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Acamprosate is an agent developed toreduce the risk of relapse in alcoholdependence. Several cases of prompt res-olution of primitive reflexes after initia-tion of acamprosate therapy suggest thatthe drug may have an impact on corticalfunction that is measurable on physicalexamination and consistent with its pro-posed mechanism of therapeutic action oncortical glutamatergic neurotransmission.We describe 3 cases that suggest that mon-itoring primitive reflexes before and afterinitiation of therapy with acamprosatemay help to identify potential treatmentresponse and prognosis. None of these pa-tients had a history of dementia or otherneurologic disorder. Lorazepam was theonly other medication started with the in-tention of affecting brain function; it wasstopped in each patient before acampro-sate was started.

Case Reports

CASE 1

A 57-year-old man presented with a long-standing his-tory of alcohol dependence. As is true for each of the pa-tients in this report, he had no history of dementia or otherneurologic disorder, nor did he have a systemic disordersuch as diabetes or hypertension that may reasonably havebeen assumed to impair neurologic function. He was ad-mitted to the hospital after 7 months of drinking 144ounces of beer per day. He had no history of medically

complicated alcohol withdrawal. Notably, on physical ex-amination he demonstrated a markedly positive snout re-flex, in which tapping on the philtrum produced a briskcontraction of the orbicularis oris.

On hospital day 3, in the absence of any evidence of al-cohol withdrawal and continued presence of the patientsprominent snout reflex, acamprosate 666 mg 3 times a daywas initiated. The next morning, after the patient received4 doses of acamprosate, the snout reflex had resolved fully.He was discharged several days later. Daily examinationshowed that the snout reflex did not return.

Acamprosate and Primitive Reflexes

Patrycya Guzik, Lindey Bankes, and Thomas M Brown

Author information provided at the end of the text.

The Annals of Pharmacotherapy I 2007 April, Volume 41 I 715www.theannals.com

OBJECTIVE: To describe 3 cases of patients with alcohol dependence whoseprimitive reflexes resolved upon initiation of acamprosate 666 mg 3 times daily.

CASE SUMMARIES: A 57-year-old man had a long-standing history of alcoholdependence and a prominent snout reflex. The snout reflex resolved within 24

hours of starting treatment with acamprosate. A 45-year-old man with a long

history of alcohol dependence had both a snout and a grasp reflex. These reflexes

were present throughout 3 admissions for alcohol detoxification and continued until

the end of his third admission, when he elected to begin treatment with acam-

prosate. Within 24 hours of starting treatment, the snout and grasp reflexes were

absent. A 55-year-old man who drank heavily for 35 years presented with both a

snout and a grasp reflex on admission. These persisted throughout his

detoxification until the day after he had begun treatment with acamprosate. His

primitive reflexes remained resolved through the next 4 days until discharge. All 3

of these patients remained on acamprosate at discharge.

DISCUSSION: Alcohol dependence is a common, debilitating disorder. One of the

difficulties in treating alcohol dependence is its adverse effect on the brain, ashigher aspects of cortical function necessary to maintain abstinence are eroded

by alcohol. Acamprosate is a drug intended to help prevent relapse among

patients with alcohol dependence. Unexpectedly, acamprosate may resolve

primitive reflexesa neurologic finding that suggests cognitive impairment

among patients with alcohol dependence.

CONCLUSIONS: Acamprosate may relieve snout and grasp reflexes among patientswith alcohol dependence.

KEY WORDS: acamprosate, primitive reflexes.

Ann Pharmacother 2007;41:715-8.

Published Online, 27 Mar 2007, www.theannals.com, DOI 10.1345/aph.1H270

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CASE 2

After 5 months of sobriety, a 45-year-old man with along history of alcohol dependence relapsed. He had con-sumed about 200 ounces of beer, in addition to severaldrinks of hard liquor, each day for over 100 days beforebeing admitted to the hospital for detoxification. He wasadmitted 3 times within 6 weeks. The first 2 admissions

were complicated by delirium tremens, and he was dis-charged both times as soon as he was medically stable.During these 2 admissions, he refused treatment beyonddetoxification. He had a snout and a grasp reflex throughthese 2 admissions.

He was admitted a third time, again for detoxification,but with a request for any help that might prevent relapse.After detoxification and medical stabilization, the patientexpressed interest in acamprosate 5 days after his last doseof a benzodiazepine. He had a prominent snout and graspreflex throughout this time. The grasp reflex consisted of afirm grasp of either hand when his palm was touched. His

upper extremity could then be pulled in various directionswithout his acknowledgment; he would continue to engagein whatever conversation had been initiated to distract himwhile the grasp reflex was being assessed. Acamprosate666 mg 3 times a day was started. The next day, both ab-normal reflexes had fully resolved and did not return.

CASE 3

A 55-year-old man began significant drinking at about20 years of age, at which time he said he would drink alot of heavy liquor. He was consuming about 72 ounces

of beer a day when he was admitted for depression. He de-nied that alcohol was a problem and stated that he had nev-er had withdrawal symptoms. On admission, the patientshowed marked snout and grasp reflexes. Lorazepam 2 mgwas administered within the first 24 hours of admission formild autonomic arousal; the patient received no further lor-azepam and had no evidence of withdrawal after that.

On hospital day 10, the patient stated that he wanted todo everything for himself, at the urging of his children. Atthat time, he continued to have a striking snout reflex, as wellas a grasp reflex. His grasp reflex was so pronounced that hecould be pulled out of his chair without realizing that this was

happening. He asked to begin acamprosate and was startedon 666 mg 3 times a day. The next day, the snout and graspreflexes were resolved. These did not return over the next 4days, at which time he was discharged.

Discussion

The phrase primitive reflex refers to a host of brain-stem reflexes that have value early in life, but which thedeveloping brain subsequently suppresses. An example isthe grasp reflex: when an infants palm is touched, the in-

fant reflexively grasps whatever has touched his or herpalm. Similarly, when the mouth of an infant is touched, heor she reflexively sucks. These adaptive reflexes are sup-pressed by the developing brain as their survival valuefades. Diseases that impair the brains ability to suppressthese reflexes in the adult, such as dementias or brainsteminjuries, may release these reflexes from their normal sup-

pression. Discussions of the proper manner of eliciting themore well-known primitive reflexes are available.1

Primitive reflexes are typically brainstem motor pro-grams triggered by specific sensory input. For example,the snout reflex begins with stimulation of the sensory areaof cranial nerve V, which is swiftly translated by the facialmotor nucleus into contraction of the orbicularis oris, orsucking movements. Higher cortical centers, often with as-sistance from brainstem centers, later override the brain-stem mechanisms that initiate reflex sucking.2 Although itspathways are less well described, the grasp reflex is classi-cally associated with impaired frontal lobe function.1 Neuro-

transmitters thought to be involved in these reflexes includedopamine, -aminobutyric acid (GABA), and glutamate.Again, as the brain develops, higher motor centers suppressmany of the early reflexes, limiting their subsequent appear-ance to willed movements. In a series of 240 healthy youngadults, for example, only 1% had a grasp reflex, and nonehad a snout reflex.3 Systemic, metabolic, and neurologic dis-eases can change this picture dramatically.

The potential value of primitive reflexes in staging vari-ous illnesses and assessing prognosis is just beginning tobe studied. A host of correlations and potential implica-tions exist for primitive reflexes, with no obvious unifying

clinical principles. In general, though, the presence ofprimitive reflexes suggests that a patient is somehow moreincapacitated than another patient who does not demon-strate primitive reflexes. There are many examples of this.For example, in Alzheimers disease, patients with similarmeasures of cognitive function on the Standardized Mini-Mental Status Examination who also demonstrate primitivereflexes have greater disturbances of behavior and less abilityto care for themselves compared with patients who lackprimitive reflexes.4 Among patients infected with HIV type1, the presence of primitive reflexes is a strong marker forseropositivity and cognitive impairment.5 Schizophrenic pa-

tients with primitive reflexes are less likely to respond toconventional antipsychotic treatment than are schizophrenicpatients without such reflexes.6 Primitive reflexes may waxand wane with the severity of psychosis.7 Resolution ofprimitive reflexes after head trauma is a measure of recov-ery of brain function.8 Drug therapy can also influence themanifestation of primitive reflexes. For example, amongpatients with structural brain injury, haloperidol may causeprimitive reflexes to emerge.9 On the other hand, amongpatients with Parkinsons disease, treatment with levodopacan lead to resolution of primitive reflexes.10

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As the clinical significance of primitive reflexes is justbeginning to be understood, so is their pathophysiology. Inrodents and cats, the importance of GABA, glycine, andglutamate in maintaining primitive reflexes has beendemonstrated.11,12 Brainstem circuits involving GABA andglycine are thought to inhibit the appearance of abnormalreflexes in humans.13 Glutamate from brainstem and high-

er cortical centers may tend to unmask primitive reflexes,especially if there is a relative deficit of GABA or glycine.2

The state of alcohol withdrawal is characterized by in-creased activity of brain glutamate and reduced activity ofbrain inhibitory mechanisms. As an agent that affects ex-tracellular levels and action of glutamate, acamprosate inthe alcohol-dependent patient may be well poised to affectthe appearance of primitive reflexes.

Acamprosate is thought to relieve craving among alco-hol-dependent patients, in part, by reducing abnormal lev-els of glutamate present in the brains of recovering alco-holics. Abnormalities in glutamate neurotransmission can

account for many findings on examination, ranging fromnonspecific findings such as irritability to specific findingssuch as motor seizures. Primitive reflexes, such as thesnout and grasp reflexes, are correlated with cerebrocorti-cal lesions and dysfunction and may indicate alcohol-in-duced abnormalities of cortical function.14 Resolution ofprimitive reflexes may indicate improved functioning ofcortical circuits. The short period of time between the initi-ation of treatment with acamprosate and resolution of ourpatients primitive reflexes suggests that acamprosate mayhave caused these abnormal reflexes to resolve. Of note,the introduction and withdrawal of lorazepam, a GABA-A

agonist, did not seem to affect the presence or resolution ofprimitive reflexes in any of our patients.The significance of primitive reflexes in assessing dis-

ease severity and the potential implications of altering theappearance of these reflexes is just beginning to be real-ized. This is the first report to suggest that acamprosatemay affect the appearance of primitive reflexes among pa-tients who are alcohol dependent. How such an effect mayalter the course of alcoholism is unknown.

Conclusions

The assessment of primitive reflexes is safe, easy to per-form, and readily reproducible. Testing for such reflexesmay be a useful component in the evaluation of the alco-hol-dependent patient. The significance of the presence ofprimitive reflexes in this population is not clear; nor is thesignificance of their resolution understood. Perhaps primi-tive reflexes may prove useful in predicting who may ben-efit, and how much, from acamprosate treatment of crav-ing in alcohol dependence.

Patrycya GuzikBBA, Medical Student, School of Medicine, Uni-versity of Texas Health Science Center at San Antonio

Lindey Bankes MD, Resident, Department of Psychiatry, Univer-sity of Texas Health Science Center at San Antonio

Thomas M Brown MD, Assistant Professor, Department of Psy-chiatry, Audie L Murphy Memorial Veterans Affairs Medical Center,San Antonio

Reprints: Dr. Brown, Department of Psychiatry, Audie L MurphyMemorial Veterans Affairs Medical Center, 7400 Merton Minter Blvd.,San Antonio, TX 78229, fax 210/949-3918, drthomasmbrown@yahoo.com

References

1. Schott JM, Rossor MN. The grasp and other primitive reflexes. J NeurolNeurosurg Psychiatry 2003;74:558-60.

2. Schmid S, Simons NS, Schnitzler HU. Cellular mechanisms of thetrigeminally evoked startle response. Eur J Neurosci 2003;17:1438-44.

3. Brown DL, Smith TL, Knepper LE. Evaluation of five primitive reflexesin 240 young adults. Neurology 1998;51:322.

4. Molloy DW, Clarnette RM, McIlroy WE, Guyatt G, Rees L, Lever J.Clinical significance of primitive reflexes in Alzheimers disease. J AmGeriatr Soc 1991;39:1160-3.

5. Tremont-Lukats IW, Serbanescu R, Teixeira GM, Iriza E, HernandezDE, Schneider C. Multivariate analysis of primitive reflexes in patientswith human immunodeficiency virus type-1 infection and neurocogni-

tive dysfunction. Ital J Neurol Sci 1999;20:17-22.6. Smith RC, Kadewari RP, Rosenberger JR, Bhattacharyya A. Nonre-

sponding schizophrenia: differentiation by neurological soft signs andneuropsychological tests. Schizophr Bull 1999;25:813-25.

7. Burra P, Powles WE, Riopelle RJ, Ferguson ML. Atypical psychosiswith reversible primitive reflexes. Can J Psychiatry 1980;25:74-7.

8. Thomas RJ. Blinking and the release reflexes. Are they clinically useful?J Am Geriatr Soc 1994;42:609-13.

9. Schilkrut R, Ruther E, Ackenheil M, Eben E, Hippius H. Clinical andbiochemical parameters during neuroleptic treatment. III. Primitive re-flexes during neuroleptic treatment. Pharmakopsychiatr Neuropsy-chopharmakol 1976;9:43-7.

10. Rey RD, Garetto NS, Bueri JA, Simonetti DD, Sanz OP, Sica RE. Theeffect of levodopa on the habituation of the acousticpalpebral reflex inParkinsons disease. Electromyogr Clin Neurophysiol 1996;36:357-60.

11. Paik SK, Oh SJ, Son YJ, et al. Neural mechanisms controlling jaw-jerkreflex in the cat. Neuroreport 2005;16:1565-8.

12. Diagne M, Valla J, Delfini C, Buisseret-Delmas C, Buisseret P. Trigemi-novestibular and trigeminospinal pathways in rats: retrograde tracingcompared with glutamic acid decarboxylase and glutamate histochem-istry. J Comp Neurol 2006;496:759-72.

13. Khasani S, Becker K, Meink HM. Hyperekplexia and stiff-man syn-drome: abnormal brainstem reflexes suggest a physiological relationship.J Neurol Neurosurg Psychiatry 2004;75:1265-9.

14. Corbett AJ, Bennett H, Kos S. Frontal signs following subcortical infarc-tion. Clin Exp Neurol 1992;29:161-71.

EXTRACTOOBJETIVO: Describir 3 casos de pacientes con dependencia a alcoholcuyos reflejos primitivos se resolvieron al iniciar el tratamiento conacamprosato.

RESUMEN DE LOS CASOS: El primer caso es un varn de 57 aos con unhistorial de dependencia alcohlica de larga duracin y un prominentereflejo de hociqueo. Este reflejo desapareci en las primeras 24 horas detratamiento con acamprosato. El segundo caso es un varn de 45 aoscon un largo historial de dependencia alcohlica que presentaba reflejosde hociqueo y de prensin. stos reflejos estuvieron presentes en 3admisiones sucesivas para desintoxicacin alcohlica y continuaronhasta el final de la tercera admisin, cuando el paciente eligi ser tratadocon acamprosato. Al cabo de 24 horas de iniciar el tratamiento losreflejos de hociqueo y de prensin estaban ausentes por primera vez en

Acamprosate and Primitive Reflexes

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las 3 admisiones. Dichos reflejos no se haban vuelto a presentar cuandose produjo el alta. El ltimo caso es un varn de 55 aos, gran bebedordesde haca 35 aos. Este paciente presentaba reflejos de hociqueo y deprensin que persistieron durante el perodo de desintoxicacin hasta elda siguiente de iniciar el tratamiento con acamprosato. Estos reflejoscontinuaron sin aparecer en los siguientes 4 das tras el alta.

DISCUSIN: La dependencia a alcohol es un trastorno comn ydebilitante. Una de las dificultades del tratamiento de esta dependenciaes la afectacin que produce a nivel cerebral, ya que los aspectos maselevados de la funcin cortical, necesarios para mantener la abstinencia,

estn afectados por el alcohol. El acamprosato es un medicamentoutilizado para prevenir la recada en los pacientes con dependenciaalcohlica. Inesperadamente este frmaco puede eliminar los reflejosprimitivos-un tipo de trastorno neurolgico que indica un dao a nivelcognitivo- en estos pacientes.

CONCLUSIONES: El acamprosato puede aliviar los reflejos de hociqueo yprensin en los pacientes con dependencia alcohlica.

Juan del Arco

RSUM

OBJECTIF: Dcrire 3 cas de patients avec une dpendance lalcool chezqui les rflexes primitifs sont disparus aprs la prise dacamprosate 666mg 3 fois par jour.

RSUM DES CAS:

Le premier cas est celui dun homme de 57 ans avecune longue histoire de dpendance lalcool et un frappant rflexe nasal(rflexe de von Bechterew). Le rflexe nasal est disparu 24 heures aprsle dbut de lacamprosate, soit aprs la quatrime dose. Le deuxime cas

est celui dun homme de 45 ans avec une longue histoire de dpendance lalcool qui prsentait la fois un rflexe nasal et un rflexe deprhension. Ceux-ci ont t observs durant 3 sjours de dsintoxicationet ont persist jusqu la fin du troisime sjour, moment olacamprosate a t dbut. Le lendemain du dbut de lacamprosate, les2 reflexes anormaux avaient compltement disparus pour la premirefois en 3 admissions. Le dernier cas est celui dun homme de 55 ansconsommant une grande quantit dalcool depuis 35 ans. Celui-ciprsentait un rflexe nasal ainsi quun rflexe de prhension au momentde ladmission. Ces rflexes ont persist durant la cure de

dsintoxication jusquau lendemain du dbut dun traitement aveclacamprosate. La prise dacamprosate a prvenu la rapparition desrflexes anormaux chez les 3 patients, tel quobserv au moment dudpart de ltablissement.

DISCUSSION: La dpendance lalcool est un problme courant etdbilitant. Une des difficults lors du traitement de la dpendance lalcool est associe ses effets indsirables sur le cerveau, les fonctionscorticales suprieures ncessaires au maintien de labstinence tantaltres par lalcool. Lacamprosate est un mdicament visant prvenirla rechute chez les patients prsentant une dpendance lalcool. Defaon inattendue, lacamprosate peut aussi liminer les rflexes primitifschez ces patients. Cette observation neurologique suggre une atteintecognitive chez les patients dpendants lalcool.

CONCLUSIONS: Lacamprosate peut liminer le rflexe nasal et le rflexede prhension chez les patients ayant une dpendance lalcool.

Marie-Claude Vanier

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