User:Fowlerta/Klazomania draft

History
The word "klazomania" comes from the Greek "klazo", meaning to scream. The term was coined by L. Benedek in 1925 when he witnessed bouts of compulsive shouting in a patient with postencephalitic parkinsonism. He reported that the attacks would last for up to several hours and seemed to be outside of the patient’s control. He characterized the shouting as extremely loud, noting that it could be in the form of syllables, vowels or even animal noises. In addition, he observed that while the nature of the shouting could suggest that the patient was in pain, the sounds themselves were unrelated to any physical discomfort. He also stated that the patient appeared to have the ability to anticipate an attack and could even prevent it through deep and rapid breathing. However, he noted that the effort required to suppress an attack could be even more tiring than enduring an attack itself. Finally, he reported that though anxiety could increase the frequency of attacks, it did not affect the overall presentation.

Two of Benedek’s colleagues, E. Von Thurzó and T. Katona, recorded two further instances of klazomania in 1927. They expanded upon Benedek’s earlier observations, describing the angry flushed face of the sufferer, as well as the patient’s extreme restlessness and agitation. Furthermore, they noted that at the end of an attack, the patient expressed their apologies over the incident, suggesting that are cognizant of the attack. From this, Thurzó and Katona proposed that there is no loss of consciousness during an attack and that the patient remains fully aware of their surroundings.

In 1961, Gunnar Wohlfart et al. reported a case of klazomania accompanied by oculogyric crises, another symptom of postencephalitic Parkinsonian syndrome. The patient, a postman known as K.R., contracted encephalitis lethargica at the age of 12. While he reported no significant ill effects from the disease, he was irritable and complained of fatigue for years after recovering. At 22, the patient received a head injury, though he did not sustain a concussion or cranial fracture from the incident. However, six months later, he developed oculogyric spasms, as well as dyskinesias of the mouth and tongue. In 1957, at the age of 44, the patient experienced his first bout of klazomania while working in the post office. He shouted for about half an hour and appeared "crazy" for hours after the shouting ended. The patient remained conscious for the entire incident. The next day, he felt better, though he did report being tired. The patient continued to suffer from the attacks for the next few years before coming under observation of Wohlfart et al. He subsequently served as a model to describe an attack of klazomania from beginning to end.

As seen in K.R., the onset of an attack was characterized by absentmindedness. The patient stared straight ahead and only responded in monosyllables in the minutes leading up to an attack. An oculogyric spasm then developed, during which he demonstrated echolalia. After 15 minutes, further motor symptoms arose, with the patient making small jerky motions with his arms that developed into larger, circular movements. At 20 minutes, the attack reached its peak, with the patient becoming bright red and making large compulsive movements with his arms and kicking his legs. He began swearing, shouting, screaming, grunting and barking loudly, with intermittent bouts of heavy panting. He remarked upon the people present, with his comments being related to the situation in question. Furthermore, he attempted at times during the attack to excuse his behavior. At the end of the attack, the patient was able to provide an account of what had happened. Wohlfart et al. concluded that the patient was aware of his surroundings during the attack, with the patient even expressing concern over missing a scheduled appointment. The patient demonstrated some ability to control his behavior during an attack when spoken to in a sharp tone, but he would inevitably return to his shouting and movements after a few seconds of stillness. The attack was accompanied by salivation, sweating, and tachycardia. Overall, the peak of the attack lasted 30 minutes. The intensity then started to subside, though the patient presented with intermittent remissions. The entire attack lasted an hour and a half from its onset.

Klazomania was proposed to be associated with chronic alcohol abuse and carbon monoxide poisoning in 1996. Gordon D. L. Bates et al. reported on a 63-year-old who was admitted to a psychiatric hospital with a two-year history of sudden episodes of shouting. He claimed to have no memory of the attacks, which he could anticipate by a few seconds. The attacks were characterized by shouting of "aagh" or "help" and he was reported to appear angry during the incidences. At the end of the outbursts he would appear surprised, though he was able to continue a conversation. The patient remained fully oriented between attacks. The attacks themselves occurred at a frequency of one or two a month, generally taking place in the evening. They got progressively worse from the time of their first presentation.

Symptoms
Klazomania presents symptoms similar to other complex tics including echolalia, palilalia and coprolalia. It is characterized by compulsive shouting, which can be in the form of swearing, grunting or even barking. The subject generally appears angry during these attacks, which can strike with increasing frequency if the patient is agitated. The duration of the attack depends on the individual in question, but it can be characterized by a peak period, followed by intermittent remissions of less intensity. Although the patient may sound like they are in pain, there does not appear to be any actual physical discomfort. The shouting can be accompanied by a number of additional symptoms, such as oculogyric crises or other involuntary movements. Overall, klazomania is comparable to psychomotor epilepsy, though the two can be distinguished by the duration of the attack and the fact that the patient appears to retain consciousness during a klazomaniac attack.

Causes
Although the cause of klazomania is still unknown at this time, researchers have hypothesized that klazomania is caused by an irritating lesion in the mesencephalon. It is believed that there is a malfunction in the control of the motor circuit from the substantia nigra in the mesencephalon to the globus pallidus in the striatum (mesostraital pathway). This circuit becomes overstimulated during a mesencephalic "fit", which could be caused by tumors in the posterior fossa comprised of the cerebellum, medulla, and pons. Researchers have noticed changes in the substantia nigra and the globus pallidus via an EEG of patients with klazomania. The mesostriatal pathway involving the substantia nigra and the globus pallidus are both dopaminergic pathways, and therefore it is believed that dopamine is one of the main neurotransmitters involved in the cause of klazomania. This belief is corroborated by the fact that dopamine antagonists, such as haloperidol, alleviate the symptoms of klazomania by blocking dopamine activity. Other brain abnormalities discovered with an EEG include slight cortical atrophy and a marginally enlarged lateral ventricle.

One hypothesis researchers have produced is that klazomania originates in the periaqueductal gray matter in the mesencephalon (4). The study proved that the vocalizing center in animals is located in the periaqueductal gray matter and a klazomania-like episode involving grunts and animal sounds can be evoked by electrical stimulation of this region. This phenomenon can be linked back to klazomania if it can be proved that humans also possess this vocalizing center.

Researchers have also hypothesized that the stimulation of the autonomic nervous system by the posterior hypothalamus is involved in klazomania. They believe that the actions produced during a klazomania attack resemble sham rage in animals, which is controlled by stimulation of the sympathetic nervous system. During an attack, a person may experience pupil dilation, tachycardia, salivation, increased blood pressure, retraction of lips, barking, grunting, and rage just as an animal would if presenting sham rage.

Studies have also shown that klazomania is very similar to disorders such as Tourette's syndrome and obsessive-compulsive disorder, which all involve tics and compulsions. Tics and compulsions are dysfunctions in self-regulatory control of habitual behaviors. Tics and compulsions are controlled by cortical striatal thalamic cortical circuits (CSTC circuits). The prefrontal cortex projects to the globus pallidus and caudate nucleus in the striatum, which projects to the thalamus, and finally back to the primary motor cortex to generate a behavior. The prefrontal cortex normally controls the stimulation and inhibition of the striatum and its motor output. However, the dysfunction of this fronto-striatal circuit leads to tics and compulsions because the prefrontal cortex cannot efficiently inhibit motor behaviors. There are two pathways that make up the CSTC circuits. The direct pathway originates in the cortex, which sends an excitatory signal to the neurons with D1 receptors (dopamine receptors) in the striatum. The striatum sends gabaergic input to the globus pallidus interna and the substantia nigra, which disinhibits the inhibitory signal sent to the thalamus. The thalamus then sends a disinhibited excitatory signal to the primary motor cortex in the frontal cortex and produces an involuntary motor movement, like excessive screaming in klazomania or any other tic. The indirect pathway also begins in the cortex, where the excitatory neurons synapse on the neurons in the striatum, which have D2 dopamine receptors. When overactivated, these D2 receptors cause less inhibition by the gabaergic neurons projecting from the striatum. Therefore, these neurons are disinhibited. These disinhibited neurons then send a weaker inhibitory gabaergic signal to the globus pallidus externa, which send a stronger inhibitory signal to glutamatergic neurons in the subthalamic nuclei. These glutamatergic neurons are more inhibited and send a weaker excitatory signal to the gabaergic neurons in the globus pallidus interna and the substantia nigra. These structures then cannot inhibit the thalamus as well and therefore cannot inhibit the motor output the thalamus sends to the primary motor cortex. The overstimulation of the cortex in both of these pathways leads to the expression of tics and compulsions, and possibly klazomania. The stimulation of these same circuits are also probably the cause of other complex phonic tics such as echolalia, palilalia, lexilalia, and coprolalia.

Finally, alcoholism and infections such as encephalitis have often been accompanied by phonic tics and occasionally klazomania. It is hypothesized that the cause of klazomania is linked to the brain damage due to alcoholism or encephalitis.

Related Disorders
Klazomania is a tic, and therefore it shares many similarities in neural activity with other tics. Tics are performed in response to some sensory perception. Asperger's syndrome and Tourette's syndrome are disorders where tics are symptomatic of the condition.

Compulsions are a result of an obsessive thought that brings mental anxiety if the thought is not acted upon. Compulsions and complex tics, such as klazomania, are difficult to differentiate from each other and share some similar neural pathophysiology. Disorders where compulsive behavior is exhibited are obsessive-compulsive disorder and autism.

Using fMRI neuroimaging researchers have identified areas of the brain that are activated prior to and during the onset of simple tic activities. Researchers coordinated fMRI scans with the exhibition of tics and found that there was activation of paralimbic networks involving anterior cingulate cortex, insular cortex, and the parietal operculum prior to tic onset. The strong activation of paralimbic areas and parietal operculum preceding tics in the present study suggests the role of this network as a potential source for the uncomfortable feelings associated with urges of tics.

Using event-related [15O]H2O positron emission tomography techniques researchers identified brain activity was significantly correlated with tic occurrence in prerolandic and postrolandic language regions, anterior cingulate cortex, insula, caudate, thalamus, and cerebellum for patients with the vocal tic coprolalia. Aberrant in these regions may account for the initiation and execution of the vocal behaviors that characterize the tic, as well as for the urge that accompanies it.

Future studies may clarify whether other subtypes of tics and compulsions are generated differentially in these brain networks.

Treatment
A variety of drug therapies have been used to treat the symptoms of klazomania. Atropine sulfate is a potent anticholinergic drug that inhibits the action of acetylcholine at postganglionic parasympathetic neuroeffector sites. In large doses, it acts as a successful treatment for klazomania by controlling the involuntary movements associated with klazomania. Attempts to treat klazomania with a combination of phenobarbital and trihexyphenidyl (also known as Artane) have also been made. Phenobarbital acts as an anticonvulsant and is generally used to treat seizures, while Artane is used to treat involuntary movements in Parkinson’s disease. However, the combination was found to have no beneficial effect. Finally, antipsychotic drugs have been shown to be useful in suppressing the tics associated with Tourette's syndrome, even if psychosis is not the cause, and could be beneficial in treating klazomania. Similarly, deep brain stimulation has been tested as an experimental treatment for Tourette’s syndrome when symptoms of the disorder are too severe to be treated by drugs. Electrodes are positioned in the areas of the brain that are believed to be involved in the expressed tics. Sufferers of klazomania could potentially benefit from a comparable treatment. Behavioral therapy has been examined as a form of treatment as well. However, for the most part, such therapies have not been evaluated.

Current Research
While klazomania is associated with other complex phonic tics, the most relatively recent research focused on the disease has suggested that the rare brain inflammatory disease encephalitis lethargica; and only a few individuals diagnosed with encephalitis lethargica placed under research observation, have exhibited klazomaniac symptoms. In fact, the most recent research study by Howard RS et al. in 1987 on individuals exhibiting klazomaniac symptoms was done with the intention of studying the involvement of the cerebral cortex in encephalitis lethargica, and it was noted during the process of the study that as was observed in the study by Wolfhart G et al. and Benedek et al. in his original study on klazomania (see History section), individuals suffering from encephalitis lethargica also exhibited compulsive shouting (along with other behavioral disorders) as an apparent result of this neurological disease.

Current research on klazomania is scarce for many different reasons. One reason is that the only diagnostic tool for physicians to attribute a phonic tic disorder to a patient is the presence of the tic, there currently exist no set protocols for diagnosing these disorders as there are for most medical illnesses. The diagnosing physician takes into account the entire clinical history and overall summation of life events of an individual showing symptoms of phonic tics. However, as these vary greatly from patient to patient and often exhibit much overlap between the various tics, it may be difficult to establish a group of individuals on which to conduct research in the case of phonic tics, and particularly in the case of klazomania since there have been so few documented cases (see History section). In addition, the difficulty of accessing the brain and obtaining uncontaminated and undamaged post-mortem brains harvested from organ donors complicates the task of studying any disease of the brain, especially one as rare as klazomania. Also, the demand for research for klazomania may not be as high due to the relatively few cases of the disease recorded, and further discouraged due to the overlap of klazomania symptoms with Tourette’s syndrome and other more common phonic tic disorders. Finally, difficulties in the passage of drugs through the blood brain barrier makes studying treatment possibilities for klazomania challenging.

Although specific current research on compulsive shouting is scarce, there are many ongoing studies and potential future studies on Tourette's syndrome and other similar neurological disorders associated with complex phonic tics and behavioral compulsions similar to those of klazomania. Most of the government funded research on this disease and other similar neurological diseases is supported and conducted by the National Institute of Neurological Disorders and Stroke (NINDS), which is a portion of the National Institute of Health (NIH). These research methods include mostly clinical trials, neuroimaging] studies, post-mortem brain [[autopsy, genome screening, and epidemiological studies . For example, current areas of focus include the potential use of stimulants used to treat ADHD in children as a possible treatment for Tourette's syndrome and to reduce frequency and severity of tics, the possible role of the autoimmune response to brain injury in Tourette's syndrome, and discovering any genetic risk factors for the disease .  Similar research methods could potentially be applied to klazomania, but such research currently does not appear to be in progress.