Pleurothotonus, commonly known as Pisa syndrome, is a rare neurological disorder which occurs due to prolonged exposure to

antipsychotic drugs Antipsychotics, previously known as neuroleptics and major tranquilizers, are a class of psychotropic medication primarily used to manage psychosis (including delusions, hallucinations, paranoia or disordered thought), principally in schizoph ...

(which may also be referred to as

neuroleptics Antipsychotics, previously known as neuroleptics and major tranquilizers, are a class of psychotropic medication primarily used to manage psychosis (including delusions, hallucinations, paranoia or disordered thought), principally in schizoph ...

). It is characterized by

dystonia Dystonia is a neurology, neurological Hyperkinesia, hyperkinetic Movement disorders, movement disorder in which sustained or repetitive muscle contractions occur involuntarily, resulting in twisting and repetitive movements or abnormal fixed po ...

, and abnormal and sustained involuntary muscle contraction. This may cause twisting or jerking movements of the body or a body part. Although Pisa syndrome develops most commonly in those undergoing long-term treatment with antipsychotics, it has been reported less frequently in patients receiving other medications, such as an

acetylcholinesterase inhibitor Acetylcholinesterase inhibitors (AChEIs) also often called cholinesterase inhibitors, inhibit the enzyme acetylcholinesterase from breaking down the neurotransmitter acetylcholine into choline and acetate, thereby increasing both the level an ...

. However, it has also been seen in those with other diseases causing

neurodegeneration A neurodegenerative disease is caused by the progressive loss of neurons, in the process known as neurodegeneration. Neuronal damage may also ultimately result in their cell death, death. Neurodegenerative diseases include amyotrophic lateral sc ...

and in those who are not receiving any medication (

idiopathic An idiopathic disease is any disease with an unknown cause or mechanism of apparent spontaneous origin. For some medical conditions, one or more causes are somewhat understood, but in a certain percentage of people with the condition, the cause ...

Pisa syndrome). The characteristic development of Pisa syndrome consists of two types of

: acute dystonia and tardive dystonia (also known as

tardive dyskinesia Tardive dyskinesia (TD) is an iatrogenic disorder that results in involuntary repetitive body movements, which may include grimacing, sticking out the tongue or smacking the lips, which occurs following treatment with medication. Additional mo ...

). The underlying pathology of drug-induced Pisa syndrome is very complex, and development may be due to an underlying

dopaminergic Dopaminergic means "related to dopamine" (literally, "working on dopamine"), a common neurotransmitter. Dopaminergic substances or actions increase dopamine-related activity in the brain. Dopaminergic pathways, Dopaminergic brain pathways facil ...

cholinergic Cholinergic agents are compounds which mimic the action of acetylcholine and/or butyrylcholine. In general, the word " choline" describes the various quaternary ammonium salts containing the ''N'',''N'',''N''-trimethylethanolammonium cation ...

imbalance, or serotonergic/noradrenergic dysfunction.Nishimura, K: Pisa Syndrome Resolved After Switching to Olanzapine. Journal of Neuropsychiatry and Clinical Neuroscience 2007; 19:202-203

Symptoms

The predominant symptom of Pisa syndrome is

. Dystonia is a neurological movement disorder characterized by sustained muscle contraction leading to abnormal posture, twisting, and repetitive movement. In Pisa Syndrome specifically there is commonly a tonic

flexion Motion, the process of movement, is described using specific anatomical terminology, anatomical terms. Motion includes movement of Organ (anatomy), organs, joints, Limb (anatomy), limbs, and specific sections of the body. The terminology used de ...

of the trunk of the body to one side, leading to a slight lean (reminiscent of the

Leaning Tower of Pisa The Leaning Tower of Pisa ( ), or simply the Tower of Pisa (), is the , or freestanding bell tower, of Pisa Cathedral. It is known for its nearly four-degree lean, the result of an unstable Foundation (engineering), foundation. The tower is on ...

, hence the name "Pisa syndrome"). This is usually associated with a backward axial rotation of the spine and indifferent to markedly abnormal posture. Patients diagnosed with Pisa Syndrome usually experience either acute dystonia or tardive dystonia, also known as

. Differential diagnosis between the two may be hard to accomplish without a complete patient history, since both types of dystonia may occur simultaneously in a patient. These symptoms generally disappear after discontinuation of the antipsychotic drug. The time of onset of symptoms may vary depending on drug being administered and the neurological characteristics of the patient in question.

Acute dystonia

Acute dystonia nearly always develops a few weeks after a

dopamine Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic chemical of the catecholamine and phenethylamine families. It is an amine synthesized ...

blocking agent/medication has begun or a substantial increase in

antipsychotic Antipsychotics, previously known as neuroleptics and major tranquilizers, are a class of Psychiatric medication, psychotropic medication primarily used to manage psychosis (including delusions, hallucinations, paranoia or disordered thought), p ...

dosage. An acute dystonic reaction consists of sustained, painful muscular spasms, producing twisting of the trunk/body and abnormal posture. The most frequent occurrences of these spasms have been reported in the neck, tongue, and jaw.

Oculogyric crisis Oculogyric crisis (OGC) is a rare sudden, paroxysmal, dystonic reaction that may manifest in response to specific drugs, particularly neuroleptics, or medical conditions, such as movement disorders. This neurological phenomenon is characterized ...

and

opisthotonus Opisthotonus or opisthotonos (from and ) is a state of severe hyperextension and spasticity in which an individual's head, neck and spinal column enter into a complete "bridging" or "arching" position. This extreme arched pose is an extrapyram ...

are also very common. Acute effects of dopamine antagonists also include Parkinsons-like symptoms, manifested by

bradykinesia Hypokinesia is one of the classifications of movement disorders, and refers to decreased bodily movement. Hypokinesia is characterized by a partial or complete loss of muscle movement due to a disruption in the basal ganglia. Hypokinesia is a sy ...

, pin rolling

tremor A tremor is an involuntary, somewhat rhythmic muscle contraction and relaxation involving neural oscillations, oscillations or twitching movements of one or more body parts. It is the most common of all involuntary movements and can affect the h ...

, and rigidity of the body. These movements may fluctuate over hours and temporarily dissipate in response to reassurance, and the individual episodes may last minutes to hours. Acute reactions are more common in older patients and females. The

pathophysiology Pathophysiology (or physiopathology) is a branch of study, at the intersection of pathology and physiology, concerning disordered physiological processes that cause, result from, or are otherwise associated with a disease or injury. Pathology is ...

underlying these reactions is unknown, but the movements usually occur during the period when blood medication level is dropping. The acute syndromes which occur due to prolonged exposure to a

dopamine antagonist A dopamine antagonist, also known as an anti-dopaminergic and a dopamine receptor antagonist (DRA), is a type of drug which blocks dopamine receptors by receptor antagonism. Most antipsychotics are dopamine antagonists, and have been used in t ...

are collectively termed

extrapyramidal symptoms Extrapyramidal symptoms (EPS) are signs and symptoms, symptoms that are wikt:archetypical, archetypically associated with the extrapyramidal system of the brain's cerebral cortex. When such symptoms are caused by medications or other drugs, they ...

, EPS.

Tardive dyskinesia

Tardive dyskinesias are involuntary movements of the lips, tongue, face, trunk, and extremities which occur in patients with prolonged exposure to dopamine antagonists or antipsychotic medications. Clinical findings have provided evidence that adenosine, a major inhibitory

neurotransmitter A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a Chemical synapse, synapse. The cell receiving the signal, or target cell, may be another neuron, but could also be a gland or muscle cell. Neurotra ...

in the

central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain, spinal cord and retina. The CNS is so named because the brain integrates the received information and coordinates and influences the activity o ...

, plays a role in the development of tardive dykinesias. Tardive dykinesias have also been associated with polymorphism in the

dopamine receptor D2 Dopamine receptor D2, also known as D2R, is a protein that, in humans, is encoded by the ''DRD2'' gene. After work from Paul Greengard's lab had suggested that dopamine receptors were the site of action of antipsychotic drugs, several groups, ...

gene,

dopamine receptor D3 Dopamine receptor D3 is a protein that in humans is encoded by the ''DRD3'' gene. This gene encodes the D3 subtype of the dopamine receptor. The D3 subtype inhibits adenylyl cyclase through inhibitory G-proteins. This receptor is expressed in ...

gene,

dopamine transporter The dopamine transporter (DAT, also sodium-dependent dopamine transporter) is a membrane-spanning protein coded for in humans by the ''SLC6A3'' gene (also known as ''DAT1''), that pumps the neurotransmitter dopamine out of the synaptic cleft ba ...

(DAT) gene, and manganese superoxide dismutase (MnSOD) gene. Tardive dyskinesias are chronic compared to acute dystonia, which occur in an episodic fashion.

Causes

Pisa syndrome is predominantly caused by a prolonged administration or an overly dosed administration of

. Although antipsychotic drugs are known to be the main drugs that are concerned with this syndrome, several other drugs are reported to have caused the syndrome as well. Certain antidepressants,

psychoactive drugs A psychoactive drug, psychopharmaceutical, mind-altering drug, consciousness-altering drug, psychoactive substance, or psychotropic substance is a chemical substance that alters psychological functioning by modulating central nervous system acti ...

, and

antiemetics An antiemetic is a drug that is effective against vomiting and nausea. Antiemetics are typically used to treat motion sickness and the side effects of opioid analgesics, general anaesthetics, and chemotherapy directed against cancer. They may be ...

have also been found to cause Pisa syndrome in patients. Drugs found to have caused Pisa Syndrome: * Atypical antipsychotic drugs- ex.

clozapine Clozapine, sold under the brand name Clozaril among others, is a psychiatric medication and was the first atypical antipsychotic to be discovered. It is used primarily to treat people with schizophrenia and schizoaffective disorder who have ...

aripiprazole Aripiprazole, sold under the brand name Abilify, among others, is an atypical antipsychotic primarily used in the treatment of schizophrenia, bipolar disorder, and irritability associated with autism spectrum disorder; other uses include as ...

Tricyclic antidepressants Tricyclic antidepressants (TCAs) are a class of medications that are used primarily as antidepressants. TCAs were discovered in the early 1950s and were marketed later in the decade. They are named after their chemical structure, which contains ...

- ex.

clomipramine Clomipramine, sold under the brand name Anafranil among others, is a tricyclic antidepressant (TCA). It is used in the treatment of various conditions, most notably obsessive–compulsive disorder but also many other disorders, including hyper ...

* Psychoactive drugs * Antiemetic drugs * Cholinesterase inhibitorsCossu et al., 2004 G. Cossu, M. Melis, G. Melis, E. Maccioni, V. Putzu, O. Catte, PF. Putzu, Reversible Pisa syndrome (pleurothotonus) due to the cholinesterase inhibitor galantamine: case report. Department of Neuroscience, Oct;19(10):1243-4. * Galantamine Based on the drugs that caused Pisa syndrome, it has been implicated that the syndrome may be due to a dopaminergic-cholinergic imbalance or a serotonergic or noradrenergic dysfunction. For the development of Pisa syndrome that cannot be alleviated by anticholinergic drugs, it has been considered that asymmetric brain functions or neural transmission may be the underlying mechanism. How these drugs interact with the biochemistry of the brain to cause the syndrome is unknown and a topic of current research.

Risk factors

Typically, females and older patients with organic brain changes are more likely to develop Pisa syndrome. Organic brain changes are physical changes in the brain which lead to neurological dysfunction, including dementia and frontal lobe syndrome. This includes the presence of neurodegenerative illnesses such as

Alzheimer's disease Alzheimer's disease (AD) is a neurodegenerative disease and the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As the disease advances, symptoms can include problems wit ...

and

Parkinson's disease Parkinson's disease (PD), or simply Parkinson's, is a neurodegenerative disease primarily of the central nervous system, affecting both motor system, motor and non-motor systems. Symptoms typically develop gradually and non-motor issues become ...

Diagnosis

Treatment and Medication

There are two lines of treatment for Pisa syndrome. The first line entails discontinuation or reduction in dose of the antipsychotic drug(s). The second line of treatment is an

anticholinergic Anticholinergics (anticholinergic agents) are substances that block the action of the acetylcholine (ACh) neurotransmitter at synapses in the central nervous system, central and peripheral nervous system. These agents inhibit the parasympatheti ...

medication. A

pharmacological therapy Pharmacotherapy, also known as pharmacological therapy or drug therapy, is defined as medical treatment that utilizes one or more pharmaceutical drugs to improve ongoing symptoms (symptomatic relief), treat the underlying condition, or act as a p ...

for Pisa syndrome caused by prolonged use of antipsychotic drugs has not been established yet.Suzuki et al., 2002 T. Suzuki, H. Matsuzaka, et al. Drug-induced Pisa syndrome (pleurothotonus): epidemiology and management. Department of Psychiatry, 16(3) (2002), pp. 165-74.

Reduction of drug dosage

Reducing the dosage of the antipsychotic drugs resulted in gradual improvement in the abnormal posture. In some cases, discontinuing the use of those drugs resulted in complete disappearance of the syndrome. The time it took for the improvement and the disappearance of the syndrome depended on the type of drug being administered or the specific cause of the syndrome itself.

Anticholinergic drugs

Anticholinergic drugs have been reported to be extremely effective in 40% of the patients with the Pisa syndrome. Patients with Pisa syndrome that is resistant to anticholinergic drugs is mostly resolved by the reduction of the administration of the antipsychotic drugs as previously mentioned. While the specific pathology underlying idiopathic Pisa syndrome is unknown, the administration of anticholinergic drugs has provided resolution in known cases.

History

Pisa syndrome was discovered by Karl Axel Ekbom, a Swedish neurologist, in the early 1970s. Cases of the syndrome were first observed in three elderly female patients with presenile dementia. Each of these women were undergoing treatment with the antipsychotic drug methylperone,

haloperidol Haloperidol, sold under the brand name Haldol among others, is a typical antipsychotic medication. Haloperidol is used in the treatment of schizophrenia, tics in Tourette syndrome, mania in bipolar disorder, delirium, agitation, acute psychos ...

or a combination of the two. The use of neuroleptic drugs caused the patients to exhibit a lateral flexion along with a rotation of the trunk. As the patients walked they experienced an increase in rotation. The postural and gait disturbances symptoms is what set this apart from any other form of acute dystonia previously observed. These symptoms proved to be the making of a new dystonic reaction, which was termed pleurothotonus or Pisa syndrome.K. Ekbom, H. Lindholm and L. Ljungerberg, New dystonic syndrome associated with butyrophenone therapy. Z Neurol, 202 (1972), pp. 94–103. The first patient, a 59-year-old woman with no family history of neuroleptic disease, was put through two periods of treatment with methylperone. The first trial of the drug was administered in February 1971. In the beginning the patient demonstrated no symptoms of dystonia. However, within the first few days the patient began to exhibit a tilting to right upon walking. The women was then taken off the methylperone treatment and as a result progressively regressed back to her previous state of exhibiting no symptoms within the first two months. The patient started a second trial of methylperone treatment in late October 1971. After a little over a week of the drug treatment, she began to express previous symptoms that including a bending of the trunk towards the right along with a rotation. The patient also experienced a pulling away from her direction of walking and a difficulty of turning. Within a couple of days of exhibiting symptoms, the patient was then treated with

orphenadrine Orphenadrine (sold under many brand names) is an anticholinergic drug of the ethanolamine antihistamine class; it is closely related to diphenhydramine. It is a muscle relaxant that is used to treat muscle pain and to help with motor control in ...

. This treatment helped regress the expressed symptoms quicker than the first time. By the end of the week the patient was able to return to her normal state. The second patient to undergo methylperone treatment was a 63-year-old woman with presenile dementia, which caused her to experience restlessness and paranoid hallucinations. The methylperone treatment was able to alleviate the woman's problems induced by her dementia. It did not take long for the woman to begin to experience symptoms of Pisa syndrome and as a result she was taken off of the methylperone treatment. Like the first patient, she was able to overcome the induced symptoms of Pisa syndrome within a month. The patient was again treated with methylperone after two months from the first treatment. Soon after the patient began to lean toward the right when standing or walking. She was then administered orphenadrine, which soon stopped the patient's tilting posture. The final patient was a 69-year-old woman, diagnosed with presenile dementia after she expressing symptoms of memory dysfunction, depression and

urinary incontinence Urinary incontinence (UI), also known as involuntary urination, is any uncontrolled leakage of urine. It is a common and distressing problem, which may have a significant effect on quality of life. Urinary incontinence is common in older women ...

. As a result, the woman was put under a methylperone treatment, which soon caused a bending and rotation to her left. These symptoms disappeared soon after being taken off of methylperone. Unlike the other two patients, when the woman was again administered methylperone she did not exhibit any previous dystonic symptoms after two weeks of treatment. The patient was then switched to a small dosage of haloperidol along with the typical dosage of orphenadrine used on the previous patients. Instead of not having symptoms of Pisa syndrome, the woman began to experience a leaning to her left side and a particular rotation of her shoulder towards the left. Once haloperidol was eliminated from the treatment the patient no longer had these symptoms. As more cases of the syndrome came about, research discovered that the switching of drug treatments can be debated as a possible inducer of the disease. Other cases of the disease have been proven to be caused by medications other than neuroleptic drugs. These patients were observed exhibiting symptoms of Pisa syndrome as a result of having a prior neurodegenerative disease.

Further research

Current research has been focusing on discovering the underlying mechanisms of Pisa syndrome, since little is known about the biological and pharmacological reasons Pisa syndrome occurs (although theories about dopaminergic dysfunction have been suggested). While Pisa syndrome is mostly associated with antipsychotic drugs, there have been incidents of idiopathic Pisa Syndrome, the development of Pisa syndrome in those with other neurological disorders, and Pisa syndrome in those with intellectual disability.Ulhaq, Inam, et al. Case Report: Pisa Syndrome in Patients with Intellectual Disability. Mental Health and Learning Disabilities: Research and Practice. 2010, v.7, pg. 59-63. Future research aims to pinpoint the essential

neurological disorder Neurological disorders represent a complex array of medical conditions that fundamentally disrupt the functioning of the nervous system. These disorders affect the brain, spinal cord, and nerve networks, presenting unique diagnosis, treatment, and ...

or disorders underlying the development of Pisa syndrome so more that more effective medication and treatment may be created and/or administered.

References

{{reflist Neurological disorders Antipsychotics Aging-associated diseases