Vertigo 2008

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  • Vertigo can be objective or subjective The illusion of movement can manifest in two ways. In objective vertigo, the patient perceives the environment moving as they are stationary. In subjective vertigo, the patients perceives that they are moving in a stationary environment. References Mukherjee A, Chatterjee SK, Chakravarty A. Vertigo and dizziness – a clinical approach. JAPI 2003;51:1095-101. Salvinelli F, Firrisi L, Casale M, et al. What is vertigo? Clin Ter 2003;154:341–8.
  • Vertigo is one of four types of dizziness Dizziness can be described as abnormal sensations relating to a person’s perception of their body in the environment (Drachman & Hart 1972, Sloane et al 2001). In their influential paper of 1972, Drachman and Hart described four different types of dizziness. These classifications of dizziness subtypes, listed below, are still used today. Vertigo – an illusion of movement typically characterized by feelings of rotation Presyncope – a feeling of impending faint Disequilibrium – a feeling of unsteadiness, particularly in the lower body, without sensations in the head. It is worse when standing or walking, and is alleviated by sitting down. Other subtypes – other feelings of dizziness not encompassed by the preceding definitions. Drachman and Hart described this type of dizziness as ‘ill-defined light-headedness’. People have since suggested that this category can include sensations of swimming or floating or feelings of dissociation. Patients falling into this category often have difficulty describing their symptoms. References Drachman DA, Hart CW. An approach to the dizzy patient. Neurology 1972;22:323–34 Sloane PD, Coeytaux RR, Beck RS, Dallara J. Dizziness: State of the Science. Ann Intern Med 2001;134:823–32.
  • Etiology of vertigo can be broadly classified into central and peripheral. Peripheral causes include all causes of labyrinthine dysfunction such as infection, BPPV, Meniere’s disease, trauma, ischemia, infarction, perilymph fistula, and drug toxicity. Central causes include all causes of central vestibular dysfunction such as physiological vertigo, demyelination as in multiple sclerosis, posterior fossa mass lesions, and vertebrobasilar insufficiency as in stroke.
  • Spatial orientation and posture is dependant on three sensory systems: the vestibular, the visual, and the somato-sensory systems. Vertigo results from a disturbance in any of these 3 systems. The most common cause of vertigo is disturbances in the vestibular system, which is made up of 3 semi-circular canals and 2 otolith organs. The semi-circular canals transduce angular acceleration and the otolith organs transduce linear acceleration and static gravitational forces. Endolymph movement, depending on the direction of flow and deflection of otoliths by gravity, either stimulates or inhibits neuronal output from the hair cells present in the semi-circular canals and otoliths. Nerve impulses are transmitted from the vestibular system to the vestibular nuclei in the brain stem and cerebellum through the 8th cranial nerve. From here connections are made to the oculomotor system, spinal cord, and cerebral cortex, which integrate the information to produce the perception of motion. Lesions anywhere along this pathway can result in vertigo.
  • Acetylcholine is an excitatory neurotransmitter in the central and peripheral pathways. Vertigo and motion sickness are often treated with anticholinergic drugs that inhibit the muscarinic receptors. Glutamate is the principal excitatory neurotransmitter in the brain. It maintains the resting discharge of the central vestibular neurons and appears to modulate the synaptic transmission in the vestibulo-ocular reflex arc. GABA is usually inhibitory in the peripheral and central nervous system and is thought to be inhibitory for the commissures of the medial vestibular nucleus.
  • The most common complaint is that of dizziness or sensation of movement. This can be subjective, where the patient feels a false sense of movement, or objective, where the surroundings appear to move. Vertigo due to central causes are usually chronic and accompanied by symptoms such as nausea, vomiting, headache, abnormal eye movements, weakness, and unsteady gait. Vertigo of vestibular nerve origin is commonly associated with auditory symptoms such as tinnitus and hearing loss. Vertigo due to peripheral causes can last for a few minutes, days, or weeks and is usually recurrent.
  • Vertigo episodes are debilitating and are more than just a sensation of movement Vertigo episodes are characterised by feelings of movement, usually rotation , of varying intensity. The onset of these episodes can be sudden or gradual , and their duration is usually dependent on the underlying cause. Vertigo often results in confinement to bed, and is frequently accompanied by nausea, vomiting and anxiety . Nystagmus (involuntary movement of the eyeball) may also be present. References Baloh RW. Vertigo. Lancet 1998;352:1841–6. Mukherjee A, Chatterjee SK, Chakravarty A. Vertigo and dizziness – a clinical approach. JAPI 2003;51:1095-101. Salvinelli F, Firrisi L, Casale M, et al. What is vertigo? Clin Ter 2003;154:341–8.
  • Vertigo is a continuous burden Patients who suffer from vertigo episodes also report a number of symptoms and negative emotions between episodes . These include headaches, instability and general malaise . Because of the unpredictable nature of vertigo crises, patients may also be fearful of the onset of the next episode, which may lead to generalised anxiety. Together these symptoms, along with the usually chronic nature of vertigo, means that vertigo patients often report reduced quality of life. References Fielder H, Denholm SW, Lyons RA, Fielder CP. Measurement of health status in patients with vertigo. Clin Otolaryngol 1996;21:124–6. H ä gnebo C, Melin L, Larsen HC, Lindberg P, Lyttkens L, Scott B. The influence of vertigo, hearing impairment and tinnitus on the daily life of Meniere patients. Scand Audiol 1997;26:69–76. Lopez-Escamez JA, Lopez-Nevot A. Prevalence of headaches and medication use in patients with recurrent vertigo. Acta Otorrinolaringol Esp 2000;51:377–82. Mendel B, Bergenius J, Langius A. Dizziness symptom severity and impact on daily living as perceived by patients suffering from peripheral vestibular disorder. Clin Otolaryngol Allied Sci 1999;24:286–93. Monzani D, Casolari L, Guidetti G, Rigatelli M. Psychological distress and disability in patients with vertigo. J Psychosom Res 2001;50:319–23. Salvinelli F, Firrisi L, Casale M, et al. What is vertigo? Clin Ter 2003;154:341–8.
  • Vertigo can have a negative impact on quality of life Vertigo can be a severely incapacitating disease, with a significant impact on quality of life , as demonstrated in this study. Patients (n = 67) with vertigo, dizziness or giddiness were asked to complete the short form health survey (SF-36), which assesses eight quality of life parameters; completed questionnaires were returned by 42 patients. The scores were transformed into a scale of 0–100 with higher scores indicating better health. The results were compared with population norms (n = 517–532; the number of subjects differed for each parameter), weighted for groups of similar age and gender. This comparison showed that quality of life was significantly affected by vertigo . Women with vertigo rated seven of the eight dimensions lower than the population norm (p = 0.035). Individual analyses of each parameter showed that limitations in role due to physical problems and vitality were particularly affected (p < 0.05 vs population norm). Men with vertigo scored lower than the population norm on all eight parameters (p = 0.004). Again, particular problems were noted in terms of role limitations due to physical problems; social functioning was also adversely affected (p < 0.05 vs population norm). The SF-36 is also frequently used to assess quality of life in other disorders. While limitations are noted in comparing data from different studies, a preliminary inspection of the available data suggest that vertigo disrupts quality of life to a similar or greater extent than several other chronic diseases including cystic fibrosis (Gee et al 2002), diabetes (Ohsawa et al 2003), and allergic rhinitis (Bousquet et al 1994). References Bousquet J, Bullinger M, Fayol C, Marquis P, Valentin B, Burtin B. Assessment of quality of life in patients with perennial allergic rhinitis with the French version of the SF-36 Health Status Questionnaire. J Allergy Clin Immunol 1994;94:182–8. Fielder H, Denholm SW, Lyons RA, Fielder CP. Measurement of health status in patients with vertigo. Clin Otolaryngol 1996;21:124–6. Gee L, Abbott J, Conway SP, Etherington C, Webb AK. Validation of the SF-36 for the assessment of quality of life in adolescents and adults with cystic fibrosis. J Cyst Fibros 2002;1:137–45. Ohsawa I, Ishida T, Oshida Y, Yamanouchi K, Sato Y. Subjective health values of individuals with diabetes in Japan: comparison of utility values with the SF-36 scores. Diabetes Res Clin Pract 2003;62:9–16.
  • Vertigo can be of central or peripheral origin Vertigo can result from a diverse range of aetiologies, originating centrally or peripherally . Central causes of vertigo involve structures within the central nervous system (cerebrum, cerebellum, brainstem or connecting white matter) that process information from the vestibular system and other areas involved in balance. Peripheral causes of vertigo involve dysfunction in areas that are not part of the central nervous system , for example, the inner ear. Central causes of vertigo are unusual (Hain & Uddin 2003); peripheral causes are more common. References Baloh RW. Vertigo. Lancet 1998;352:1841–6. Hain TC, Uddin M. Pharmacological Treatment of Vertigo. CNS Drugs 2003;17:85–100. Mukherjee A, Chatterjee SK, Chakravarty A. Vertigo and dizziness – a clinical approach. JAPI 2003;51:109–101. Puri V, Jones E. Childhood vertigo: a case report and review of the literature. J Ky Med Assoc 2001;99:316–21. Salvinelli F, Firrisi L, Casale M, et al. What is vertigo? Clin Ter 2003;154:341–8. Strupp M, Arbusow V. Acute vestibulopathy. Curr Opin Neurol 2001;14:11–20.
  • Vertigo of peripheral origin: causes Peripheral causes of vertigo typically involve the structures of the inner ear Benign paroxysmal positional vertigo : probably the most common cause of vertigo (e.g., Toupet et al 2003). It is characterised by brief, position-provoked vertigo episodes usually caused by freely floating particles in the semicircular canal (Parnes et al 2003). Meniere’s disease : Accounting for 10–15% of vertigo cases (Mukherjee et al 2003), Meniere’s disease is often associated with hearing loss and tinnitus, and is usually chronic. Meniere’s disease occurs in the vestibular system and appears to result from distention of the membranous labyrinth and an excess of endolymph. Patients often complain of a feeling of fullness or pressure in the ear (Baloh 1998). Vertigo episodes may result from reversible mechanical dysfunction or from ruptures in the membrane separating the endolymph and perilymph. Vestibular neuronitis : refers to inflammation of the vestibular nerves, that may be the consequence of a virus, or have an ischaemic cause. (Strupp & Arbusow 2001). This type of vertigo is accompanied by nausea, vomiting and disequilibrium. Patients may present with a deep, burning ear pain. Acute labyrinthitis : inflammation of the labyrinth due to viral or bacterial infection. It often follows infections such as acute otitis media, chicken pox, mumps or measles. Labyrinthine infarct : The blood supply to the inner ear originates in the vertebrobasilar system. Infarct or haemorrhage in this system compromises blood flow to the labyrinthine and has a profound effect on labyrinthine function. Labyrinthine concussion : damage to the labyrinthine may occur after head trauma. Perilymph fistula : Leakage of the perilymph from the inner to the middle ear can result following damage to the labyrinth membranes. Such damage may result from head trauma, cholesteatoma, or a pressure altering event (Baloh 1998, Strupp & Arbusow 2001). Autoimmune inner ear disease : in some rare cases autoimmune disorders destroy inner ear cells, which may lead to hearing loss and/or vertigo. The autoimmune disease may only target the inner ear, or the inner ear damage may be a feature of a systemic disorder (Baloh 1998). References Baloh RW. Vertigo. Lancet 1998;352:1841–6. Mukherjee A, Chatterjee SK, Chakravarty A. Vertigo and dizziness – a clinical approach. JAPI 2003;51:109–101. Parnes LS, Agrawal SK, Atlas J. Diagnosis and management of benign paroxysmal positional vertigo (BPPV). CMAJ 2003;169:681– 93. Puri V, Jones E. Childhood vertigo: a case report and review of the literature. J Ky Med Assoc 2001;99:316–21. Salvinelli F, Firrisi L, Casale M, et al. What is vertigo? Clin Ter 2003;154:341–8. Strupp M, Arbusow V. Acute vestibulopathy. Curr Opin Neurol 2001;14:11–20. Toupet M, Rothoft J, Bremaud des Ouilleres L. Prise en charge des plaintes vertigineuses en ORL de ville. Rev SFORL 2004;83:57–63.
  • Vertigo of central origin: causes Central causes of vertigo originate in the central nervous system Migraine : vertigo may occur separately or with migraines; migraines are one of the most common central causes of vertigo Vascular disease : ischaemia in the vertebrobasilar system can lead to infarction in the brain stem or cerebellum. The resultant reduced blood supply to these areas can result in vertigo symptoms. It should be noted that cerebrovascular disease can also cause peripheral infarctions (structures in the inner ear each have their own blood flow which also originates in the vertebrobasilar arterial system), or a combination of peripheral and central infarctions may occur. Multiple sclerosis : vertigo may be the presenting feature of multiple sclerosis in approximately 5% of cases, and 50% of patients with multiple sclerosis are likely to suffer from vertigo during the course of their disease (Solomon 2000) Vestibular epilepsy : a rare cause of vertigo related to focal epileptic discharges in the temporal or parietal association cortex (Strupp & Arbusow, 2001) Cerebellopontine tumours : a rare cause of vertigo, these are most often benign tumours in the internal auditory meatus. References Baloh RW. Vertigo. Lancet 1998;352:1841–6. Mukherjee A, Chatterjee SK, Chakravarty A. Vertigo and dizziness – a clinical approach. JAPI 2003;51:109–101. Salvinelli F, Firrisi L, Casale M, et al. What is vertigo? Clin Ter 2003;154:341–8. Solomon D. Distinguishing and treating causes of central vertigo. Otolaryngol Clin North Am 2000;33:579–601. Strupp M, Arbusow V. Acute vestibulopathy. Curr Opin Neurol 2001;14:11–20.
  • Distinguishing peripheral and central peripheral causes of vertigo Vertigo can result from peripheral or central dysfunction. While the overall presenting symptom (e.g., an illusion of rotation) may be the same regardless of the cause, a number of features can provide an indication as to the location of the specific dysfunction . For example, peripheral causes usually result in vertigo of a sudden onset , with nausea and vomiting commonly reported; neurological symptoms and changes in consciousness are rare . In contrast, vertigo due to central causes is more likely to have a gradual onset and a persisting duration accompanied by severe imbalance and other neurological symptoms . Identifying the underlying aetiology is paramount to appropriate management. References Baloh RW. Differentiating between peripheral and central causes of vertigo. Otolaryngol Head Neck Surg 1998;119:55–9. Puri V, Jones E. Childhood vertigo: a case report and review of the literature. J Ky Med Assoc 2001;99:316–21.
  • A nootropic drug has the following features: The enhancement of cognitive processes such as learning and memory Protection and restoration of cognitive abilities after cerebral insults Facilitation of interhemispheric flow of information and efficient tonic cortical/subcortical mechanism. Don't have any sedative or psychostimulant effect Piracetam is a cyclic derivative of GABA, and the first nootropic agent. Piracetam alleviates vertigo after head injury or vertigo of central origin. It also causes a significant decrease in the frequency and the severity of exacerbations in patients with chronic or recurrent vertigo.
  • Treating the cause: pharmacotherapy can eliminate some vertigo causes Once the cause of vertigo is known, treatment can be tailored accordingly . For example: Treatment for Meniere’s disease could involve restriction of salt intake to 1–2 g daily, diuretics (hydrochlorothiazide, acetazolamide), or more recently, transtympanic low-dose gentamicin is being increasingly used. Treatment for migraine could involve beta-blockers (propranolol 120–240 mg/day), calcium channel blockers (verapamil 120–240 mg/day), and tricyclic amines (nortriptyline 75–100 mg/day). Treatment for vertebrobasilar insufficiency or transient ischaemic attacks could involve aspirin 75–330 mg/day or ticlopidine 500 mg/day. References Baloh RW. Vertigo. Lancet 1998;352:1841–6. Goebel JA. Management options for acute versus chronic vertigo. Otolaryngol Clin North Am 2000;33:483–93.
  • Treating the cause: a simple particle repositioning manoeuvre effectively treats most BPPV cases BPPV is a common type of vertigo believed to be caused by canalithiasis or cupulolithiasis (Parnes et al 2003). Canalithiasis refers to freely moving particles within the endolymph of the semicircular canals, whereas cupulolithiasis describes particles adhered to the cupula within the ampulla. The presence of particles in the semicircular canals is understood to cause inappropriate stimulation of sensory hair cells, resulting in vertigo symptoms. Repositioning manoeuvres to alleviate BPPV increased in popularity in the 1980s (e.g., Brandt & Daroff, 1980). The aim of these manoeuvres is to return the offending particles to the utricle. One of the most commonly used procedures is based on the canalith repositioning manoeuvre, first described by Epley in 1992. This procedure involves moving the head sequentially through five positions while the patient is sedated and mechanical skull vibrations applied. Since this first report, a modified three-position manoeuvre is more typically used by physicians. This modified manoeuvre does not require sedation nor skull vibration, and is performed as follows: Seat patient Move the head into the hanging Dix-Hallpike position of the affected ear (position B); observe for nystagmus and maintain position for 1–2 minutes Turn head 90 º to the opposite Dix-Hallpike position, maintaining full extension of the neck (Position C) Roll the patient another 90º until head is diagonally opposite the first Dix-Hallpike position (Position D) Moving from position B, to C, to D should take less than 5 seconds Observe nystagmus (for the particles to be moving into the utricle, this nystagmus should be in the same direction as the nystagmus in Position ) Maintain position D for 30–60 seconds, then ask patient to sit up; if the manoeuvre is successful there should be no vertigo or nystagmus Traditionally, following repositioning manoeuvres, patients are instructed to remain upright for 48 hours to allow the particles to settle. However, recent evidence suggests that this may not be necessary; allowing patients to sleep or move as they wish following repositioning appears to have no effect on its outcome ( Massoud & Ireland 1996, Nuti et al 2000 ). Trials show that, on average, the revised Epley manoeuvre (or variants of it) is effective in around 80% of patients with BPPV . It should be noted that repositioning manoeuvres are not vestibular rehabilitation exercises as they work at a mechanical level to treat a cause of vertigo, rather than encouraging central neural compensation processes. References Brandt T, Daroff RB. Physical therapy for benign paroxysmal positional vertigo. Arch Otolaryngol 1980;106:484–5. Epley JM. The canalith repositioning procedure: for treatment of benign paroxysmal positional vertigo Otolaryngol Head Neck Surg 1992;107:399 Massoud EA, Ireland DJ. Post-treatment instructions in the nonsurgical management of benign paroxysmal positional vertigo. J Otolaryngol 1996;25:121–5 Nuti D, Nati C, Passali D. Treatment of benign paroxysmal positional vertigo: no need for postmaneuver restrictions. Otolaryngol Head Neck Surg 2000;122:440–4 Parnes LS, Agrawal SK, Atlas J. Diagnosis and management of benign paroxysmal positional vertigo (BPPV). CMAJ 2003;169:681– 93. Figure reprinted by permission of the publisher. © 2003 CMA Media Inc.
  • Treating the cause: surgery is appropriate in only a small fraction of vertigo patients Surgery is appropriate in only a small number of dizziness cases (<5%; Goebel 2000). For example, when vertigo is caused by a tumour, surgical removal of the tumour is likely to be the best option. Surgery can also be useful as a last resort in some cases of severe recurrent vertigo, but only when the dysfunctional ear can be clearly established. In these cases, surgery can be ablative or non-ablative, and may or may not cause hearing loss. For patients with uncontrolled Meniere’s disease or peripheral vestibulopathy, labyrinthectomy or vestibular nerve section may be useful. Labyrinthectomy destroys the offending labyrinthine and is accompanied by complete unilateral hearing loss. In contrast, selective section of the vestibular portion of the eighth nerve spares hearing in around 90% of cases. Non-ablative endolymphatic sac surgery may also be effective in uncontrolled Meniere’s disease, and posterior canal occlusion is reserved for patients with BPPV that is nonresponsive to canalith repositioning manoeuvres. With all these surgical techniques, it is important to ensure that vertigo is caused by peripheral damage as opposed to central dysfunction. References Goebel JA. Management options for acute versus chronic vertigo. Otolaryngol Clin North Am 2000;33:483–93. Salvinelli F, Firrisi L, Casale M, et al. What is vertigo? Clin Ter 2003;154:341–8.
  • Pharmacotherapy can help manage symptoms in the short term Pharmacotherapy can be either specific to the underlying cause (for example, for Meniere’s disease, migraine, and vertebrobasilar insufficiency) or aspecific. Aspecific drugs are useful in managing symptoms, regardless of their cause. These include: Vestibular suppressants – These drugs fall into three major classes: anticholinergics, antihistamines and benzodiazepines. Anticholinergics suppress neural activity in the vestibular nucleus (most antihistamines also have anticholinergic activity); benzodiazepines suppress central neurone activity by modulating GABA. Examples of vestibular suppressants include: meclizine (antihistamine, anticholinergic), dimenhydrinate (antihistamine, anticholinergic), and diazepam (benzodiazepine). Antiemetics – These drugs control nausea and vomiting. Examples include prochlorperazine (dopamine antagonist) or metoclopramide (dopamine antagonist that facilitates gastric emptying) These treatments do not address the underlying vertigo cause but can help control initial acute symptoms , or while patient is waiting further treatment or investigations, or if no underlying cause can be identified. These symptomatic treatments should be discontinued as soon as possible as they may interfere with vestibular compensation processes. References Baloh RW. Vertigo. Lancet 1998;352:1841–6. Hain TC, Uddin M. Pharmacological Treatment of Vertigo. CNS Drugs 2003;17:85–100.
  • Rehabilitation exercises can encourage vestibular adaptation and compensation In many cases of vertigo, effective recovery depends on adaptation and compensation in areas of the central nervous system that process information on balance and equilibrium. Central adaptation requires neural reorganisation, allowing the patient to compensate for vestibular damage. It is a slow process and, because it involves neural learning, its benefits are sustained after the rehabilitation programme is discontinued. With time, this process of neural reorganisation is likely to occur naturally. However, vestibular exercises aim to facilitate this process providing more rapid relief from vertigo symptoms. Vestibular suppressants should be discontinued during rehabilitation. References Baloh RW. Vertigo. Lancet 1998;352:1841–6. Goebel JA. Management options for acute versus chronic vertigo. Otolaryngol Clin North Am 2000;33:483–93. Konnur MK. Vertigo and vestibular rehabilitation. J Postgrad Med 2000;46:222–3. Mukherjee A, Chatterjee SK, Chakravarty A. Vertigo and dizziness – a clinical approach. JAPI 2003;51:1095–101.
  • There are several types of vestibular rehabilitation exercises Vestibular rehabilitation exercises are used to promote neural reorganisation within areas of the central nervous system that process information on balance and disequilibrium. This process of neural reorganisation provides long-lasting relief from vertigo symptoms . Several types of rehabilitation exercises exist involving the head, neck, oculomotor, and general motor systems. References Konnur MK. Vertigo and vestibular rehabilitation. J Postgrad Med 2000;46:222–3.
  • Treatment is dependent on vertigo type Wherever possible, treatment should be directed at the underlying cause of the disease . This table shows specific treatments that can target certain types of vertigo. Treatment for Meniere’s diseases could involve: restriction of salt intake to 1–2 g daily, diuretics (hydrochlorothiazide, acetazolamide), and surgery if these treatments fail. Recently, transtympanic low-dose gentamicin has been increasingly used. Treatment for migraine could involve: beta-blockers (propranolol 120–240 mg/day), calcium channel blockers (verapamil 120–240 mg/day), and tricyclic amines (nortriptyline 75–100 mg/day). Treatment for vertebrobasilar insufficiency or transient ischaemic attacks could involve aspirin 75–330 mg/day or ticlopidine 500 mg/day. References Baloh RW. Vertigo. Lancet 1998;352:1841–6. Goebel JA. Management options for acute versus chronic vertigo. Otolaryngol Clin North Am 2000;33:483–93.
  • Nootropil ® : an alternative treatment for vertigo Theory behind its use Key points of this chapter: To examine how piracetam differs from other vertigo treatments
  • What is Piracetam? Piracetam was the first of a new class of drugs termed nootropics (agents that act on cognitive function without causing sedation or stimulation). While Nootropil ® is a cyclic derivative of  -aminobutyric acid (GABA), its mode of action appears unrelated to the actions of this neurotransmitter. Instead, Nootropil ® exerts a range of effects on neurones and the vascular system. Consistent with this range of effects, Nootropil ® has demonstrated efficacy in a variety of conditions. First registered in 1971 by UCB Pharma, Nootropil ® was initially marketed in 1972 for the treatment of vertigo , and is now indicated for use in age-related cognitive disorders, cortical myoclonus, sickle cell anaemia and dyslexia*. *In adults • Symptomatic treatment of the psycho-organic syndrome whose features, improved by treatment, are memory loss, attention disorders and lack of drive. • Treatment of cortical myoclonus, alone or in combination. • Treatment of vertigo and associated disorders of balance, with the exception of dizziness of vasomotor or psychic origin. • For prophylaxis and remission of sickle cell vaso-occlusive crises. In children • Treatment of dyslexia, in combination with appropriate measures such as speech therapyin children from 8 years old and adolescents, • For prophylaxis and remission of sickle cell vaso-occlusive crises. Piracetam can be administered to children from 3 years old onwards suffering from sickle cell anemia References Winblad B. Piracetam: a review of pharmacological properties and clinical uses. CNS Drug Rev 2005;11(2):169-82
  • Balance requires information of similar intensity from both vestibular systems Movement of the head in any direction leads to movement of sensory hair cells in both left and right semicircular canals. Both vestibular systems (labyrinths) will then send similar information of the same intensity to the central vestibular nuclei located in the brain stem (e.g., information of intensity 10). The central nervous system integrates this information from the left side and the right side, and balance is maintained providing that the information is coherent and similar in intensity .
  • Central vertigo results from a dysfunction in central processing In central vertigo , the problem lies in the central nervous system, particularly in the vestibular nuclei of the brain stem. Several diseases can be responsible for dysfunction of the central nervous system by altering normal neuronal functioning or the transfer of information between vestibular nuclei. It is important to diagnose these conditions; if vertigo is a symptom of a more severe brain disease, then treatment is imperative. The process of ageing can also be responsible for central dysfunction . Ageing may cause an excessive loss of neurons in the vestibular nuclei, a local decrease in microcirculation or a local decrease of neuronal metabolism. Changes to neurotransmission and transfer of information between the left and right nuclei can also be a consequence of ageing. These processes (alone or in combination) can result in vertigo. Indeed, vertigo is more frequently observed in older people (Sloane 1989). In central vertigo the treatment must be focused on the brain. Nootropil ® is suited for the treatment of central vertigo in aged people because of its activities on microcirculation, neuronal metabolism, neurotransmission and transfer of information inside the central nervous system. References Sloane PD. Dizziness in primary care: results from the national ambulatory medical care service. J Fam Pract 1989;29:33–8.
  • Peripheral vertigo results from a dysfunction in vestibular system functioning In peripheral vertigo , the problem is located in one peripheral vestibular system or in the acoustic nerve (nerve number VIII), most often on one single side. This pathology means that there is an imbalance in the intensity of information sent from the vestibular apparatus to the vestibular nuclei in the brainstem . When the difference is important (e.g., an intensity of 5 on one side compared to the normal intensity of 10 on the other side), the central process is not able to compensate or integrate the information, and thus vertigo appears. Any of the structural components of the peripheral vestibular system may be affected in peripheral vertigo (e.g., the sensory cells, endolymph or local microcirculation). The damage can result from several pathophysiological mechanisms including trauma, infection, and tumor. When a cause can be identified, curative treatments can restore normal balance. However, it can be difficult to establish the exact cause because access to the vestibular apparatus is restricted by their encapsulation in bone. In the absence of an identifiable cause, or if the patient does not respond to treatment, this type of vertigo may still improve over time as spontaneous, physiological mechanisms adapt to the difference (a ‘compensation process’). This ‘mechanism of compensation’ is reinforced by vestibular rehabilitation exercises but usually takes time, and is often only partially successful.
  • Vestibular suppressants suppress vestibular function in both ears Symptomatic treatment may be useful in patients with peripheral vertigo . One of the most commonly used treatments is vestibular inhibition (e.g., anticholinergics or first generation sedative antihistamines: Giurgea CE, Moeyersoons FE, Evraerd AC. A GABA-related hypothesis on the mechanism of action of the antimotion sickness drugs. Arch Int Pharmacodyn 1967;166(1):238 ). These drugs suppress both normal and abnormal vestibular function, which leads to a reduction in the difference between the levels of input from each vestibular system (e.g., 10:5 vs 2:1). This smaller difference is more readily managed by central processing. These types of drugs can rapidly control vertigo. Unfortunately, central adaptation processes are also inhibited, and when the drug is stopped, vertigo often returns. With these drugs, eliminating vertigo and facilitating compensation appear incompatible .
  • Piracetam offers an interesting alternative to existing treatments Piracetam appears to enhance the normal processes of vestibular compensation - recovery of oculomotor and postural functions - in patients with both peripheral and central vertigo.  Such a mode of action provides a logical approach to symptomatic treatment, which is distinct from that of other agents, in particular that of vestibular suppressant agent.
  • Piracetam’s mode of action: the membrane hypothesis Piracetam exerts a range of effects on neurones and the vascular system, suggesting that its primary mode of action is neither cell nor organ specific. Consistent with this proposal, it appears that many of the effects of Piracetam may result from restoration of membrane fluidity . Studies using synthetic membranes have shown that piracetam interacts with the polar head groups of phospholipid membranes in a dose-dependent manner. This action is likely to modify the shape of the phospholipids, inducing reorganisation of the lipid molecules. References M üller WE, Eckert GP, Eckert A . Piracetam: novelty in a unique mode of action. Pharmacopsychiatr 1999;32(Suppl. 1):2–9. Peuvot J, Schanck A, Deleers M, Brasseur R. Piracetam-induced changes to membrane physical properties. Biochem Pharmacol 1995;50:1129–34.
  • Restored membrane fluidity may account for Piracetam’s efficacy in vertigo The mode of action of Piracetam is not yet fully elucidated. However, it appears to exert a range of neuronal and vascular effects. Neuronal effects: Nootropil ® has been shown to influence cholinergic, serotoninergic, dopaminergic, noradrenergic and glutaminergic systems without direct receptor agonism or antagonism. Nootropil ® has been reported to have neuroplastic effects , such as increasing synapse numbers in animals. Nootropil ® may facilitate glucose utilization , thus increasing metabolism Nootropil ® has been reported to facilitate transfer of information between brain hemispheres Vascular effects: Nootropil ® exerts several effects on erythrocytes , enhancing their deformability and decreasing their adhesion to the endothelium. These properties, coupled with an observed prevention of vasospasm , and normalised platelet hyperaggregability are likely to facilitate microcirculation . By increasing neurotransmitter function, promoting neuroplasticity, and enhancing microcirculation, Nootropil ® is likely to facilitate vestibular compensation and adaptation, which may underlie its efficacy in vertigo. References Winblad B. Piracetam: a review of pharmacological properties and clinical uses. CNS Drug Rev 2005;11(2):169-82.
  • A number of studies have examined the use of Piracetam in vertigo A number of studies have examined the use of Piracetam in patients with vertigo due to a range of aetiologies. Although the studies generally involve small, fairly heterogeneous samples, this reflects the range of vertigo typically encountered in the clinic. References Aantaa E, Meurman OH. The effect of piracetam (Nootropil ® , UCB-6215) upon the late symptoms of patients with head injuries. J Int Med Res 1975;3:352–5. Dauman R, Billardon M, Fondarai J. Preliminary, double-blind, comparative study of the efficacy of Nootropyl® (piracetam) versus placebo, in the treatment of vertigo. Les Cahiers d'O. R. L. 1995;4:241–8. Deza Bringas L. Treatment of the subjective post-traumatic syndrome with piracetam. Revista de Neuro-Psiquiatria 1984;47:74–86. Gavalas G, Vathilakis I, Dokianakis G, Papazoglou G. Piracetam in the treatment of vertigo of vascular origin; a double-blind study in patients with vertigo of central character. Proceedings of the XVth Scientific meeting of the Neurootological and Equilibriometric Society. Bad Kissingen, 17-20 March 1988. (Excerpta Medica), 533–8. 1988. Haguenauer JP. Clinical study of piracetam in the treatment of vertigo. Les Cahiers d'O. R. L. 1986;21:460–6. Hakkarainen H, Hakamies L. Piracetam in the treatment of post-concussional syndrome. A double-blind study. Eur Neurol 1978;17:50–5 Oosterveld WJ. The efficacy of Piracetam in vertigo. Arzneimittelforschung 1980;30:1947–1949. Rosenhall U, Deberdt W, Friberg U, Kerr A, Oosterveld W. Piracetam in patients with chronic vertigo. Clin Drug Invest 1996;11:251–60.
  • Piracetam eliminates vestibular symptoms in more patients with peripheral vertigo than placebo In this double-blind study, 50 patients with vertigo of peripheral origin (labyrinthine [n = 22], retrolabyrinthine [n = 26], or unclassified [n = 2]), were randomised to 60 days’ treatment with Piracetam (2.4 g/day) or placebo. This slide shows that Piracetam had a substantial impact on vestibular symptoms , as assessed by the clinician. Following Nootropil ® treatment, nystagmus and index deviation were eliminated in all patients who presented with these symptoms, and the number of patients with imbalance and star gait was markedly reduced. In contrast, placebo treatment had little effect on vestibular symptoms; the number of patients presenting with nystagmus, index deviation, imbalance or star gait was unchanged at study end. Consistent with these findings, both physicians and patients rated vertigo intensity as markedly reduced with Nootropil ® treatment but relatively unchanged with placebo. References Haguenauer JP. Clinical study of piracetam in the treatment of vertigo. Les Cahiers d'O. R. L. 1986;21:460–6.
  • Piracetam significantly reduces frequency and intensity of vertigo crises This double-blind study assessed the effect of Nootropil ® on a range of vertigo symptoms in patients with vertigo of peripheral origin (labyrinthine [n = 22], retrolabyrinthine [n = 26], or unclassified [n = 2]). Vertigo was assessed using a visual analogue scale (0–100 mm) and results expressed as percentage change from baseline. At baseline, vertigo was severe; patients reported a monthly average of 40 episodes, equating to over 1 episode a day. After 60 days’ treatment, vertigo frequency and intensity as assessed by the clinician using a visual analogue scale had significantly decreased with Piracetam relative to placebo . Similar results were reported by the patients, who rated vertigo frequency as decreased by 51% with Nootropil ® and increased by 41% with placebo (p < 0.05); the equivalent values for vertigo intensity were -65% and -7%, respectively (p < 0.0001). References Haguenauer JP. Clinical study of piracetam in the treatment of vertigo. Les Cahiers d'O. R. L. 1986;21:460–6. Oosterveld WJ. Piracetam in vertigo: a review. 2000. UCB Report
  • Piracetam ’s beneficial effect on vertigo persists following treatment cessation This study examined the effect of Piracetam in 143 patients with vertigo due to varying causes. Patients received 2.4 g/day Nootropil ® or placebo for 8 weeks. 89 patients fulfilled the protocol and were included in the presented analysis. The reduction in number of vertigo episodes compared with baseline was significantly greater with Piracetam than with placebo. Furthermore, this reduction in vertigo episodes remained significant 4 weeks after treatment cessation , suggesting that Piracetam exerts a long-term effect on vertigo . Date from week 4 are data on file. (While promising, these results should be interpreted with some caution as patients allocated Nootropil ® reported a significantly greater number of episodes at baseline.) References Rosenhall U, Deberdt W, Friberg U, Kerr A, Oosterveld W. Piracetam in patients with chronic vertigo. Clin Drug Invest 1996;11:251–60.
  • Piracetam rapidly and markedly improves intensity of unspecified chronic vertigo Patients with vertigo (n = 20) were randomised to treatment with Nootropil ® (3 g/day) or placebo for 30 days. Several variables were evaluated including number, duration and intensity of vertigo crises, instability between crises, and impact of vertigo on professional and social activity. As shown in the figure, Piracetam had a pronounced effect on vertigo intensity . After 15 days the percentage improvement in intensity was significantly greater with Nootropil ® than placebo (p < 0.002). These results were supported by several other analyses. For example, the calculation of a vertigo index (composite of number, duration and intensity of crises) showed that, while there was no difference between groups at baseline, after 30 days, vertigo was improved to a significantly greater extent with Nootropil ® than placebo (p < 0.02). Additionally, Nootropil ® had a significantly greater positive impact on nausea intensity (p < 0.02) and tinnitus (p < 0.01) than placebo. References Dauman R, Billardon M, Fondarai J. Preliminary, double-blind, comparative study of the efficacy of Nootropyl ® (piracetam) versus placebo, in the treatment of vertigo. Les Cahiers d'O. R. L.1995;4:241–8.
  • More patients achieved remission of vertigo symptoms with Piracetam than placebo This study examined the efficacy of Nootropil ® compared with placebo in 20 patients with vertigo of central vascular origin. Patients received Nootropil ® (2.4 g/day) or placebo for 8 weeks. At the end of treatment, only 20% of placebo-treated patients showed marked improvement. In contrast, 50% of Nootropil ® -treated patients had achieved total remission of symptoms as assessed by clinicians; no patients achieved remission with placebo. Similar findings were reported by patients. References Gavalas G, Vathilakis I, Dokianakis G, Papazoglou G. Piracetam in the treatment of vertigo of vascular origin; a double-blind study in patients with vertigo of central character. Proceedings of the XVth Scientific meeting of the Neurootological and Equilibriometric Society. Bad Kissingen, 17-20 March 1988. (Excerpta Medica), 533–8. 1988.
  • Fewer patients experience instability between crises after Piracetam treatment In addition to showing a significant effect of Piracetam on the characteristics of vertigo (e.g., intensity of episodes), this study also reported that fewer patients experience instability between vertigo episodes with Piracetam treatment than with placebo . Patients were randomised to Nootropil ® (3 g/day) or placebo for 30 days. At trial end, only 30% of patients presented with instability after Nootropil ® treatment compared with 80% of placebo-treated patients (p < 0.05). (Corresponding baseline values were 60 and 70%, respectively.) The results from this small sample are consistent with those of Rosenhall et al (1996), who reported that 8 weeks’ Nootropil ® treatment significantly reduced severity of malaise (p < 0.01) and imbalance (p < 0.001) between vertigo episodes relative to placebo. Together these findings suggest that Nootropil ® ’s efficacy in vertigo patients goes beyond its effects on vertigo episodes . References Dauman R, Billardon M, Fondarai J. Preliminary, double-blind, comparative study of the efficacy of Nootropyl ® (piracetam) versus placebo, in the treatment of vertigo. Les Cahiers d'O. R. L.1995;4:241–8. Rosenhall U, Deberdt W, Friberg U, Kerr A, Oosterveld W. Piracetam in patients with chronic vertigo. Clin Drug Invest 1996;11:251–60.
  • Piracetam reduces vertigo-related symptoms between episodes Many patients with vertigo report symptoms between vertigo attacks such as imbalance and general malaise. This study of 143 patients with vertigo due to varying causes investigated the effect of Nootropil ® on vertigo during and between crises. Patients received 2.4 g/day Nootropil ® or placebo for 8 weeks. 89 patients fulfilled the protocol and were included in the presented analysis. Nootropil ® significantly decreased the number of vertigo episodes relative to placebo (data not shown). However, these data are difficult to interpret as patients allocated Nootropil ® reported a significantly greater number of episodes at baseline. In terms of symptoms between crises, the groups were equally matched at baseline. After 8 weeks’ treatment, there were significantly greater reductions in severity of malaise and imbalance with Nootropil ® than with placebo (p < 0.01 and 0.001, respectively). Furthermore, incapacity was reduced by approximately 2 days with Nootropil ® but increased by approximately 1 day with placebo (p < 0.001). Nootropil ® therefore offers significant advantages over placebo in treating symptoms between vertigo crises . References Rosenhall U, Deberdt W, Friberg U, Kerr A, Oosterveld W. Piracetam in patients with chronic vertigo. Clin Drug Invest 1996;11:251–60.
  • Piracetam: an alternative treatment for vertigo Efficacy in post-concussion vertigo Key points of this chapter: Vertigo after head trauma is common. Nootropil ® alleviates symptoms in patients with post-concussion vertigo (patients with post-concussion vertigo are normally younger than patients with vertigo resulting from other causes).
  • Vertigo complaints after head trauma are common Head or neck injuries can cause a range of pathologies that can manifest as vertigo . For example, even blunt injuries can dislodge particles into the semicircular canals, leading to benign paroxysmal positional vertigo, or cause rupture of structures in the inner ear, resulting in vestibular dysfunction. Head trauma can also impinge on central mechanisms of balance. For example, damage to the temporal or parietal association cortices (which process vestibular information) can result in epileptic vertigo. Given the range of aetiologies that can cause vertigo in patients following head trauma, it is important to assess each patient individually to ensure their specific pathology is accurately identified in order to initiate the most appropriate treatment strategy. References Friedman JM. Post-traumatic vertigo. Med Health RI 2004;84:296–300.
  • Three studies of similar design have been conducted with Piracetam in Post Concussion Vertigo (Aanta 1975, Hakkarainen 1978, Deza Bringas 1984). All were double-blind and placebo-controlled, with an 8-week treatment period. Piracetam was given as either a total dose of 2.4 g/day or 4.8 g/day. References Aantaa E, Meurman OH. The effect of piracetam (Nootropil ® , UCB-6215) upon the late symptoms of patients with head injuries. J Int Med Res 1975;3:352–5. Deza Bringas L. Treatment of the subjective post-traumatic syndrome with piracetam. Revista de Neuro-Psiquiatria 1984;47:74–86. Hakkarainen H, Hakamies L. Piracetam in the treatment of post-concussional syndrome. A double-blind study. Eur Neurol. 1978;17(1):50-5.
  • The three studies examined 157 patients suffering from Post-concussion vertigo. The table here shows results from the 3 studies, with regards to improvement in vertigo.
  • The mechanism of action of piracetam in vertigo is thought to be mediated through enhancement of central compensation and adaptation to vestibular dysfunction thanks to restoration of central neurotransmission and neuronal metabolism, and enhancement of blood flow in the microcirculation in areas where vascularisation is inadequate, centrally but also in the vestibular labyrinth. The increase of microperfusion associated with piracetam may therefore be relevant. Piracetam has also been shown to improve cognition in the ageing brain, and may therefore help to improve concentration and memory problems associated with post-concussion vertigo.
  • Vertigo 2008

    1. 1. Vertigo A slide kit Picture adapted from Borg E, Counter A. Pour la Science 1989;144:65. © Pour la scienceGPSRC PCP 058 PROM 0608 PIR_Nootropil Slide Kit Vertigo – © UCB PHARMA S.A. 2008. All rights reserved
    2. 2. What is vertigo? Vertigo is: • A type of dizziness • A sensation of movement typically characterised by feelings of rotation or spinning Baloh RW. Lancet 1998;352:1841–6. Mukherjee A et al. JAPI 2003;51:1095–101. Sloane PD et al. Ann Intern Med 2001;134:823–32. 2GPSRC PCP 058 PROM 0608 PIR_Nootropil Slide Kit Vertigo – © UCB PHARMA S.A. 2008. All rights reserved
    3. 3. Vertigo can be objective or subjective Objective vertigo: • the patient perceives that the environment is moving around him/her Subjective vertigo: • the patient feels himself/herself moving in a static environment Mukherjee A et al. JAPI 2003;51:1095–101. Salvinelli F et al. Clin Ter 2003;154:341–8. 3GPSRC PCP 058 PROM 0608 PIR_Nootropil Slide Kit Vertigo – © UCB PHARMA S.A. 2008. All rights reserved
    4. 4. Vertigo is one of four types of dizziness Dizziness Other Vertigo Presyncope Disequilibrium subtypes • An illusion of • A feeling of • A sense of • Swimming or movement, faintness or unsteadiness in the floating usually loss of lower body sensations rotation consciousness • No effect on feelings • Feelings of in head dissociation • Relieved when • Difficult to sitting down describe Drachman DA, Hart CW. Neurology 1972;22:323–4. Sloane PD et al. Ann Intern Med 2001;134:823–32. 4GPSRC PCP 058 PROM 0608 PIR_Nootropil Slide Kit Vertigo – © UCB PHARMA S.A. 2008. All rights reserved
    5. 5. Etiology of vertigo Vertigo related to inner ear • Benign paroxysmal positional vertigo (BPPV) • Meniere’s disease • Labyrinthitis • Trauma (labyrinthine concussion) • Aminoglycoside toxicity Vertigo related to the vestibular nerve • Vestibular neuritis • Nerve compression due to meningioma or schwannoma Vertigo related to brain stem • Physiological (visual-vestibular mismatch) • Demyelination (multiple sclerosis) • Migraine • Vertebrobasilar insufficiency (as in stroke or TIA) • Drug toxicities (with anticonvulsants, aspirin, alcohol) Allen CMC, Lueck CJ. Neurological disease. In: Christopher H, Edwin RC, Nicholas AB, eds. Davidson’s Principles and Practice of Medicine. 19th ed. Edinburgh: Churchill Livingstone;2002:1103-12310. 5GPSRC PCP 058 PROM 0608 PIR_Nootropil Slide Kit Vertigo – © UCB PHARMA S.A. 2008. All rights reserved
    6. 6. Vertigo: Pathophysiological Pathways Endolymph movement, depending on the direction of flow and deflection of otoliths by gravity, either stimulates or inhibits neuronal output from the attached hair cells Nerve impulses from the vestibular system are transmitted to the vestibular nuclei in the brain stem and cerebellum through the eighth cranial nerve From there, connections are made to the oculomotor system, spinal cord, and cerebral cortex, which integrate the information to produce the perception of motion Vertigo results from lesions or disturbances along this pathway Robert BD, Mark DC. Syncope, Faintness, Dizziness, And vertigo. In: Dennis LK, Eugene B, Anthony SF et al, eds. Harrison’s Principles of Internal Medicine.16th ed. New York:McGraw-Hill;2005:126-133. 6GPSRC PCP 058 PROM 0608 PIR_Nootropil Slide Kit Vertigo – © UCB PHARMA S.A. 2008. All rights reserved
    7. 7. Vertigo: Role of Neurotransmitters Neurotransmitters that work centrally and peripherally include: • Acetylcholine: Functions as an excitatory neurotransmitter in central and peripheral pathways • Glutamate: Maintains the resting discharge of the central vestibular neurons; may modulate synaptic transmission in the VOR arc • GABA: Thought to be inhibitory for commissures of the medial vestibular nucleus McLean MJ. Principles of neuropharmacology and therapeutics. In: Bradley WG, Daroff RB, Fenichel GM, Marsden CD, eds. Neurology in Clinical Practice. 3rd ed. Boston: Butterworth Heinemann;2000:867-898. 7GPSRC PCP 058 PROM 0608 PIR_Nootropil Slide Kit Vertigo – © UCB PHARMA S.A. 2008. All rights reserved
    8. 8. Vertigo: Presentation Sensation of motion either of the person or the environment In addition, the following may be present: • Nausea or vomiting • Abnormal eye movements • Sweating Duration of symptoms can vary from a few minutes to hours and can be constant or episodic May also be associated with visual disturbances, weakness, decreased level of consciousness, difficulty in speaking Troost BT. Dizziness and vertigo. In: Bradley WG, Daroff RB, Fenichel GM, Marsden CD, eds. Neurology in Clinical Practice. 3rd ed. Boston: Butterworth Heinemann;2000:239-240. 8GPSRC PCP 058 PROM 0608 PIR_Nootropil Slide Kit Vertigo – © UCB PHARMA S.A. 2008. All rights reserved
    9. 9. Vertigo episodes are debilitating and are more than just a sensation of movement Vertigo episodes: • are characterised by a sensation of movement, usually spinning or rotating • vary in intensity and duration • are usually unpredictable • are often accompanied by:  nausea  vomiting  imbalance  anxiety  sweating  nystagmus Baloh RW. Lancet 1998;352:1841–6. Mukherjee A et al. JAPI 2003;51:1095–101. Salvinelli F, Firrisi L, Casale M, et al. Clin Ter 2003;154:341–8. 9GPSRC PCP 058 PROM 0608 PIR_Nootropil Slide Kit Vertigo – © UCB PHARMA S.A. 2008. All rights reserved
    10. 10. Vertigo is a continuous burden Between vertigo episodes there may be: • Headaches • Instability • General malaise • Anxiety and depression • Fear over recurrence of episodes These symptoms may have a negative effect on quality of life Fielder H et al. Clin Otolaryngol 1996;21:124–6. Hägnebo C et al. Scand Audiol 1997;26:69–76. Lopez-Escamez JA, Lopez-Nevot A. Acta Otorrinolaringol Esp 2000;51:377–82. Mendel B et al. Clin Otolaryngol Allied Sci 1999;24:286–93. Monzani D et al. J Psychosom Res 2001;50:319–23. Salvinelli F et al. Clin Ter 2003;154:341–8. 10GPSRC PCP 058 PROM 0608 PIR_Nootropil Slide Kit Vertigo – © UCB PHARMA S.A. 2008. All rights reserved
    11. 11. Vertigo can have a negative impact on quality of life Women with vertigo Weighted population mean Men with vertigo Mean score (scale of 0-100) Mean score (scale of 0-100) QoL parameter (SF-36) Physical functioning Limitations due to emotions Limitations due p<0.05 p<0.05 to physical problems p<0.05 Social functioning Mental health Bodily pain Vitality p<0.05 General health perception Do we take vertigo seriously enough? Fielder H et al. Clin Otolaryngol 1996;21:124–6. SF-36, short form health questionnaire, higher scores indicate better health. QoL, Quality of Life. 11GPSRC PCP 058 PROM 0608 PIR_Nootropil Slide Kit Vertigo – © UCB PHARMA S.A. 2008. All rights reserved
    12. 12. Vertigo can be of central or peripheral origin Central Involving structures in the central nervous system (e.g., cerebrum, cerebellum, brainstem) Peripheral Involving structures not part of the central nervous system, most frequently the inner ear Baloh RW. Lancet 1998;352:1841–6. Mukherjee A et al. JAPI 2003;51:1095-101. Puri V, Jones E. J Ky Med Assoc 2001;99:316–21. Salvinelli F et al. Clin Ter 2003;154:341–8. Strupp M, Arbusow V, Curr Opin Neurol 2001;14:11–20. 12GPSRC PCP 058 PROM 0608 PIR_Nootropil Slide Kit Vertigo – © UCB PHARMA S.A. 2008. All rights reserved
    13. 13. Vertigo of peripheral origin: Conditions & causes Condition Details Benign paroxysmal Brief, position-provoked vertigo episodes caused by positional vertigo abnormal presence of particles in semicircular canalDecreasing frequency Meniere’s disease An excess of endolymph, causing distension of endolymphatic system Vestibular neuronitis Vestibular nerve inflammation, most likely due to virus Acute labyrinthitis Labyrinth inflammation due to viral or bacterial infection Labyrinthine infarct Compromises blood flow to the labyrinthine Labyrinthine concussion Damage to the labyrinthine after head trauma Perilymph fistula Typically caused by labyrinth membrane damage resulting in perilymph leakage into the middle ear Autoimmune inner ear Inappropriate immunological response that attacks inner ear disease cells Baloh RW. Lancet 1998;352:1841–6. Mukherjee A et al. JAPI 2003;51:1095-101. Parnes LS et al. CMAJ 2003;169:681– 93. Puri V, Jones E. J Ky Med Assoc 2001;99:316–21. Salvinelli F et al. Clin Ter 2003;154:341–8. 13 GPSRC PCP 058 PROM 0608 PIR_Nootropil Slide Kit Vertigo – © UCB PHARMA S.A. 2008. All rights reserved
    14. 14. Vertigo of central origin: Conditions & causes Condition Details Migraine Vertigo may precede migraines or occur concurrentlyDecreasing frequency Ischaemia or haemorrhage in vertebrobasilar system can Vascular disease affect brainstem or cerebellum function Demyelination disrupts nerve impulses which can result in Multiple sclerosis vertigo Vertigo resulting from focal epileptic discharges in the Vestibular epilepsy temporal or parietal association cortex Cerebellopontine tumours Benign tumours in the internal auditory meatus Baloh RW. Lancet 1998;352:1841–6. Mukherjee A et al. JAPI 2003;51:1095-101. Salvinelli F et al. Clin Ter 2003;154: 341–8. Solomon D. Otolaryngol Clin North Am 2000;33:579–601. Strupp M, Arbusow V, Curr Opin Neurol 2001;14:11–20. 14GPSRC PCP 058 PROM 0608 PIR_Nootropil Slide Kit Vertigo – © UCB PHARMA S.A. 2008. All rights reserved
    15. 15. Distinguishing peripheral and central causes of vertigo Symptom Likely aetiology Peripheral Central Vertigo episodes Mild/moderate Chronic and unremitting Symptom onset Sudden Gradual Imbalance Mild/moderate Severe Nausea, vomiting Severe Varying Auditory symptoms Common Rare Neurological symptoms Rare Common Changes in mental status/ consciousness Infrequent Sometimes Compensation/resolution Rapid Slow Baloh RW. Otolaryngol Head Neck Surg 1998;119:55–9. Puri V, Jones E. J Ky Med Assoc 2001;99:316–21. 15GPSRC PCP 058 PROM 0608 PIR_Nootropil Slide Kit Vertigo – © UCB PHARMA S.A. 2008. All rights reserved
    16. 16. Treatment modalities in vertigo Pharmacological interventions: • Anticholinergics • Antihistamines • Benzodiazepines • Calcium channel antagonists (especially verapamil and nimodipine) • GABA modulators (like gabapentin and baclofen) • Neurotransmitter reuptake inhibitors (SSRIs, SNRIs and tricyclics) • Nootropics (piracetam) Troost BT, Arguello LC. Neuro-Otology. In: Bradley WG, Daroff RB, Fenichel GM, Marsden CD, eds. Neurology in Clinical Practice. 3rd ed. Boston: Butterworth Heinemann;2000:740-742. Oosterveld WJ. Arzneimittelforschung.1980;30(11)1947-1949. 16GPSRC PCP 058 PROM 0608 PIR_Nootropil Slide Kit Vertigo – © UCB PHARMA S.A. 2008. All rights reserved
    17. 17. Nootropics in Vertigo Nootropics as a class • Enhance cognitive processes such as learning and memory • Protect and restore cognitive abilities after cerebral insults • Facilitate interhemispheric flow of information and efficient tonic cortical/subcortical mechanism • Do not have sedative or psychostimulant effects Piracetam, a cyclic derivative of GABA, and the first nootropic agent • Alleviates vertigo after head injury/vertigo of central origin • Significantly decreases the frequency and the severity of exacerbations in patients with chronic or recurrent vertigo Balaraman, Shingala J. Indian Journal of Pharmacology. 2002;34(6)439-440 Trkanjec Z, Aleksic-Shibabi A, Demarin V. Rad za medicinske znanosti. 2007;69-73. 17GPSRC PCP 058 PROM 0608 PIR_Nootropil Slide Kit Vertigo – © UCB PHARMA S.A. 2008. All rights reserved
    18. 18. Treating the cause: pharmacotherapy can control some vertigo causes Meniere’s disease • Diuretics • Transtympanic gentamicin Migraine • Beta-blockers • Calcium channel blockers • Tricyclic amines Vertebrobasilar insufficiency or transient ischaemic attacks • Antiplatelet agents Baloh RW. Lancet 1998;352:1841–6. Goebel JA. Otolaryngol Clin North Am 2000;33:483–93. 18GPSRC PCP 058 PROM 0608 PIR_Nootropil Slide Kit Vertigo – © UCB PHARMA S.A. 2008. All rights reserved
    19. 19. Treating the cause: a simple particle repositioning manoeuvre effectively treats most BPPV cases Modified 3- position canalith repositioning manoeuvre, not requiring sedation or skull vibration Diagram shows treatment of BPPV in the right ear. Parnes LS, Agrawal SK, Atlas J. CMAJ 2003;169:681– 93. BPPV, Benign paroxysmal positional vertigo. Figure reprinted by permission of the publisher. © 2003 CMA Media Inc. 19GPSRC PCP 058 PROM 0608 PIR_Nootropil Slide Kit Vertigo – © UCB PHARMA S.A. 2008. All rights reserved
    20. 20. Treating the cause: surgery is appropriate in only a small fraction of vertigo patients Clinical picture Patient presents with Vertigo-inducing tumour Recurrent episodes of acute vertigo due to (e.g., cerebellopontine tumour) established unilateral vestibular damage unresponsive to medical therapy Surgery Tumour removal Ablative Non-Ablative Meniere’s disease or Meniere’s disease: peripheral vestibulopathy: Endolymphatic sac shunt or Labyrinthectomy decompression Vestibular nerve section BPPV: Posterior canal occlusion Goebel JA. Otolaryngol Clin North Am 2000;33:483–93. Salvinelli F et al. Clin Ter 2003;154:341–8. 20GPSRC PCP 058 PROM 0608 PIR_Nootropil Slide Kit Vertigo – © UCB PHARMA S.A. 2008. All rights reserved
    21. 21. Pharmacotherapy can help manage symptoms in the short term Treatments to manage vertigo symptoms • Vestibular suppressants  Meclizine, dimenhydrinate, diazepam • Anti-emetics  Prochlorperazine, metoclopramide Side effects include sedation and extrapyramidal reactions Baloh RW. Lancet 1998;352:1841–6. Hain TC, Uddin M. CNS Drugs 2003;17:85–100. 21GPSRC PCP 058 PROM 0608 PIR_Nootropil Slide Kit Vertigo – © UCB PHARMA S.A. 2008. All rights reserved
    22. 22. Rehabilitation exercises can encourage vestibular adaptation and compensation Effective recovery from vertigo often requires neural reorganisation and adaptation Vestibular rehabilitation exercises aim to promote adaptation and compensation of the nervous system They instigate sensory conflicts to promote neural learning Rehabilitation exercises are particularly useful when: • Medical therapy is ineffective • Patients have poor central integration or motor function Baloh RW. Lancet 1998;352:1841–6. Goebel JA. Otolaryngol Clin North Am 2000;33:483–93. Konnur MK. J Postgrad Med 2000;46:222–3. Mukherjee A et al. JAPI 2003;51:1095–101. 22GPSRC PCP 058 PROM 0608 PIR_Nootropil Slide Kit Vertigo – © UCB PHARMA S.A. 2008. All rights reserved
    23. 23. There are several types of vestibular rehabilitation exercises Vestibular rehabilitation exercises Visual-vestibular Head and neck Postural stability interaction • Performed lying, sitting or • Promotes visual-vestibular • Improves static and standing interaction dynamic posture • Vertigo-provoking • Involves ocular and hand- • Manipulates visual, movements of head & eye co-ordination exercises somatosensory and neck in different planes • Uses the vestibulo-ocular vestibular cues (ex: flexion, extension, reflex • Involves trunk rotation, etc.) head rotations, and gait • Uses cervical-ocular reflex exercises Rehabilitation exercises differ in their target Konnur MK. J Postgrad Med 2000;46:222–3. 23GPSRC PCP 058 PROM 0608 PIR_Nootropil Slide Kit Vertigo – © UCB PHARMA S.A. 2008. All rights reserved
    24. 24. Treatment is dependent on vertigo type Vertigo type Treatment Peripheral causes BPPV Canalith repositioning manoeuvre Labyrinthine concussion Vestibular rehabilitation Meniere’s disease Low-salt diet, diuretic, surgery, transtympanic gentamicin Labyrinthitis Antibiotics, removal of infected tissue, vestibular rehabilitation Perilymph fistula Bed rest, avoidance of straining Vestibular neuritis Brief course of high-dose steroids, vestibular rehabilitation Central causes Migraine Beta-blockers, calcium channel blockers, tricyclic amines Vascular disease Control of vascular risk factors, e.g., antiplatelet agents Cerebellopontine tumours Surgery Baloh RW. Lancet 1998;352:1841–6. Goebel JA. Otolaryngol Clin North Am 2000;33:483–93. 24GPSRC PCP 058 PROM 0608 PIR_Nootropil Slide Kit Vertigo – © UCB PHARMA S.A. 2008. All rights reserved
    25. 25. Piracetam: an alternative treatment for vertigo Theory behind its useGPSRC PCP 058 PROM 0608 PIR_Nootropil Slide Kit Vertigo – © UCB PHARMA S.A. 2008. All rights reserved
    26. 26. What is Piracetam? Piracetam: • is a nootropic drug, acting on cognitive function without causing sedation or stimulation • is a cyclic derivative of the neurotransmitter, γ-aminobutyric acid (GABA) • has neuronal and vascular effects Winblad B. CNS Drug Rev 2005; 11(2):169-82 26GPSRC PCP 058 PROM 0608 PIR_Nootropil Slide Kit Vertigo – © UCB PHARMA S.A. 2008. All rights reserved
    27. 27. Balance requires information of similar intensity from both vestibular systems Head movement Activation of cells in Activation of cells in left vestibular right vestibular system system Central nuclei 10 10 Normally, the input from left and right vestibular system is of similar intensity (e.g. of size ‘10’) 27GPSRC PCP 058 PROM 0608 PIR_Nootropil Slide Kit Vertigo – © UCB PHARMA S.A. 2008. All rights reserved
    28. 28. Central vertigo results from a dysfunction in central processing Input from left and right vestibular system remains of similar intensity Central nuclei 10 10 Impaired information transfer between vestibular nuclei causes central vertigo (e.g. of size ‘10’) Central vertigo requires central treatment 28GPSRC PCP 058 PROM 0608 PIR_Nootropil Slide Kit Vertigo – © UCB PHARMA S.A. 2008. All rights reserved
    29. 29. Peripheral vertigo results from a dysfunction in vestibular system functioning Central nuclei 5 10 29GPSRC PCP 058 PROM 0608 PIR_Nootropil Slide Kit Vertigo – © UCB PHARMA S.A. 2008. All rights reserved
    30. 30. Vestibular suppressants suppress vestibular function in both ears Central nuclei 5 10 1 2 Vestibular suppressants modify peripheral function bilaterally 30GPSRC PCP 058 PROM 0608 PIR_Nootropil Slide Kit Vertigo – © UCB PHARMA S.A. 2008. All rights reserved
    31. 31. Piracetam offers an interesting alternative to existing treatments Central nuclei 5 10 Piracetam appears to enhance the normal processes of vestibular compensation - recovery of oculomotor and postural functions - in patients with both peripheral and central vertigo. Such a mode of action provides a logical approach to symptomatic treatment, which is distinct from that of other agents, in particular that of vestibular suppressant agent. Rosenhall U. et al, Clin. Drug Invest. 1996;11 (5): 251-260. 31GPSRC PCP 058 PROM 0608 PIR_Nootropil Slide Kit Vertigo – © UCB PHARMA S.A. 2008. All rights reserved
    32. 32. Piracetam’s mode of action: the membrane hypothesis Nootropil® (piracetam) interacts polar head groups with the polar head groups of phospholipid membranes - + - + + Induces reorganisation of lipid phospholipid molecules bilayer piracetam Formation of mobile drug- phospholipid complexes May account for restored membrane fluidity Müller WE et al. Pharmacopsychiatr 1999;32(Suppl.1):2–9. Peuvot J et al. Biochem Pharmacol 1995;50:1129–34. 32GPSRC PCP 058 PROM 0608 PIR_Nootropil Slide Kit Vertigo – © UCB PHARMA S.A. 2008. All rights reserved
    33. 33. Restored membrane fluidity could account for Piracetam’s efficacy in vertigo Neuronal effects Vascular effects • Restored neurotransmission • Enhanced erythrocyte • Enhanced neuroplasticity deformability • Improved metabolism • Decreased adhesion of erythrocytes to endothelial wall • Facilitation of interhemispheric information transfer • Prevention of vasospasm • Normalised platelet hyperaggregability Improved neuronal function Improved microcirculation Facilitates vestibular compensation and adaptation Adapted from Winblad B. CNS Drug Rev 2005; 11(2):169-82. 33GPSRC PCP 058 PROM 0608 PIR_Nootropil Slide Kit Vertigo – © UCB PHARMA S.A. 2008. All rights reserved
    34. 34. A number of studies have examined the use of Piracetam in vertigo Patients Study Author Vertigo type randomised Intervention period (completed) Aantaa Post-concussion 60 (57) Piracetam 2.4 g/d or placebo 8 wks Deza Bringas Post-concussion 50 (50) Piracetam 4.8 g/d or placebo 8 wks Hakkarainen Post-concussion 60 (51) Piracetam 4.8 g/d or placebo 8 wks Dauman Peripheral 20 (20) Piracetam 3 g/d or placebo 30 days Haguenauer Peripheral 50 (50) Piracetam 2.4 g/d or placebo 60 days Gavalas1 Central 20 (20) Piracetam 2.4 g/d or placebo 8 wks Oosterveld* Central 22 (22) Piracetam 2.4 g/d or placebo 4 wks Rosenhall Central/peripheral 143 (89) Piracetam 2.4 g/d or placebo 8 wks *Cross over study, 2 weeks of each treatment. Aantaa. J Int Med Res 1975;3:352–5. Dauman. Les Cahiers d’O.R.L. 1995;4:241–8. Deza Bringas. Revista de Neuro-Psiquiatria 1984;47:74–86. Gavalas(1). Excerpta Medica 1988;533–8. Gavalas(2). Procs XIXth NES Meeting. March 1992. Guidetti. Riv Orl Aud Fond 1991;2:148–55. Haguenauer. Les Cahiers d’O.R.L 1986;21:460–6. Hakkarainen. Eur Neurol 1978;17:50–5. Oosterveld. Arzneimittelforschung 1980;30:1947–9. Rosenhall. Clin Drug Invest 1996;11:251–60. 34GPSRC PCP 058 PROM 0608 PIR_Nootropil Slide Kit Vertigo – © UCB PHARMA S.A. 2008. All rights reserved
    35. 35. Piracetam eliminates vestibular symptoms in more patients with peripheral vertigo than placebo Piracetam 2.4 g/day (n = 25) Placebo (n = 25) At baseline After 60 days’ treatment Nystagmus Index Imbalance Star Nystagmus Index Imbalance Star deviation gait deviation gait Haguenauer JP. Les Cahiers d’O.R.L 1986;21:460–6. 35GPSRC PCP 058 PROM 0608 PIR_Nootropil Slide Kit Vertigo – © UCB PHARMA S.A. 2008. All rights reserved
    36. 36. Piracetam significantly reduces frequency and intensity of vertigo crises Piracetam 2.4 g/day (n = 25) Placebo (n = 25) Peripheral vertigo treated for 60 days Before the study: • average of 40 vertigo episodes per month • average duration of vertigo > 6 months p<0.001 p<0.001 Haguenauer JP. Les Cahiers d’O.R.L 1986;21:460–6. Additional data on file (Oosterveld 2000) 36GPSRC PCP 058 PROM 0608 PIR_Nootropil Slide Kit Vertigo – © UCB PHARMA S.A. 2008. All rights reserved
    37. 37. Piracetam’s beneficial effect on vertigo persists without treatment following treatment cessation p<0.05 Day 84 Follow-up Piracetam 2.4 g/day Placebo n = 89 p<0.01 Day 56 treatment During Day 28 p<0.01 Adapted from Rosenhall U et al. Clin Drug Invest 1996;11:251–60. Day 84 is 4 weeks after cessation of treatment. 37GPSRC PCP 058 PROM 0608 PIR_Nootropil Slide Kit Vertigo – © UCB PHARMA S.A. 2008. All rights reserved number of vertigo episodes
    38. 38. Piracetam rapidly and markedly improves intensity of unspecified chronic vertigo Piracetam 3 g/day (n = 10) Placebo (n = 10) Worse Vertigo intensity Better Percentage improvement in vertigo intensity from baseline to day 15 was significantly greater with Piracetam than placebo (p<0.002) Dauman R et al. Les Cahiers d’O.R.L. 1995;4:241–8. 38GPSRC PCP 058 PROM 0608 PIR_Nootropil Slide Kit Vertigo – © UCB PHARMA S.A. 2008. All rights reserved
    39. 39. More patients achieved remission of vertigo symptoms with Piracetam than placebo Patients with vertigo of central origin treated for 8 weeks Piracetam 2.4 g/day (n = 10) Placebo (n = 10) % patients Clinician’s assessment of symptoms Gavalas G et al. Proceedings of the XVth Scientific meeting of the Neurootological and Equilibriometric Society. Bad Kissingen, 17-20 March 1988. (Excerpta Medica), 533–538. 1988. 39GPSRC PCP 058 PROM 0608 PIR_Nootropil Slide Kit Vertigo – © UCB PHARMA S.A. 2008. All rights reserved
    40. 40. Fewer patients experience instability between crises after Piracetam treatment Patients with chronic, unspecified vertigo of central origin Piracetam 3 g/day (n = 10) Placebo (n = 10) p<0.05 % patients without instability Dauman R et al. Les Cahiers d’O.R.L. 1995;4:241–8 40GPSRC PCP 058 PROM 0608 PIR_Nootropil Slide Kit Vertigo – © UCB PHARMA S.A. 2008. All rights reserved
    41. 41. Piracetam reduces vertigo-related symptoms between episodes Patients with vertigo of varying aetiologies received Piracetam or placebo for 8 weeks Piracetam 2.4 g/day (n = 47) Placebo (n = 42) Improvement -16 p<0.001 p<0.01 Change in VAS score (mm) -12 relative to baseline -8 -4 Deterioration 0 4 Imbalance Malaise Symptom severity between vertigo episodes Rosenhall U et al. Clin Drug Invest 1996;11:251–60. 41GPSRC PCP 058 PROM 0608 PIR_Nootropil Slide Kit Vertigo – © UCB PHARMA S.A. 2008. All rights reserved
    42. 42. Piracetam: Efficacy in post-concussion vertigoGPSRC PCP 058 PROM 0608 PIR_Nootropil Slide Kit Vertigo – © UCB PHARMA S.A. 2008. All rights reserved
    43. 43. Vertigo complaints after head trauma are common Dizziness occurs in approximately 50% of individuals after head or neck injury Usually due to pathologies in the vestibular, central nervous system or cervical structures Friedman JM. Med Health RI 2004;84:296–300 43GPSRC PCP 058 PROM 0608 PIR_Nootropil Slide Kit Vertigo – © UCB PHARMA S.A. 2008. All rights reserved
    44. 44. Three studies of similar design have been conducted with PIRACETAM IN POST-CONCUSSION VERTIGO Aantaa E. The effect of piracetam upon the late symptoms of patients with head injuries– 1975 Hakkarainen H, Hakamies L. Piracetam in the treatment of Post-Concussional Syndrome– 1978 Deza Bringas L. Treatment of the subjective post-traumatic syndrome with piracetam - 1984 ALL 3 STUDIES WERE: Double-blind and placebo-controlled With a 8-week treatment period Piracetam was administered as either a total dose of 2.4 g/day or 4.8 g/day Aantaa E, Meurman OH. J Int Med Res 1975;3:352–5; Deza Bringas L. Revista de Neuro-Psiquiatria 1984;47:74–86; Hakkarainen H, Hakamies L. A double-blind study. Eur Neurol. 1978;17(1):50-5. 44GPSRC PCP 058 PROM 0608 PIR_Nootropil Slide Kit Vertigo – © UCB PHARMA S.A. 2008. All rights reserved
    45. 45. Results of the 3 studies after 8 weeks Hakkarainen H, Aantaa E Deza Bringas L Hakamies L Patients analysed (n) 57 51 49 Patients with vertigo at 57/57 (100%) 51/51 (100%) 39/49 (79.6%) baseline (n%) Patients on piracetam 24/30 (80%) 22/26 (84.6%) 17/20 (85%) with improvement in p < 0.01 p <0.05 p < 0.001 vertigo (n%) Aantaa E, Meurman OH. J Int Med Res. 1975;3:352-5; Deza Bringas L. Revista de Neuro-Psiquiatria. 1984;47:74-86; Hakkarainen H, Hakamies L. A double-blind study. Eur Neurol. 1978;17(1):50-5. 45GPSRC PCP 058 PROM 0608 PIR_Nootropil Slide Kit Vertigo – © UCB PHARMA S.A. 2008. All rights reserved
    46. 46. Mechanism of action of piracetam in post-concussion vertigo Enhancement of central compensation and adaptation to vestibular dysfunction Enhancement of blood flow in the peripheral and central microcirculation Improvement of cognitive processes Improvement of concentration and memory problems Guidetti G., Cognition & Nootropics Summit, Athens, 2006. 46GPSRC PCP 058 PROM 0608 PIR_Nootropil Slide Kit Vertigo – © UCB PHARMA S.A. 2008. All rights reserved
    47. 47. Piracetam: Contraindications & Drug Interactions [Refer to your local full SPC before prescribing] Major Contraindications Piracetam should not be prescribed to patients with cerebral hemorrhage, end-stage renal impairment. Patients with Huntington Chorea, hypersensibility to piracetam, or other pyrrolidone derivatives, or any of the excipients. Avoid piracetam in pregnant or lactating women Drug interactions Piracetam is neither metabolized by the liver nor bound to plasma albumin. The potential for drug-drug interaction is, therefore, low. No interactions with sodium valproate have been reported. There are no known interactions of piracetam with any other drugs. Winblad B. CNS Drug Rev 2005;11(2):174. 47GPSRC PCP 058 PROM 0608 PIR_Nootropil Slide Kit Vertigo – © UCB PHARMA S.A. 2008. All rights reserved
    48. 48. Piracetam: Warnings and common undesirable effects [Refer to your lcoal full SPC before prescribing] Warnings Caution in patients with disorders of hemostasis, major surgery, or severe haemorrhage Caution in patients with renal impairment For long-term treatment in elderly, regular evaluation of Creatinine clearance is required to allow dosage adaptation if needed More common undesirable effects Hyperkinesia, weight increase, nervousness, somnolence, depression, asthenia. Winblad B. CNS Drug Rev 2005;11(2):174. 48GPSRC PCP 058 PROM 0608 PIR_Nootropil Slide Kit Vertigo – © UCB PHARMA S.A. 2008. All rights reserved
    49. 49. - Prescribing InformationNOOTROPIL®Piracetam Tablets/ Syrup/ InjectionsIntroduction:Pharmacotherapeutic group: Nootropics, The active substance, piracetam, is a pyrrolidone (2-oxo-1-pyrrolidine-acetamide), a cyclic derivative of gamma-amino butyric acid (GABA).Mechanism of action:Nootropil binds to the polar heads of membrane phospholipids physically in a dose dependent manner. It induces the restoration of the membrane lamellar structure characterized by the formation of mobile drug-phospholipid complexes. This probablyaccounts for improved membrane stability, allowing the membrane and transmembrane proteins to maintain or recover their three-dimensional folded structure essential for their function.Pharmacodynamics:Nootropil: neuronal and vascular effectsNootropil exerts its membrane activity in various ways at the level of the neurones. In animals, Nootropil enhances different types of neurotransmission, primarily through postsynaptic modulation of receptor density and activity.In both animals and man, the functions involved in cognitive processes such as learning, memory, attention and consciousness were enhanced, in the normal subject as well as in deficiency states, without the development of sedative orpsychostimulant effects. Nootropil protects and restores cognitive abilities in animals and humans after various cerebral insults such as hypoxia, intoxications and electroconvulsive therapy. It protects against hypoxia-induced changes in brain functionand performance, as assessed by electroencephalographic (EEG) and psychometric evaluations.Nootropil exerts its haemorrheological effects on the platelets, red blood cells, and vessel walls by increasing erythrocyte deformability and by decreasing platelet aggregation, erythrocyte adhesion to vessel walls and capillary vasospasm.Effects on red blood cellsNootropil improves the deformability of the erythrocyte membrane, decreases blood viscosity and prevents rouleaux formation in patients with sickle cell anemia.Effects on plateletsOpen studies with healthy volunteers and with patients have shown that gradually increasing the dose of Nootropil up to 12 g was associated with a dose-dependent reduction in platelet function compared with pretreatment values (tests of aggregationinduced by ADP, collagen, epinephrine and bTG release), without significant change in platelet count. In these studies, Nootropil prolonged bleeding time. Another study in healthy volunteers did not show any statistically significant difference betweenNootropil (up to 12 g b.i.d) and placebo regarding effects on haemostasis parameters and bleeding time.Effects on blood vesselsIn animal studies, Nootropil inhibited vasospasm and counteracted the effects of various spasmogenic agents. It lacked any vasodilatory action and did induce ‘steal’ phenomenon, nor low or neither reflow, nor hypotensive effects. In healthy volunteers,Nootropil reduced the adhesion of red blood cells to the vascular endothelium and directly stimulated prostacyclin synthesis in the healthy endothelium.Effects on coagulation factorsIn healthy volunteers, compared with pre-treatment values, Nootropil up to 9.6 g reduced plasma levels of fibrinogen and von Willebrand’s factors (VIII: C; VIII R: AG; VIII R: vW) by 30–40%, and increased bleeding time. In patients with both primaryand secondary Raynaud’s phenomenon, compared with pretreatment values, Nootropil 8 g/d administered over 6 months reduced plasma levels of fibrinogen and von Willebrand’s factors (VIII: C; VIII R: AG; VIII R: vW (RCF)) by 30–40%, reducedplasma viscosity, and increased bleeding time.PharmacokineticsThe pharmacokinetic profile of Nootropil is linear and time-independent with low inter-subject variability over a wide range of doses. This is consistent with its high permeability, high solubility and minimal metabolism. Plasma half-life of Nootropil is 5hours. It is similar in adult volunteers and in patients. It is increased in elderly patients (primarily due to impaired renal clearance) and in patients with renal impairment. Steady state plasma concentrations are achieved within 3 days of dosing.AbsorptionNootropil is rapidly and extensively absorbed following oral administration. In fasted subjects, peak plasma concentrations are achieved 1 hour after dosing. The absolute bioavailability of Nootropil oral formulations is close to 100%. Food does notaffect the extent of absorption of Nootropil but it decreases Cmax by 17% and increases tmax from 1 to 1.5 hours. Peak concentrations are typically 84 µg/ml and 115 µg/ml following a single oral dose of 3.2 g and repeat dose of 3.2 g t.i.d., respectively.DistributionNootropil is not bound to plasma proteins and its volume of distribution is approximately 0.6 l/kg. It is known to cross the blood-brain barrier as it has been measured in the cerebrospinal fluid following intravenous administration. In cerebrospinal fluid,the tmax was achieved at about 5 hours post-dose and the half-life was about 8.5 hours. In animals, NOOTROPIL highest concentrations in the brain were in the cerebral cortex (frontal, parietal and occipital lobes), in the cerebellar cortex and in thebasal ganglia. Nootropil diffuses to all tissues except the adipose tissues. It crosses placental barrier and penetrates the membranes of isolated red blood cells.BiotransformationNootropil is not known to be metabolized in the human body. This lack of metabolism is supported by its lengthy plasma half-life in anuric patients and by the high rate of recovery of the parent compound in the urine.EliminationThe plasma half-life of Nootropil in adults is about 5 hours following either intravenous or oral administration. The apparent total body clearance is 80–90 ml/min. The major route of excretion is via the urine, accounting for 80–100% of the dose.Nootropil is excreted by glomerular filtration.Renal impairmentNootropil clearance correlated with creatinine clearance. It is therefore recommended that the daily dose of Nootropil is adjusted according to creatinine clearance in patients with renal impairment. In anuric end-stage renal disease patients, the half-lifeof Nootropil is increased up to 59 hours. The fractional removal of Nootropil was 50–60% during a typical 4-hour dialysis session.Hepatic impairmentThe effect of hepatic impairment on the pharmacokinetics of Nootropil has not been evaluated. Because 80 to 100% of the dose is excreted in the urine as unchanged drug, hepatic impairment solely would not be expected to have a significant effect onpiracetam elimination. 49 GPSRC PCP 058 PROM 0608 PIR_Nootropil Slide Kit Vertigo – © UCB PHARMA S.A. 2008. All rights reserved
    50. 50. - Prescribing Information Preclinical safety data The preclinical data include that piracetam has a low toxicity potential. In vitro and in vivo studies have shown no potential for genotoxicity and carcinogenicity. Therapeutic indications In adults Symptomatic treatment of psycho-organic syndrome whose features, improved by treatment, are memory loss, attention disorders and lack of drive. Treatment of cortical myoclonus, alone or in combination Treatment of vertigo and associated disorders of balance, with the exception of dizziness of vasomotor or psychic origin For prophylaxis and remission of sickle cell vaso-occlusive crises. In children Treatment of dyslexia, in combination with appropriate measures such as speech therapy. For prophylaxis and remission of sickle cell vaso-occlusive crises. Dosage Cognitive impairment and post stroke sequelae : 4.8gms per day for 12 weeks. Cerebrovascular insufficiency Initiate treatment with 12 IV infusion (as a bolus given over 20 minutes) followed by 3gm IV infusion every 6 hour for at least 2-4 weeks. Further it is followed by 4.8gm orally for at least 12 weeks. Treatment of myoclonus of cortical origin: Nootropil is effective within a range of 7.2-24 gm/day. The starting dose could be 7.2 gm/day increasing by 4.8 gm/day every 3 days. Treatment of vertigo The recommended dosage of NTP is 2.4- 4.8 gm in BID or TID Treatment of dyslexia in combination with speech therapy NTP in 3.3 gm/day in 2 divided doses or 10 ml TID for one full school year Dosage adjustment Renal impairment The daily dose must be individualized according to Creatinine clearance. Creatinine clearanceSerum creatinine mg/100mlRecommended Dosage60-40 ml/min1.25-1.71/2 usual dosage40-20 ml/min1.7-31/4 usual dosage<20ml/min>3Contraindicated Adverse drug reactions: Psychiatric disorders, central and peripheral nervous system disorders, metabolic and nutritional disorders, were found to be associated as adverse effects with Nootropil. Contraindications • Hypersensitivity to piracetam or other pyrrolidone derivatives or any of the excipients • Patients with severe cerebral hemorrhage • End-stage renal disease patients Pregnancy and lactation • Animal studies have not indicated any direct or indirect harmful effects on pregnancy, embryonal/fetal development, parturition or post-natal development. • Insufficient data are available on the use of Nootropil in pregnant women. Nootropil should not be used during pregnancy unless absolutely necessary. • Nootropil is excreted in human breast milk and should be avoided during breastfeeding. PRESENTATION Nootropil tablets: Each film coated tablet contains Piracetam 800 mg and 1200 mg. Strip of 30 tablets. Nootropil Syrup: Each 5 ml contains Piracetam 500 mg. Bottle of 100 ml. Nootropil Injection Each ml contains Piracetam 200 mg. Bottle of 60 ml. Box of 4 ampoules of 15 ml each. Should any complaint arise, please mention the batch control number indicated on the package. UCB India Ltd. 133/2, G.I.D.C., Selvas Road, VAPI 396 195 ®Regd. Trade Mark of UCB, Belgium. 50GPSRC PCP 058 PROM 0608 PIR_Nootropil Slide Kit Vertigo – © UCB PHARMA S.A. 2008. All rights reserved

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