Acessibilidade / Reportar erro

Dopamine dysregulation syndrome in Parkinson's disease: case report

Síndrome de desregulação dopaminérgica na doença de Parkinson: relato de caso

Abstracts

We report a 67-year-old man with Parkinson's disease for 9 years who developed compulsive use of levodopa. This phenomenon is the main feature of the dopamine dysregulation syndrome. Other related symptoms presented by our patient were mood fluctuation and increased writing activity suggestive of punding.

Parkinson's disease; dopamine dysregulation syndrome; punding


Relatamos sobre um homem de 67 anos de idade com doença de Parkinson por 9 anos e que desenvolveu uso compulsivo de levodopa. Esse fenômeno é a principal característica da síndrome de desregulação dopaminérgica. Outros sintomas apresentados pelo paciente foram flutuações do humor e atividade de escrita aumentada, comportamento este sugestivo de punding.

doença de Parkinson; síndrome de desregulação dopaminérgica; punding


Dopamine dysregulation syndrome in Parkinson's disease: case report

Síndrome de desregulação dopaminérgica na doença de Parkinson: relato de caso

Arthur KummerI; Débora Palma MaiaII; João Vinícius SalgadoIII; Francisco E.C. CardosoIV; Antonio Lucio TeixeiraV

IMédico Psiquiatra

IIMédica Neurologista

IIIMédico Psiquiatra, Professor da Universidade Fumec

IVCoordenador da Clínica de Distúrbios do Movimento do Hospital das Clínicas da Universidade Federal de Minas Gerais, Belo Horizonte MG, Brazil (UFMG). Professor Adjunto do Departamento de Clínica Médica da Faculdade de Medicina da UFMG

VMédico Neurologista e Psiquiatra, Professor Adjunto do Departamento de Clínica Médica da Faculdade de Medicina da UFMG

ABSTRACT

We report a 67-year-old man with Parkinson's disease for 9 years who developed compulsive use of levodopa. This phenomenon is the main feature of the dopamine dysregulation syndrome. Other related symptoms presented by our patient were mood fluctuation and increased writing activity suggestive of punding.

Key words: Parkinson's disease, dopamine dysregulation syndrome, punding.

RESUMO

Relatamos sobre um homem de 67 anos de idade com doença de Parkinson por 9 anos e que desenvolveu uso compulsivo de levodopa. Esse fenômeno é a principal característica da síndrome de desregulação dopaminérgica. Outros sintomas apresentados pelo paciente foram flutuações do humor e atividade de escrita aumentada, comportamento este sugestivo de punding.

Palavras-chave: doença de Parkinson, síndrome de desregulação dopaminérgica, punding.

Parkinson's disease (PD) is associated with a progressive dysfunction of the dopaminergic neurotransmission in the basal ganglia. On pathological examination, the dopaminergic neurons in the pars compacta of the substantia nigra are markedly reduced, and cytoplasmic proteinaceous aggregates known as Lewy bodies are present in the residual neurons. Dopamine replacement therapy (DRT), with the dopamine precursor levodopa or synthetic dopamine agonists, is considered the mainstem of the pharmacological approach for the symptoms of PD1,2. However long-term DRT is commonly associated with a series of motor complications, such as dyskinesias and the on-off phenomenon. More recently, interest has been drawn to non-motor complications of PD and treatment-related psychiatric symptoms, such as depressive disorders, fatigue, apathy and cognitive impairment3.

We describe a man with PD since 58 year-old who developed compulsive use of levodopa. In off periods he presented severe non-motor symptoms, including craving for levodopa, intense feelings of dysphoria, worsening of depressive symptoms, painful trunk sensations and profuse sweating. During peak dose period, he also became hypomanic and had difficulty in perceiving his severe dyskinesias. This behavior has been recently described in literature as a quite rare non-motor complication of DRT. This syndrome of increased use of levodopa beyond that needed to achieve relief of motor symptoms, associated with disabling mood and behavioral features is referred by some authors as dopamine dysregulation syndrome (DDS)4,5. To the best of our knowledge, this is the first case of this syndrome reported in the Brazilian literature. The patient gave informed consent for this case report.

CASE

A 67-year-old man, married, a retired surgeon had PD for 9 years. He had no previous history of alcohol or any drug abuse and his past history was unremarkable. There was no familiar history of psychiatry or neurological diseases. His first parkinsonian symptoms were rigidity and bradykinesia in his left hemibody. At first he was controlled with trihexifenidil and amantadine. These symptoms worsened progressively and new ones appeared, such as mild rest tremor and gait disturbance. Two years after the onset of the illness levodopa was started. Despite some improvement of symptoms, he decided to quit his medical practice. Within 3 years of use of levodopa he developed wearing off, motor fluctuations and mild generalized choreiform movements at peak dose. He also complained of low back pain. These pain episodes were sparse, mild to moderate in intensity and tolerable. A careful work-up was performed to investigate this symptom, including magnetic resonance image of the thoraco-lumbar spine and electroneuromyographic studies of inferior limbs, and the exams were unrevealing.

In the following two years, motor fluctuations worsened considerably, requiring the optimization of treatment with pramipexole. The low back pain also became more intense and frequent, appearing several times a day during off periods. Non-steroidal anti-inflammatory drugs, analgesics, including opioids (tramadol), and tricyclic antidepressants were of no benefit in ameliorating pain. According to the patient only levodopa could bring symptomatic relief. Then he started using progressive larger doses of levodopa up to 30 tablets a day of levodopa/carbidopa 250/25. As a consequence, he developed dramatic peak dose dyskinesias.

He was hospitalized. During levodopa washout, he presented only mild back pain despite evolving with marked bradykinesia. Of note he exhibited dysphoria and craving for levodopa, i.e. an impatient and an intense desire for it, and a dependence disorder was hypothesized. It was possible to adjust the dose of levodopa/carbidopa 250/25 to one tablet 3/3 h. He was also using pramipexole 1 mg QID, amantadine 100 mg TID. Entacapone 200 mg QID was added. Two months after hospital discharge he stopped taking entacapone and began the abuse of levodopa again. Then he was referred to our neuropsychiatric unit.

The patient confirmed the high dose consumption of levodopa. He justified this was the only way to be free of low back pain that had always appeared soon after levodopa effect faded. Furthermore he was not bored by peak dose dyskinesias. He also complained about depressive symptoms, such as feelings of sadness, anhedonia, fatigue and reduced interest with social retraction. These symptoms were present for at least three years, but they were getting worse. He had used paroxetine irregularly without improvement in this period of time. He denied cognitive symptoms of depression, i.e. negativism or ideas of death. He was prescribed with sertraline 50 mg a day and oriented to follow scheduled doses of levodopa/carbidopa 250/25, one tablet 3/3h, pramipexole 1 mg QID and amantadine 100 mg TID. He was also offered psychological support.

On subsequent evaluations, he denied misuse of levodopa, but he persisted with unaltered low back pain during off periods. These periods occurred approximately every two hours and half, and lasted 30 minutes. He noticed that feelings of sadness and apathy were more distressing during off episodes. Interestingly, sometimes he experienced feelings of euphoria with pressure of speech at the peak medication effect. Only mild generalized dyskinesias appeared with this therapeutic schema. Punding, an intense fascination with repetitive tasks, was suspected as the patient developed the habit of writing excerpts of his daily living. His writings were detailed, meaningful and with moral tones. Every day he wrote several pages just to throw them away. Then the diagnosis of DDS was established.

He did not show improvement in depressive symptoms with sertraline up to 100 mg a day for 12 weeks. Thus bupropion 150 mg a day was tried as it has both noradrenergic and dopaminergic mechanisms of actions, but no change in depressive symptoms or craving for levodopa was noticed after 8 weeks. Entacapone 200 mg QID was reintroduced in order to achieve more stable levels of levodopa but, again, there was no benefit. On one year follow-up he evolved with periods of exacerbation of low back pain when he abused levodopa for limited interval.

DISCUSSION

Long-term levodopa therapy in PD is commonly associated with a series of motor complications, which include fluctuations or the on-off phenomenon and dyskinesias. Also as consequence of the treatment, some patients develop non-motor complications such as sleep disturbances, depressive disorders, mood fluctuations, anxiety, psychosis, stereotyped behaviors and delirium3,6,7. Recently, it was associated with the compulsive use of levodopa (or other DRT) called by some authors DDS. In PD, the DDS is the equivalent of the hedonic or hedonistic homeostatic dysregulation, a behavioral change initially described in association with addiction and substance misuse8-10. The core features of DDS are self-medication and levodopa-seeking and hoarding associated with disabling mood and behavioral changes. The later include pathological gambling, obsessional shopping, punding, hypersexuality, aggression and social isolation. Walkabouts are common and sometimes may last for hours8,11,12.

In the case reported, the patient developed severe non-motor symptoms with DRT. Initially he presented trunk pain that worsened specially during off periods. As he only achieved relief with levodopa, he began using progressive larger doses of levodopa. His dramatic dyskinesias during on states did not discourage an escalation of doses, as they seemed not to bore him. It is common that patients who present DDS also have a marked alteration of the perception of the on state. They may develop severe but surprisingly well-tolerated drug-induced dyskinesias which do not act as a deterrent to further increases in the dosages of drugs8,11,12.

When hospitalized and after levodopa washout, he became dysphoric and exhibited an intense desire for the medication. Though those symptoms may be correlated to mood fluctuation due to an intense off period, it may be considered a real withdrawal state commonly seen in other drugs dependence. Nevertheless, a withdrawal state from levodopa has not yet been confirmed13.

He had a minor depressive disorder which was lasting for three years. However, a mood fluctuation was perceived by the patient as his depressive symptoms became worse when medication wore off and he turned euphoric and felt a pressure to speak during the peak dose. Also an abnormal writing activity was displayed. Automatic writing behavior has already been observed in PD and was also suggested to be punding14. Despite the writing hyperactivity of our case resembles more hypergraphia (detailed and meaningful) than automatic behavior, we hypothesized it would be another form of punding or any other repetitive behavior of PD.

The compulsive use of levodopa is a newly described syndrome associated with PD that has been increasingly recognized. Two studies figured out the frequencies of DDS in PD between 3.4 and 4%8,11. However these data may be biased as the population studied came from tertiary referral centers. Since milder forms may occur, the real prevalence remains uncertain. Some risk factors are a previous history of mood disorders, the use of dopaminergic agents (specially chronic exposure to high doses of DRT), and possibly, other risk factor such as family history of psychiatric disorders and past history of alcohol dependence4,11,15. In the case reported, apart from the use of high doses of levodopa the patient had none of these risk factors. Some personality traits were also linked to DDS like the high novelty seeking and the low harm avoidance traits15. These personality traits would not be adequate to describe him either. DDS may occur with all forms of DRT, but the addition of apomorphine often acts as a catalyst for the progression of the disorder4,8, suggesting that the drugs with faster onset of action tend to be a crucial factor in determining misuse of dopaminergic agents. In a similar way, punding is more common between those patients using subcutaneous apomorphine or fast-acting formulations of levodopa16. It is uncertain whether the use of dopaminergic agonists, pramipexol and ropinirol, is related with a higher risk for DDS. However, recent case series reported behavioral changes such as pathological gambling and hypersexuality in PD patients using these drugs17,18.

The DSM-IV diagnostic criteria for drug dependence were thought to be not adequately applicable to DDS as PD patients use medication due to a chronic medical condition. Nevertheless, PD patients with DDS fulfill the core operational criteria of drug dependence according to DSM-IV: they manifest tolerance, "withdrawal" and escalating doses as symptoms become more severe with disease progression or pharmacokinetic changes occur like wearing off4,8,13.

Dysregulation of brain dopamine systems mediating reward is proposed to underlie the development of DDS4,15. The PD patients with DDS may seek for artificial rewards to compensate their intrinsic reward deficit due to dopaminergic hypoactivity in the basal ganglia. This basal ganglia hypoactivity occurs mainly in the off periods and seems to be worsened by compensatory neuronal changes induced by the chronic use of levodopa19.

Regions of both ventral and dorsal striatum have been implicated in the reinforcement for drug addiction. The nucleus accumbens (or ventral striatum) shell is supposed to mediate the psychomotor stimulus of dopaminergic drugs and its primary reinforcing effect, possibly, via descending neural influences over autonomic and motor responses. The nucleus accumbens core is thought to mediate the effects of the conditioned reinforcer. This is important to maintain seeking behavior in the presence of a drug associated conditioned stimulus, but in the absence of the drug itself. The dorsal striatum seems to mediate the development of habits, i.e. stimulus-response learning mechanisms with less involvement of the goal itself. The habit formation underlies some features of compulsive drug seeking and other stereotyped behavior like punding. The medial prefrontal cortex (mPFC) is another region affected in PD that receives dopaminergic innervation, and it is involved in reward and addiction20. In PD, although dopaminergic neurons of the ventral tegmental area that projects to nucleus accumbens, caudate and PFC may be affected in some patients, the dopaminergic projection from the pars compacta of the substantia nigra to the putamen is the most compromised circuit. This nigro-putamen circuit is also affected by levodopa-induced neuronal changes. Perhaps, this could be an explanation for the low prevalence of addiction among PD patients19. It may be hypothesized that patients who are more prone to develop DDS, as the case reported here, have dopaminergic lesions preferentially outside the nigro-putamen circuit. In conclusion, DDS, although rare, is of both clinical and theoretical importance.

Psychiatric symptoms often go unrecognized in PD although they are potentially treatable and may be important factor to the morbidity of the disease. Nevertheless, as highlighted by our case, they may become a real challenge for the clinician. Despite the first step in the treatment of psychiatric conditions in PD is the optimization of its treatment, the progression of PD turns it into a real Procust’s bed: the control of motor symptoms can cause psychiatric symptoms and their treatment may worse neurological symptoms. Then, the quality of life in PD patients is indeed determined by non-motor symptoms as much as it is by the motor disorder itself21.

Received 22 February 2006, received in final form 13 June 2006. Accepted 25 July 2006.

Dr. Antonio Lucio Teixeira - Departamento de Clínica Médica, Faculdade de Medicina / UFMG - Avenida Prof. Alfredo Balena 190 - 30130-100 Belo Horizonte MG- Brasil. E-mail: altexr@gmail.com

  • 1. Nutt JG, Wooten GF. Diagnosis and initial management of Parkinson's disease. N Engl J Med 2005;335:1021-1027.
  • 2. Teixeira AL, Cardoso F. Tratamento inicial da doença de Parkinson. Rev Neurociências 2004;12:146-151.
  • 3. Schrag A. Psychiatric aspects of Parkinsons disease: an update. J Neurol 2004;251:795-804.
  • 4. Lawrence AD, Evans AH, Lees AJ. Compulsive use of dopamine replacement therapy in Parkinson's disease: reward systems gone awry? Lancet Neurol 2003;2:595-604.
  • 5. Evans AH, Lees AJ. Dopamine dysregulation syndrome in Parkinson's disease. Curr Opin Neurol 2004;17:393-398.
  • 6. Molina JA, Jiménez-Jiménez FJ, Ortí-Pareja M. Complicaciones motoras y psíquicas en el tratamiento prolongado con levodopa de la enfermedad de Parkinson complicada. Rev Neurol 1999;28:982-990.
  • 7. Noé-Sebastián E, Irimia-Sieira P, Pomares-Arias E, Martinez-Vila E, Luquin-Piudo MR. Trastornos neuropsiquiátricos en la enfermedad de Parkinson. Rev Neurol 2001;32:676-681.
  • 8. Giovannoni G, O'Sullivan JD, Turner K, Manson AJ, Lees AJ. Hedonistic homeostatic dysregulation in patients with Parkinson's disease on dopamine replacement therapies. J Neurol Neurosurg Psychiatry 2000; 68:423-428.
  • 9. Witjas T, Baunez C, Henry JM, et al. Addiction in Parkinsons disease: impact of subtalamic nucleus deep brain stimulation. Mov Disord 2005; 20:1052-1055.
  • 10. Koob GF, Le Moal M. Drug abuse: hedonic homeostatic dysregulation. Science 1997;278:52-58.
  • 11. Pezzella FR, Colosimo C, Vanacore N, et al. Prevalence and clinical features of hedonistic homeostatic dysregulation in Parkinsons disease. Mov Disord 2005;20:77-81.
  • 12. Pezzella FR, Di Rezze S, Chianese M, et al. Hedonistic homeostatic dysregulation in Parkinson's disease: a short screening questionnaire. Neurol Sci 2003;24:205-206.
  • 13. Bearn J, Evans A, Kelleher M, Turner K, Lees A. Recognition of a dopamine replacement therapy dependence syndrome in Parkinsons disease: a pilot study. Drug Alcohol Depend 2004;76:305-310.
  • 14. Miwa H, Kondo T. Increased writing activity in Parkinsons disease: a punding-like behavior? Parkinsonism Relat Disord 2005;11:323-325.
  • 15. Evans AH, Lawrence AD, Potts J, Appel S, Lees AJ. Factors influencing susceptibility to compulsive dopaminergic drug use in Parkinsons disease. Neurology 2005;65:1570-1574.
  • 16. Evans AH, Katzenschlager R, Paviour D, et al. Punding in Parkinsons disease: its relation to the dopamine dysregulation syndrome. Mov Disord 2004;19:397-405.
  • 17. Klos KJ, Bower JH, Josephes KA, Matsumoto JY, Ahlskog JE. Pathological hypersexuality predominantly linked to adjuvant dopamine agonist therapy in Parkinsons disease and multiple system atrophy. Parkinsonism Relat Disord 2005;11:381-386.
  • 18. Dodd ML, Klos KJ, Bower JH, Geda YE, Josephes KA, Ahlskog JE. Pathological gambling caused by drugs used to treat Parkinsons disease. Arch Neurol 2005;62:1377-1381.
  • 19. Linazasoro G, van Blercom N, Lasa A. Hipótesis: enfermedad de Parkinson, síndrome de deficiencia de recompensa y efectos adictivos de la levodopa. Neurologia 2004;19:117-127.
  • 20. Everitt BJ, Robbins TW. Neural systems of reinforcement for drug addiction: from actions to habits to compulsion. Nat Neurosci 2005;8: 1481-1489.
  • 21. Burn DJ. Depression in Parkinsons disease. Eur J Neurol 2002;9:44-54.

Publication Dates

  • Publication in this collection
    21 Dec 2006
  • Date of issue
    Dec 2006

History

  • Accepted
    25 July 2006
  • Received
    22 Feb 2006
  • Reviewed
    13 June 2006
Academia Brasileira de Neurologia - ABNEURO R. Vergueiro, 1353 sl.1404 - Ed. Top Towers Offices Torre Norte, 04101-000 São Paulo SP Brazil, Tel.: +55 11 5084-9463 | +55 11 5083-3876 - São Paulo - SP - Brazil
E-mail: revista.arquivos@abneuro.org