 ~g/dl, sedimen-
379
PERIPHERAL NEUROPATHY WITH PROTRIPTYLINE
FIG.
I.
Cross-section of sural nerve showing moderate loss of myelinated fibers. Notethe absence of inflammatory response around vessels.
tation rate 6 mm/hr. Urinalysis was negative. Heavy metals were not found in the urine. Cryoglobulin and antinuclear F levels were negative. A lumbar puncture was performed and the cerebrospinal fluid had a protein level of 46.0 mg/ I00 ml and a glucose of 59.0 mg/100 ml, no microbial growth, and a cell count of I WBC and 7 RBC/cmm. Cerebrospinal fluid protein electrophoresis showed an essentially normal pattern and no elevated myelin basic protein levels. Electromyographic studies were done and showed a generalized mixed motor and sensory polyneuropathy of axonal degeneration type of considerable severity. This was characterized by absent sensory and motor responses in the legs, low amplitude motor and sensory responses in the arms, and mild slowing of motor conduction velocities in the arms. Needle electromyography of selected lower extremity muscles revealed dense fibrillation potentials and poor recruitment of motor unit potentials. A sural nerve biopsy was performed. Light microscopy showed no evidence of inflammation nor of necrosis. There was a slight increase in endoneural collagen, a few foci of myelin breakdown products, and a decrease in the number of large diameter myelinated fibers. There was moderate patchy demyelination. There was a relative increase in small thinly-myelinated fibers and some axonal sprouting. There was no evidence of vasculitis (Fig. I). Electron microscopic studies were consistent with this. The patient was unable to walk without a walker; he was given a program of physical therapy. His discharge medications were hydrocortisone sodium succinate 25 rug/day, methylphenidate 10 mg t.i.d., and Iypressin nasal spray. S. T. slowly recovered the strength in his legs over the next several months. Two months after the protriptyline was stopped, S. T. was admitted with auditory hallucinations and hyponatremia (Na 119 mliq/L), The hallucinations disappeared as the dose of Iypressin was lowered and the serum sodium was corrected. At that time, neurologic examination showed the peripheral neuropathy to be resolving. Six weeks
later, S. T. was admitted again after a generalized grand mal seizure secondary to hyponatremia. He sustained fractures of both humeri and vertebral bodies T6-7 during the seizure. S. T. became inactive and, in a passive manner, refused to walk, although his leg strength had continued to improve. He was transferred to the Mississippi Children's Rehabilitation Center where he responded to physical therapy and continued psychiatric consultation. The methylphenidate was increased to a total dose of 50 mg/day, S. T. was seen in Child Psychiatry Clinic on March 28, 1986. He was walking well with minimal use of a walker and was staying awake better. The Iypressin nasal spray had been stopped by his parents. On July 18, 1986, 10 months after the protriptyline was discontinued, he was walking without a walker, maintaining alertness moderately well, and had no hallucinations. He was able to express his anger more openly and his mood was active, mobile, and happy. There were no hallucinations. He had no problems with electrolyte imbalance. He continued to have problems regulating his food intake and temperature. A repeat electromyographic examination performed that day revealed modest improvements. The sensory response amplitudes in the upper limbs had become marginally larger and their distal latencies had become shorter. Motor nerve conduction velocities in the upper limbs were now in the normal range. S. T. continued to lack sensory and motor responses in the lower limbs. One year after the peripheral neuropathy developed, his parents reported that he was walking almost as well as he did before the neuropathy and was near full recovery. Discussion
The tricyclic antidepressants, particularly amitriptyline, have been reported to cause peripheral neuropathies, although this has never been reported with protriptyline (Isaacs and Carlish, 1963; Nimmo Smith and Grieve, 1963). In the case
380
STEPT AND SUBRAMONY
reported here, the patient's clinical picture, comprising profound distal weakness, distal sensory loss, and areflexia in the lower extremities, indicates a peripheral polyneuropathy. Electromyographic studies further confirmed the presence of a moderately severe generalized sensorimotor polyneuropathy of axonal degeneration type. Sural nerve biopsy showed axonal degeneration, loss of myelinated fibers, demyelination, and no evidence of inflammation or vasculitis. This was compatible with a toxic neuropathy. The onset of symptoms in this patient was temporally related to the use of protriptyline. The motor weakness began to improve after the protriptyline was stopped, although gradually, as one would expect with axonal degeneration. Methlyphenidate was started apparently after the onset of symptoms of weakness. Near complete clinical recovery had occurred despite continued use of the methylphenidate. Lack of improvement in lower limb responses on electromyography is related to the fact that these responses are recorded very distally and are the last changes to reverse. The mechanism responsible for the nerve damage in this case is unclear. The sural nerve pathology is similar to that in a case of peripheral neuropathy caused by amitriptyline overdose reported by Lewitt and Formo (1985). (Their patient also had diabetes mellitus.) Meadows et al. (1982) reported a case of peripheral neuropathy related to the use of amitriptyline. In their patient, the parasthesias were relieved by high doses of pyridoxine (400 mg/per day). They speculated that their patient belonged to a subgroup of individuals who rapidly metabolize amitriptyline to the primary amine desmethyl nortriptyline, which would then bind with the aldehyde moiety pyridoxal phosphate. This would decrease the amount of biologically available pyridoxal phosphate. Protriptyline is similar in structure and metabolism to amitriptyline (Goodman et al., 1985). However, in this patient pyrixdoxine replacement was not used. The picture is complicated by possible metabolic abnormalities secondary to the hypopituitarism and to the hypo-
thalamic disorder. However, the patient's metabolic status was normal at the time he developed the peripheral neuropathy. The authors suggest that tricyclics be used cautiously in patients with neural disease and metabolic abnormalities. In these individuals, particular attention should be paid to the signs and symptoms of peripheral neuropathy (paresthesias, weakness, imbalance). If these occur, the medications should be discontinued and pyridoxine supplementation considered. Caution should be exercised because large does of pyridoxine may themselves cause peripheral neuropathy (Schaumberg et al., 1983). References Casarino J. P. (1977), Neuropathy associated with amitriptyline. NY State J. Med., 77:2124. Goodman A. G., Goodman L. S., Rail W. R., & Murad, F. (1985), Goodman and Gilman's The Pharmacological Basis of Therapeutics 7th ed. New York: Macmillan. Isaacs A. D. & Carlish S. (1963), Peripheral neuropathy after amitriptyline (letter). Br. Med. J. [Clin. Res.}, I: 1739. LeWitt P. A. (1981), Transient opthalmoparesis with doxepin overdosage. Ann. Neurol., 9:618. - - Formo L. S. (1985), Peripheral neuropathy following amitriptyline overdose (letter). Muscle Nerve, 8:723. Meadows, G., Huff M. R. & Fredericks S. (1982), Amitriptyline related peripheral neuropathy relieved during pyridoxine hydrochloride administration. Drug Intell. Clin. Pharm., 16:876. Nimmo Smith R. C; & Grieve R. C. (1963), Peripheral neuropathy after amitriptyline. Br. Med. J. [Clin. Res.}, 2:254. Puig-Antich J. (1982), Psychobiological correlates of major depressive disorder in children and adolescents. In: American Psychiatric Association Annual Review, Vol. I, ed. L. Grinspoon. Washington, D.C.: APA, p, 288. Schaumberg H., Kaplan J., Windebank A. et al. (1983), Sensory neuropathy from pyridoxine abuse: a new megavitamin syndrome. N. Engl. J. Med., 309:488. Spector E. H. & Schnapper R. (1981), Amitriptyline-induced opthalmoplegia. Neurology 31:1188. Wiener J. M. (1984), Psychopharmacology of childhood disorders. Psychiatr. Clin. N. Am., 7:831.
AND
S.H. SUBRAMONY, M.D.
Abstract. A case is reported of a 14-year-old boy with a hypothalamic disorder whodeveloped a peripheral neuropathy while being treated with protriptyline for depressive symptoms. Electromyographic studies and sural nerve biopsy support the clinical evidence that the etiology of the polyneuropathy was a toxic effect of the protriptyline, A possible mechanism forthis isdiscussed. J. Am. Acad. Child Adolesc. Psychiatry, 1988,27,3:377380. Key Words: peripheral neuropathy, protriptyline, As childhood depression has been more closely studied and defined in recent years, some clinical investigators are recommending the use of tricyclic antidepressants (Puig-Antich, 1982; Weiner, 1984). These medications have their side effects. One rare side effect, reported mainly with amitriptyline, is peripheral neuropathy. This has occurred after both acute overdose and regular long-term administration (Casarino, 1977; Isaacs and Carlish, 1963; Lewitt and Forrno, 1985; Meadows et aI., 1982; Nimmo Smith and Grieve, 1963). Ophthalmoplegia has been reported with tricyclic antidepressant overdose (LeWitt, 1981; Spector and Schnapper, 1981). In his report, LeWitt states that the gaze paresis might have a peripheral basis but does not suggest a mechanism for this. In the following case, a 14-year-old boy who had a hypothalamic disorder developed a severe peripheral neuropathy after taking protriptyline for 3 months for depressive symptoms. This boy had had a hypothalamic disorder since the age of 8. One could not distinguish whether the psychiatric symptoms and signs were of an organic-neurologic basis, were caused by a primary affective disorder whose manifestations were influenced by the physiologic and metabolic effects of the hypothalamic disorder, or were caused by the emotional and social stresses of his chronic illness. This is the first reported case of peripheral neuropathy associated with the tricyclic antidepressant protriptyline where electromyographic studies and sural nerve biopsy have confirmed a severe axonal degeneration compatible with a toxic mechanism.
age, he began to gain about 2 pounds a month. Several months later, he gradually became apathetic and lethargic. He began sleeping more at night, going to bed earlier and awakening later, and he began falling asleep in class or in the middle of activities at home. He was started on methylphenidate with some decrease of the lethargy. He was initially hospitalized in Mississippi in the fall of 1980 with severe dehydration and electrolyte abnormalities. He had a sodium of 179 mliq/L, which was partially attributed to a dysfunctional thirst mechanism. He responded to hydration. During that time, his temperature fluctuated from 96° to 103° F with no source of infection found. Subsequent neurologic and endocrinologic evaluations have not revealed an etiology for the hypothalamic disorder. Several CT scans of the head have been unremarkable. S.T. has had difficulties in the regulation of food and water intake, wakefulness, and temperature as well as hyperprolactinemia. He has hypothalamic hypopituitarism with deficiencies of ACTH, FSH, LH, TSH, ADH, and HGH. His lethargy has continued as has the hypersomnolence. The methylphenidate was discontinued in 1983. The family moved to Pennsylvania in 1981, and S. T. was hospitalized several times with hypothermia and/or electrolyte imbalance. In 1983, at the age of 12, he was begun on levothyroxine sodium and hydrocortisone and Iypressin nasal spray. The family returned to Mississippi in November, 1983, and S. T. was followed at the University Medical Center Pediatric Endocrine Clinic. At the time of his admission in April 1985, his medications were levothyroxine sodium 0.1 mg per day and hydrocortisone 20 mg per day. Several months before his admission in April 1985, S. T. 's parents noted changes in his behavior. In school, he began to sleep more during class but could stay awake during recess. He was sleeping more at home and he was either not doing his chores or did them quite slowly. Both his teachers and his mother thought that S. T. was not trying and that this might not be just a manifestation of his difficulty maintaining an alert state. He had begun having temper tantrums, which was unusual for this exceptionally placid boy. He began scavenging food in the middle of the night and refusing to cooperate with the restricted diet he had been placed on because of his lack of normal control of his appetite. About I month before admission, S. T. began talking about "the Devil trying to take over his body because he has special powers." He told his father that he was hearing three voices: the Devil, his old self (before the onset of his illness), and his new self. A few days before admission, his mother was hospitalized for a respiratory
Case Report The patient (S. T.) is a 14-year-old boy who first came to the attention of the Child Psychiatry Department in April 1985. He was hospitalized at that time because of auditory hallucinations, deteriorating school performance, increasing daytime sleeping, and an aggressive change in his behavior. Since the age of 8, the patient had a hypothalamic disorder of undetermined etiology. Before that, he was described by his parents as being an active, lean, and robust boy who had a normal development with normal milestones. At 8 years of Accepted January 25. 1988. Dr. Stept is Assistant Professor. Department ofPsychiatry. and Dr. Subramony is Associate Professor. Department ofNeurology. University ofMississippi Medical Center. 2500 North State St .. Jackson. M1 39216. Reprint requests to Dr. Stept.
0890-8567/88/2703-O377$02.00/0© 1988 by the American Academy of Childand Adolescent Psychiatry. 377
378
STEPT AND SUBRAMONY
illness. The morning of admission, he approached his father and said that the Devil was inside him telling him to do things and that his father had better get him to the hospital. His father was frightened by S. T.'s forcefulness of expression and demeanor. On admission, S. T. was noted to have slow mentation and to be lethargic. His height was 61 112 inches and his weight 205 lb. His temperature was 97° F, pulse 88 per min, respirations 19 per minute. Physical examination was remarkable for an obese body habitus, somewhat masked facies, and small genitalia. Except for the slow mentation, auditory hallucinations, and lethargy, mental status and neurologic examinations were unremarkable. He was oriented to person, place, time, and situation. Laboratory studies were essentially unremarkable, except for mild liver enzyme elevation: Na 143 mliq/L, K 4.6 mEq/L, CI 107 mEq/L, CO2 29 mEq/L, BUN 14 mg/dl, creatinine 0.6 mg/dl, glucose 85 mg/dl, Ca lOA mg/dl, P04 5.5 mg/dl, GGT 20 ru/t, GPT 77 tun, GOT 64 ru/t, LDH 221 lUlL, alkaline phosphate 272 iu/t, bilirubin (total) 0.3 mg/dl, thyroxine (T4) 9.2 ~g/dl, Hgb 12.0 g/iOO ml, Hct 35.6%, WBC, 5,IOO/cmm, platelets 102,OOO/cmm; urinalysis: pH 4.5, specific gravity 1.012, negative for protein, glucose, and blood. A CT scan of the head did not reveal any abnormalities. On psychiatric interview, S. T. was an obese young man with a sad childlike face. He moved little and quite slowly when he did. He spoke slowly, clearly, coherently, and in a dull monotone. He was alert and oriented; he showed no difficulties with either attention or memory. He appeared to be of average intelligence and he could abstract well. His mood was sad and his affect restricted. S. T. described hearing voices as if in a dream. The voices were his self, his "old" self, and the Devil. The voices came from inside of him; the Devil's voice was similar to his own and told him to do whatever he wanted to do and not to stick to his diet. He talked about struggling with this Devil for control of his actions. These hallucinations occurred mainly at night while he was falling asleep and occasionally during the day. S. T. talked about what it was like when he was "skinny." He mentioned with sadness the anticipated departure of an older sister who was about to graduate from high school. He had a particularly close relationship with her. His family had limited financial resources, and he felt guilty that he needed special low calorie food and yet argued with his mother about his diet and sneaked food at night. He remarked that entering school (he had been in a Home Bound program in Pennsylvania) was a difficult adjustment for him. He was concerned about his mother's recent illness, the fact that she worked, and his father's absences (he is a long-distance truck driver). The auditory hallucinations appeared congruent with his mood and expressed his conflicts and feeling of anger and grief about his chronic illness, his body image, and his dependency upon his family and upon medical care. He showed adequate insight. After a few days of hospitalization and supportive interviewing, the hallucinations receded and his mood brightened. Studies of S. T. in the Sleep Disorders Center showed a diffuse delta pattern, absent K complexes, almost no REM sleep, and absent sleep spindles. Neither narcolepsy nor ob-
structive apnea were found. It was thought that the patient's hypersomnolence was caused by posterior hypothalamic damage with possible involvement of the brainstem and thalamus. It was thought that there was a significant affective component to this boy's depressed mood, poor school performance, auditory hallucinations, filching of food, and increased daytime sleepiness. Because he lived 100 miles away and his family could not bring him for regular psychotherapy, it was elected to attempt a therapeutic trial of a stimulating antidepressant to treat the affective symptoms and to see if his alertness could be improved. He was started on protriptyline on May 3, 1985, at 5 mg b.i.d. He was discharged on May II on hydrocortisone 25 mg, levothyroxine sodium 0.1 mg, and protriptyline 5 mg t.i.d. (15 mg total dose). He was seen I month later in the Child Psychiatry Clinic and was noted to have improved sleep and a better ability to stay awake. His family thought he was more outgoing. He had no further hallucinations. There were no side effects from the protriptyline. Two months after beginning the protriptyline the patient seemed somewhat lessdepressed and lethargic. Again, no side effects were noted. In mid-July 1985, he had an episode of dozing and auditory hallucinations that occurred during the visit of an older sister. These symptoms receded after his sister departed. He was seen in clinic 3 weeks later and he had no hallucinations. The protriptyline was increased to 10 mg t.i.d. (30 mg total dose). Three and one half months after the protriptyline was begun, S. T. was seen in clinic and noted to be walking differently. He stated this was because he had new shoes and they did not fit properly. His sleep, alertness, and mood were unchanged. On August 30, methylphenidate 5 mg b.i.d. was started because of continued hypersomnolence. The protriptyline was changed to 20 mg in the morning and 20 mg h.s. (40 mg total dose). Three weeks later, he was sent home from school because he appeared disoriented, was sleeping in class, and could not walk from one class to another. The protriptyline was decreased to 20 mg h.s. and the methylphenidate increased to 10 mg t.i.d. Four and one half months after the protriptyline was started, S. T. was examined and found to have a shuffling gait, decreased coordination, decreased strength in his lower extremities, and flat plantar reflexes. His mother stated that this had begun before the methylphenidate was started and that he was more alert since then. The protriptyline was discontinued. Two weeks after the protriptyline was stopped, the patient was admitted to UMC because he was unable to walk without assistance. He had no hallucinations and was cooperative and alert. Neurologic examination showed intact cranial nerves, pronounced weakness of both lower extremities with bilateral foot drop, and decreased vibratory and proprioceptive sensation over his toes. The Achilles tendon reflex was trace and other deep tendon reflexes were 2+ and symmetrical. The plantar reflex could not be elicited. Cerebellar function was normal. Laboratory studies on admission were unremarkable, except for a low sodium: Glu 79 mg/dl, NA 129 mliq/L, K 4.2 mEq/L, CI 94 mEq/L, CO2 28 mEq/L, Mg 1.6 mEq/L, BUN 8 mg/dl, Ca 9.2 mg/dl, creatinine 0.5 mg/dl, uric acid 2.9 mg/dl, Hgb 12.0 g/iOO ml, Hct 34.6%, WBC 4,OOO/cmm, folate 2.9 ng/rnl, BI2 868.0 pg/rnl, T4 11.8 ~g/dl, sedimen-
379
PERIPHERAL NEUROPATHY WITH PROTRIPTYLINE
FIG.
I.
Cross-section of sural nerve showing moderate loss of myelinated fibers. Notethe absence of inflammatory response around vessels.
tation rate 6 mm/hr. Urinalysis was negative. Heavy metals were not found in the urine. Cryoglobulin and antinuclear F levels were negative. A lumbar puncture was performed and the cerebrospinal fluid had a protein level of 46.0 mg/ I00 ml and a glucose of 59.0 mg/100 ml, no microbial growth, and a cell count of I WBC and 7 RBC/cmm. Cerebrospinal fluid protein electrophoresis showed an essentially normal pattern and no elevated myelin basic protein levels. Electromyographic studies were done and showed a generalized mixed motor and sensory polyneuropathy of axonal degeneration type of considerable severity. This was characterized by absent sensory and motor responses in the legs, low amplitude motor and sensory responses in the arms, and mild slowing of motor conduction velocities in the arms. Needle electromyography of selected lower extremity muscles revealed dense fibrillation potentials and poor recruitment of motor unit potentials. A sural nerve biopsy was performed. Light microscopy showed no evidence of inflammation nor of necrosis. There was a slight increase in endoneural collagen, a few foci of myelin breakdown products, and a decrease in the number of large diameter myelinated fibers. There was moderate patchy demyelination. There was a relative increase in small thinly-myelinated fibers and some axonal sprouting. There was no evidence of vasculitis (Fig. I). Electron microscopic studies were consistent with this. The patient was unable to walk without a walker; he was given a program of physical therapy. His discharge medications were hydrocortisone sodium succinate 25 rug/day, methylphenidate 10 mg t.i.d., and Iypressin nasal spray. S. T. slowly recovered the strength in his legs over the next several months. Two months after the protriptyline was stopped, S. T. was admitted with auditory hallucinations and hyponatremia (Na 119 mliq/L), The hallucinations disappeared as the dose of Iypressin was lowered and the serum sodium was corrected. At that time, neurologic examination showed the peripheral neuropathy to be resolving. Six weeks
later, S. T. was admitted again after a generalized grand mal seizure secondary to hyponatremia. He sustained fractures of both humeri and vertebral bodies T6-7 during the seizure. S. T. became inactive and, in a passive manner, refused to walk, although his leg strength had continued to improve. He was transferred to the Mississippi Children's Rehabilitation Center where he responded to physical therapy and continued psychiatric consultation. The methylphenidate was increased to a total dose of 50 mg/day, S. T. was seen in Child Psychiatry Clinic on March 28, 1986. He was walking well with minimal use of a walker and was staying awake better. The Iypressin nasal spray had been stopped by his parents. On July 18, 1986, 10 months after the protriptyline was discontinued, he was walking without a walker, maintaining alertness moderately well, and had no hallucinations. He was able to express his anger more openly and his mood was active, mobile, and happy. There were no hallucinations. He had no problems with electrolyte imbalance. He continued to have problems regulating his food intake and temperature. A repeat electromyographic examination performed that day revealed modest improvements. The sensory response amplitudes in the upper limbs had become marginally larger and their distal latencies had become shorter. Motor nerve conduction velocities in the upper limbs were now in the normal range. S. T. continued to lack sensory and motor responses in the lower limbs. One year after the peripheral neuropathy developed, his parents reported that he was walking almost as well as he did before the neuropathy and was near full recovery. Discussion
The tricyclic antidepressants, particularly amitriptyline, have been reported to cause peripheral neuropathies, although this has never been reported with protriptyline (Isaacs and Carlish, 1963; Nimmo Smith and Grieve, 1963). In the case
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reported here, the patient's clinical picture, comprising profound distal weakness, distal sensory loss, and areflexia in the lower extremities, indicates a peripheral polyneuropathy. Electromyographic studies further confirmed the presence of a moderately severe generalized sensorimotor polyneuropathy of axonal degeneration type. Sural nerve biopsy showed axonal degeneration, loss of myelinated fibers, demyelination, and no evidence of inflammation or vasculitis. This was compatible with a toxic neuropathy. The onset of symptoms in this patient was temporally related to the use of protriptyline. The motor weakness began to improve after the protriptyline was stopped, although gradually, as one would expect with axonal degeneration. Methlyphenidate was started apparently after the onset of symptoms of weakness. Near complete clinical recovery had occurred despite continued use of the methylphenidate. Lack of improvement in lower limb responses on electromyography is related to the fact that these responses are recorded very distally and are the last changes to reverse. The mechanism responsible for the nerve damage in this case is unclear. The sural nerve pathology is similar to that in a case of peripheral neuropathy caused by amitriptyline overdose reported by Lewitt and Formo (1985). (Their patient also had diabetes mellitus.) Meadows et al. (1982) reported a case of peripheral neuropathy related to the use of amitriptyline. In their patient, the parasthesias were relieved by high doses of pyridoxine (400 mg/per day). They speculated that their patient belonged to a subgroup of individuals who rapidly metabolize amitriptyline to the primary amine desmethyl nortriptyline, which would then bind with the aldehyde moiety pyridoxal phosphate. This would decrease the amount of biologically available pyridoxal phosphate. Protriptyline is similar in structure and metabolism to amitriptyline (Goodman et al., 1985). However, in this patient pyrixdoxine replacement was not used. The picture is complicated by possible metabolic abnormalities secondary to the hypopituitarism and to the hypo-
thalamic disorder. However, the patient's metabolic status was normal at the time he developed the peripheral neuropathy. The authors suggest that tricyclics be used cautiously in patients with neural disease and metabolic abnormalities. In these individuals, particular attention should be paid to the signs and symptoms of peripheral neuropathy (paresthesias, weakness, imbalance). If these occur, the medications should be discontinued and pyridoxine supplementation considered. Caution should be exercised because large does of pyridoxine may themselves cause peripheral neuropathy (Schaumberg et al., 1983). References Casarino J. P. (1977), Neuropathy associated with amitriptyline. NY State J. Med., 77:2124. Goodman A. G., Goodman L. S., Rail W. R., & Murad, F. (1985), Goodman and Gilman's The Pharmacological Basis of Therapeutics 7th ed. New York: Macmillan. Isaacs A. D. & Carlish S. (1963), Peripheral neuropathy after amitriptyline (letter). Br. Med. J. [Clin. Res.}, I: 1739. LeWitt P. A. (1981), Transient opthalmoparesis with doxepin overdosage. Ann. Neurol., 9:618. - - Formo L. S. (1985), Peripheral neuropathy following amitriptyline overdose (letter). Muscle Nerve, 8:723. Meadows, G., Huff M. R. & Fredericks S. (1982), Amitriptyline related peripheral neuropathy relieved during pyridoxine hydrochloride administration. Drug Intell. Clin. Pharm., 16:876. Nimmo Smith R. C; & Grieve R. C. (1963), Peripheral neuropathy after amitriptyline. Br. Med. J. [Clin. Res.}, 2:254. Puig-Antich J. (1982), Psychobiological correlates of major depressive disorder in children and adolescents. In: American Psychiatric Association Annual Review, Vol. I, ed. L. Grinspoon. Washington, D.C.: APA, p, 288. Schaumberg H., Kaplan J., Windebank A. et al. (1983), Sensory neuropathy from pyridoxine abuse: a new megavitamin syndrome. N. Engl. J. Med., 309:488. Spector E. H. & Schnapper R. (1981), Amitriptyline-induced opthalmoplegia. Neurology 31:1188. Wiener J. M. (1984), Psychopharmacology of childhood disorders. Psychiatr. Clin. N. Am., 7:831.