Use of a selective serotonin reuptake inhibitor for treatment of episodes of hypertonia and kyphosis in a young adult Scottish Terrier

Kelly M. Geiger Veterinary Medical Center, Colorado State University, Fort Collins, CO 80523.

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 DVM, MA
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Lisa S. Klopp Veterinary Medical Center, Colorado State University, Fort Collins, CO 80523.

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 DVM, MS, DACVIM

Abstract

Case Description—A 2.5-year-old 12.4-kg (27.3-lb) castrated male Scottish Terrier was evaluated because of episodes of hypertonia and kyphosis for which a presumptive diagnosis of so-called Scottie cramp had been made when the dog was a puppy.

Clinical Findings—Findings of general physical, orthopedic, and neurologic examinations were within reference limits. Pelvic limb hypertonicity and kyphosis without signs of pain were induced with minimal exercise; ambulation returned to normal after a period of rest.

Treatment and Outcome—Fluoxetine, a selective serotonin reuptake inhibitor, was administered orally at a dosage of 1.2 mg/kg (0.55 mg/lb) once daily for 1 month. After this period of treatment, clinical signs of the disease were greatly reduced; the dosage of fluoxetine was changed to 0.8 mg/kg (0.36 mg/lb) twice daily, and response to treatment continued.

Clinical Relevance—Administration of benzodiazepines, vitamin E, or phenothiazines has been recommended for treatment of episodes of hypertonicity, but often does not result in control of clinical signs. It has been suggested that the pathogenesis of this disease is related to deficiencies in concentration or function of serotonin in the CNS; thus, a logical choice for treatment is administration of a serotonin reuptake inhibitor. In the dog of this report, fluoxetine resulted in good control of clinical signs. The use of an effective medication (other than a controlled substance) that is administered once or twice daily, has minimal adverse effects on the patient's mental status, and is inexpensive may lead to better owner compliance and an improved quality of life for affected dogs.

Abstract

Case Description—A 2.5-year-old 12.4-kg (27.3-lb) castrated male Scottish Terrier was evaluated because of episodes of hypertonia and kyphosis for which a presumptive diagnosis of so-called Scottie cramp had been made when the dog was a puppy.

Clinical Findings—Findings of general physical, orthopedic, and neurologic examinations were within reference limits. Pelvic limb hypertonicity and kyphosis without signs of pain were induced with minimal exercise; ambulation returned to normal after a period of rest.

Treatment and Outcome—Fluoxetine, a selective serotonin reuptake inhibitor, was administered orally at a dosage of 1.2 mg/kg (0.55 mg/lb) once daily for 1 month. After this period of treatment, clinical signs of the disease were greatly reduced; the dosage of fluoxetine was changed to 0.8 mg/kg (0.36 mg/lb) twice daily, and response to treatment continued.

Clinical Relevance—Administration of benzodiazepines, vitamin E, or phenothiazines has been recommended for treatment of episodes of hypertonicity, but often does not result in control of clinical signs. It has been suggested that the pathogenesis of this disease is related to deficiencies in concentration or function of serotonin in the CNS; thus, a logical choice for treatment is administration of a serotonin reuptake inhibitor. In the dog of this report, fluoxetine resulted in good control of clinical signs. The use of an effective medication (other than a controlled substance) that is administered once or twice daily, has minimal adverse effects on the patient's mental status, and is inexpensive may lead to better owner compliance and an improved quality of life for affected dogs.

A 2.5-year-old castrated male Scottish Terrier for which a presumptive diagnosis of so-called Scottie cramp had been made when the dog was a puppy was admitted to the Veterinary Medical Center at Colorado State University for evaluation. Clinical history included episodes of kyphosis and pelvic limb spasticity that were elicited by exercise or excitement; these episodes had occurred since the clients had acquired the dog as a puppy. Exercise-induced episodes occurred on walks of > 10 minutes' duration, but sometimes after walks as short as 2 minutes' duration. The clients had resorted to use of a pet stroller to take the dog on long walks. Typically, the dog remained in the stroller during most walks. No treatment for the dog had been recommended previously.

On physical examination, the dog's mentation was considered normal. It weighed 12.4 kg (27.3 lb) and had a body condition score of 6 (on a scale of 1 through 9).1 There were no obvious physical abnormalities. Results of orthopedic and neurologic examinations were within reference limits. Clinicopathologic variables assessed within the last 6 months were also within reference limits. The dog's response to exercise was evaluated. Within 15 seconds of commencement of trotting and running, stiffening of the pelvic limbs became evident and the dog began to bunny-hop. During continued exercise, the dog's posture became kyphotic and spasticity in the pelvic limbs became more marked; stiffness developed in the thoracic limbs as well. The dog had no signs of pain and was aware of its surroundings. Following a 5-minute period of rest, the dog was able to walk more normally again. The clinical features of the dog's condition were considered classic for Scottie cramp. Other potential causes included myasthenia gravis, primary metabolic or inflammatory myopathy or neuropathy, and seizure-like disorders. Further diagnostic testing such as electromyography and nerve conduction assessments, histologic examination of muscle biopsy specimens, evaluation of anti-acetylcholinesterase receptor antibody titers, and CSF analysis were declined by the clients.

On the basis of previous research,2,3 Scottie cramp has been associated with a deficiency in serotonin concentration in the spinal cord. Therefore, treatment with fluoxetine,a which is a selective serotonin reuptake inhibitor, was initiated to determine whether the drug had any effect on the frequency, duration, or severity of episodes in this dog. A standard dosage is 1 mg/kg (0.45 mg/lb) administered orally once to twice daily, up to 3 mg/kg/d (1.36 mg/lb/d).4 For this dog, a dosage of 1.2 mg/kg (0.55 mg/lb) administered orally once daily was chosen. The clients were asked to keep a log of activity and occurrence of episodes and to return the dog after 1 month for reassessment.

One month later, the dog was returned for progress evaluation. The owners reported that the dog could now walk for almost an hour with few, if any, exercise-induced episodes. However, during the latter part of the month, the owners had observed 3 episodes each of < 10 seconds' duration. Scottie cramp episodes no longer occurred during periods of excitement. As part of the reevaluation, the dog was exercised by running in the hallway of the hospital. No evidence of cramping occurred during 5 minutes of exercise and excitement. The dosage of fluoxetine was adjusted to 0.8 mg/kg (0.36 mg/lb) administered orally twice daily, and the owners were instructed to return the dog for a follow-up examination after 1 month. At the 2-month recheck visit, it was evident that the dog continued to respond well to treatment with fluoxetine. A follow-up telephone conversation with the owners at 1 year revealed that the dog's episodes continued to be well controlled.

Discussion

The term Scottie cramp refers to nonpainful disease that affects the posture and locomotion of Scottish Terriers and was first described in 1942.5 The classic feature of the disease involves a progression of signs with increasing levels of exercise or excitement. Initially, the thoracic limbs may become abducted or there may be arching or kyphosis of the lumbar portion of the vertebral column, followed by overflexion of the pelvic limbs. The neck may become extended with the nose pointing to the ground. With increasing activity, tonicity of the muscles increases; as the pelvic limbs become increasingly affected, the dog develops a goose-stepping or stringhalt gait. Increasing resistance to movement may cause walking in place, somersaulting, or falling. In a severely affected dog, forward progression of movement may become limited and respiratory and facial muscles may be affected; the patient may curl into a ball. After 10 minutes or less of rest, the hypertonicity usually resolves and the dog is able to ambulate more normally. This disease is not associated with a loss or change in mentation or with behavioral abnormalities.6–8 Scottie cramp does not alter life span, nor is it associated with neonatal deaths.6–9

Clinical signs associated with Scottie cramp can be detected as early as 6 weeks of age and as late as 18 months. Severity of clinical signs can vary considerably among affected dogs, ranging from barely noticeable effects to severe incapacitating changes. It is thought that the differences in clinical signs are related to behavioral factors, environment, nutrition, and temperament of the affected dogs. The severity of the clinical signs in subsequent episodes rarely worsens. However, changes in the dog's health and environment are believed to cause stressors that may result in onset of signs when they were not previously apparent.6–9 Some dogs can learn to self-modify their activity, which can lead observers to believe that remission of the disease has occurred. Results of pedigree analyses and inbreeding and outcross matings have suggested that this is an inherited autosomal recessive disorder.6,9 To explain the variability in clinical signs among dogs, it has been proposed that other genes may be associated with the defective gene and that those other genes modify or influence the clinical expression of the disease.6

Diagnosis is made primarily on the basis of signalment and clinical signs. Tests performed in 10 affected Scottish Terriers in the late 1960s and the early 1970s did not reveal any biochemical, hematologic, or radiographic abnormalities.6 In other affected dogs, gross and histologic examinations of skeletal muscles, peripheral nerves, and connective tissues did not reveal lesions, and no cardiovascular, endocrine, respiratory, digestive, or CNS abnormalities were detected.2 In addition, blood lactate and pyruvate concentrations in affected dogs were comparable to values in control dogs without the disease (Scottish Terriers and other breeds). Electromyographic investigations of dogs with Scottie cramp have revealed increased interference patterns during episodes but no abnormal spontaneous discharges at rest.8

A considerable amount of experimental work2,3,7–10 has been performed in an attempt to understand the underlying pathogenesis of Scottie cramp. In those studies, Scottie cramp was compared with previously reported diseases of muscle. McArdle disease11,12,b (a glycogen storage disease that is caused by a deficiency of the enzyme glycogen phosphorylase) was ruled out by evidence of apparently normal muscle glycogen stores and normal function of myophosphorylase in affected dogs.8 Core myopathy13 was ruled out because core structures were not detected during histologic examination of skeletal muscle specimens.8 Myotonic myopathy is characterized by prolonged muscle contraction upon voluntary contraction or can be initiated by mechanical (percussion), pharmacologic, or electrical stimulation.14–17 Results of electromyographic investigations have indicated that abnormal relaxation is responsible for myotonic myopathy; because myotonia is maintained even after neuromuscular block with procurare18 and spinal anesthesia,16 the abnormality appears to be at the level of the myomembrane. In attempt to determine whether the defect in Scottie cramp was at the level of the muscle, neuromuscular junction, or peripheral nerve, Meyers et al8 performed a series of tests to inhibit function of these structures in affected dogs. Affected Scottish Terriers were anesthetized and administered tubocurarine as a neuromuscular blocking agent, and the quadriceps femoris, biceps femoris, gastrocnemius, biceps brachii, supraspinatus, deltoideus, and pectoralis muscles were both mechanically and electrically stimulated. Poststimulation discharge of the muscle could not be elicited. The function of the muscles was also evaluated following epidural administration of procurare; this treatment also blocked electrical activity. From these experiments, the authors proposed that the Scottie cramp defect is not in the peripheral nervous or muscular system, but within the CNS; they postulated that the abnormality was related to abnormal physiologic functioning of a neurotransmitter.

On the basis of results of pharmacologic experiments, it was suggested that the disease was related to mechanisms of serotonin within the CNS. When amphetamine or parachlorophenyalanine (a noncompetitive inhibitor of tryptophan hydroxylase involved in serotonin synthesis19,20) was administered to affected dogs, the severity of clinical signs increased.8 Furthermore, administration of tryptophan typically ameliorated the effects of parachlorophenylalanine. Administration of nialamide, a selective monoamine oxidase inhibitor that prevents catabolism of serotonin, prevented the onset of signs or substantially reduced the severity of an episode.8 In addition, administration of methysergide, a selective serotonin receptor blocker, increases clinical signs in a dose-dependent manner and has been used as a provocative test for purposes of diagnosis.6 Following administration of methysergide at a dose of 0.1 to 0.3 mg/kg (0.045 to 0.14 mg/lb), clinical signs can be provoked and maintained for as long as 2 hours.

Another study2 was undertaken to further define the nature of the serotonin abnormality within the CNS and other body systems. In that study, the concentration of the serotonin metabolite 5-HIAA was measured in urine collected over 24-hour periods for 3 days and in a minimum of 3 CSF samples that were collected at least 1 week apart from Welsh Terriers and affected and unaffected Scottish Terriers. No significant differences in 5-HIAA concentrations in urine and CSF were identified among groups. Concentrations of serotonin were also measured in whole blood samples and multiple areas of the brain and the lumbar portion of the spinal cord from affected and unaffected Scottish Terriers, and there were no significant differences between those groups. Probenecid blocks the amino acid transport mechanism that removes 5-HIAA from the brain and allows 5-HIAA accumulation in the cisternal pool of CSF21 and in brain tissues.22 When pobenecid was administered to the Welsh terriers and the affected and unaffected Scottish Terriers, the overall turnover rate was not significantly different among groups.2 From these findings, it was proposed that the biochemical defect was unlikely directly related to serotonin concentrations. Later, studies3,6 revealed that the turnover of serotonin in the CNS of affected dogs is decreased following an episode of Scottie cramp, which suggests that neuronal function is normal at rest but there may be a functional deficiency during periods when clinical signs are apparent.

Recommended treatment options for Scottie cramp have included drugs that act on the CNS to facilitate muscle relaxation. Chlorpromazine was evaluated initially because of its ability to antagonize the effects of amphetamine,23–25 which was shown to promote episodes of Scottie cramp.2,7 Following IM injection of chlorpromazine, clinical signs of Scottie cramp resolved within 15 minutes in 5 affected dogs.7 Acepromazine maleate (0.1 to 0.75 mg/kg [0.045 to 0.34 mg/lb], IM) has been used to treat dogs in clinical settings. Treatment with IM injection of diazepam during an acute episode of Scottie cramp results in reduction of clinical signs. Chronic usage of oral diazepam has been used to reduce the severity and number of episodes.6 Both of these treatments present a challenge to practical management of affected dogs by clients. For a dog that has an episode of Scottie cramp once daily or more frequently, treatment via injection would likely not be tolerated for long by the patient, assuming that the client was able and willing to perform the injections. Also, acepromazine can cause profound sedation, an undesired effect. Although diazepam can also cause mild sedation, its status as a controlled substance also complicates its use, especially when required on a lifelong basis. Diazepam has a short duration of action, which necessitates administration 3 times daily, and recommended dosages of diazepam are fairly high (0.5 to 1.5 mg/kg [0.23 to 0.68 mg/lb], PO, q 8 h). These facts, coupled with the cost, potentially decrease the likelihood of compliance by owners to medicate their pets. It has also been suggested that vitamin E administered orally at doses > 125 U/kg/d (56.8 U/lb/d) may be effective in reducing the likelihood of episode occurrence but not the severity of an episode.6

An ideal treatment for Scottie cramp would be an effective medication (other than a controlled substance) that is administered orally no more than twice daily, that has minimal adverse effects, and that is inexpensive. The selective serotonin reuptake inhibitor fluoxetine is generally used for behavior modification in animals. It has a wide safety margin and minimal adverse effects. Because fluoxetine is now available as various generic products, it can also be obtained inexpensively from pharmacies. Once ingested, fluoxetine is detectable in the CNS within 1 hour.1 The half-life of the drug is approximately 2 to 3 days, allowing for a once- or twice-daily adminsitration.4 Selective serotonin reuptake inhibitors prevent uptake of serotonin by presynaptic neurons; thus, the extracellular concentration of serotonin increases for use by postsynaptic neurons. Given that the pathogenesis of this disease appears to be related to deficiencies in concentration or function of serotonin in the CNS and that clinical improvement is associated with experimentally induced increases in serotonin concentration, it seems likely that maintenance of higher serotonin concentrations would decrease the severity and frequency of the episodes of Scottie cramp, thereby allowing affected dogs to have more normal lives.

In the dog of this report, the dosage of fluoxetine administered was within the recommended range. The dog's clinical signs were greatly reduced, and it was able to lead a more normal life, including accompanying its owners on walks for longer than a few minutes. Treatment with fluoxetine is inexpensive and appears to be effective and associated with few adverse effects when administered once or twice daily, compared with several other treatment options. On the basis of the apparent success of fluoxetine treatment in the dog of this report, the use of and response to this medication in dogs with Scottie cramp warrant further investigation.

ABBREVIATION

5-HIAA

5-hydroxyindoleacetic acid

a.

Fluoxetine, PAR Pharmaceutical Co Inc, Spring Valley, NY.

b.

Mommaerts WF, Allingworth HM, Pearson CM, et al. A functional disorder of muscle associated with the absence of phosphorylase (abstr). Proc Natl Acad Sci U S A 1959;45:791.

References

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    Purina. Understanding Your Dog's Body Condition. www.purina.com/dogs/health/bodycondition.aspx. Accessed Mar 23, 2008.

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    Meyers KM, Schaub RG. The relationship of serotonin to a motor disorder of Scottish terrier dogs. Life Sci 1974;14:18951906.

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    Peters RI Jr, Meyers KM. Precursor regulation of serotonergic neuronal function in Scottish Terrier dogs. J Neurochem 1977;29:753755.

    • Crossref
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    • Export Citation
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    Plumb DC. Fluoxetine. In: Veterinary drug handbook. 6th ed. Ames, Iowa: Blackwell Publishing, 2008;404405.

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    Klavenbeck AS. Een aavalsgewijs optrendende stoornes in de regulatie van de spiertonus: Waargenomen bij Schotsche terriers. Tijdschr Diergeneeskd 1942;69:1421.

    • Search Google Scholar
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    Clemmons RM, Peters RI, Meyers KM. Scotty cramp: a review of cause, characteristics, diagnosis, and treatment. Compend Contin Educ Pract Vet 1980;2:385388.

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    Meyers KM, Lund JE, Padgett G, et al. Hyperkinetic episodes in Scottish Terrier dogs. J Am Vet Med Assoc 1969;155:129133.

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    Meyers KM, Dickson WM, Lund JE, et al. Muscular hypertonicity. Episodes in Scottish terrier dogs. Arch Neurol 1971;25:6168.

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    Meyers KM, Padgett GA, Dickson WM. The genetic basis of a kinetic disorder of Scottish terrier dogs. J Hered 1970;61:189192.

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    Peters RI, Meyers KM. Serotonergic-catecholaminergic antagonism and locomotor control. Exp Neurol 1980;69:2229.

  • 11.

    McArdle B. Myopathy due to a defect in muscle glycogen breakdown. Clin Sci 1951;10:1333.

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    Schmid R, Mahler R. Chronic progressive myopathy with myoglobinuria: demonstration of a glycogenolytic defect in the muscle. J Clin Invest 1959;38:20442058.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 13.

    Bethlem J, van Gool J, Hülsmann WC, et al. Familial non-progressive myopathy with muscle cramps after exercise. A new disease associated with cores in the muscle fibres. Brain 1966;89:569588.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 14.

    Brown GL, Harvey AM. Congenital myotonia in the goat. Brain 1941;62:118.

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    Denny-Brown D, Nevin S. The phenomenon of myotonia. Brain 1941;64:118.

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    Kennedy F, Wolfe A. Experiments with quinine and prostigmine in the treatment of myotonia and myasthenia. Arch Neurol Psychiatry 1937;37:6874.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 17.

    Landau WM. The essential mechanism in myotonia; an electromyographic study. Neurology 1952;2:369388.

  • 18.

    Buchthal F, Clemmesen S. Electromyographical observations in congenital myotonia. Acad Psychiatry 1941;16:389403.

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    Koe BK, Weissman A. p-Chlorophenylalanine: a specific depletor of brain serotonin. J Pharmacol Exp Ther 1966;154:499516.

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    Jéquier E, Lovenberg W, Sjoerdsma A. Tryptophan hydroxylase inhibition: the mechanism by which p-chlorophenylalanine depletes rat brain serotonin. Mol Pharmacol 1967;3:274278.

    • Search Google Scholar
    • Export Citation
  • 21.

    Guldberg HC, Ashcroft GW, Crawford TB. Concentrations of 5-hydroxyindolylacetic acid and homovanillic acid in the cerebrospinal fluid of the dog before and during treatment with probenecid. Life Sci 1966;5:15711575.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 22.

    Neff NH, Spano PF, Groppetti A, et al. A simple procedure for calculating the synthesis rate of norepinephrine, dopamine and serotonin in rat brain. J Pharmacol Exp Ther 1971;176:701710.

    • Search Google Scholar
    • Export Citation
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    Henatsch HD, Ingvar DH. Chlorpromazine and spasticity; an experimental electrophysiological study [in German]. Arch Psychiatr Nervenkr Z Gesamte Neurol Psychiatr (Bucur) 1956;195:7793.

    • Search Google Scholar
    • Export Citation
  • 24.

    Hudson RD, Domino EF. Comparative effects of three substituted phenothiazines on the patellar reflex and mean arterial blood pressure of the rabbit. Arch Int Pharmacodyn Ther 1964;147:3642.

    • Search Google Scholar
    • Export Citation
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    Lasagna L, McCann WP. Effect of tranquilizing drugs on amphetamine toxicity in aggregated mice. Science 1957;125:12411242.

  • 1.

    Purina. Understanding Your Dog's Body Condition. www.purina.com/dogs/health/bodycondition.aspx. Accessed Mar 23, 2008.

  • 2.

    Meyers KM, Schaub RG. The relationship of serotonin to a motor disorder of Scottish terrier dogs. Life Sci 1974;14:18951906.

  • 3.

    Peters RI Jr, Meyers KM. Precursor regulation of serotonergic neuronal function in Scottish Terrier dogs. J Neurochem 1977;29:753755.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 4.

    Plumb DC. Fluoxetine. In: Veterinary drug handbook. 6th ed. Ames, Iowa: Blackwell Publishing, 2008;404405.

  • 5.

    Klavenbeck AS. Een aavalsgewijs optrendende stoornes in de regulatie van de spiertonus: Waargenomen bij Schotsche terriers. Tijdschr Diergeneeskd 1942;69:1421.

    • Search Google Scholar
    • Export Citation
  • 6.

    Clemmons RM, Peters RI, Meyers KM. Scotty cramp: a review of cause, characteristics, diagnosis, and treatment. Compend Contin Educ Pract Vet 1980;2:385388.

    • Search Google Scholar
    • Export Citation
  • 7.

    Meyers KM, Lund JE, Padgett G, et al. Hyperkinetic episodes in Scottish Terrier dogs. J Am Vet Med Assoc 1969;155:129133.

  • 8.

    Meyers KM, Dickson WM, Lund JE, et al. Muscular hypertonicity. Episodes in Scottish terrier dogs. Arch Neurol 1971;25:6168.

  • 9.

    Meyers KM, Padgett GA, Dickson WM. The genetic basis of a kinetic disorder of Scottish terrier dogs. J Hered 1970;61:189192.

  • 10.

    Peters RI, Meyers KM. Serotonergic-catecholaminergic antagonism and locomotor control. Exp Neurol 1980;69:2229.

  • 11.

    McArdle B. Myopathy due to a defect in muscle glycogen breakdown. Clin Sci 1951;10:1333.

  • 12.

    Schmid R, Mahler R. Chronic progressive myopathy with myoglobinuria: demonstration of a glycogenolytic defect in the muscle. J Clin Invest 1959;38:20442058.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 13.

    Bethlem J, van Gool J, Hülsmann WC, et al. Familial non-progressive myopathy with muscle cramps after exercise. A new disease associated with cores in the muscle fibres. Brain 1966;89:569588.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 14.

    Brown GL, Harvey AM. Congenital myotonia in the goat. Brain 1941;62:118.

  • 15.

    Denny-Brown D, Nevin S. The phenomenon of myotonia. Brain 1941;64:118.

  • 16.

    Kennedy F, Wolfe A. Experiments with quinine and prostigmine in the treatment of myotonia and myasthenia. Arch Neurol Psychiatry 1937;37:6874.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 17.

    Landau WM. The essential mechanism in myotonia; an electromyographic study. Neurology 1952;2:369388.

  • 18.

    Buchthal F, Clemmesen S. Electromyographical observations in congenital myotonia. Acad Psychiatry 1941;16:389403.

  • 19.

    Koe BK, Weissman A. p-Chlorophenylalanine: a specific depletor of brain serotonin. J Pharmacol Exp Ther 1966;154:499516.

  • 20.

    Jéquier E, Lovenberg W, Sjoerdsma A. Tryptophan hydroxylase inhibition: the mechanism by which p-chlorophenylalanine depletes rat brain serotonin. Mol Pharmacol 1967;3:274278.

    • Search Google Scholar
    • Export Citation
  • 21.

    Guldberg HC, Ashcroft GW, Crawford TB. Concentrations of 5-hydroxyindolylacetic acid and homovanillic acid in the cerebrospinal fluid of the dog before and during treatment with probenecid. Life Sci 1966;5:15711575.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 22.

    Neff NH, Spano PF, Groppetti A, et al. A simple procedure for calculating the synthesis rate of norepinephrine, dopamine and serotonin in rat brain. J Pharmacol Exp Ther 1971;176:701710.

    • Search Google Scholar
    • Export Citation
  • 23.

    Henatsch HD, Ingvar DH. Chlorpromazine and spasticity; an experimental electrophysiological study [in German]. Arch Psychiatr Nervenkr Z Gesamte Neurol Psychiatr (Bucur) 1956;195:7793.

    • Search Google Scholar
    • Export Citation
  • 24.

    Hudson RD, Domino EF. Comparative effects of three substituted phenothiazines on the patellar reflex and mean arterial blood pressure of the rabbit. Arch Int Pharmacodyn Ther 1964;147:3642.

    • Search Google Scholar
    • Export Citation
  • 25.

    Lasagna L, McCann WP. Effect of tranquilizing drugs on amphetamine toxicity in aggregated mice. Science 1957;125:12411242.

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