Perbexiline Levels in Blood and Urine in u Patient with Polyneuropathy Blood Levels (pg/ml)
Urine Levels (mg/dl)
Date
Px
M1
M3
Px/M 1 Ratio
6/3/76 6/9/76
2.40 2.20 1.70
2.25 2.20 2.10
0.55 0.55 0.30
1.06 1.oo 0.8 1
6/12/76
M3
px
M1
...
...
...
0.20 0. 10
1.70 1.20
0.90 0.60
MUM3 Ratio
... 1.90 2.00
Px = perhexiline maleate; MI, M3 = monohydroxylated metabolites of perhexiline.
kg). She had been given anticoagulant therapy with perhexiline maleate, 100 mg twice daily, for 15 months before admission because of severe myocardial infarction. Examination disclosed a diffuse polyneuropathy with sensory and motor signs. The cerebrospinal fluid contained 1.28 gm of protein per liter (5% gamma globulins) and 4 cells per cubic millimeter. The optic fundi were hyperemic but were not edematous. Sensory conduction velocity was very low (2 mlsec in the common peroneal nerve); motor conduction velocity was 32 rn/sec in the common peroneal and 16 mlsec in the tibia1 nerve. Muscle and nerve preparations showed polymorphous osmiophilic inclusions in muscle fibers, Schwann cells, fibroblasts, and pericytes, as previously described [4]. After one month the patient started to recover, though electromyographic findings were still abnormal. Wright et a1 [5] showed that in a normal population, approximately 20% of individuals are slow metaboliters of perhexiline. The ratio in the blood between perhexiline maleate and one of the monohydroxylated metabolites of perhexiline ( M l ) was greater than 2.2, and in urine the ratio between the two main monohydroxylated metabolites, M1 and M3, was approximately 0.4. In our patient, the measurements indicated in the Table were obtained after perhexiline was discontinued. The data indicate that the patient’s characteristics are not those of a slow metabolizer. Thus, delayed perhexilene metabolism cannot explain the appearance of a toxic polyneuropathy.
References 1. Abaza A, Cattan D, Aziza C, et al: Effets secondaires mais
r6versibles a la prise de perhexiline. Nouv Presse Med 2:2820, 1973 2. Bourrat C, Viala JJ, Guastala JP: Neuropathie ptriphGrique apris absorption prolongee du maleate de perhexiline. Deux cas. Nouv Presse Med 4:2528, 1975 3. Bousser MG, Bouche P, Brochard C, et al: Neuropathies pGriphtriques au rnaliate de perhexiline. A propos de 7 observations. Coeur Med Intern 15:181-188, 1976 4. Lhermitte F, Fardeau M, Chedru F, et al: Polyneuropathy after perhexiline maleate therapy. Br Med J 1:1256, 1976 5. Wright GJ, Zeiger AV, Leeson GA, e t al: The absorption, excretion and metabolism of perhexiline maleate by the human. Presented at the Sixth International Congress of Pharmacology, Helsinki, Finland, 1975
Quinine Sulfate for Pain in the Guillain-Bark Syndrome Ralph A. Nixon, PhD, MD Pain is often a prominent discomforting symptom in Guillain-Barri syndrome. Opiates may be required for adequate pain relief, but their effect on respiration could complicate the respiratory compromise that frequently occurs in the disease. Recently we have used quinine sulfate successfully to treat pain in 3 patients with Guillain-BarrP syndrome [3]. In each case the pain was severe muscular cramping and stiffness of the extremities and back that was worse at night, often preventing sleep. Two of the 3 patients also developed a transient reduction in vital capacity (40%). All 3 received steroids (80 mg daily, tapered subsequently) although in 1 the steroids were discontinued after five days, about one week before pain appeared. The pain in these patients had initially been treated unsuccessfully with either codeine (0.25 to 0.75 grains) or propoxyphene (100 mg) with or without acetaminophen (650 mg) every 3 to 4 hours. By contrast, Q u i n m m (quinine sulfate, 260 mg, and aminophylline, 195 mg) or, in 1 patient, quinine sulfate (300 mg) proved to be effective in relieving the symptoms for 8 to 12 hours without producing evident cinchonism. Resubstitution of the initial analgesic drug or drugs for the quinine sulfate preparation resulted in incomplete pain relief. Quinine sulfate has previously been shown to be effective in preventing nocturnal leg cramps and in relieving muscle spasm in myotonia congenita or during hemodialysis for renal failure [2]. Quinine resembles salicylate and related drugs in its analgesic properties [I]. In addition, it has a dual effect on skeletal muscle. Quinine acts directly in prolonging the refractory period of muscle, resulting in a diminished response to tetanic stimulation [ 11. It also exerts a curarelike effect on neuromuscular transmission by
From the Department of Medicine, Salem Hospital, Salem, and the Department of Psychiatry, Massachusetts General Hospital, Boston, MA. Accepted for publication Apr 7, 1978. Address reprint requests to Dc Nixon, Department of Psychiatry, Massachusetts General Hospital, Boston, MA 02 114.
386 Annals of Neurology Vol 4 No 4 October 1778
increasing the threshold of excitability of the motor endplate, thereby reducing the response to repetitive nerve stimulation [I]. These effects may contribute to the relative specificity of quinine for relieving muscle spasm and its associated pain.
References Goodman L, Gilman A: The Pharmacological Basis of Therapeutics. New York, Macmillan, 1970, p 1105 Kaji DM, Ackad A, Nottagc WG, et al: Prevention of muscle cramps in hemodialysis patients by quinine sulphate. Lancet 2:66-67, 1976 Osler LD, Side11 AD: The Guillain-Bar& syndrome. N Engl J Med 262:964-969, 1060
Improvement in Gilles de la Tourette Syndrome after Corticosteroid Therapy Kiyotaro Kondo, MD, and Takeo Kabasawa, MD Gilles de la Tourette syndrome, o r generalized tic disease, is a rare but conspicuous neuropsychiatric affliction of unknown cause, characterized by rapid ticlike movements of the face, vocal muscles, extremities, and trunk and accompanied by impulsive symptoms of echolalia, echopraxia, and obscene behaviors. Numerous cases have been reported, and Abuzzahab and Anderson [l] were able to review 485 examples of the disorder by 1973. Postinfectious cases have rarely been described. An 11-year-old boy, examined by us in June, 1972, was the product of a normal pregnancy and delivery. His parents were normal and not consanguineous. His mental and somatic development was normal. I n December, 1971, he had had an unexplained high fever that soon subsided spontaneously. About ten days later he was noted to blink his eyes, grimace, shake the head to both sides, and occasionally to tremble over the whole body. These symptoms gradually intensified until July, 1972, when he began to make abrupt, brief, uncontrollable, birdlike cries about every ten minutes during wakefulness. Episodes developed of body tensing, neck flexion, arm arching, and shoulder shrugging. At the same time he became more irritable. O n examination the tendon jerks were exaggerated and the muscles hypotonic. He grimaced, blinked his eyes, twisted his neck toward the right, flexed the right arm and leg abruptly, and showed other small, recurrent, bizarre, brisk movements. These were suppressible voluntarily to a ~~~~~~~~
~
certain extent, but the movements became more pronounced after such an effort. His cries were sharp, often monosyllabic, and sometimes interfered with speech. Echopraxia was noted. T h e patient spoke little and appeared unfriendly. Verbal I Q was 102 and performance IQ 80 o n the Wechsler Intelligence Scale for children. An electroencephalogram contained prominent alpha activity of 11 cps symmetrically and posteriorly. About a second or two before cries or abrupt body movements, a theta burst of 4 to 7 cps with an amplitude of 40 to 60 p v sometimes emerged diffusely, with dominance in the left parietal lead. In a sleep record, a few 6 and 14 cps positive spikes appeared in the occipital regions. The blood sedimentation rate was 20/45; antistreptolysin 0 titers were elevated; C-reactive protein (CRP) and rheumatoid arthritis (RA) tests were positive. Other laboratory examinations, including lumbar puncture, were normal. Diazepam, 6 mg orally, was initiated. This reduced the cries and body movements, but concurrently the patient became more restless and irritable and began to interject abrupt obscenities. O n several occasions, nurses reported that the boy was excessively reaching out to touch them. The diazepam was discontinued after eleven days and replaced by carbamazepine, 200 mg daily for seven days, without beneficial effect. Haloperidol was added, beginning at a dosage of 1.5 mg and increasing to 3 mg daily after four days, but no change was noted clinically. Meanwhile, results of the C R P reaction and RA test became negative although antistreptolysin 0 titers remained above the normal limit of 125 units. Blood sedimentation rates returned to normal. Prednisolone, SO mg daily, was initiated and tapered to 15 mg daily after two weeks. Within three days, the restlessness and obscenities diminished and motor abnormalities such as tics, grimacings, and cries disappeared. Examination three months later revealed no abnormality except for occasional shoulder shruggings. Prednisolone was discontinued. No recurrence was noted during the next four years. Abuzzahab and Anderson [ 11 extensively evaluated the efficacy of various treatments in 430 reported cases of Tourette syndrome. T h e highest total percentage improvement was 89%, achieved with haloperidol, the next being 56% and 54% with physical therapy and sleep therapy, respectively. The effects of corticosteroids were not reported in their series. The present experience suggests that corticosteroids may be useful in patients in whom there is evidence that Gilles de la Tourette syndrome follows an acute infection.
Reference 1 . Abuzzahab FE, Anderson FO: Gilles d e la Tourette's syndrome, international registry. Minn Med 56:492-496, 1973
~~
From the Department of Neurology, Brain Research Institute, Niigata University, Niigata, Japan.
Accepted for publication Apr 20, 1978. Address reprint requests to Dr Kondo, Department of Neurology, Brain Xesearch Institute, Niigata University, Asahimachi 1, Niigata, Japan.
Notes and Letters
387
Urine Levels (mg/dl)
Date
Px
M1
M3
Px/M 1 Ratio
6/3/76 6/9/76
2.40 2.20 1.70
2.25 2.20 2.10
0.55 0.55 0.30
1.06 1.oo 0.8 1
6/12/76
M3
px
M1
...
...
...
0.20 0. 10
1.70 1.20
0.90 0.60
MUM3 Ratio
... 1.90 2.00
Px = perhexiline maleate; MI, M3 = monohydroxylated metabolites of perhexiline.
kg). She had been given anticoagulant therapy with perhexiline maleate, 100 mg twice daily, for 15 months before admission because of severe myocardial infarction. Examination disclosed a diffuse polyneuropathy with sensory and motor signs. The cerebrospinal fluid contained 1.28 gm of protein per liter (5% gamma globulins) and 4 cells per cubic millimeter. The optic fundi were hyperemic but were not edematous. Sensory conduction velocity was very low (2 mlsec in the common peroneal nerve); motor conduction velocity was 32 rn/sec in the common peroneal and 16 mlsec in the tibia1 nerve. Muscle and nerve preparations showed polymorphous osmiophilic inclusions in muscle fibers, Schwann cells, fibroblasts, and pericytes, as previously described [4]. After one month the patient started to recover, though electromyographic findings were still abnormal. Wright et a1 [5] showed that in a normal population, approximately 20% of individuals are slow metaboliters of perhexiline. The ratio in the blood between perhexiline maleate and one of the monohydroxylated metabolites of perhexiline ( M l ) was greater than 2.2, and in urine the ratio between the two main monohydroxylated metabolites, M1 and M3, was approximately 0.4. In our patient, the measurements indicated in the Table were obtained after perhexiline was discontinued. The data indicate that the patient’s characteristics are not those of a slow metabolizer. Thus, delayed perhexilene metabolism cannot explain the appearance of a toxic polyneuropathy.
References 1. Abaza A, Cattan D, Aziza C, et al: Effets secondaires mais
r6versibles a la prise de perhexiline. Nouv Presse Med 2:2820, 1973 2. Bourrat C, Viala JJ, Guastala JP: Neuropathie ptriphGrique apris absorption prolongee du maleate de perhexiline. Deux cas. Nouv Presse Med 4:2528, 1975 3. Bousser MG, Bouche P, Brochard C, et al: Neuropathies pGriphtriques au rnaliate de perhexiline. A propos de 7 observations. Coeur Med Intern 15:181-188, 1976 4. Lhermitte F, Fardeau M, Chedru F, et al: Polyneuropathy after perhexiline maleate therapy. Br Med J 1:1256, 1976 5. Wright GJ, Zeiger AV, Leeson GA, e t al: The absorption, excretion and metabolism of perhexiline maleate by the human. Presented at the Sixth International Congress of Pharmacology, Helsinki, Finland, 1975
Quinine Sulfate for Pain in the Guillain-Bark Syndrome Ralph A. Nixon, PhD, MD Pain is often a prominent discomforting symptom in Guillain-Barri syndrome. Opiates may be required for adequate pain relief, but their effect on respiration could complicate the respiratory compromise that frequently occurs in the disease. Recently we have used quinine sulfate successfully to treat pain in 3 patients with Guillain-BarrP syndrome [3]. In each case the pain was severe muscular cramping and stiffness of the extremities and back that was worse at night, often preventing sleep. Two of the 3 patients also developed a transient reduction in vital capacity (40%). All 3 received steroids (80 mg daily, tapered subsequently) although in 1 the steroids were discontinued after five days, about one week before pain appeared. The pain in these patients had initially been treated unsuccessfully with either codeine (0.25 to 0.75 grains) or propoxyphene (100 mg) with or without acetaminophen (650 mg) every 3 to 4 hours. By contrast, Q u i n m m (quinine sulfate, 260 mg, and aminophylline, 195 mg) or, in 1 patient, quinine sulfate (300 mg) proved to be effective in relieving the symptoms for 8 to 12 hours without producing evident cinchonism. Resubstitution of the initial analgesic drug or drugs for the quinine sulfate preparation resulted in incomplete pain relief. Quinine sulfate has previously been shown to be effective in preventing nocturnal leg cramps and in relieving muscle spasm in myotonia congenita or during hemodialysis for renal failure [2]. Quinine resembles salicylate and related drugs in its analgesic properties [I]. In addition, it has a dual effect on skeletal muscle. Quinine acts directly in prolonging the refractory period of muscle, resulting in a diminished response to tetanic stimulation [ 11. It also exerts a curarelike effect on neuromuscular transmission by
From the Department of Medicine, Salem Hospital, Salem, and the Department of Psychiatry, Massachusetts General Hospital, Boston, MA. Accepted for publication Apr 7, 1978. Address reprint requests to Dc Nixon, Department of Psychiatry, Massachusetts General Hospital, Boston, MA 02 114.
386 Annals of Neurology Vol 4 No 4 October 1778
increasing the threshold of excitability of the motor endplate, thereby reducing the response to repetitive nerve stimulation [I]. These effects may contribute to the relative specificity of quinine for relieving muscle spasm and its associated pain.
References Goodman L, Gilman A: The Pharmacological Basis of Therapeutics. New York, Macmillan, 1970, p 1105 Kaji DM, Ackad A, Nottagc WG, et al: Prevention of muscle cramps in hemodialysis patients by quinine sulphate. Lancet 2:66-67, 1976 Osler LD, Side11 AD: The Guillain-Bar& syndrome. N Engl J Med 262:964-969, 1060
Improvement in Gilles de la Tourette Syndrome after Corticosteroid Therapy Kiyotaro Kondo, MD, and Takeo Kabasawa, MD Gilles de la Tourette syndrome, o r generalized tic disease, is a rare but conspicuous neuropsychiatric affliction of unknown cause, characterized by rapid ticlike movements of the face, vocal muscles, extremities, and trunk and accompanied by impulsive symptoms of echolalia, echopraxia, and obscene behaviors. Numerous cases have been reported, and Abuzzahab and Anderson [l] were able to review 485 examples of the disorder by 1973. Postinfectious cases have rarely been described. An 11-year-old boy, examined by us in June, 1972, was the product of a normal pregnancy and delivery. His parents were normal and not consanguineous. His mental and somatic development was normal. I n December, 1971, he had had an unexplained high fever that soon subsided spontaneously. About ten days later he was noted to blink his eyes, grimace, shake the head to both sides, and occasionally to tremble over the whole body. These symptoms gradually intensified until July, 1972, when he began to make abrupt, brief, uncontrollable, birdlike cries about every ten minutes during wakefulness. Episodes developed of body tensing, neck flexion, arm arching, and shoulder shrugging. At the same time he became more irritable. O n examination the tendon jerks were exaggerated and the muscles hypotonic. He grimaced, blinked his eyes, twisted his neck toward the right, flexed the right arm and leg abruptly, and showed other small, recurrent, bizarre, brisk movements. These were suppressible voluntarily to a ~~~~~~~~
~
certain extent, but the movements became more pronounced after such an effort. His cries were sharp, often monosyllabic, and sometimes interfered with speech. Echopraxia was noted. T h e patient spoke little and appeared unfriendly. Verbal I Q was 102 and performance IQ 80 o n the Wechsler Intelligence Scale for children. An electroencephalogram contained prominent alpha activity of 11 cps symmetrically and posteriorly. About a second or two before cries or abrupt body movements, a theta burst of 4 to 7 cps with an amplitude of 40 to 60 p v sometimes emerged diffusely, with dominance in the left parietal lead. In a sleep record, a few 6 and 14 cps positive spikes appeared in the occipital regions. The blood sedimentation rate was 20/45; antistreptolysin 0 titers were elevated; C-reactive protein (CRP) and rheumatoid arthritis (RA) tests were positive. Other laboratory examinations, including lumbar puncture, were normal. Diazepam, 6 mg orally, was initiated. This reduced the cries and body movements, but concurrently the patient became more restless and irritable and began to interject abrupt obscenities. O n several occasions, nurses reported that the boy was excessively reaching out to touch them. The diazepam was discontinued after eleven days and replaced by carbamazepine, 200 mg daily for seven days, without beneficial effect. Haloperidol was added, beginning at a dosage of 1.5 mg and increasing to 3 mg daily after four days, but no change was noted clinically. Meanwhile, results of the C R P reaction and RA test became negative although antistreptolysin 0 titers remained above the normal limit of 125 units. Blood sedimentation rates returned to normal. Prednisolone, SO mg daily, was initiated and tapered to 15 mg daily after two weeks. Within three days, the restlessness and obscenities diminished and motor abnormalities such as tics, grimacings, and cries disappeared. Examination three months later revealed no abnormality except for occasional shoulder shruggings. Prednisolone was discontinued. No recurrence was noted during the next four years. Abuzzahab and Anderson [ 11 extensively evaluated the efficacy of various treatments in 430 reported cases of Tourette syndrome. T h e highest total percentage improvement was 89%, achieved with haloperidol, the next being 56% and 54% with physical therapy and sleep therapy, respectively. The effects of corticosteroids were not reported in their series. The present experience suggests that corticosteroids may be useful in patients in whom there is evidence that Gilles de la Tourette syndrome follows an acute infection.
Reference 1 . Abuzzahab FE, Anderson FO: Gilles d e la Tourette's syndrome, international registry. Minn Med 56:492-496, 1973
~~
From the Department of Neurology, Brain Research Institute, Niigata University, Niigata, Japan.
Accepted for publication Apr 20, 1978. Address reprint requests to Dr Kondo, Department of Neurology, Brain Xesearch Institute, Niigata University, Asahimachi 1, Niigata, Japan.
Notes and Letters
387
