PD is named after James Parkinson, an English physician, in 1817. He observed patients with this disease and called it ‘shaking palsy’. Later it was discovered that this is not exactly palsy but the stiffness is due to the rigidly increased muscle tone which manifests throughout the disease. Bulgaria has also contributed to the world history with the work of Ivan Raev who discovered treatment for parkinsonism, particularly for von Economo encephalitis. He isolated atropine from the herb belladonna called ‘cura bulgara’. Thus he managed to cure the Queen of Italy Elena di Savoia as a result of which he was honored with the title of ‘doctor’. As of today, as a token of appreciation, an Italian hospital is named after Ivan Raev. PD is a chronic, progressive, degenerative disorder with a morbidity rate of more than 1% of the world population at the age of over 60 years. It is caused by the loss of dopaminergic neurons in substantia nigra, gliosis, and accumulation of Lewy bodies. The balance between the suppressive neuromediator, dopamine, and the excitatory mediators, glutamate and acetylcholine, is destroyed which leads to imbalance between the direct and indirect path and occurrence of Parkinson’s disease symptoms. As the first symptoms occur, about 50-80% of dopaminergic neurons are already lost. PD is a multifactor disorder in the genesis of which are involved environmental agents, free radicals with toxic effects, genetic and age factors. Genetic studies have discovered PARK 1 to 16 genetic loci associated with the disease. As far as the environmental toxic factors are concerned, a large number of chemical compounds have been discovered with a structure similar to the substance MPTP (metil-phenil-tetrahydro-piridin) which is considered to be involved in the destruction of dopaniergic neurons. The incidence of PD increases with the age as a result of the action of external and internal factors. It is believed that the use of nicotine and caffeine lowers the risk of development of PD. The pathogenesis of the disease is due to the interaction among oxidative stress resulting from released free radicals, excitotoxicity and inflammatory changes.

PD can be classified as follows:

A) By onset of the disease:
1) Juvenile onset: Below the age of 20
2) Early onset: Between the age of 21 and 40 years
3) Adult onset: Above the age of 40 years

B) By symptoms:
1) Tremor dominant form
2) Akinetic rigid form
3) Mixed form

C) By clinical progression:
1) Slowly progressive
2) Rapidly progressive

D) By heredity:
1) Sporadic
2) Hereditary

E) By stage of progression:
1) Early
2) Late (terminal)

The onset of the disease is undistinguishable and the symptoms are nonspecific, such as tiredness, loss of the sense of smell, pain in the joints. The patients complain of loss of dexterity, difficulty in writing, and tightness of limbs. With PD there are motor, autonomous and mental symptoms. It is characterized by three general symptoms: resting tremor, rigidly increased muscle tone, bradykinesia (slowness of movements). Early onset PD, the so called ‘honeymoon’, is the period from the moment of the first symptoms to the occurrence of motor fluctuations. The first 3-4 years following the first complaints are characterized by comparatively good compensatory possibilities in terms of treatment and management of symptoms. Initially the symptoms occur in one limb, usually the arm, then the leg on the same side is affected, and later the other two limbs. The progression of the disease is individual but, in general, in case of early onset the progression is slower, and in case of adult onset the progression is more rapid. Practically, it is believed that 10 years after onset of the Parkinson’s disease the patient enters into the late phase of the disease characterized by marked motor fluctuations, such as dyskinesias, dystonias, ‘on-off’ phenomena, quick reduction of the effect of a single dose of levodopa (‘wearing off’ phenomenon), freezing phenomenon, narrowing the therapeutic window, need of higher doses if medicines, non-motor symptoms, etc. Dyskinesias and dystonias are involuntary movements in the body and limbs which occur throughout the disease or as a result of the levodopa treatment. These disorders often are disabling and interfere with the patients’ daily activities. The off-period is characterized by the occurrence of unpredictable numbness or slowness of movements. Wearing-off effect means that the effect of a single dose of the medicine has reduced. With the progression of the disease, the period in which the patient feels well after intake of the medicine gets shorter, i.e. if it used to be 4 hours it may be reduced to 1.5 - 2 hours. The freezing phenomenon is characterized by a sudden impossibility of the patient to lift their feet while walking, i.e. they remain stuck to the floor; this effect may last from several seconds to several minutes. The autonomic disorders include urinary problems (frequent urination, nocturia), or sexual problems (decreased or increased libido, erection problems), cardiovascular symptoms, gastrointestinal disorders (most common of which is constipation), etc. The sleep disorders with insomnia (sleeplessness) and night-time akinesia are very common. The neuropsychiatric disorders include cognitive impairment, dementia, depression, psychoses, hallucinations, delirium, as the latter are often due to side effects of the treatment.
The PD diagnostics is based on anamnestic data, neurological assessment and tests (electromyography), pharmacological diagnostic samples, neuroimaging methods (CT, MRT, SPECT). The differential diagnosis is hard to make and includes a wide range of diseases, such as different types of tremor, Parkinson-plus syndromes, Wilson’s disease, Alzheimer’s disease, neuroleptic-induced parkinsonism, vascular parkinsonism, etc.
The PD treatment is symptomatic and aimed at the dopamine metabolism; the aim is to restore dopamine, slow down its decomposition and re-uptake. Contemporary treatment requires a levodopa-sparing therapy, i.e. treatment with other agents is started and levodopa is added at a later stage. The early-onset PD is treated with neuroprotective agents slowing down the progression of the disease. MAO-B inhibitors (rarasagiline, selegiline) and dopamine agonists (mirapexin, pramipexol, ropinirole) are used and when their effect is reduced levodopa is added. An antidepressant drug often has to be included. When patients enter a late PD stage the response to treatment becomes considerably difficult to be maintained and, therefore, the doses of medications have to be increased and the intervals between intakes have to be reduced. Thus, some of them may manifest their side effects, patients experience dyskinesias and dystonias. The severity of complications is greater and their onset is earlier when the patient is treated with high doses of levodopa. The pulsed release of levodopa and dopamine into the brain causes the occurrence of dyskinesias and motor fluctuations. Usually, after 5 years of levodopa treatment, 50% of the patients develop complications of Parkinson’s disease and within 10 years after the start of treatment, such complications were developed in 80% of the patients. Besides motor fluctuations, the levodopa treatment causes oxidative stress and speeds up the degeneration of neurons in the substantia nigra due to the generation of free radicals. Usually, the monothearpy is not effective enough at a late PD stage. The combined therapy allows reduction of the doses of levodopa. Besides levodopa, dopamine agonists, COMT-inhibitors and glutamate antagonists are also administered. When the effect of oral drugs is reduced, there are three methods of treatment of patients with terminal PD: DBS (deep brain stimulation), subcutaneous apomorphine, and treatment with Duodopa intestinal gel. DBS is implantation of electrodes in the subthalamic nuclei and ensures continuous dopaminergic stimulation in basal ganglia. It is used in patients with severe tremor or levodopa-induced motor complications. Apomorphine is a dopamine agonist for subcutaneous administration. Duodopa is an entheral gel suspension of levodopa/carbidopa delivered via a portable pump through a permanent probe using a percutaneous endoscopic gastrostomy tube. The medication is infused directly to the duodenum avoiding problems with the gastric passage and competition with the aminoacids. The pulsed delivery of levodopa, which is continuously infused by a computer, is also avoided. It is administered when all other options are used and the motor complications are threatening the patients’ lives. In Bulgaria, patients are successfully treated with Duodopa, and recently the DBS was also adopted as a method for PD treatment.

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) characterized with demyelinating plaques scattered throughout the white matter of the brain and the spinal cord. In the areas of demyelination, gliosis develops which causes ‘multiplication’ of the brain matter which inspired the name of the disease. The incidence of MS varies in the different parts of the world. It increases with distance from the equator in both hemispheres. The Caucasians are more susceptible to developing the disease. A high-risk area with morbidity rate of >30/100,000 people covers North Europe, North America, South Canada and New Zealand. The rest of Europe and Australia with a morbidity rate of 5-29/100,000 fall within the medium-risk area. The low-risk area includes Asia, large part of Africa, Latin America and the Middle East. In Bulgaria, the morbidity rate is estimated to over 40/100,000 people.
Susceptibility to MS is determined by gender; it is more common in women. MS is the disease of young people as it most frequently affects individuals at the ages between 20 and 40 years, with a peak of the disease at about 30 years. Recently, there is a tendency of the disease to increasingly occur among young people of 15-16 years of age. MS is rare after the age of 59 years.
The etiological cause of MS is still not known. Various infectious agents (viruses, bacteria, spirochetes) are identified as its main factors. Most important of them are the viruses of Herpes simplex, rabies, measles, cytomegalovirus, influenza. It is believed that these agents activate human T-lymphocytes using the so called ‘molecular mimicry’. This means that the disease agents produce proteins similar to the proteins of unaffected cells. Therefore, the immune system destructs its own structural units by attacking the pathogenic cause. This is followed by a complex cascade of autoimmune processes resulting in the release of inflammatory factors. They cause changes to the blood-brain barrier and ultimately lead to the destruction of myelin and oligodendrocytes. Myelin is the sheath surrounding nerve cell axon. The nerve current flows through Na channels located in the so called ‘voltage-clamped nodes of Ranvier’. Then the integrity of myelin is damaged, then the nerve current is slowed down and the symptoms of MS occur.
Demyelinating plaques are formed as a result of the process of demyelination. They have a typical positioning, mainly surrounding the small vessels where the inflammatory foci are formed. Plaques are usually localized around the lateral ventricles, corpus callosum, cerebellum, brainstem, optic nerves, and cervical segment of the myelon. Plaques can be fresh (active) with marked manifestations of inflammation (edema, perivascular infiltrates of lymphocytes and macrophages). The myelin is destroyed leading to axon exposure. Development of gliosis can be observed in the chronic inactive plaques.
The symptoms of MS are diverse and significantly vary among different patients and in the different moments of disease progression in a single patient. Some patients with multiple sclerosis may not develop symptoms for different periods of time. Others experience 2-3 seizures per year. Symptoms can be divided in several groups:
1) Sensory disorders: These are one of the most common complaints. They may include numbness, tingling or impaired sensitivity of one or more limbs. Typical symptom is the electric shock-like sensation that occurs when abruptly bending the head forward (Lhermitte's sign). Patients often experience chronic pain in the limbs.
2) Visual disorders: The optic neuritis (retrobulbar neuritis) is the first sign of the disease in approximately 25% of the patients. It is characterized by partial or complete loss of vision of one eye which develops for hours to days. At a later stage, most of the patients develop the other MS symptoms. Some patients experience relapsing retrobulbar neurites.
3) Stem disorders: Double vision, disturbed eye movement, internuclear ophthalmoparesis. They are the results of affected eye movement nerves and brain structures (fasciculus longitudinalis medialis).
4) Motor disorders and muscle weakness: Loss of muscle strength due to pyramidal lesions of deep tendon reflexes and occurrence of pathological reflexes of the Babinski and Rossolimo group, typical loss of abdominal reflexes. Development of mono-, hemi-, para-, or quadriparesis and plegias.
5) Changes in muscle tone: Developing spasticity with difficulty in walking.
6) Coordination disorders: Developing paleocerebellar and neocerebellar syndrome (dysmetria, dysdiadochokinesia, ataxia, slurred speech, intentional tremor). The cerebellar symptoms are one of the most disabling.
7) Pelvic floor dysfunction: Miction disorders with the occurrence of imperative urges to urinate, incontinence (involuntary leakage of urine) or retention (inability to empty the bladder and pass urine).
8) Fatigue syndrome: This is one of the most typical symptoms with multiple sclerosis. It is characterized with the lack of energy and motivations. It is the result of immune dysfunction.
9) Cognitive disorders and mental changes: Depression or euphoria, problems with memory, attention or concentration.
10) Seizures and paroxysmal symptoms: Observed in about 5% of the patients, they can be manifested in partial motor and sensory seizures or generalized tonic-clonic seizures. Paroxysmal tonic spasms or paroxysmal dysarthria can also be observed.
There are four clinical forms of disease progression:
1) Relapsing-remitting form (RRMS): The most common form of all where patients experience exacerbations followed by total or partial remission of symptoms.
2) Primary progressive form (PPMS): It is defined by slow and gradual progression from the very onset of the disease and frequent lack of clear exacerbations.
3) Secondary progressive form (SPMS): With the progression of disease, patients with relapsing-remitting MS convert into secondary progression. It may run with or without further attacks, with progression between cycles.
4) Progressive relapsing form (PRMS): Progression begins from the very onset of the disease. Clear attacks with or without total remission, and constant progression in between-attack periods are observed.

Different clinical, laboratory, neuroimaging and electrophysiological methods are used to diagnose patients with MS. A mild to moderate pleocytosis and increased gamma globulins are observed during the CSF test, or oligoclonality during electrophoresis. Magnetic resonance tomography is the most sensitive method for evidencing MS. There are diagnostic X-ray criteria for dissemination of lesions in time and space. Evidence of dissemination of lesions in space is demonstrated by >1 Т2 lesions present in two of four of the following areas of the CNS: periventricular, juxtacortical, infratentorial, or spinal cord. Dissemination of lesions in time is demonstrated by either a new T2 or contract-enhanced lesion on follow-up MRI. The most typical of all are the lesions located next to the lateral ventricles, corpus callosum or spinal cord. Testing of visual and auditory evoked potentials is also used. Differential diagnosis is used with different diseases that can cause multifocal CNS disorders, such as systemic lupus erythematosus, Sjögren's syndrome and other vasculites, neuroborreliosis, spinocerebellar degeneration, strokes, vitamin B12 deficiency, Wegener’s granulomatosis (WG), etc.
The treatment of MS is administered during exacerbations, in between-attack periods, and symptomatically.
MS during exacerbations is treated with corticosteroids (CS). CS have an anti-inflammatory, immunomodulating and brain-blood-barrier stabilizing action. Often the therapy is pulsed at high CS doses (500÷1000 mg i.v.) The treatment regime varies from three to seven days based on the severity of the attack, followed by a CS therapy with dose tapering.
MS in between-attack periods is treated with beta interferons, glatiramer acetate, immunoglobulins, immunomodulators, immunosuppressants. Beta interferons and glatiramer acetate are medications of first choice which modify the course of the disease. The aim is to extend the attack-free period and reduce the number of exacerbations.
The symptomatic treatment is aimed at influencing the spasticity, chronic fatigue, tremor, pelvic floor dysfunction, pain. Physiotherapy and rehabilitation have an important role in MS therapy.

Essential tremor (ET) is the most common type of tremor belonging to the group of neurodegenerative diseases with hyperkinetic movement disorders. The group of tremors also includes enhanced physiological, Parkinson’s, orthostatic, cerebellum, rubral and psychogenic tremor.
ET is a monosymptomatic disorder, with no other neurological symptoms besides shaking. The disease was reported for the first time in 1836, but only in 1930 it was described in detail by Minor. It is also called ‘familial tremor’ or ‘senile tremor’. It affects 5% of the population and can develop at any age. Three subtypes of ET exist: familial, sporadic and senile. There are data that the first subtype runs in the families and another member of a family can have the same disease. It starts at a younger age, at about 20. The second type starts after the age of 40, and the senile type comes after the age of 65.
While the pathogenesis is still knot known, the studies demonstrated loss of Purkinje cells and accumulation of Lewy bodies in cerebral structures.
There are clinical manifestations of postural tremor (when outstretching arms in front of body) which is more marked in the dominant arm. It can affect the head, lips, chin, voice, and more rarely the legs. It is not characterized by resting tremor, rigidly increased muscle tone and slowness of movement (bradykinesia). ET can manifest mainly as the inability to make fine, directed movements and feeding gets considerably difficult. Any psychoemotional stress tends to make the tremor worse, and the consumption of small amounts of alcohol has been shown to give short term relief from tremor. ET progresses slowly, therefore patients ask a neurologist for help several years after the occurrence of first symptoms.
Based on electromyographic criteria, ET can be divided into two types: Type A of 6-8 Hz frequency and synchronous activity; and Type B of alternating pattern. Type B patients can develop symptoms of Parkinson’s disease at a later stage. A patient is diagnosed with Minor’s essential tremor based on diagnostic clinical and electromyographic criteria.
In differential and diagnostic plan, ET should be distinguished from Parkinson’s tremor which is characterized by mainly resting tremor and the usual age of occurrence is >55-65 years. Rigidly increased muscle done and bradykinesia are observed as part of the Parkinson’s disease. Unlike ET which can be treated with beta-blockers (propranolol) and/or antiepileptics (primidone, gabapentin, clonazepam), Parkinson’s tremor can be treated with anticholinergics and levodopa.
It is assumed that patients with ET have a higher survival rate compared to the rest of the population. The disease does not result in severe disability; however, it can affect the fine movements of arms.
Treatment is administered with specific medications.

Dystonia is defined as a neurological disorder characterized by involuntary, sustained, repetitive, similar muscule contractions that result in twisting movements or abnormal postures of the affected body areas.
The ethiology of different types of dystonia is not entirely clear; however, a significant number of genetic loci have been discovered attributed to the disease. The occurrence of dystonia is due to degenerative changes in different brain structures and tracts, mainly in substantia nigra, nucleus caudatus, thalamus, locus ceruleus, damage to the strio-palido-thalamic links with the premotory cortex. Glutamatergic stimulation and dopaminergic afferentation from substantiа nigra to striatum are important mediatory systems.

Classification of dystonia:
A) By etiology:
1) Primary dystonia (idiopathic)
2) Secondary dystonia (symptomatic)
3) Dystonia-plus syndromes

Primary dystonias are the most common dystonias. They can be of spontaneous or hereditary nature. Secondary dystonias are less common. They are associated with inflammatory and autoimmune diseases, structural and vascular CNS disorders, medication intake, toxins, mental factors. The have a sudden onset and rapid progression. Dystonia-plus syndromes demonstrate additional symptoms, including Parkinson’s syndrome, myoclonic seizures, etc.
B) By the age of onset:
1) Childhood-onset dystonia (0 to age of 12)
2) Adolescent-onset dystonia (age 13 to 20)
3) Adult-onset dystonia (older than the age of 21)
The younger one is at onset, the greater the chance that the disease will be severe and symptoms will spread.
C) By anatomic areas affected:
1) Focal
2) Segmental
3) Multifocal
4) Generalized
5)Hemidystonia

Focal dystonia symptoms are limited to one area of the body, i.e. upper or lower limbs, neck, facial muscles, etc. Focal dystonia oalso includes cervical dystonia (tirticollis), professional dystonias (of typewriters, tailors, artists, piano players): graphospasm, blepharospasm, oromandibular, lingual, pharyngeal and laryngeal (spasmodic) dystonia.
Segmental dystonia affects two connected parts of the body. Examples include craniocervical, brachial and axial dystonia. Multifocal dystonia affects two or more parts of the body which are not connected.
Generalized dystonia affects several parts of the body. Hemidystonia affects only one half of the body.
Some common dystonias include:
Blepharospasm: Belongs to the group of focal dystonias. When combined with oromandibular dystonia, it may be referred to as the Meige’s syndrome. It is characterized with involuntary, bilateral, synchronic muscle contractions around the eye, and is more common in women at the mean age of 50. Contractions increase when watching televisions, reading and driving and will resolve after a period of rest.
Oromandibular dystonia: Affects the muscles of the lower face and jaw. It is more common in women of middle and advanced age. It includes involuntary movements of the lower jab, tongue, lips. Patients tend to shift their lower jaw to the side, make grimaces and often have lip or tongue biting, and difficulty with speaking and chewing.
Cervical dystonia (torticollis spastica): The most common of the focal dystnonias. It begins with neck muscle constriction or pulling the head forwards or backwards, which later affects the position of the head causing it to tilt towards the opposite shoulder. The process affects different groups of muscles. In the event of long-term progression of the disease, muscle contractures and spondylosis changes can be observed in the neck region of the spine accompanied by severe pain. The so called sensory tricks can be used to suppress dystonia, i.e. applying pressure to certain areas of the neck and chin. Cervical dystonia disappears during sleep.
Graphospasm: This is the strong grip of the pen or pencil while writing or strong muscular spasms of fingers. This causes arm contractions and pain, and difficulty with writing.
Acute neuroleptic dystonia: This form belongs to the secondary dystonias and occurs with patients receiving neuroleptic agents immediately after treatment onset. It is more common in young women. Acute neuroleptic dystonia causes muscle spasms and abnormal postures of the body. In most cases it affects the cranial muscles, neck and torso. It can be influenced by the administration of anticholinergic agents and antihistamines.
Late dyskinesia or dystonia: It occurs months or years after neuroleptic treatmet or upon sudden discontinuation of treatment. Similarly, it is more common in women at the age of 50 and more. It involves involuntary movements, such as protruding tongue, making faces, sucking lips, blepharospasm, cervical dystonia, etc. In 50-90% of the cases it disappears spontaneously within one or two years after the end of neuroleptic therapy but it is also possible to persist and progress.
Dyskinesia and dystonia with levodopa treatment: One of the most common complication following continuous levodopa treatment in patients with Parkinson’s disease. There are several types of dyskinesia and dystonia. Dyskinesias at ‘peak concentration of levodopa’ occur with the maximum drug concentration in the blood. Usually they are choreiform movements. With the so called two-phase dyskinesias, changes can be observed immediately upon increase, or decrease, respectively, of the plasma concentration of levodopa. They seem to reduce and even disappear at peak plasma concentrations. Such dyskinesias are very hardly tolerated by patients; they are also a therapeutic issue for neurologists.
Treating them is not easy. However, different groups of medicines can be used: anticholinergic agents, dopamine receptor antagonists, GABAergic and noradrenergic agonists, tricyclic antidepressants, botulinum toxin, stereotaxic thalamotomy, etc. Botulinum toxin is the most effective treatment of focal dystonias.