Category Archive Autoimmune and Rare Diseases A – Z

HELLP Syndrome – Causes, Symptoms, Treatment

HELLP syndrome means Hemolysis, Elevated Liver enzymes, and Low Platelets otherwise referred to as HELLP syndrome, has historically been classified as a complication or progression of severe preeclampsia. This progression, however, has been challenged with recent publications that suggest these pathologies have their own etiologies. This activity reviews the evaluation and treatment of HELLP syndrome and highlights the role of the interprofessional team in the care of patients with this condition.

HELLP syndrome is a group of symptoms that occur in pregnant women who have:

  • H: hemolysis (the breakdown of red blood cells)
  • EL: elevated liver enzymes
  • LP: low platelet count

The syndrome of hemolysis, elevated liver enzymes, and low platelets, otherwise referred to as HELLP syndrome, has historically been classified as a complication or progression of severe preeclampsia. This progression, however, has been challenged with recent publications that suggest these pathologies have their own etiologies. Although there is still an overlap between pre-eclamptic pregnant women who develop HELLP syndrome, their association is not as straightforward as once thought to be. Genetic analysis of the inheritability of predisposition for preeclampsia and/or HELLP syndrome in pregnancy has also been explored. Results show both genetic and immunological factors that play a role in pathogenesis.

Classification

A classification system, which was developed in Mississippi, measures the severity of the syndrome using the lowest observed platelet count in the patients alongside the appearance of the other two main clinical criteria. Class I is the most severe, with a relatively high risk of morbidity and mortality, compared to the other two classes.[rx]

  • Class I HELLP syndrome is characterized by a platelet count below 50,000/µL.
  • Class II HELLP syndrome is characterized by a platelet count of 50,000-100,000/µL.
  • Class III HELLP syndrome is characterized by a platelet count of 100,000-150,000/µL.

Another classification system, introduced in Memphis, categorizes HELLP syndrome based on its expression.

  • Partial expression of the condition is characterized by the manifestation of one or two of the main diagnostic criteria.
  • The complete expression of the condition is characterized by the manifestation of all three main diagnostic criteria.[rx]

Causes of HELLP Syndrome

Although the precise etiology of HELLP syndrome has not been established, current hypotheses include genetic mutations (both maternal and fetal) as well as an inflammatory origin. A review published in 2013 expressed that poor placentation in the early stages of pregnancy could account for the subsequent development of preeclampsia. Similarly, HELLP syndrome entails poor placentation during early pregnancy in conjunction with hepatic and coagulation cascade involvement. Studies done on women diagnosed with early HELLP syndrome showed clinical and laboratory value improvement when taking complement C5 protein inhibitors.

The maternal immunologic response can impair placentation as early as the first trimester by affecting trophoblast cell invasion. One case series found that fetal deficiency in long-chain 3-hydroxy acyl-coenzyme A dehydrogenase, not just maternal enzyme deficiency alone, was linked to maternal development of HELLP syndrome as well as fatty liver, providing strong evidence that the fetal-maternal interaction can cause hepatic disease in mothers carrying enzyme-deficient fetuses. Evidence from these studies supports genetic testing in affected mothers, partners, and children. Prospective diagnosis can provide the proper counseling of the risks involved to mothers as well as potential harms that come with this type of deficiency in the affected child.

An ischemic-reperfusion injury starts the liver damage in HELLP syndrome. The spiral arteries which fail to remodel because of inadequate trophoblast invasion or defective endothelial apoptosis result in ischemia of the placenta. This causes activation of endothelium, which is accompanied by an increased release of antiangiogenic factors to cause hypertension and proteinuria. It may lead to multiorgan microvascular injury, which is the reason for liver damage in HELLP syndrome. In addition, abnormal oxidation of fatty acids by the fetus and release of metabolic intermediates into the mother’s circulation causes liver and vascular dysfunction. This occurs when the fetus has an inherited defect in mitochondrial fatty acid oxidation. The inflammatory component includes an increase in leukocytes and pro-inflammatory cytokines with a reduction in anti-inflammatory cytokines.

The coagulation cascade is activated by the adhesion of platelets on the activated and damaged endothelium. Platelets release thromboxane A and serotonin, causing vasospasm, platelet aggregation, and further endothelial damage. The cascade only terminates with the delivery of the fetus. This causes the usage of platelets and hence, thrombocytopenia. The red blood cells break down while passing through these platelet-fibrin-rich capillaries, causing microangiopathic hemolytic anemia. Multiorgan microvascular injury and hepatic necrosis lead to the development of HELLP syndrome.

Symptoms of HELLP Syndrome

The physical symptoms of HELLP Syndrome may seem at first like preeclampsia. Pregnant women developing HELLP syndrome have reported experiencing one or more of these symptoms:

  • Headache
  • Nausea/vomiting/indigestion with pain after eating
  • Abdominal or chest tenderness and upper right upper side pain (from liver distention)
  • Shoulder pain or pain when breathing deeply
  • Bleeding
  • Fatigue or feeling unwell
  • Fluid retention and excess weight gain
  • Changes in vision
  • Swelling
  • Pain in the upper right or mid part of the abdomen
  • Blurry vision
  • Nosebleed or another bleeding that will not stop easily (rare)
  • Seizures or convulsions (rare)

HELLP syndrome patients suffer from general discomfort followed by severe epigastric pain or right upper abdominal quadrant pain, accompanied by nausea, vomiting, backache, anemia, and hypertension. Some patients may also suffer from a headache and visual issues. These symptoms may also become more severe at night.[rx][rx]As the condition progresses and worsens, a spontaneous hematoma occurs following the rupture of the liver capsule, which occurs more frequently in the right lobe. The presence of any combinations of these symptoms, subcapsular liver hematoma in particular, warrants an immediate check-up due to the high morbidity and mortality rates of this condition.[rx][rx][rx]

Signs to look for include:

  • High blood pressure
  • Protein in the urine

The most common reasons for mothers to become critically ill or die are liver rupture or stroke (cerebral edema or cerebral hemorrhage). These can usually be prevented when caught in time. If you or someone you know has any of these symptoms, please see a healthcare provider immediately.

Signs and symptoms of HELLP syndrome are the same as for other health conditions. So sometimes HELLP is misdiagnosed as:

  • Flu or other illness caused by a virus
  • Gallbladder disease – The gallbladder is an organ under your liver that stores bile, a fluid your liver makes to help the body break down fat.
  • Hepatitis. This is inflammation (swelling) of the liver.
  • Idiopathic thrombocytopenic purpura (also called ITP) – This is a bleeding disorder. If you have ITP, you may bruise easily or have a lot of bruising (also called purpura). You also may bleed easily or heavily. For example, you may have bleeding from the gums or nose or bleeding into the skin that looks like a rash of pinpoint red spots.
  • Lupus flare – A lupus flare is a period of time when you have many or intense lupus symptoms. Lupus is an autoimmune disorder that can cause health problems during pregnancy. Autoimmune disorders are health conditions that happen when antibodies (cells in the body that fight off infections) attack healthy tissue by mistake. Lupus and other autoimmune disorders can cause swelling, pain, and sometimes organ damage. Lupus also can affect joints, skin, kidneys, lungs, and blood vessels.
  • Thrombotic thrombocytopenic purpura – This is a rare condition that causes blood clots to form in small blood vessels throughout the body. These clots can cause serious health problems if they block the flow of blood to organs, like the brain, kidneys, and heart.

What health problems can HELLP cause?

HELLP syndrome can cause:

  • Bleeding and blood clotting problems. Some women with HELLP develop disseminated intravascular coagulation (also called DIC). This is a blood clotting disorder that can lead to heavy bleeding (also called hemorrhage).
  • Fluid buildup in the lungs (also called pulmonary edema). This can cause breathing problems.
  • Kidney failure
  • Liver hemorrhage or failure
  • Placental abruption. This is a serious condition in which the placenta separates from the wall of the uterus before birth.

Diagnosis of HELLP Syndrome

One of the features of HELLP syndrome is microangiopathic hemolytic anemia. Schistocytes or helmet cells, present on a peripheral blood smear is diagnostic of microangiopathic hemolytic anemia, making peripheral smears useful in the workup for HELLP syndrome. In the liver, intravascular fibrin deposits give rise to sinusoidal obstruction, intrahepatic vascular congestion, increased hepatic pressures leading to hepatic necrosis. This may eventually result in intraparenchymal or subcapsular hemorrhage and capsular rupture.

History and Physical

The average gestational age of presentation of HELLP syndrome is 34 weeks. The majority of women with HELLP syndrome have hypertension and proteinuria prior to diagnosis. Patients are usually multiparous and over the age of 35 years old. Patients are often overweight and have edema in 50% of the cases. Many present with right upper quadrant or epigastric colicky pain with nausea and vomiting. This is usually preceded by malaise 1 to 2 days earlier. 30% to 60% also have a headache, and 20% have a visual disturbance. The condition exacerbates during the night. The symptoms continuously progress.

Lab Test and Imaging

Apart from the clinical signs and symptoms, laboratory investigations are required to diagnose HELLP syndrome. Two classifications are used to diagnose HELLP syndrome: Tennessee and Mississippi.

Main diagnostic criteria of the HELLP syndrome

The Tennessee classification system diagnostic criteria for HELLP are:

  • Hemolysis
  • Increased LDH (> or =600 IU/L)
  • Increased AST (>or =70 IU/L)
  • Low platelets (< 100 x 10(9)/L)

The HELLP syndrome may be complete or incomplete.

Mississippi classification measures the severity of the syndrome using the lowest observed platelet count along with the other two main clinical criteria (LDH and AST). Class I is the more severe, with a relatively high risk of morbidity and mortality, compared to the other two classes.

  • Class I HELLP syndrome is characterized by a platelet count below 50,000/microL. (LDH> or=600 IU/L, AST> or= 70 IU/L)
  • Class II HELLP syndrome is characterized by a platelet count of 50,000 to 100,000/microL. (LDH> or=600 IU/L, AST> or=70 IU/L)
  • Class III HELLP syndrome is characterized by a platelet count of 100,000 to 150,000/microL. (LDH>OR=600 IU/L, AST> or= 40 IU/L)

There is a general consensus regarding the main three diagnostic criteria of HELLP syndrome, which include hepatic dysfunction, thrombocytopenia, and microangiopathic hemolytic anemia in patients suspected to have preeclampsia.

  • A blood smear will often exhibit abnormalities, such as schistocytes, bur cells, and helmet cells, which indicate erythrocyte damage.
  • Thrombocytopenia, which is the earliest coagulopathy present in all HELLP syndrome patients, is indicated by low platelet count (below 100 x 109 L-1) or by testing the levels of fibrin metabolites and antithrombin III.
  • Elevated serum levels of certain proteins, in particular, LDH, alanine transaminase (ALT), and aspartate transaminase (AST), are indicative of hepatic dysfunction. Extremely high serum levels of these proteins, specifically LDH levels > 1,400 IU/L, AST levels > 150 IU/L, and ALT levels > 100 IU/L, significantly elevate the risk of maternal mortality.

A number of other, but less conclusive, clinical diagnostic criteria are also used in diagnosis alongside the main clinical diagnostic criteria for HELLP syndrome.

  • De novo manifestation of hypertension with systolic pressure and diastolic pressure above 160mmHg and 110 mmHg, respectively.
  • Proteinuria, leucocytosis, and elevated uric acid concentrations > 7.8 mg.
  • Decreased serum haptoglobin and hemoglobin levels.
  • Increased serum bilirubin levels and visual disturbances.[rx][rx]

Imaging tests, such as ultrasound, tomography, or magnetic resonance imaging (MRI), are instrumental in the correct diagnosis of HELLP syndrome in patients with suspected liver dysfunction. Unurgent cases must undergo MRI, but laboratory tests, such as glucose determination, are more encouraged in mild cases of HELLP syndrome.[rx][rx]

Treatment of HELLP Syndrome

Given the lack of clinical trials for the management of HELLP syndrome based on the gestational age of presentation, many treatments are experimental in nature, and there has been little significance in the improvement of perinatal outcomes between expectant management versus delivery before 34 weeks. That being said, the course of true HELLP syndrome has the potential to quickly turn life-threatening for both mother and fetus. Therefore the recommendation is always to hospitalize patients for strict monitoring of laboratory values. During hospitalization, patients should be treated as severely pre-eclamptic and should receive magnesium sulfate for seizure prophylaxis along with blood pressure control with hydralazine, labetalol, or nifedipine in the usual recommended fashion.

Maternal-fetal monitoring should be performed throughout each step of management since typically, immediate delivery is recommended for true HELLP patients except those with stable maternal-fetal conditions between 24 to 34 weeks gestation. For this group of patients, a recommendation is to give corticosteroids (betamethasone 12mg intramuscular every 12 hours for 2 doses or dexamethasone 12mg intravenously every 12 hours for 4 doses) then deliver 24 hours after the last dose. Steroid administration is not only beneficial to the fetus for lung maturity but also for the improvement of laboratory values in patients, particularly in elevating platelet counts. Some patients may benefit from transfusions of red cells, platelets, and plasma. A study performed to assess the rate of epidural anesthesia in patients with HELLP saw an increase in rates of neuro-axial anesthesia in those who achieved a latency period after the administration of steroids.

Differential Diagnosis

HELLP syndrome should be differentiated from other disorders of pregnancy with similar features:

  • Pre-eclampsia: It has normal liver enzymes and platelet count. Schistocytes are also absent.
  • Acute fatty liver of pregnancy (AFL): Hypoglycemia is present in AFL but absent in HELLP syndrome.
  • Thrombotic thrombocytopenic purpura (TTP): It usually manifests in 2nd or 3rd trimester, and liver abnormalities are not as elevated as in HELLP syndrome. Patients are typically normotensive and have undetectable ADAMTS 13 activity.
  • Hemolytic-uremic syndrome (HUS): It has the same findings as TTP except that its incidence is higher in the post-partum period, and patients have signs of renal failure.
  • Lupus flare: Liver pathology is absent in lupus.
  • Antiphospholipid syndrome (APS): Dominant features of APS are arterial/venous thrombosis and repeated pregnancy loss. Lupus anticoagulant, cardiolipin antibodies, beta-glycoprotein antibodies, prothrombin time (PT), and an activated partial thromboplastin time (aPTT) should be checked to confirm the diagnosis.
  • Other: Viral hepatitis, cholecystitis, cholangitis, gastritis, gastric ulcer, acute pancreatitis, upper UTI.

Prognosis

HELLP syndrome is a life-threatening condition. The mortality rate of women with HELLP syndrome is 0%-24%, with a perinatal death rate of up to 37%. Maternal death occurs due to disseminated intravascular coagulation (DIC), placental abruption, postpartum hemorrhage, or acute renal failure. DIC occurs in 15% to 62.5% of the cases. Placental abruption occurs in 11% to 25% of women with HELLP syndrome. Postpartum hemorrhage occurs in 12.5% to 40% and acute renal failure in 36% to 50% of the cases. Poor perinatal prognosis is because of placental abruption, intrauterine hypoxia and asphyxia, prematurity, and low birth weight.

Patients with HELLP syndrome have a 19%-27% risk of developing HELLP syndrome in subsequent pregnancies. Class 1 HELLP syndrome has the highest recurrence rate. Recurrent cases occur in the latter part of the gestation period and are less severe after two episodes.

Early diagnosis and treatment, along with maternal and neonatal intensive care, can help to reduce the mortality in HELLP syndrome.

Complications

HELLP syndrome is a life-threatening condition with high maternal and infant mortality rates. Maternal complications include

  • Eclampsia
  • Placental abruption
  • Cesarean section
  • DIC
  • Recurrent thrombosis
  • Liver rupture
  • Cerebral infarction
  • Cerebral hemorrhage
  • Pulmonary/cerebral edema
  • Cardiovascular instability
  • Acute renal failure
  • Infection/sepsis
  • Maternal death

Fetal complications include

  • Perinatal death
  • Intrauterine growth restriction (IUGR)
  • Preterm delivery
  • Neonatal thrombocytopenia
  • Respiratory distress syndrome

Complications may include:

  • Poor blood flow to your organs
  • Seizures
  • Anemia
  • Blood clotting problems
  • Placenta problems
  • Liver problems
  • Fluid buildup in your lungs
  • Early delivery

If HELLP syndrome is severe, you and your baby may be in danger. You may need to deliver the baby early to prevent more problems. It may take several days after delivery to recover from HELLP syndrome.

Next steps

Tips to help you get the most from a visit to your healthcare provider:

  • Know the reason for your visit and what you want to happen.
  • Before your visit, write down questions you want to be answered.
  • Bring someone with you to help you ask questions and remember what your provider tells you.
  • At the visit, write down the name of a new diagnosis, and any new medicines, treatments, or tests. Also, write down any new instructions your provider gives you.
  • Know why a new medicine or treatment is prescribed, and how it will help you. Also, know what the side effects are.
  • Ask if your condition can be treated in other ways.
  • Know why a test or procedure is recommended and what the results could mean.
  • Know what to expect if you do not take the medicine or have the test or procedure.
  • If you have a follow-up appointment, write down the date, time, and purpose for that visit.
  • Know how you can contact your provider if you have questions.

References

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Bernard-Soulier Syndrome – Causes, Symptoms, Treatment

Bernard-Soulier syndrome is a rare inherited blood clotting disorder that is characterized by unusually giant platelet cells, thrombocytopenia, and prolonged bleeding time. Affected individuals tend to bleed excessively and incur spontaneous ecchymoses. This activity reviews the evaluation and treatment of Bernard-Soulier syndrome and highlights the role of the healthcare team in evaluating and managing patients with this condition.

Bernard-Soulier syndrome (BSS) is an extremely rare inherited blood clotting disorder that is characterized by giant platelet cells, thrombocytopenia, and prolonged bleeding time. In 1948, Jean-Bernard and Jean-Pierre Soulier described the first male patient who presented with repeated episodes of bleeding throughout his life and eventually died at the age of 28 years from an intracranial hemorrhage sustained after a bar fight. BSS involves a defect of the GPIb-IX-V complex, an essential platelet receptor complex that principally binds with the von Willebrand factor (vWF). However, it has multiple other functions in inducing thrombosis and hemostasis.

Causes of Bernard-Soulier syndrome

BSS is the result of genetic mutations encoding for GPIb-alpha (GPIBA), GPIB-beta (GPIBB), and GPIX (GP9), which are 3 of the four subunits that make the GPIb-IX-V complex. Nearly 112 mutations were identified in a study of nearly 211 families with BSS. The mutations were mainly identified in the GP1BA (28%), GP1BB (28%), or GP9 (44%) genes. These mutations are heterogeneous and could be nonsense, missense, frameshift, deletion, or insertion. The majority of these mutations inherited in an autosomal recessive pattern; however, rare cases of autosomal dominant inheritance have been reported. Patients with mutations in both alleles (autosomal recessive inheritance) are referred to as having biallelic BSS (bBSS), and those with a mutation in only a single allele (autosomal dominant inheritance) are often referred to as monoallelic BSS (mBSS).

The GPIb-IX-V complex is expressed on the platelet surface. By facilitating platelet adhesion to the subendothelium, the GPIb-IX-V complex leads to clot formation whenever the vascular subendothelium is exposed or a plaque ruptures, hence the activity of the GPIb-IX-V complex is also critical in deep venous thrombosis (DVT).

The most important function of the GPIb-IX-V complex is to bind with VWF and initiate a signaling cascade that would activate the platelet integrin GPIIb-IIIa leading to platelet aggregation. Although VWF is also a weak agonist, a full activation signal is required via the thromboxane A2 and ADP-dependent signaling pathway to activate the platelets.

The N-Terminal of GPIb-Alpha plays a critical role in platelet mediated coagulation by providing binding sites to high molecular weight (HMW) kininogen, Factors XI, and XII and alpha-thrombin. The same N-terminal of GPIb-alpha is a primary binding site for multiple ligands. It serves as a pivotal point for the cross-talk between platelets and leukocytes in thrombosis and inflammatory response.

The GPIb-IX-V also plays a role in maintaining platelet shape by linking the platelet surface to a sub-membranous network of actin filaments, the platelet membrane skeleton. This involves the central portion of the cytoplasmic tail of GPIb-alpha, particularly Phe568 and Trp570, which provides a binding site for the actin-associated protein, filamin A.

Considering all the functions of the GPIb-IX-V complex, one can understand that a mutation in the encoding genes could lead to reduced activation of the platelets, defective adhesion, and subsequently inadequate clot-forming capability. In addition to this, the defects in the complex can also explain the giant platelets in patients with BSS.

Diagnosis of Bernard-Soulier syndrome

The typical presentation of Bernard-Soulier syndrome starts at birth and continues throughout life. It is characterized by bleeding from different sites, epistaxis, cutaneous bleeding, hemorrhage post-trauma, e.g., brain hemorrhage after head trauma, prolonged bleeding after dental procedures, and heavy menstrual bleeding in females. More rarely reported symptoms are gastrointestinal bleeding and hematuria. Clinical features could be limited to unexplained purpura or bruising only. On the other hand, bleeding could be fatal in about 16% of reported cases. Spontaneous intracranial hemorrhage or intraarticular hemorrhages are not common. Fatalities from BSS are very rare.

The patients with BSS who present in adulthood are usually those with mBSS. Such patients have less bleeding episodes due to preserved platelet numbers. A significant monoallelic mutation is the ‘Ala156Val’ mutation in the GPIB-alpha, called the Bolzano mutation. Although most patients will only have mild thrombocytopenia, and infrequent bleeding episodes, a few patients have been described where the bleeding was very severe. Similarly, other mutations have also been described where only mild thrombocytopenia was noted with mild bleeding episodes.

The International Society on Thrombosis and Haemostasis Bleeding Assessment Tool (ISTH-BAT) is a useful assessment tool for assessing bleeding disorders. Its utility was tested in a small study, including patients with known inherited platelet disorders. The study demonstrated a specificity of 100%, a positive predictive value of 90%, and a negative predictive value of 100% with the use of this assessment tool. Similarly, other bleeding assessment tools like Molecular and Clinical Markers for the Diagnosis and Management of type 1-VWD and World Health Organization Bleeding Assessment Tool are also present for similar purposes. An electronic version of MCMDM-type-1 vWD was developed in 2010.

Test and Imaging

BSS should be considered in the differential diagnosis of any patient who presents with a prolonged bleeding history, especially if the bleeding history started from early childhood.

Most patients with BSS have a platelet count between 20 to 100 billion/L. However, a count as low as 10 x 10^9/L has been reported. The peripheral smear would usually present with thrombocytopenia and large platelets. The bleeding time is significantly prolonged. The platelet function analyzer (PFA-100) closure time is prolonged, usually in the adenosine-diphosphate (ADP) and epinephrine cartridges.

The platelet aggregation studies (also called light transmission aggregometry) demonstrate a reduced response to ristocetin that is not corrected by the addition of normal plasma. This feature helps to distinguish BSS from von Willebrand disease (VWD). The responses to ADP, collagen and arachidonic acid are normal. However, in a few patients, platelet aggregation in response to thrombin is reduced.

Flow cytometry of platelet glycoprotein is a confirmatory test. It demonstrates marked reduction of CD42a (GPIX) and CD42b (GPIb-alpha). Since flow cytometry requires only small volumes of blood, this is an appropriate test for neonates, infants, and young children. Molecular genetics can identify genetic abnormalities and identify affected family members as well.

In patients with mBSS, specifically, in those with Bolzano mutation or other similar mutations, the GPIb-IX-V complex is present in normal numbers, albeit is defective and cannot bind to VWF. In such patients, the near absent ristocetin-induced platelet aggregation serves as a good diagnostic tool. It is crucial to maintain a high index of suspicion in such patients and pursue molecular testing.

Treatment of Bernard-Soulier syndrome

Preventive Care

  • Patients diagnosed with BSS should be educated extensively about the risks of bleeding. They should carry ‘alert cards’ or wear ‘alert bracelets’ clearly identifying the diagnosis of BSS. They should be registered with a center that can provide emergent treatment 24 hours a day should they present with a bleeding episode. The patients should also be educated on maintaining dental hygiene, avoiding high-risk sports (especially contact sports), and applying pressure for epistaxis.
  • Patients, their family members, and their providers should be advised extensively over which medications can increase the risk of bleeding (anti-histamines, non-steroidal anti-inflammatory drugs, and certain antibiotics). Similarly, foods, beverages, and herbal medicines that can affect the platelet function or number must be avoided.
  • All patients with BSS, especially women, can suffer from iron deficiency due to excessive bleeding and should be monitored closely for the same and supplemented with iron if needed.
  • HLA-typing should be done for each patient at the time of diagnosis. All attempts should be made to procure HLA-matched platelets before transfusion.

Treatment Directed Towards Bleeding Episodes

  • Platelet transfusions – These are the first line of treatment in patients with BSS, who present with acute hemorrhage or are preparing for elective surgery. However, with each transfusion comes the risk of alloantibody formation and a minuscule risk of transmission of pathogens.

    • Transmission of bacteria – As platelets are stored at a higher temperature (20 to 24 degrees Celcius), there is always a risk of bacterial growth and transmission. The risk is much higher with whole-blood-derived platelets compared to apheresis-derived platelets.
    • Alloimmunization – HLA-matched platelets are ideal for transfusion; however, they may not be available in emergent conditions.
    • Antibodies against glycoproteins – Although this is a more common phenomenon in patients with Glanzman thrombocytopenia (GT); patients with BSS can also develop antibodies against glycoproteins that they lack.
  • Antifibrinolytic therapy – Tranexamic acid has been used successfully in the management of mucocutaneous bleeding, menorrhagia, in conjunction with local efforts like nasal packing, compression sponges, hormonal treatment, etc. However, the use of antifibrinolytics should be avoided in patients with pulmonary hemorrhage or those with active hematuria due to the risk of formation of intraluminal clots leading to respiratory failure and renal failure, respectively.
  • Desmopressin (DDAVP) – Releases vWF from the platelets. Due to a defective GPIB-IX-V complex, the utility of DDAVP in the management of BSS is severely limited. Only anecdotal reports suggest the use of DDAVP. However, clinicians must be aware of the potential adverse effect of severe hyponatremia and seizures associated with repeated DDAVP use.

Potentially beneficial strategies not approved for patients with BSS

  • In a small phase II clinical trial, the thrombopoietin receptor agonist, Eltrombopag, was successfully used in increasing the platelet count in patients diagnosed with inherited thrombocytopenias. One of the five patients had monoallelic BSS. Eltrombopag is not approved for treating thrombocytopenia secondary to BSS.
  • Recombinant factor VII (rfVII) has been approved for use in patients with Glanzmann’s thrombasthenia (GT), but not in patients with BSS. There are reports of successful use of rfVII in patients with BSS. The United Kingdom Haemophilia Centre Doctors’ Organisation (UKHCDO) 2006 guidelines and the British Society of Haematology (BSH) platelet transfusion guidelines both recommend the use of recombinant factor VII (rfVII) in patients with GT or BSS in the event of severe bleeding.
  • Allogeneic stem cell transplant has been used in patients with BSS. However, there is scarce data. This is usually reserved for patients with too many antibodies and with a severe bleeding disorder.

Pregnancy in patients with BSS requires special consideration.

  • Counseling prospective parents: Identify potential risk factors (consanguineous marriage, parents are carriers, etc.) for the fetus to develop BSS. In women with BSS, the potential risk of hemorrhage should be discussed. Neonates will not develop homozygous BSS unless both parents are carriers.
  • Antenatal: Manage specialized units in consultation with high-risk obstetrics and hematology. The mother should be checked for HLA type, anti-platelet antibodies, and assessed for the risk of developing neonatal alloimmune thrombocytopenia (FNAIT).
  • Labour: Neuraxial anesthesia is contraindicated as hemostasis cannot be guaranteed. The use of uterotonics is encouraged in the second stage of labor. HLA-matched platelets and tranexamic acid should be used if needed. The rfVII can be used in severe bleeding.
  • Post-partum: All patients must be monitored for eight weeks, at least for bleeding symptoms.
  • Neonates: The risk of FNAIT is high, especially in mothers diagnosed with BSS requiring multiple platelet transfusions throughout their lives. Such patients have anti-GPI antibodies that can cross the placenta and affect the normal platelets of the neonate. Monitor the blood count of neonates very closely.

Differential Diagnosis

The differential diagnosis for BSS starts with considering a wide variety of bleeding disorders, including factor deficiencies. Mucocutaneous bleeding, coupled with large platelets and thrombocytopenia, points towards a platelet disorder. The presence of large platelets or thrombocytopenia on peripheral smear review is NOT a feature of hemophilia.

Immune Thrombocytopenia

Many patients with BSS are diagnosed with immune thrombocytopenia due to similar presentations. Features that may help in differentiating BSS from ITP are:

  • Presence of family history of ITP
  • Failure to respond to first-line treatment like intravenous immunoglobulin and steroids
  • Typical findings for BSS on light aggregation studies and flow cytometry

Despite this, many patients mistakenly diagnosed with ITP end up receiving splenectomy before being diagnosed with BSS.

Von-Willebrand Disease (vWD)

The patients with type IIB vWD has the closest clinical phenotype with BSS. Due to the increased affinity of large multimers with platelets, the platelets are cleared rapidly, leading to thrombocytopenia. The platelets are also large in type IIB vWD. However, the platelets express an increased aggregation in response to ristocetin. In comparison, patients with BSS always have low to absent aggregation of platelets in response to ristocetin. Also, patients with platelet type vWD carry a mutation in the GP1b-alpha. However, this mutation increases the affinity of platelets to vWF.

Other Inherited Disorders in the Differential Diagnosis of BSS

  • May-Hegglin abnormality
  • Myosin-Heavy chain 9 (MYH-9) disorders
  • Grey Platelet syndrome-lack of intra-platelet granules and confirmed by electron microscopy.
  • Paris Trousseau Platelet disorder (PTPD) – deletion of the terminal end of the long arm of chromosome 11 that includes band 11q24.1, 11q terminal deletion disorder.
  • DiGeorge syndrome (DGS); velocardiofacial syndrome (VCFS, or Shprintzen syndrome); conotruncal anomaly face – all syndromes share the microdeletion of chromosome 22q11.2 – Patients usually are heterozygotes for BSS.
  • Mediterranean macrothrombocytopenia

Rare cases of autoantibody to GPIb complex have been described, which are called Pseudo-BSS.

Complications

Patients with BSS frequently suffer from bleeding complications due to the nature of the disease. Other complications include:

  • Transmission of bloodborne pathogens – although the risk is minimal due to extensive screening of blood products. Still, bacterial transmission can occur due to platelets being stored at a higher temperature.
  • Development of autoantibodies due to repeated blood transfusions.
  • Iron deficiency anemia, especially in women who suffer from menorrhagia- results in constant fatigue and loss of work hours.
  • Transmission of antibodies across the placenta may lead to fetal/neonatal alloimmune thrombocytopenia.

References

 

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Wiskott-Aldrich Syndrome – Causes, Symptoms, Treatment

Wiskott-Aldrich syndrome (WAS) is a rare X-linked disorder that classically includes the characteristic triad of immunodeficiency, thrombocytopenia, and eczema. It results from a genetic mutation in the gene encoding the Wiskott-Aldrich syndrome protein (WASp). The disease has variable presentation ranging from the severe phenotype (classic WAS) to milder ones (X-linked thrombocytopenia and X-linked neutropenia). This activity describes the pathophysiology, etiology, presentation, and evaluation of Wiskott-Aldrich syndrome, and highlights the role of the interprofessional team in the management of affected patients.

Wiskott-Aldrich syndrome is a rare X-linked disorder with a characteristic triad of immunodeficiency, thrombocytopenia, and eczema. It results from a genetic mutation in the gene encoding Wiskott-Aldrich syndrome protein (WASp) affecting the immune system and inducing a state of immunodeficiency. The disease follows a broad spectrum depending on gene mutations ranging from severe phenotype (classic WAS) to milder ones (X-linked thrombocytopenia (XLT) and X-linked neutropenia).

Causes of Wiskott-Aldrich Syndrome

The etiology of Wiskott-Aldrich syndrome is mutations in the WAS gene responsible for the production of WAS protein involved in cellular signaling and immunological synapse formation. These mutations alter the protein configuration in several ways leading to phenotypic variability in disease manifestations.

Wiskott-Aldrich syndrome is the result of an X-linked genetic defect in the WAS gene located on the short arm of the X-chromosome at Xp 11.22-23 position. The gene product Wiskott-Aldrich protein (WASp) is a 502 amino acid protein expressed in the cytoplasm of non-erythroid hematopoietic cells.  More than 300 gene mutations have been identified leading to impaired protein configuration. The most common mutations are missense mutations followed by nonsense, splice site, and short deletion mutations. Because of the wide range of genetic mutations, the disease itself has phenotypic variability ranging from severe (classic WAS) to mild disease X-linked thrombocytopenia and X-linked neutropenia.

As mentioned earlier, the WAS protein expresses in non-erythroid hematopoietic cells where it functions as a bridge between signaling and movement of actin filaments in the cytoskeleton. This ultrastructural component of the cellular architecture is primarily responsible for intracellular and cell-substrate interactions and signaling because of its role in cell morphology and movements. The actin cytoskeleton is involved in various cellular functions such as growth, cytokinesis, endocytosis, and exocytosis. It also has involvement in the formation of an immunologic synapse, which is the site of interaction between T cells and antigen-presenting cells like dendritic cells. The interaction depends on the generation of lipid rafts, which provide a platform to recruit crucial molecules to ensure the stability of the immunologic synapse. In Wiskott-Aldrich syndrome, there is abnormal cytoskeleton reorganization because of impaired gene expression leading to T cell dysfunction causing impaired migration, adhesion, and insufficient interaction with other cells due to abnormal synapse formation; this affects B cells homeostasis resulting in selective depletion of circulating mature B cells splenic marginal zone precursors, and marginal zone B cells.  This event of lymphocyte numbers declining over time is due to accelerated cell death. Circulating natural killer cells are normal or increased, but cytotoxicity of these WAS protein-deficient cells is impeded as a result of impaired immunologic synapse formation. Interleukin-2 can help to restore cytotoxicity in natural killer (NK) cells by inducing the expression of a functionally related protein. Invariant natural killer T cells are completely absent in patients with WAS and X-linked thrombocytopenia, which predisposes patients to increased risks for autoimmunity and cancer. Mechanisms of autoimmunity in WAS include inadequate Treg cell function, B cell-intrinsic loss of tolerance via a positive selection of self-reactive transitional B cells, expansion of autoreactive B cells and production of autoantibodies, impaired Fas-mediated apoptosis of self-reactive lymphocytes, and defective phagocytosis of apoptotic cells resulting in chronic inflammation.

WASp-deficient myeloid lineage cells exhibit impaired phagocytosis and chemotaxis. Also, monocytes, macrophages, and dendritic cells from WASp-deficient patients demonstrate almost completely abrogated assembly of actin-rich structures responsible for cellular migration leading to impaired chemotaxis to specific chemoattractants. The explanation for thrombocytopenia is increased clearance, ineffective thrombocytopoiesis, reduced platelet survival due to intrinsic platelet abnormalities, and immune-mediated events.

Whereas “loss-of-function” mutations in the were gene cause either XLT or WAS, unique “gain-of-function” missense mutations impair the autoinhibitory conformation of the molecule and lead to increased actin polymerization, resulting in congenital neutropenia.

Diagnosis of Wiskott-Aldrich Syndrome

The disease manifests as follows:

  • Bleeding:  Thrombocytopenia is present at birth. It is the most common finding present at the time of diagnosis. Affected patients may present in the first days of life with petechiae and prolonged bleeding from the umbilical stump or after circumcision. Other manifestations may include purpura, hematemesis, melena, epistaxis, hematuria, and such life-threatening symptoms as oral, gastrointestinal, and intracranial bleeding. A subset of infants less than or equal to 2 years of age may present with “severe refractory thrombocytopenia,” possibly due to antiplatelet autoantibody, a complication that is associated with poor prognosis.
  • Immunodeficiency:  The severity of immunodeficiency depends largely on the type of mutations and resulting protein expression. Patients usually present with multiple recurrent infections and failure to thrive. Patients are susceptible to encapsulated organisms as Streptococcus pneumoniaeNeisseria meningitides, and Haemophilus influenzae. Manifestations include otitis media, sinusitis, pneumonia, meningitis, sepsis, and colitis. Splenectomy, which is occasionally performed to decrease the risk of bleeding, further increases the risk of severe infections and sepsis. This immunodeficiency also predisposes patients to opportunistic infections with Pneumocystis jiroveciiMolluscum contagiosum, as well as systemic varicella and cytomegalovirus infection. Fungal infections are relatively rare consisting primarily of mucocutaneous infection due to Candida albicans.
  • Eczema:  Eczema of varying severity develops in approximately one-half of WAS patients during the first year of life and resembles classical atopic dermatitis.
  • Autoimmune manifestations:  Reports exist of autoimmune diseases include hemolytic anemia, neutropenia, vasculitis involving both small and large vessels, inflammatory bowel disease, and renal diseases. A broad spectrum of autoantibodies has been observed both in classic WAS and in XLT.
  • Malignancies:  Malignancies can occur during childhood but are most frequently present in adolescent and young adult males with the classic WAS phenotype. B cell lymphoma (often Epstein-Barr virus-positive) and leukemia are common in a classic WAS but do occur in XLT.

The disease has three main clinical phenotypic manifestations:

  • Classic (severe) Wiskott-Aldrich syndrome:  This is the severe phenotype of WAS. Affected boys present in early childhood with a hemorrhagic diathesis due to thrombocytopenia; recurrent bacterial, viral, and fungal infections; and extensive eczema. Lymphadenopathy is frequently present, especially in those WAS patients with chronic eczema, and hepatosplenomegaly is common. Patients with classic were tended to develop autoimmune disorders and lymphoma or other malignancies, often leading to early death.
  • X-linked neutropenia (XLN):  XLN presents mainly as congenital neutropenia. Patients with XLN present with infections characteristic of neutropenia but may also develop infections associated with lymphocyte dysfunction. These patients also have an elevated risk for myelodysplasia.
  • X-linked thrombocytopenia (XLT):  XLT presents as congenital thrombocytopenia that is sometimes intermittent (IXLT). Eczema is usually mild. These patients generally have a benign disease course and good long-term survival. They still carry an increased risk (lower than that for WAS) for severe events such as life-threatening infections (especially post-splenectomy), serious hemorrhage, autoimmune complications, and cancer. Any male with thrombocytopenia and small platelets should be evaluated for WASp expression and WAS gene mutations.

Test and Imaging

A diagnosis of Wiskott-Aldrich syndrome or X-linked thrombocytopenia (XLT) is a consideration in any male patient who presents with petechiae, bruises, and congenital or early-onset thrombocytopenia associated with small platelet size. For diagnostic confirmation, a deleterious mutation in the WAS gene is necessary. The presence of mild or severe eczema supports the diagnosis. Infections and immunologic abnormalities may be absent, mild, or severe. Autoimmune diseases and malignancies develop more often in patients with classic WAS than in those with XLT. Screening for the presence or absence of WAS protein (WASp) can be performed in lymphocytes by flow cytometry using an anti-WASp antibody. The diagnosis of XLN should be considered in any male patient presenting with severe congenital neutropenia.

  • Immunology:  Abnormal immunologic findings in patients with WAS include decreased number and function of T cells and regulatory T cells, abnormal immunoglobulin (Ig) isotypes, defective antigen-antibody response, impaired cytotoxicity of natural killer cells with normal to increased cell numbers, impaired chemotaxis of neutrophils and phagocytic cells. Absolute lymphocyte counts are usually normal during infancy, but T and B cell numbers decrease later in life in patients with classic WAS. Reported variations in the levels of Ig including normal levels of serum IgG, decreased levels of IgM, and elevated levels of IgA and IgE also exist.
  • Histopathology:  Abnormal findings in lymphoreticular tissue are commonly present, including varying degrees of T cell zone depletion in lymph nodes and spleen, decreased number of follicles and abnormal follicular formation devoid of marginal zone, and regressive or “burned out” germinal centers.
  • Thrombocytopenia and platelet abnormalities:  Thrombocytopenia associated with small platelet volume is a consistent finding in patients with WAS gene mutations, except for those presenting with an XLN phenotype. Platelet counts are generally 20000 to 50000 per mm but may drop below 10000 per mm.

Treatment of Wiskott-Aldrich Syndrome

The management of Wiskott-Aldrich syndrome mainly depends on conventional and supportive care which includes broad-spectrum antibiotics for bacterial infections, antivirals/antifungals for viral and fungal infections respectively. Patients also require platelet transfusions to prevent bleeding. Topical steroids are used to treat eczema. A discussion of further treatment falls under the following subheads:

  • Intravenous immune globulin therapy:  Intravenous immunoglobin (IVIG) therapy is indicated in WAS and XLT patients with significant antibody deficiency. The dose is usually higher than that used for other primary immunodeficiencies due to an increased catabolic rate observed in WAS patients. Immune globulin may also be given subcutaneously. This route of administration requires caution in this patient population because of the bleeding tendency.
  • Eltrombopag:  An oral thrombopoietin receptor agonist approved for the treatment of immune thrombocytopenia (ITP), may be useful in preventing bleeding in patients with WAS who are awaiting hematopoietic cell transplantation (HCT).
  • Immunosuppressive treatment:   Immunosuppressive treatment may be necessary for autoimmune manifestations. Autoimmune cytopenias often respond to the monoclonal antibody rituximab which is relatively safe for those patients already receiving therapy with IVIG.
  • Splenectomy:  Elective splenectomy has been advocated in selected patients to reverse the thrombocytopenia and arrest the bleeding tendency by increasing the number of circulating platelets. Patients who undergo splenectomy require lifelong antibiotic prophylaxis and are at increased risk of septicemia.
  • Hematopoietic cell transplantation:  HCT is the only available curative treatment, with excellent results for patients with human leukocyte antigen (HLA)-matched family or unrelated donors (URDs) or partially matched cord-blood donors.
  • Gene therapy:  Gene therapy is an alternative, potentially curative therapy under investigation for WAS.

References

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Evans Syndrome – Causes, Symptoms, Treatment

Evans syndrome is an autoimmune condition that presents with two or more cytopenias, which commonly include autoimmune hemolytic anemia (AIHA) and immune thrombocytopenia (ITP), with or without immune neutropenia. This activity reviews the presentation, evaluation, and management of Evans syndrome and stresses the role of an interprofessional team approach to the care of affected patients.

Evans syndrome is an autoimmune condition that presents with two or more cytopenias, which commonly includes autoimmune hemolytic anemia (AIHA) and immune thrombocytopenia (ITP), with or without immune neutropenia (only in 15% of cases according to a report) . The type of AIHA that presents in Evans syndrome is warm AIHA, in which IgG antibodies react with red blood cell (RBC) surface antigens at body temperature, as opposed to cold AIHA. In ITP, the immune system is directed against GPIIb/IIIa on the platelets.

Recently, a proposition has been laid out to classify the condition as primary (idiopathic) or secondary (associated with an underlying disorder) . Secondary Evans syndrome has been associated with diseases such as systemic lupus erythematosus (SLE), common variable immunodeficiency (CVID), and autoimmune lymphoproliferative syndrome (ALPS) in  Non-Hodgkin’s lymphoma (NHL) in patients older than 50 years, chronic lymphocytic leukemia (CLL), viral infections (such as HIV, hepatitis C) and following allogeneic hematopoietic cell transplantation. Identifying Evans syndrome as secondary when associated with a disease is important because cytopenias have been observed to be more severe when with Evans syndrome in contrast to when presenting alone as AIHA or ITP. Also, the treatment options differ according to the classification.

Causes of Evans Syndrome

The exact cause of this condition is unknown, which is why it is usually considered an idiopathic condition. It is an autoimmune disease, in which B cells produce auto-antibodies that attack their own cells, in this case, red blood cells, platelets, and white blood cells. More recently, there has been speculation that the condition is likely a result of excessive immune dysregulation.

Diagnosis of Evans Syndrome

Signs and symptoms of Evans syndrome are variable and depend on the type of blood cell lines that are affected. In the presence of AIHA, they can present with fatigue, pallor, dizziness, shortness of breath, and limitation of physical activity. Physical examination usually shows pallor and jaundice. The spleen can be enlarged. Easy bruising or bleeding on minor injuries, petechiae, and purpura occur in those with ITP and recurrent infections in those with neutropenia.

ITP in Evans syndrome, in some cases, has been reported to be severe enough to lead to a life-threatening hemorrhage . There have been cases of increased risk of ischemic complications such as events related to the acute coronary syndrome or cerebrovascular events secondary to AIHA, frequently in those older than 60 years .

Lab Test and Imaging

Once anemia is diagnosed on complete blood count and differential, if Evans syndrome is suspected, further workup such as levels of lactate dehydrogenase, haptoglobin, bilirubin, and the reticulocyte count is usually required to evaluate for hemolysis. Positive direct antiglobulin test (DAT) and spherocytes on peripheral smear further confirm warm AIHA. Evans syndrome is a diagnosis of exclusion. Therefore, ruling out common etiologies such as cold agglutinin disease, thrombotic thrombocytopenic purpura (TTP) through careful evaluation of the peripheral blood smear, infectious causes (such as HIV, Hepatitis C), other autoimmune conditions and malignancies is required before the diagnosis of Evans syndrome can be made.

There are no established guidelines regarding which tests should be performed in patients suspected to have secondary Evans syndrome to look for an underlying disease. However, with common disorders such as SLE, ALPS in young patients, a minimal workup to evaluate for malignancy, including a chest and abdominal computed tomography scan should be performed.

Treatment of Evans Syndrome

Management of Evans syndrome is challenging as many patients are refractory to common treatments that work very well with isolated AIHA. Treatment depends on various factors, including the severity of the condition, presenting signs and symptoms, and patient co-morbidities. Symptomatic management such as transfusions is required in those with low blood counts presenting with symptoms secondary to anemia or bleeding in those with thrombocytopenia.

For definitive management, first-line treatment is usually corticosteroids or intravenous immunoglobulin (IVIG). Steroids are given at 1 to 2 mg/kg per day tapered over weeks in case of isolated ITP or over months when warm AIHA is present. In the presence of ITP, IVIG is used relatively more frequently compared with patients with isolated AIHA.

Although most of the patients have been observed to respond to corticosteroids initially, the duration of response can vary, and more than half relapse, making the use of additional or alternative treatment options imperative .

Rituximab or splenectomy may be considered in those refractory to the standard treatment or if steroid-dependent (that is, at least prednisone greater than or equal to 15 mg required daily to prevent relapse). Again, the responses can be variable. Rituximab is usually preferred due to increased response and particularly when Evans syndrome is likely secondary to an underlying condition such as a malignancy or SLE, and also in those at increased risk of infections due to co-morbidities making it necessary to avoid splenectomy . Its combined use with steroids has been reported to have remission rates as high as 76% according to one study . Splenectomy is becoming less frequent now, usually reserved for those refractory to medical treatment due to low response rates, higher relapse and increased risk of increased sepsis.  Danazol has frequently been used as a second-line treatment option especially with its corticosteroid-sparing effects .

Immunosuppressive drugs can be used in those unresponsive to corticosteroids or rituximab. Various immunosuppressants have been tried, but cyclosporin A   and mycophenolate mofetil  are the preferred ones due to increased efficacy in autoimmune conditions. Others that have also been used include cyclophosphamide,  azathioprine , and sirolimus.  The choice of immunosuppressant is dependant on patient factors, co-morbidities, and disease severity. Hematopoietic stem cell transplant has been used very rarely as a last resort in those unresponsive to all medical treatments. Both autologous and allogeneic stem cell transplantation has been tried in a small number of patients, with mixed results .

Differential Diagnosis

  • Autoimmune lymphoproliferative syndrome (ALPS)
  • Thrombotic thrombocytopenic purpura (TTP)
  • Systemic lupus erythematosus (SLE)
  • Antiphospholipid syndrome (APLA)
  • Sjogren syndrome
  • Common variable immunodeficiency (CVID)
  • IgA deficiency
  • Lymphomas
  • Chronic lymphocytic leukemia (CLL)

Other Issues

  • Evans syndrome is an autoimmune condition that presents with two or more cytopenias, which commonly includes autoimmune hemolytic anemia (AIHA) and immune thrombocytopenia (ITP), with or without immune neutropenia.
  • It can be primary (or idiopathic) or secondary (i.e., associated with an underlying disorder). When secondary, it has been associated with diseases such as systemic lupus erythematosus (SLE), common variable immunodeficiency (CVID) and autoimmune lymphoproliferative syndrome (ALPS) in younger patients, Non-Hodgkin’s lymphoma (NHL) in patients older than 50 years and chronic lymphocytosis leukemia (CLL).
  • Because it is an idiopathic condition, other common diagnoses should be ruled out before diagnosing the condition.
  • Corticosteroids and IVIG are the first-line treatment options for Evans syndrome. Rituximab is the preferred second-line treatment. Other treatment options include splenectomy, danazol, and immunosuppressants.
  • Even with treatment, responses can be variable, and relapses are common, commonly requiring multimodal management.

References

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Hyperesthesia – Causes, Symptoms, Treatment

Hyperesthesia is a condition that involves an abnormal increase in sensitivity to stimuli of the sense. Stimuli of the senses can include sound that one hears, foods that one tastes, textures that one feels, and so forth. Increased touch sensitivity is referred to as “tactile hyperesthesia”, and increased sound sensitivity is called “auditory hyperesthesia”. In the context of pain hyperaesthesia can refer to an increase in sensitivity where there is both allodynia and hyperalgesia.[rx]

Hyperesthesia is a condition that involves an abnormal increase in sensitivity to stimuli of the sense. Stimuli of the senses can include sound that one hears, foods that one tastes, textures that one feels, and so forth. Increased touch sensitivity is referred to as “tactile hyperesthesia”, and increased sound sensitivity is called “auditory hyperesthesia”. In the context of pain hyperaesthesia can refer to an increase in sensitivity where there is both allodynia and hyperalgesia.[rx]

Hyperesthesia occurs as a symptom of neuropathic pain and can be present in any disease process that affects the somatosensory nervous system. Treatment involves treating underlying conditions and symptomatic support. A multidisciplinary approach that is able to provide timely diagnosis and treatment, has the best outcomes. This activity outlines the evaluation and management of hyperesthesia and reviews the role of the interprofessional team in evaluating and treating patients with this condition.

The International Association for the Study of Pain defines hyperesthesia as “increased sensitivity to stimulation, excluding the special senses,” which “may refer to various modes of cutaneous sensibility including touch and thermal sensation without pain, as well as to pain.” While hyperesthesia can be used to describe any increased sensitivity to a stimulus, it is commonly used to describe a painful sensation from a stimulus.

Hyperesthesia is a common symptom of neuropathic pain. Neuropathic pain is defined by the International Association for the Study of Pain as “pain caused by a lesion or disease of the somatosensory system.” The neuropathic pain phenotype contains a spectrum of symptoms that can be roughly categorized into positive and negative symptoms. Hyperesthesia is a positive symptom of neuropathic pain. Positive symptoms are categorized as stimulus-dependent pain, stimulus-independent pain, and paresthesias. Neuropathic pain affects about 7-8% of the general population.

In this article, hyperesthesia will be defined as an increased cutaneous sensitivity manifesting as stimulus-dependent neuropathic pain. The most common hyperesthesias are allodynia and hyperalgesia. Allodynia is a pain caused by a stimulus that usually does not elicit a painful response (i.e., pain on light touch). Hyperalgesia is an exaggerated pain response to a stimulus that usually causes pain (i.e., out of proportion pain from a pinprick). While most neuropathic pain symptoms are contained within the dermatomal distribution of the affected nerve, hyperesthesia has been known to extend beyond the affected nerve’s distribution. This can sometimes obscure the correct diagnosis and lead to the inappropriate diagnosis of a psychosomatic disorder.

A detailed history and a thorough physical examination should be sufficient to identify the underlying etiology. Routine laboratories should be ordered as part of the workup. Special laboratory, diagnostic, and imaging tests may have to be ordered to make a definitive diagnosis of the etiology. Treatable and reversible etiologies should be promptly treated. The mainstay of treatment is symptomatic relief via pharmacological, non-pharmacological, and interventional therapies. Symptoms are typically challenging to eliminate, and patients will most likely continue to experience persistent symptoms. A multidisciplinary team approach has been shown to provide the most effective and lasting results.

Causes of Hyperesthesia

Neuropathic pain symptoms, including hyperesthesia, develop secondarily to a disease or a lesion of the nervous system that results in abnormal functioning of the somatosensory system. The etiology of hyperesthesia can be categorized anatomically or etiologically. Anatomically speaking, the source can be either central or peripheral.

Peripheral

  • Systemic disease: diabetes mellitus (DM), nutritional deficiency, hypothyroidism, vasculitis, sarcoidosis, carcinoma/paraneoplastic, Guillain-Barre syndrome/acute inflammatory demyelinating polyneuropathy, chronic demyelinating inflammatory neuropathies, monoclonal gammopathy (amyloidosis, multiple myeloma, plasmacytoma, monoclonal gammopathy of undetermined significance), porphyria, Sjogren’s syndrome, and critical illness.
  • Infectious: human immunodeficiency viruses (HIV), human T-cell lymphotropic virus, herpes simplex virus, varicella-zoster virus, Ebstein-Barr virus, West Nile virus, hepatitis C virus, rabies virus, cytomegalovirus, diphtheria, Campylobacter jejuni, Mycobacterium tuberculosis, Mycobacterium leprae, Brucella spp., Clostridium botulinum, and Borrelia burgdorferi.
  • Toxic:
    • Drugs: isoniazid, chemotherapeutics (vinca-alkaloids, taxanes, platinum compounds), statins, amiodarone, antimicrobials (isoniazid, linezolid, and metronidazole), and immunosuppressants (tumor necrosis factor inhibitors, leflunomide, and nucleoside analog reverse-transcriptase inhibitors).
    • Other toxins: ethanol and heavy metals
  • Mechanical: trauma, compressive mononeuropathies, complex regional pain syndrome type, post-amputation pain/phantom limb pain, trigeminal neuralgia, post-mastectomy pain syndrome, failed back surgery syndrome, and radiculopathies (nerve root compression)
  • Hereditary: Charcot-Marie-Tooth disease and metachromatic leukodystrophy

Central

  • Systemic disease: B12 myelopathy, multiple sclerosis, spinal cord stroke, brain stroke/central post-stroke pain syndrome(CPSP), opioid-induced hyperalgesia, and infectious (Herpes simplex virus, myelitis, encephalitis)
  • Mechanical: spinal cord injury, tumor compression (brain and spinal cord), syringomyelia, and myelopathy

Hyperesthesia Symptoms

Depending on which sense or senses are affected, people with hyperesthesia may experience a range of different symptoms. A person with acoustic hyperesthesia may experience auditory hallucinations, while someone with olfactory hyperesthesia may be overwhelmed by scents that are not actually present.

Hyperesthesia symptoms start slowly and get worse over time. Some general symptoms may include:

  • Tingling or burning sensation
  • Numbness or lack of feeling
  • Pain and sensitivity to touch
  • Muscle weakness

In rare or severe cases, hyperesthesia can cause inflammation of nerves and lead to seizures.

Diagnosis of Hyperesthesia

History: A thorough history should be performed, as this should be sufficient to make a diagnosis of hyperesthesia.

  • Past medical history (diabetes mellitis, stroke, fractures, irritable bowel syndrome)
  • Psychiatric history (mood disorders)
  • Medications (use of neurotoxic drugs) 
  • Surgery
  • Family history
  • Sexual history
  • Substance abuse (alcohol or opioid)
  • Functional history: A functional history that examines the effect of the patient’s symptoms on their ability to function should be performed. It should focus on any impairments to the patient’s activities of daily living, instrumental activities of daily living, ambulatory status (use of assistive devices), work, or sleep.
  • History of presenting illness: The examiner should gather a thorough description of the patient’s pain symptoms. The description of the patient’s symptoms should include all of the following components.

    • Location
    • Intensity (0-10 rating scale)
    • Quality (burning, cold, hot, or allodynia) Pain descriptors such as burning, tingling, or shooting are the most characteristic of neuropathic pain syndrome and have a high likelihood of being present along with hyperesthesia.
    • Onset (did the symptoms occur after an inciting event)
    • Temporal variation: At what time of the day is the pain worse? (neuropathic pain tends to be worse towards the end of the day) Has the pain progressively worsened over some time?
    • Radiation (does the pain have axial origin)
    • Positional variation (i.e., is the pain worse in the lower pack or the thigh)
    • Aggravating/alleviating factors
    • Attempted treatments (neuropathic pain symptoms are typically non-responsive to acetaminophen or nonsteroidal anti-inflammatory drugs)
    • Frequency
    • Associated symptoms (loss of range of motion, skin or hair changes, muscle spasms, muscle weakness, changes in sensation, redness, or swelling)

Physical exam: A complete neurological exam should be performed in addition to a general focused physical exam.

  • Cranial nerve testing (CNS lesions may have cranial nerve involvement)
  • Manual motor testing (weakness may be present in both peripheral and central etiologies, and any weakness should be differentiated as either real weakness or antalgic weakness)
  • Deep tendon reflexes (may be brisk in central etiologies and diminished in peripheral etiologies)
  • Sensory testing
    • Light touch (allodynia)
    • Pinprick (hyperalgesia)
    • Vibration and  proprioception
  • Temperature (ice and hot packs for possible thermal allodynia)
  • Straight leg test or slump test (radiculopathy)
  • Tinel’s sign (peripheral nerve entrapment)
  • Myofascial trigger points
  • For complex regional pain syndrome (CRPS), a skin examination should be performed focusing on cutaneous temperature discrepancies, color changes, hidrosis, scars in a dermatomal distribution, and hair changes.

Evaluation

The first step should be to determine whether the etiology is peripheral or central. It is essential to accurately diagnose the cause of hyperesthesia to provide treatment of any treatable underlying cause.

Laboratory tests:

  • Routine: Should be considered as part of a standard workup of peripheral hyperesthesia
    • Complete blood count
    • Comprehensive metabolic panel
    • Fasting blood glucose
    • Erythrocyte sedimentation rate
    • Thyroids stimulating hormone
    • Vitamine B12
  • If indicated, based on clinical suspicion:
    • Hemoglobin A1c (HbA1c)
    • HIV antibodies
    • Liver panel
    • Lyme antibodies
    • Rapid plasma reagin (RPR), venereal disease research laboratory (VDRL)
    • Urinalysis
    • Urine protein electrophoresis
    • Serum protein electrophoresis
    • Angiotensin-converting enzyme levels
    • Antinuclear antibody (ANA) test
    • Perinuclear anti-neutrophil cytoplasmic antibodies (P-ANCA) test
    • Antineutrophil cytoplasmic antibodies (C-ANCA) test
  • Tests for rare conditions
    • Paraneoplastic panel
    • Antimyelin associated glycoprotein
    • Antiganglioside antibodies
    • Salivary flow rate
    • Cerebrospinal fluid analysis
    • Genetic testing

Imaging: imaging is typically not needed to diagnose hyperesthesia, but it helps diagnose specific conditions.

  • Computed tomographic scan and magnetic resonance imaging (nerve root compression, herniated disc, myelopathy, tumor in the brain or spinal cord)
  • Triple phase bone scan (can be used to support a diagnosis of CRPS)

Special Tests:

  • Electrodiagnostics: electromyography and nerve conduction studies (only tests large fibers)
  • Punch skin biopsy (identifies small-fiber neuropathy)
  • Diagnostic tests: Your doctor may recommend an electrodiagnostic test such as a nerve conduction study to measure the electrical activity of muscles and nerves. Diagnostic tests can help identify any nerve damage and the degree to which damage has occurred.
  • Neurological evaluations: A neurological evaluation includes a physical examination and several painless tests to determine your neurological function. These tests help check muscle strength and your response to different sensory stimulations.

Treatment of Hyperesthesia

Treatment of hyperesthesia and other neuropathic pain symptoms is challenging but is best achieved by using a multidisciplinary team approach that can focus on treating underlying causes, administer pharmacotherapy, apply interventional therapy, address functional impairments, and provide mental health services if needed. Realistic goals for hyperesthesia should be established early on. Any comorbidities such as mood disorders or sleep disturbances should be addressed promptly. Patients typically require close follow-up to monitor response to therapy and continued evaluation of the underlying cause.

For peripheral neuropathy, the most common treatable causes are diabetes mellitis, hypothyroidism, and nutritional deficiencies. Other causes of hyperesthesia, such as nerve root compression or peripheral nerve entrapment, may be initially treated conservatively with symptomatic pharmacotherapeutic support, physical therapy, lifestyle modifications, and minimally invasive procedures (i.e., epidural steroid injection or peripheral nerve injection). However, if there is worsening or stagnation of function, surgery may be required.

Pharmacological treatments can be used to treat both central and peripheral causes of hyperesthesia. Of the pharmacological options available, antidepressants and antiepileptic drugs are the most widely used. General guidelines for treatment are provided below; however, recommendations for the treatment of choice for specific etiologies are provided.

First-line drugs: These drugs have the most substantial evidence to support their treatment of neuropathic pain symptoms. This group contains two classes of antidepressants and one class of antiepileptic drugs.

  • Antidepressants: all medications in this class have the added benefit of treating comorbid mood disorders.
    • TCAs: Amitryptiline, imipramine, and nortriptyline
      • Indications: painful diabetic neuropathy (PDN), postherpetic neuralgia (PHN), central poststroke pain (CPSP)
    • SNRIs: duloxetine and venlafaxine
      • Indications: PDN, post-traumatic neuropathic pain, CRPS, radiculopathy, and central pain
  • Antiepileptic drugs:
    • Gabapentinoids: Gabapentin and pregabalin
      • Indications: PDN, PHN, central pain, posttraumatic neuropathic pain, CRPS, radiculopathy. Pregabalin has proven to be effective in the treatment of spinal cord injury central pain.

Second-line treatments:

  • Topicals
    • Lidocaine 5% patch
    • Capsaicin 8% patch: should ideally be applied by specially trained healthcare providers, as it requires pretreatment with topical lidocaine. May require postprocedural analgesics for 7-10 days. Relief may last up to 3 months.
      • Indications: PHN and HIV associated neuropathy
  • Analgesic
    • Tramadol: Nonspecific analgesic, Mu-opioid receptor agonist but also blocks serotonin and norepinephrine reuptake.

Third-line treatments:

  • Strong Opioids
    • Indications: Phantom pain, CRPS, central pain, PHN, and PDN
  • Botulinum toxin-A
    • Indications: PHN

Not all patients will respond to monotherapy; in fact, 45% of individuals with neuropathic pain are on two or more medications for their pain. If a patient fails first-line monotherapy, they can be used in combination (i.e., gabapentinoid + TCA or SNRI).

Interventional Therapies:

  • Epidural steroid injections: considered third-line therapy.
  • Sympathetic nerve block
    • Indications: CRPS patients who have failed other treatments.
  • Neurostimulation: Fourth-line treatment
    • Spinal cord stimulation:
      • Indications: CRPS and failed back surgery syndrome (FBSS)
    • Motor cortex stimulation:
      • Indication: CPSP and facial pain
  • Transcutaneous electrical nerve stimulation (TENS)

Some interventional treatments currently being practiced lack robust trials to be recommended by the guidelines. Some of the interventions that require continued research are radiofrequency denervation of the dorsal root ganglion, adhesiolysis for FBSS, TENS, spinal cord stimulation, and motor cortex stimulation.

REferences

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What Is Transverse Myelitis? – Causes, Symptoms, Treatment

Transverse myelitis is a demyelinating and immune-mediated inflammatory disorder of the spinal cord, the part of the central nervous system that sends impulses from the brain to nerves in the body. This inflammation can cause damage to the ensheathing nerve cell fiber myelin, with resultant neurological dysfunction including weakness, sensory impairments, and autonomic problems including the bowel and bladder., ,  The spinal cord also carries sensory information back to the brain. The term myelitis refers to inflammation of the spinal cord; transverse refers to the pattern of changes in sensation—there is often a band-like sensation across the trunk of the body, with sensory changes below. Symptoms may develop suddenly (over a period of hours) or over days or weeks and include:

  • pain
  • sensory problems
  • weakness in the legs and possibly arms, and
  • bladder and bowel problems.

Transverse myelitis can affect people of any age, gender, or race. It does not appear to be genetic or run in families. The disorder typically occurs between ages 10 and 19 years and 30 and 39 years.

Although some people recover from transverse myelitis with minor or no residual problems, the healing process may take months to years. Most people with transverse myelitis have at least partial recovery, with most recovery taking place within the first 3 months after the attack. Others may suffer permanent impairments that affect their ability to perform ordinary tasks of daily living. Some individuals will have only one episode of transverse myelitis; other individuals may have a recurrence, especially if an underlying illness caused the disorder. There is no cure for transverse myelitis, but there are treatments to prevent or minimize permanent neurological deficits.

What causes transverse myelitis?

The exact cause of transverse myelitis and extensive damage to the bundles

of nerve fibers of the spinal cord is unknown in many cases. Cases in which a cause cannot be identified are called idiopathic. Viral, bacterial, and fungal infections affecting the spinal cord may cause the disorder.

A number of conditions appear to cause transverse myelitis, including:

  • Immune system disorders appear to play an important role in causing damage to the spinal cord. Such disorders are:
    • an aquaporin-4 autoantibody associated neuromyelitis optic. Neuromyelitis Optica is a disorder that affects the eye nerves and spinal cord. Aquaporin-4 is a channel on the cell membrane that lets water enter the cell and helps maintain the chemical balance for processes to take place within the central nervous system. An antibody is a protein that binds to foreign substances that can attack the host organism.
    • multiple sclerosis, a disorder in which immune system cells that normally protect us from viruses, bacteria, and unhealthy cells mistakenly attack the protective coating of myelin in the brain, optic nerves, and spinal cord
    • the post-infectious or post-vaccine autoimmune phenomenon, in which the body’s immune system mistakenly attacks the body’s own tissue while responding to the infection or, less commonly, a vaccine
    • an abnormal immune response to underlying cancer that damages the nervous system; or
    • other antibody-mediated conditions that are still being discovered.
  • Viral infections including herpes viruses such as varicella-zoster (the virus that causes chickenpox and shingles), herpes simplex, cytomegalovirus, and Epstein-Barr; flaviviruses such as West Nile and Zika; influenza, echovirus, hepatitis B, mumps, measles, and rubella. It is often difficult to know whether a direct viral infection or a post-infectious response causes transverse myelitis.
  • Bacterial infections such as syphilis, tuberculosis, actinomyces, pertussis, tetanus, diphtheria, and Lyme disease. Bacterial skin infections, middle-ear infections, campylobacter jejuni gastroenteritis, and mycoplasma bacterial pneumonia have also been associated with the condition.
  • Fungal infections in the spinal cord, including aspergillus, Blastomyces, coccidioides, and cryptococcus.
  • Parasites, including toxoplasmosis, cysticercosis, schistosomiasis, and angtiostrongyloides.
  • Other inflammatory disorders that can affect the spinal cord, such as sarcoidosis, systemic lupus erythematosus, Sjogren’s syndrome, mixed connective tissue disease, scleroderma, and Bechet’s syndrome.
  • Vascular disorders such as arteriovenous malformation, dural arterial-venous fistula, intra-spinal cavernous malformations, or disk embolism.

or

1.Acquired demyelinating disorders
  • a.Multiple sclerosis
  • b.NMO
  • c.ADEM
2.Systemic inflammatory autoimmune disorders
  • a.SLE
  • b.SS
  • c.Antiphospholipid syndrome
  • d.Behçet disease
  • e.Vogt-Koyanagi Harada disease
  • f.Ankylosing spondylitis
  • g.Mixed connective tissue disease
  • h.Others: systemic sclerosis, anti-Jo-1 antibody, urticarial vasculitis, psoriatic arthritis, perinuclear ANCA systemic vasculitis, graft-versus-host disease, common variable immunodeficiency, celiac disease
3.Neurosarcoidosis
  • a.Viral: hepatitis A, hepatitis B, hepatitis C, hepatitis E, measles, mumps, rubella, varicella-zoster, Epstein-Barr, cytomegalovirus, herpes simplex, influenza A/B, lymphocytic choriomeningitis virus, chikungunya, Hanta virus, HIV, human T-cell lymphotropic virus, human herpesvirus 6, Japanese encephalitis, Murray Valley encephalitis, St. Louis encephalitis, tick-borne encephalitis, vaccnia. Rocky Mountain spotted fever, dengue virus, enterovirus 71, coxsackievirus A and B, West Nile virus, parvovirus B19, human corona virus, and echovirus
  • b.Bacterial: Mycoplasma pneumoniae, Campylobacter jejuni, Borrelia burgdorferi, Acinetobacter baumanii, Coxiella burnetii, Bartonella henselae, Chlamydia psittaci, Leptospira, Chlamydia pneumoniae. Legionella pneumonia, Orientia tsutsugamushi (scrub typhus). Salmonella paratyphi B, Mycobacterium tuberculosis, Treponema pallidum, Brucellosis melitensis, and groups A and B strep to cocci
  • c.Fungal: Actinomyces, Blastomyces, Coccidioides, Aspergillus, Cryptococcus, and Cladophialophora bantiana
  • d.Parasitic: Toxocara species. Schistosoma species, Gnasthostoma spinigerum, Echinococcus granulosus, Taenia solium, Toxoplasma gondii, Acanthamoeba species, Paragonimus westermani, and Trypanosoma brucei
4.Parainfectious TM
  • a.Anti-Ri (ANNA-2) antibody
  • b.CRMP-5-lgG antibody
  • c.Anti-amphiphysin IgG antibody
  • d.Anti-GAD65 antibody
  • e.NMDAR antibody
5.Paraneoplastic syndromes
6.Atopic myelitis
7.Drugs and toxins
  • a.Tumor necrosis factor-alpha inhibitors

    In some people, transverse myelitis represents the first symptom of an autoimmune or immune-mediated disease such as multiple sclerosis or neuromyelitis optica.“Partial” myelitis—affecting only a portion of the cord cross-section—is more characteristic of multiple sclerosis. Neuromyelitis Optica is much more likely as an underlying condition when the myelitis is “complete” (causing severe paralysis and numbness on both sides of the spinal cord). Myelitis attacks with neuromyelitis optica spectrum disorder (NMOSD) tend to be more severe and are associated with less recovery than attacks with multiple sclerosis.

    What are the symptoms of transverse myelitis?

    Transverse myelitis may be either acute(developing over hours to several days) or subacute(usually developing over one to four weeks).

    The segment of the spinal cord at which the damage occurs determines which parts of the body are affected. Damage at one segment will affect function at that level and below. In individuals with transverse myelitis, myelin damage most often occurs in nerves in the upper back.

    Four classic features of transverse myelitis are:

    • Weakness of the legs and arms. People with transverse myelitis may have weakness in the legs that progresses rapidly. If the myelitis affects the upper spinal cord it affects the arms as well. Individuals may develop paraparesis(partial paralysis of the legs) that may progress to paraplegia(complete paralysis of the legs), requiring the person to use a wheelchair.
    • Pain. Initial symptoms usually include lower back pain or sharp, shooting sensations that radiate down the legs or arms or around the torso.
    • Sensory alterations. Transverse myelitis can cause paresthesias(abnormal sensations such as burning, tickling, pricking, numbness, coldness, or tingling) in the legs and sensory loss. Abnormal sensations in the torso and genital region are common.
    • Bowel and bladder dysfunction. Common symptoms include an increased frequency or urge to use the toilet, incontinence, and constipation.

    Many individuals also report experiencing muscle spasms, a general feeling of discomfort, headache, fever, and loss of appetite, while some people experience respiratory problems. Other symptoms may include sexual dysfunction and depression and anxiety caused by lifestyle changes, stress, and chronic pain.

    or

    Symptoms of transverse myelitis may develop within a few hours or days. Or, they may develop over 1 to 4 weeks. Symptoms can quickly become severe. Symptoms tend to occur at or below the damaged area of the spinal cord. Both sides of the body are often affected, but sometimes only one side is affected. Symptoms include:

    Abnormal sensations

    • Numbness
    • Pricking
    • Tingling
    • Coldness
    • Burning
    • Sensitivity to touch or temperature

    Bowel and bladder symptoms

    • Constipation
    • Frequent need to urinate
    • Difficulty holding urine
    • Urine leakage (incontinence)

    Pain

    • Sharp or blunt
    • May start in your lower back
    • May shoot down your arms and legs or wrap around your trunk or chest

    Muscle weakness

    • Loss of balance
    • Difficulty walking (stumbling or dragging your feet)
    • Partial loss of function, which may develop into paralysis

    Sexual dysfunction

    • Difficulty having an orgasm (men and women)
    • Erectile dysfunction in men

    Other symptoms can include loss of appetite, fever, and respiratory problems. Depression and anxiety can occur as a result of dealing with chronic pain and illness.

    How is transverse myelitis diagnosed?

    Motor symptoms may vary depending on the level of the spinal cord involved. Upper cervical lesions (C1-C5) may affect all four extremities. Additionally, if the lesion affects the phrenic nerve (C3, C4, C5), it could lead to diaphragmatic dysfunction and respiratory failure.

    Lesions in the lower cervical levels (C5-T1) many develop upper and lower motor neuron signs in the upper extremities and exclusive upper motor neuron signs in the lower extremities. Cervical lesions account for approximately 20% of cases.

    Lesions in the thoracic region (T1-T12) may cause both upper and lower motor neuron signs in the lower extremities. The thoracic region is the most commonly affected in TM cases (70%).

    Lesions in the lumbosacral regions (L1-S5) may cause both upper and lower motor neuron signs in the lower extremities. Lumbar lesions account for approximately 10% of cases.

    Sensory symptoms generally affect the level of the lesion or one of the levels above or below the lesion.

    Back pain in the corresponding area of the lesion may also be present.

    To diagnose transverse myelitis, a compressive cord lesion must be excluded first. Exclusion is usually performed by magnetic resonance imaging (MRI). This is followed by a confirmation of inflammation either by a gadolinium-enhanced MRI or lumbar puncture (LP). A set of diagnostic criteria was developed but is generally reserved for research purposes as not all features are required to make the diagnosis in a clinical setting.

    Diagnostic criteria include:

    • Sensory, motor, or autonomic dysfunction originating from the spinal cord
    • T2 hyperintense signal changes on MRI
    • No evidence of a compressive lesion
    • Bilateral signs/symptoms.
    • Clearly defined sensory level.
    • Evidence of inflammatory process demonstrated by gadolinium enhancement on MRI, cerebrospinal fluid (CSF) analysis showing pleocytosis, or elevated immunoglobulin G (IgG) index.
    • Progression to nadir between 4 hours and 21 days

    Most important of the above criteria are the first 3.

    When considering TM as a possible diagnosis, it is recommended the following investigative analyses be performed:

    • MRI of the entire spine with and without gadolinium contrast to differentiate compressive vs. non-compressive lesions.
    • Brain MRI with and without gadolinium contrast to evaluate for evidence of brain lesions.
    • LP for CSF analysis including cell count with differential, protein, glucose, the Venereal Disease Research Laboratory (VDRL) test, oligoclonal bands, immunoglobulin G (IgG) index, and cytology.
    • Serum anti-aquaporin-4 (APQ-4)-IgG autoantibodies, anti-myelin oligodendrocyte glycoprotein (MOG) autoantibodies, B12 level, methylmalonic acid, serum antinuclear antibodies (ANA), Ro/SSA, and La/SSB autoantibodies, syphilis serologies, HIV antibodies, TSH and viral etiology tests as applicable.

    Patients with evidence of longitudinally extensive spinal cord lesions additionally will require the following additional studies:

    • Serum erythrocytes sedimentation rate (ESR), C-reactive protein (CRP), ANA, antibodies to extractable nuclear antigens, rheumatoid factor, antiphospholipid antibodies, and antineutrophil cytoplasmic antibodies (ANCA)
    • Computed tomography (CT) of the chest to evaluate for evidence of sarcoidosis.

    Additional testing may be performed in the appropriate clinical setting.

    • Neuro-ophthalmologic evaluation
    • Paraneoplastic evaluation
    • Infectious serologic and CSF studies
    • Nasopharyngeal swab for enteroviral PCR
    • Serum copper and ceruloplasmin (copper deficiency may mimic TM)
    • Serum vitamin B12 and vitamin E levels
    • Spinal angiogram
    • Prothrombotic evaluation
    • Salivary gland biopsy

    Physicians diagnose transverse myelitis by taking a medical history and performing a thorough neurological examination. Tests that can indicate a diagnosis of transverse myelitis and rule out or evaluate underlying causes include:

    • Magnetic resonance imaging(MRI) produces a cross-sectional view or three-dimensional image of tissues, including the brain and spinal cord. A spinal MRI will almost always confirm the presence of a lesion within the spinal cord, whereas a brain MRI may provide clues to other underlying causes, especially MS. In some instances, computed tomography (CT) may be used to detect inflammation.
    • Blood tests may be performed to rule out various disorders, including HIV infection and vitamin B12 deficiency. Blood is tested for the presence of autoantibodies (anti- aquaporin-4, anti-myelin oligodendrocyte) and antibodies associated with cancer (paraneoplastic antibodies). The presence of autoantibodies (proteins produced by cells of the immune system) is linked to autoimmune disorders and point to a definite cause of transverse myelitis.
    • Lumbar puncture and spinal fluid analysis (also called a spinal tap) can identify more protein than usual in some people with transverse myelitis and an increased number of white blood cells (leukocytes) that help the body fight infections.

    If none of these tests suggests a specific cause, the person is presumed to have idiopathic transverse myelitis.

    How is transverse myelitis treated?

    Non-Pharmacological

    Common neurological deficits resulting from transverse myelitis include incontinence, chronic pain, and severe weakness, spasticity, or paralysis. In some cases, these may be permanent. Individuals with lasting or permanent neurological defects from transverse myelitis typically consult with a range of rehabilitation specialists, which may include physiatrists, physical therapists, occupational therapists, vocational therapists, and mental health care professionals.

    • Physical therapy – can help retain muscle strength and flexibility, improve coordination, reduce spasticity, regain greater control over bladder and bowel function, and increase joint movement. Individuals are also taught to use assistive devices such as wheelchairs, canes, or braces.
    • Occupational therapy – teaches people new ways to maintain or rebuild their independence by participating in meaningful, self-directed, everyday tasks such as bathing, dressing, preparing meals, and house cleaning.
    • Vocational therapy – involves offering instructions to help people develop and promote work skills, identify potential employers, and assist in job searches. Vocational therapists act as mediators between employees and employers to secure reasonable workplace accommodations.
    • Psychotherapy – for people living with permanent includes strategies and tools to deal with stress and a wide range of emotions and behaviors.

    Medication

    Treatments are designed to address infections that may cause the disorder, reduce spinal cord inflammation, and manage and alleviate symptoms.

    Initial treatments and management of the complications of transverse myelitis include:

    • Intravenous corticosteroid drugs – may decrease swelling and inflammation in the spine and reduce immune system activity. Such drugs may include methylprednisolone or dexamethasone. These medications may also be given to reduce subsequent attacks of transverse myelitis in individuals with underlying disorders.
    • Plasma exchange therapy – (plasmapheresis) may be used for people who don’t respond well to intravenous steroids. Plasmapheresis is a procedure that reduces immune system activity by removing plasma (the fluid in which blood cells and antibodies are suspended) and replacing it with special fluids, thus removing the antibodies and other proteins thought to be causing the inflammatory reaction.
    • Intravenous immunoglobulin (IVIG) – is a treatment thought to reset the immune system. IVIG is a highly concentrated injection of antibodies pooled from many healthy donors that bind to the antibodies that may cause the disorder and remove them from circulation.
    • Pain medicines – that can lessen muscle pain include acetaminophen, ibuprofen, and naproxen. Nerve pain may be treated with certain antidepressant drugs (such as duloxetine), muscle relaxants (such as baclofen, tizanidine, or cyclobenzaprine), and anticonvulsant drugs (such as gabapentin or pregabalin).
    • Antiviral medications – may help individuals who have a viral infection of the spinal cord.
    • Medications can treat other symptoms and complications – including incontinence, painful muscle contractions called tonic spasms, stiffness, sexual dysfunction, and depression.

    Following initial therapy, it is a critical part to keep the person’s body functioning during the recovery period. This may require placing the person on a respirator in the uncommon scenario where breathing is significantly affected.

    Management of Neuromyelitis Optica

    Medication Use Typical dose Evidence
    High dose IV methylprednisolone Acute 1 gm IV daily for 5 days with or without a taper Observational studies
    Plasma exchange Acute as a rescue therapy 5 exchanges (each exchange 250 ml) over 5-10 days Randomized trials in TM patients
    Rituximab Maintenance 1 gm (or 375 mg/m2) IV every 1-2 weeks for 2-4 weeks then redoes based on CD19 count (typically every 6-8 month) for ≤ 2 years Several open label and retrospective clinical trials
    Azathioprine Maintenance 2 mg/kg PO divided BID (typically 100 mg BID) for ≤2 years Observational studies
    Mycophenolate Maintenance 1-3 gm PO daily divided BID or TID for ≤2 years Retrospective trial
    Methotrexate Maintenance 5-15 mg PO weekly for ≤2 years Open label trial
    Mitoxantrone Maintenance 12 mg/mevery 3 months (maximum dose 140 mg/m2) Open label trial
    Cyclophosphamide Maintenance 0.5-1.5 mg/m2 (typically 1 gm) IV every month until absolute lymphocyte count<1000/mm(typically 6 cycles) or immunoablative dose of 200 mg/kg divided over 4 days Open label trial
    IVIG Maintenance 2 gm/kg induction followed by 0.4-0.5 gm/kg every month Case series

    Management options for addressing long term mobility issues following transverse myelitis

    Therapy/Device/Concept Description References
    Conventional therapy Focuses on compensatory strategies for nonremediable neurologic deficits.
    Focuses on strengthening muscles above the level of the lesion, and unaffected muscles below the level of the lesion.
    Activity-based therapy Interventions that provide activation of the neuromuscular system below the level of lesion with the goal of retraining the nervous system to recover a specific motor task.
    Ankle-foot orthoses (AFOs) AFOs can support the weakened musculature around the ankle.
    AFOs address excess plantar flexion during initial contact, stabilize the ankle for effective push-off during late stance, and prevent toe-drag during swing.
    Functional electrical stimulator devices Can reduce toe drag, circumduction, pelvic obliquity, and genu recurvatum, improving energy efficiency and facilitating safety and walking duration.
    Long-term use results in stable improvements of walking performance that persist even when the device is turned off.
    Adherent use of a dorsiflexion assist device may enhance the fidelity of activation of motor cortical regions and the descending corticospinal connections that control the swing phase of ambulation.
    Robot-assisted gait training Different systems are commercially available, including the “Lokomat,” the “LokoHelp,” and the “Gait trainer.”
    Neuromuscular electrical stimulation (NMES) Helpful in improving interlimb coordination during locomotion
    Dalframpridine Dalframpridine is the extended-release, oral form of 4-aminopyridine approved by the Food and Drug Administration that has been shown to improve the walking ability in patients with multiple sclerosis by improving conduction along demyelinated axons.

    Management options for spasticity in patients with transverse myelitis

    Management Strategy Comment
    Nonpharmacologic measures Physical therapy, stretching exercises, orthotics, and aquatic therapy
    Useful for mild cases.
    Pharmacologic therapy Baclofen
    Tizanadine
    Dantrolene (must monitor liver function tests)
    Anticonvulsants
    Benzodiazepines
    Anticonvulsants and benzodiazepines are useful for paroxysmal tonic spasms.
    Sedation may limit the use of the above-mentioned drugs.
    Botolinum neurotoxin Particularly useful for nonambulatory patients with severe adductor spasms that complicate adequate perineal hygiene.
    Intrathecal baclofen (ITB) May be used when oral medications cause too much sedation.
    Patients must be carefully evaluated before ITB use because of serious risks associated with baclofen withdrawal.

    Managing the urinary dysfunction following transverse myelitis

    Treatment Options Comments
    Detrusor hyperreflexia (failure to store)
    • • Anticholinergic agents (eg, trospium, fesoterodine, oxybutynin, tolterodine)
    • • Selective M2- and M3-antimuscarinics (darifenacin and solifenacin)
    Common side effects include dry mouth and constipation. Contraindicated in patients with angle-closure glaucoma and mechanical bladder outlet obstruction.
    Nonselective agents should be used cautiously, if at all, in patients with cognitive dysfunction.
    • • Intravesical atropine, oxybutinin, capsaicin, or resiniferatoxin
    • • Detrusor muscle botulinum toxin A injection
    • • Suprapubic vibration (“Queen Square bladder stimulator”)
    Detrusor-sphincter dyssynergia
    • • Alpha-1 adrenergic antagonists (eg, tamsulosin)
    • • Clean intermittent catheterization (CIC)
    • • Suprapubic vibration (“Queen Square bladder stimulator”)
    • • Neuromodulation (InterStim)
    • • Intrasphincteric botulinum toxin
    • • Indwelling Foley catheter
    • • Suprapubic catheter
    Alpha antagonists may cause hypotension, tachycardia, and bladder incontinence, particularly in those patients with coincident bladder spasms.
    CIC should be considered if postvoid residual volume exceeds 100 mL.
    Patients with sacral nerve stimulators cannot undergo MRIs.
    Indwelling Foley catheters are contraindicated in females.
    Frequent urinary tract infections Appropriate antibiotics
    Prophylactic antibiotic therapy
    Cranberry preparations
    Vitamin C supplementation
    Cystoscopic evaluation may be needed to look for bladder trabeculations that serve as a nidus for infections.
    Painful bladder spasms Pharmacotherapy
    Timed voiding
    Neuromodulation
    Pharmacotherapy: baclofen, benzodiazepines, hyoscine butylbromide, gabapentin and cannabinoids.
    Nocturia Behavioral measures
    Pelvic floor exercises
    Imipramine
    Desmopressin (DDAVP)
    Bladder rehabilitation
    Avoid alcoholic and caffeinated beverages after 5 pm, to limit fluid intake in the evening, to avoid any fluids 2 h before bedtime and to void before going to bed.

    Management of gastrointestinal dysfunction in patients with transverse myelitis

    Problem Management Strategies
    Gastroparesis Stop drugs that inhibit gastrointestinal motility (eg, narcotics, calcium channel blockers, anticholinergics).
    Consultation with a gastroenterologist for endoscopy, gastric emptying studies, and investigations to characterize the nature of dysmotility.
    Gastric decompression with a nasogastric tube, bowel rest, intravenous fluids, and proton-pump inhibitors or gastric H2-receptor blockers should be considered.
    Prokinetic agents (eg, metoclopramide, macrolide antibiotics, bethanecol or pyridostigmine) may be used. Tardive dyskinesia is a risk of metoclopramide use.
    Gastric electrical stimulation (Enterra therapy) and endoscopic injection of botulinum neurotoxin may be of potential benefit.
    In refractory cases, surgical interventions like pyloroplasty may be needed.
    Constipation General measures: high-fiber diet, bulking agents, increased fluid intake (at least 2 L daily), physical exercise, and establishing a regular toileting routine (best accomplished after breakfast to take advantage of the gastrocolic response, which peaks about 30 minutes after eating).
    Stimulant or osmotic laxatives (senna and bisacodyl) can be titrated to produce a satisfactory response (without producing liquid stool).
    Osmotic laxatives, although effective, can produce liquid stool with subsequent incontinence.
    Rectal stimulants have a predictable time of response. Begin with a glycerine suppository, progressing to bisacodyl, sodium citrate micro-enema, and ultimately a phosphate enema.
    Biofeedback may help, particularly in pelvic floor incoordination.
    Neostigmine in combination with glycopyrrolate has been shown to be effective.
    4-aminopyridine may improve constipation.
    Digital stimulation of the anal canal serves to manually disimpact the rectum.
    Abdominal massage may be helpful.
    For refractory cases: colostomy, neuromodulation, Malone Antegrade Continence Enema.
    Transanal irrigation (TAI).
    Fecal incontinence Mild and infrequent: loperamide, codeine phosphate.
    Antidiarrheal drugs should be used with caution if incontinence and constipation coexist, and periodic checks for impaction may be required. Fecal impaction is a common complication and patients experience anorexia, nausea, and spurious diarrhea (liquid stool passing around the blockage).
    Biofeedback is another useful tool.
    Anal plugs or pads may be needed.
    Severe cases: surgical intervention (eg, dynamic graciloplasty, artificial bowel sphincter, and sacral nerve stimulation).
    TAI

    Management strategies for sexual dysfunction in patients with transverse myelitis

    Problem Management Strategies
    Reduced libido Stop any offending medication (particularly selective serotonin reuptake inhibitors).
    Consider using bupropion.
    Check free testosterone levels (in both men and women) – testosterone replacement therapy for deficient states.
    Erectile dysfunction Phosphodiesterase 5 inhibitors (sildenafil, tadalafil, and vardenafil).
    If unresponsive to oral agents, intracavernosal alprostadil injection, intraurethral alprostadil pellet, penile tension rings, vacuum devices, implantable penile prostheses, and sacral neuromodulation (Sacral Anterior Root Stimulator Implants) may be considered.
    Ejaculatory dysfunction (affecting fertility) Strong afferent stimulation and intense activation of the autonomic nervous system is needed to trigger the ejaculatory reflex.
    Penile vibratory stimulation (PVS) is the first line of treatment.
    Midodrine may be used as an adjunct to PVS in men who failed PVS alone.
    Rectal probe electro-ejaculation may be used but frequently results in retrograde ejaculation and may cause significant discomfort.
    Surgical techniques for sperm retrieval (eg, Brindley reservoir, microsurgical aspiration of spermatozoa from the vas deferens, or testicular biopsy) may also be considered if other measures fail.
    Female orgasmic dysfunction Manual and vibratory clitoral stimulation (eg, Eroscillator).
    Clitoral vacuum suction device (Eros) is approved by the Food and Drug Administration for female orgasmic dysfunction.
    Lubrication dysfunction Lubricants
    Topical estrogen
    Clitoral vacuum suction device (Eros)
    Estrogen replacement therapy

     

    Prevention of future transverse myelitis episodes

    Multiple sclerosis and neuromyelitis optica typically require long-term treatment to modify the immune system response. Treatment of MS with immunomodulatory or immunosuppressant medications such as alemtuzumab, dimethyl fumarate, fingolimod, glatiramer acetate, interferon-beta, natalizumab, or teriflunomide may be needed.

    Immunosuppressant treatments are used for neuromyelitis optica spectrum disorder and recurrent episodes of transverse myelitis that are not caused by multiple sclerosis. They are aimed at preventing future myelitis attacks (or attacks at other sites) and include steroid-sparing drugs such as mycophenolate mofetil, azathioprine, and rituximab.

    What research is being done?

    The mission of is to seek fundamental knowledge about the brain and nervous system and to use that knowledge to reduce the burden of neurological disease. NINDS is a component of the National Institutes of Health, the leading supporter of biomedical research in the world.

    NINDS researchers are working to better understand how the immune system destroys or attacks the nerve-insulating substance called myelin in autoimmune diseases or disorders. Other work focuses on strategies to repair demyelinated spinal cords, including approaches using cell transplantation. This research may lead to a greater understanding of the mechanisms responsible for damaging myelin and may ultimately provide a means to prevent and treat transverse myelitis.

    Glial cell studies. Glia, or neuroglia, are non-neuronal cells (they do not provide electrical impulses) in the nervous system that form myelin and provide support and protection for neurons. Oligodendrocyte progenitor cells (OPCs) are stem cells that generate myelin-producing oligodendrocytes, a type of glial cell. NINDS-funded scientists are studying cellular mechanisms that control the generation and maturation of OPCs to allow remyelination, which could be an effective therapy for transverse myelitis and spinal cord injury. Other NINDS-funded investigators are focusing on mechanisms and interventions designed to increase oligodendrocyte proliferation and remyelination after spinal cord injury.

    Astrocytes are another type of glial cell. The aquaporin-4 IgG antibody binds to astrocytes, which has led to an increased interest in its role in transverse myelitis of neuromyelitis optica spectrum disorder (NMOSD). The antibody appears to cause myelitis in NMOSD by activating other components of the immune system, resulting in injury to the spinal cord. Many studies are trying to better understand the role of astrocytes in autoimmune diseases.

    Genetic studies. NINDS-funded scientists hope to develop a better understanding of the molecular control of central nervous system myelination and remyelination by studying the theBrg1(Brahma-related) gene that appears to be involved in oligodendrocyte myelination. The long-term objective of this research is to develop drugs that modulate the activity ofBrg1and other genes to promote myelination and remyelination.

    Animal models. NINDS funds research using animal models of spinal cord injury aimed at replacing or regenerating spinal cord nerve cells. The ultimate goals of these studies are to develop interventions for the regeneration or remyelination of spared nerve fibers in humans and to restore function to paralyzed individuals.

    Neuroimaging with MRI. Research funded by aims to develop and implement new MRI techniques to quantitatively assess the relationship between spinal cord pathology and neurological dysfunction in MS. This new approach may assess changes in lesions and myelin in MS and possibly transverse myelitis. Other NIH-funded researchers plan to develop MRI methodologies to non-invasively detect and characterize networks to identify the extent of injury to the spinal cord and to monitor the progression of recovery after injury. These techniques may aid in earlier detection of transverse myelitis and other neurological disorders such as MS.

    Brain-machine interfaces and prosthetic devices. Scientists are developing brain-machine interfaces and neural prostheses to help people with spinal cord damage regain functions by bypassing the injury site. These sophisticated electrical and mechanical devices connect with the nervous system to supplement or replace lost motor and sensory function.

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    Resting Tremor – Causes, Symptoms, Diagnosis, Treatment

    Resting tremor occurs when the muscle is relaxed, such as when the hands are resting on the lap.  With this disorder, a person’s hands, arms, or legs may shake even when they are at rest.  Often, the tremor only affects the hand or fingers.  This type of tremor is often seen in people with Parkinson’s disease and is called a “pill-rolling” tremor because the circular finger and hand movements resemble the rolling of small objects or pills in the hand.

    Causes of Resting Tremor

    Generally, tremor is caused by a problem in the deep parts of the brain that control movements.  Most types of tremors have no known cause, although there are some forms that appear to be inherited and run in families.

    Tremor can occur on its own or be a symptom associated with a number of neurological disorders, including

    • Multiple sclerosis
    • Stroke
    • Traumatic brain injury
    • Neurodegenerative diseases that affect parts of the brain (e.g.,  Parkinson’s disease).
    • Neurologic disorders, including multiple sclerosis, Parkinson’s disease, stroke, and traumatic brain injury
    • Certain medicines, such as asthma medicines, amphetamines, caffeine, corticosteroids, and medicines used for certain psychiatric and neurological disorders
    • Alcohol use disorder or alcohol withdrawal
    • Mercury poisoning
    • Hyperthyroidism (overactive thyroid)
    • Liver or kidney failure
    • Anxiety or panic

    Some other known causes can include

    • the use of certain medicines (particular asthma medication, amphetamines, caffeine, corticosteroids, and drugs used for certain psychiatric and neurological disorders)
    • alcohol abuse or withdrawal
    • mercury poisoning
    • overactive thyroid
    • liver or kidney failure
    • anxiety or panic.

    Common Causes of  tumors due to Medication- or Toxin-Induced Tremors

    Class of Medication or Toxin Examples
    Beta-adrenergic agonists Terbutaline, metaproterenol, isoetharine, epinephrine (adrenaline)
    Antidepressants Bupropion, lithium, tricyclic antidepressants
    Neuroleptics Haloperidol
    Anticonvulsants Valproate sodium
    Dopamine agonists Amphetamine
    Heavy metals Mercury, lead, arsenic, bismuth
    Xanthines or derivatives coffee, tea, theophylline, cyclosporine

    Genetic Causes

    • In familial cases, ET has traditionally been viewed as being inherited as an autosomal dominant trait, although other modes of inheritance are increasingly being considered. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50 percent for each pregnancy regardless of the sex of the resulting child.
    • In ET, there is evidence of reduced penetrance and gene expression, meaning that individuals vary within families in terms of their clinical manifestations. This suggests that additional factors, most likely environmental or additional genetic (e.g. modifier genes) ones are necessary for the development the disorder in an individual (multifactorial development).
    • Investigators believe that as-yet-unidentified genes located on the long arm (q) of chromosome 3 (3q13.31), the short arm (p) of chromosome 2 (2p25-p22), and the short arm of chromosome 6 (6p23) may be involved in some cases of ET. Aside from this, a small number of specific genes seem to play a role in a few ET families, but further confirmatory work is needed. Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 3q13.31” refers to band 13.31 on the long arm of chromosome 3. The numbered bands specify the location of the thousands of genes that are present on each chromosome.
    • The exact underlying cause of ET is not fully understood, although recent research suggests that ET may be a neurodegenerative disorder. Controlled postmortem studies have demonstrated a variety of degenerative changes within the cerebellum affecting the Purkinje cell population, and some patients have other degenerative changes, including Lewy bodies. Additional work remains to be performed and more research is necessary to determine the complex, underlying mechanisms that cause ET.

    Symptoms of Resting Tremor

    Symptoms of tremor may include

    • A tremor is involuntary, rhythmic contractions of various muscles. Shaky legs syndrome causes feelings of “vibration”, unsteadiness or imbalance in the legs.
    • A rhythmic shaking in the hands, arms, head, legs, or torso
    • Balance and muscle coordination problem
    • Spasticity and muscle spasm with wasting
    • Shaky voice
    • Difficulty writing or drawing
    • Problems holding and controlling utensils, such as a spoon.
    • Begin gradually, usually more prominently on one side of the body
    • Worsen with movement
    • Usually occur in the hands first, affecting one hand or both hands
    • Can include a “yes-yes” or “no-no” motion of the head
    • It May be aggravated by emotional stress, fatigue, caffeine, or temperature extremes
    • Tremors that get worse during emotional stress
    • Tremors that get worse when you move on purpose
    • Tremors that lessen with rest
    • Balance problems (in rare cases)
    • Begin gradually, usually more prominently on one side of the body
    • Worsen with movement

    Essential tremor vs. Parkinson’s disease

    Many people associate tremors with Parkinson’s disease, but the two conditions differ in key ways:

    Timing of tremors. Essential tremor of the hands usually occurs when you use your hands. Tremors from Parkinson’s disease are most prominent when your hands are at your sides or resting in your lap.

    Associated conditions. Essential tremor doesn’t cause other health problems, but Parkinson’s disease is associated with stooped posture, slow movement and shuffling gait. However, people with essential tremor sometimes develop other neurological signs and symptoms, such as an unsteady gait (ataxia).

    Parts of body affected. Essential tremor mainly involves your hands, head and voice. Parkinson’s disease tremors usually start in your hands, and can affect your legs, chin and other parts of your body.

    Signs

    Accompanying symptoms and signs of dystonic tremors may include

    • Mild blepharospasm
    • Alterations in phonation due to spasmodic dysphonia
    • Unnoticed torticollis
    • Family history of dystonia because of its often familial nature
    • The tremor rapidly reduces or disappears in response to sensory tricks (gestes antagonistiques)
    • Task-specific tremor; for example, it may occur only when one is doing a task such as writing, and be mistaken to be an action tremor, but may actually represent dystonic tremor
    • It may be a position-specific tremor
    • It may persist at rest
    • It may affect nearby parts of the body
    • Dystonic tremor may often disappear in certain positions, called null points

    What we feel in both legs simultaneously is extreme straining, fatigue, unsteadiness, and a fear of falling. The muscles in our legs become hard, our ankles feel weak and our toes curl under as our legs fail to support us. We can stand for only a short period of time, in some cases only seconds. There is a feeling of panic to find a place to sit, or if possible, walk to gain some relief from our symptoms. Some tremors /shaky legs syndrome may be triggered by or become worse during times of stress or strong emotion, when an individual is physically exhausted, or when a person is in certain postures or makes certain movements.

    Diagnosis of Resting Tremor

    Medical history

    During the physical evaluation, a doctor will assess the tremor based on:

    • whether the tremor occurs when the muscles are at rest or inaction
    • the location of the tremor on the body (and if it occurs on one or both sides of the body)
    • the appearance of the tremor (tremor frequency and amplitude).

    The doctor will also check other neurological findings such as impaired balance, speech abnormalities, or increased muscle stiffness.  Blood or urine tests can rule out metabolic causes such as thyroid malfunction and certain medications that can cause tremors/shaky legs syndrome.  These tests may also help to identify contributing causes such as drug interactions, chronic alcoholism, or other conditions or diseases.  Diagnostic imaging may help determine if the tremor is the result of damage to the brain.

    Clinical observations

    The diagnosis is based on a combination of a number of clinical observations and recognition of typical characteristics (phenomenology) that include, but are not necessarily limited to the following:

    • Onset of the movements is abrupt/sudden.
    • Movements are triggered by emotional or physical trauma, or by some conflict (marital, sexual, work-related).
    • Movements are episodic or appear intermittent.
    • There are spontaneous remissions of the movements.
    • Movements disappear with distraction.
    • Movements are suggestible, meaning they may disappear by making a suggestion. For example, suggesting that the application of a tuning fork to the body part affected may help relieve the movements.
    • Underlying psychiatric disturbances (depression, anxiety) are present.
    • There are multiple somatizations and undiagnosed conditions.
    • There is a lack of emotional concern about the disorder (“la belle indifference”).
    • There has been exposure to neurologic disorders during one’s occupation (e.g. nurse, physician) or while caring for someone with similar problems.
    • Slurred speech, soft voice, gibberish, foreign accent
    • Delayed and excessive startle (bizarre movements in response to sudden, unexpected noise or threatening movement)
    • Presence of additional types of abnormal movements that are not known to be part of the primary or principal movement disorder pattern that the patient manifests
    • Active resistance against passive movement
    • Fixed posture

    Physical Exam

    • Finger-to-nose and heel-to-shin tests can be useful to evaluate for end-point intention tremors, especially when the patient is asked to do the maneuver quickly.
    • Fine finger movements can be used as well to assess coordination and speed in tasks such as finger or foot tapping, buttoning/unbuttoning shirt, grabbing an object such as a cup or pencil.  The tremor will increase when the extremity is approaching the target.
    • Another characteristic of intention tremors is that the oscillating amplitude can be decreased when the eyes are closed.
    • Rapid alternating movement maneuvers can be used to identify dysdiadochokinesia.
    • Proprioception of the great toes can be impaired as well. Gait testing may reveal wide-based ataxia, with difficulties with tandem gait and a positive Romberg. The patient may have slow saccadic movements and nystagmus.
    • Depending on the etiology, patients may have increased reflexes and extensor Babinski reflexes.
    • Additional tests may be administered to determine functional limitations such as difficulty with handwriting or the ability to hold a fork or cup.  Individuals may be asked to perform a series of tasks or exercises such as placing a finger on the tip of their nose or drawing a spiral.

    Lab Test and Imaging

    • Magnetic resonance imaging (MRI) is the gold standard study to evaluate the brain and cerebellum. Many of the etiologies will be identified by this study.
    • Complete metabolic panel (CMP) – a good history and physical, complete metabolic panel (CMP), psychiatric history, nonpharmacological management, stressful situations (anxiety, fear, anger, and fatigue).
    • Echocardiogram – The doctor may order an electromyogram to diagnose muscle or nerve problems. This test measures involuntary muscle activity and muscle response to nerve stimulation. A comprehensive stroke workup including a good history and physical, screening of vascular risk factors, A1C, lipid panel, blood pressure measurements, brain and vessel imaging (head computed tomographic (CT) scan, head CT angiography, CT perfusion, brain MRI), 2D Echocardiogram with bubble study, Holter monitoring.
    • Complete blood count (CBC) – coagulation studies, head CT scan, CT angiography, brain MRI, MR venous, electromyography, or nerve conduction.
    • Neuroinflammatory, autoimmune or paraneoplastic – CMP, CBC, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), antinuclear antibodies, extractable nuclear antigen panel, Sjogren and lupus anticoagulant studies, antineutrophil cytoplasmic antibodies, angiotensin-converting enzyme test, head CT, brain and spine MRI, chest/abdomen/pelvis CT scan, and lumbar puncture with laboratory studies including cells with differential, glucose, protein, IgG index, myelin basic protein, oligoclonal bands, aquaporin four antibodies, myelin oligodendrocyte glycoprotein antibodies, paraneoplastic panel, flow cytometry/cytology.
    • Metabolic test – CBC, CMP, vitamin deficiency workup, ammonia level, liver ultrasound, abdomen/pelvis CT scan with contrast, advanced metabolic testing.
    • Toxic test –  urine toxicology, ethanol level, heavy metal testing.
    • Hereditary test – CBC, CMP, ESR, CRP, copper/ceruloplasmin, slit eye lamp examination, head CT scan, brain MRI, genetic testing.
    • EMG – measures the electrical impulses of muscles at rest and during contraction. A surface electromyogram can often rapidly establish a diagnosis of primary orthostatic tremor by reproducing the characteristic tremor in the legs. With a surface, electromyogram electrodes are placed on the skin overlying the muscles that are to be tested.

    Treatment of Resting Tremor

    Non-pharmacological

    • Physical, speech-language, and occupational therapy – may help to control tremors and meet daily challenges caused by the tremor.  A physical therapist can help people improve their muscle control, functioning, and strength through coordination, balancing, and other exercises.  Some therapists recommend the use of weights, splints, other adaptive equipment, and special plates and utensils for eating.  Speech-language pathologists can evaluate and treat speech, language, communication, and swallowing disorders.  Occupational therapists can teach individuals new ways of performing activities of daily living that may be affected by tremors.
    • Eliminating or reducing tremor-inducing substances such as caffeine and other medication – (such as stimulants) can help improve tremor. Though small amounts of alcohol can improve tremors for some people, tremors can become worse once the effects of the alcohol wear off.
    • Interventional Therapy – For patients who fail pharmacologic treatment with the above drugs or are unable to tolerate the side effects, surgical options include deep brain stimulation (DBS), focused ultrasound, or radio-surgical gamma knife thalamotomy to treat persistently disabling limb tremor, and botulinum toxin injections to treat persistently disabling head or vocal cord tremor.
    • Deep-brain stimulation This is the most common surgical treatment for essential tremors. Most series report 70% to 90% hand tremor control. In deep-brain stimulation, electrical stimulation is delivered to the brain through an electrode implanted deep into the ventral intermediate nucleus (VIM) of the thalamus. This is typically done by implanting 4 electrodes in the VIM using stereotactic methods. Computerized programming of the pulse generator is most commonly done with a handheld device after the patient leaves the hospital to optimize the electrode montage, voltage, pulse frequency, and pulse width. Deep-brain stimulation can be done unilaterally or bilaterally depending on the patient’s symptoms. There is an increased risk of speech and balance difficulties with bilateral procedures. If the tremor significantly affects both hands, the dominant hand is targeted, bilateral procedures may be considered.
    • Focused ultrasound – Approved by the FDA in 2016, magnetic resonance imaging-guided, high-intensity, focused ultrasound thalamotomy is an innovative method for the treatment of essential tremors. Although it is transcranial and does not require an incision, skull penetration, or an implanted device, it is an invasive therapy that produces a permanent thalamic lesion.
    • Radio-surgical gamma knife thalamotomy Gamma-knife thalamotomy fo­cuses high-energy gamma rays on the ventral intermediate resulting in the death of neurons. It is an unproven treatment that has not generally been adopted due to concerns about potential radiation side effects, including a theoretical, long-term risk of secondary tumor formation.
    • Ultrasound Therapy – A new treatment for essential tremors uses magnetic resonance images to deliver focused ultrasound to create a lesion in tiny areas of the brain’s thalamus thought to be responsible for causing the tremors.  The treatment is approved only for those individuals with essential tremors who do not respond well to anticonvulsant or beta-blocking drugs.
    • Biofeedback – is a mind-body technique that involves using visual or auditory feedback to teach people to recognize the physical signs and symptoms of stress and anxiety, such as increased heart rate, body temperature, and muscle tension.
    • Relaxation techniques – can reduce stress symptoms and help you enjoy a better quality of life, especially if you have an illness. Explore relaxation techniques you can do by yourself.
    • Learn to relax – Stress and anxiety tend to make tremors worse, and being relaxed may improve tremors. Although you can’t eliminate all stress from your life, you can change how you react to stressful situations using a range of relaxation techniques, such as massage or meditation.
    • Noninvasive techniques – Include gait rehabilitation, visually guided techniques, tendon vibration, weighting extremities, positioning techniques, and manual techniques, all of which can be useful for the recovery of functional activities.
    • Invasive techniques – Thalamic deep brain stimulation can alleviate the tremor in MS, providing better functional performance. Stereotactic radiosurgery thalamotomy at the nucleus ventralis intermedius with a median maximum dose of 140 Gy also provides good functional outcomes in patients with MS. Radiofrequency thalamotomy had been successfully used in the past but has been replaced with the newer techniques of radiosurgery and deep brain stimulation as they had fewer adverse effects.
    • Physical therapy – can help some patients control their tremors better, as can reducing the intake of substances such as caffeine, which can induce tremors. Many patients experience an increase in the severity of their tremors when they are stressed. Therefore, trying to reduce sources of anxiety and engaging in complementary therapies (such as yoga or aromatherapy) may help some patients.
    • Speech and occupational therapy – may be useful not only in improving physical and psychological functioning, such as activities of daily living, but also to alter the abnormally learned pattern of movement – “motor reprograming.” Antidepressants and muscle relaxants may be also beneficial. Rarely, transcutaneous electrical stimulation applied to the area of spasm or involuntary movement may be helpful, analogous to the application of a tuning fork during clinic evaluation. Most importantly, however, the patient should try to understand which stress factors may be playing a role and seek the expertise of a psychologist experienced and skilled in stress management. The role of a psychiatrist is not to make the diagnosis but to provide insights into underlying psychological or psychiatric issues and to aid in the treatment of psychiatric issues such as depression or anxiety.
    • Psychogenic movement Therapy –  It may be difficult to treat, especially if the patient is diagnosed late or is not accepting of the diagnosis. Indeed, patients with the best prognosis are those who initially accept the diagnosis and work with the movement disorder neurologist, psychologist, psychiatrist and physical, speech and occupational therapists in implementing a short-term and long-term therapeutic program. The diagnosis should be disclosed to patients in a manner that is empathetic and nonjudgmental.

    For example, tremors due to thyroid hyperactivity will improve or even resolve (return to the normal state) with the treatment of thyroid malfunction.  Also, if the tremor is caused by medication, discontinuing the tremor-causing drug may reduce or eliminate this tremor.

    Medical Therapy

    The therapeutic approach to essential tremors many times follows a trial and error approach, and patients should be challenged by several medications if the first choice is ineffective or associated with debilitating adverse effects. Medical therapy can be divided into first, second, and third-line therapies.

    First-line therapy – It is either approved by the FDA or supported by double-blinded, placebo-controlled studies that meet the criteria for the class I evidence. This class of medications includes propranolol and primidone. If both primidone and propranolol are not effective alone, combinations of both may provide relief in selected patients.

    Second-line therapy – Second-line therapy is supported by double-blinded, placebo-controlled trials that do not meet other requirements for the class I evidence studies. This includes gabapentin, pregabalin, topiramate, benzodiazepines (clonazepam, alprazolam), beta-blockers (atenolol and metoprolol) and zonisamide.

    Third-line therapy These therapies are based on open-label studies or case series. Drugs in this class include nimodipine and clozapine.

    Medication

    Pharmacological Agents to Treat Tremor
    Medication Dosage Clinical Efficacy Comment
    Clonazepam 0.5–6 mg/day +++ Documented effect
    Gabapentin 300–2400 mg/day ++ Documented effect
    Levodopa 300–800 mg/day ++ Only short-term benefit
    Pramipexole 0.75 mg/day + Anecdotal effect
    Primidone 125–250 mg/day + Anecdotal effect
    Valproic acid 500–1000 mg/day +/– Anecdotal effect
    Carbamazepine 400 mg/day +/– Anecdotal effect
    Phenobarbital 100 mg/day +/– Anecdotal effect
    Intravenous immunoglobulin1 2 g/kg over 3 days + Anecdotal effect
    Propanolol 120 mg/day Without effect
    Levetiracetam 3000 mg/day Without effect
    Botulinum toxin 200 mU in the tibialis anterior bilaterally Without effect
    Alcohol Without effect
    • Beta-blocking drugs such as propranolol are normally used to treat high blood pressure but they also help treat essential tremors.  Propranolol can also be used in some people with other types of action tremors.  Other beta-blockers that may be used include atenolol, metoprolol, nadolol, and sotalol.
    • Anti-seizure medications such as primidone can be effective in people with essential tremors who do not respond to beta-blockers.  Other medications that may be prescribed include gabapentin and topiramate.  However, it is important to note that some anti-seizure medications can cause tremors.
    • Tranquilizers (also known as benzodiazepines) such as alprazolam and clonazepam may temporarily help some people with tremors.  However, their use is limited due to unwanted side effects that include sleepiness, poor concentration, and poor coordination.  This can affect the ability of people to perform daily activities such as driving, school, and work.  Also, when taken regularly, tranquilizers can cause physical dependence and when stopped abruptly can cause several withdrawal symptoms.
    • Parkinson’s disease medications (levodopa, carbidopa) are used to treat tremors associated with Parkinson’s disease.
    • Botulinum toxin – injections can treat almost all types of tremors.  It is especially useful for head tremor, which generally does not respond to medications.  Botulinum toxin is widely used to control dystonic tremors.  Although botulinum toxin injections can improve tremors for roughly three months at a time, they can also cause muscle weakness.  While this treatment is effective and usually well tolerated for head tremors, botulinum toxin treatment in the hands can cause weakness in the fingers.  It can cause a hoarse voice and difficulty swallowing when used to treat voice tremors.

    Additional drug therapies that have been used to treat individuals with primary orthostatic tremors include primidone (Mysoline), chlordiazepoxide (Librium), pregabalin (Lyrica), pramipexole (Mirapex), phenobarbital, and valproic acid (Depakote). Drugs commonly used to treat people with Parkinson’s disease (levodopa or pramipexole) may also be prescribed for individuals with primary orthostatic tremors.


    Surgery

    When people do not respond to drug therapies or have a severe tremor that significantly impacts their daily life, a doctor may recommend surgical interventions such as deep brain stimulation (DBS) or very rarely, thalamotomy.  While DBS is usually well-tolerated, the most common side effects of tremor surgery include dysarthria (trouble speaking) and balance problems.

    • Deep brain stimulation (DBS) – is the most common form of surgical treatment of tremors.  This method is preferred because it is effective, has low risk, and treats a broader range of symptoms than thalamotomy.  The treatment uses surgically implanted electrodes to send high-frequency electrical signals to the thalamus, the deep structure of the brain that coordinates and controls some involuntary movements.  A small pulse generating device placed under the skin in the upper chest (similar to a pacemaker) sends electrical stimuli to the brain and temporarily disables the tremor.  DBS is currently used to treat parkinsonian tremors, essential tremors, and dystonia.


    • Thalamotomy – is a surgical procedure that involves the precise, permanent destruction of a tiny area in the thalamus.  Currently, surgery is replaced by radiofrequency ablation to treat severe tremors when deep brain surgery is contraindicated—meaning it is unwise as a treatment option or has undesirable side effects.  Radiofrequency ablation uses a radio wave to generate an electric current that heats up a nerve and disrupts its signaling ability for typically six or more months.  It is usually performed on only one side of the brain to improve tremors on the opposite side of the body.  Surgery on both sides is not recommended as it can cause problems with speech.
    • Focused ultrasound thalamotomy – This non-invasive surgery involves using focused sound waves that travel through the skin and skull. The waves generate heat to destroy brain tissue in a specific area of the thalamus to stop a tremor. A surgeon uses magnetic resonance imaging to target the correct area of the brain and to be sure the sound waves are generating the exact amount of heat needed for the procedure. Focused ultrasound thalamotomy creates a lesion that can result in permanent changes to brain function. Some people have experienced the altered sensation, trouble with walking or difficulty with movement. However, most complications go away on their own or are mild enough that they don’t interfere with the quality of life.
    •  Stereotactic surgical techniques – can be used to create a lesion in the ventral intermediate (VIM) nucleus of the thalamus.

    Rehabilitation

    Exercise is an important part of healthy living for everyone. For people with tremors, exercise is more than healthy it is a vital component to maintaining balance, mobility, and activities of daily living. Exercise and physical activity can improve many tremors symptoms. These benefits are supported by research.

    The tremors show that people with tremors who start exercising earlier and a minimum of 2.5 hours a week, experience a slowed decline in quality of life compared to those who start later. Establishing early exercise habits is essential to overall disease management.

    What Type of Exercise Should I Do?

    To help manage the symptoms of tremors, be sure your exercise program includes a few key ingredients:

    • Aerobic activity
    • Strength training
    • Balance, agility, and multitasking
    • Flexibility

    These elements are included in many types of exercise. Biking, running, Tai chi, yoga, Pilates, dance, weight training, non-contact boxing, qi gong, and more — all have positive effects on tremors symptoms.

    There is no “exercise prescription” that is right for every person with tremors. The type of exercise you do depends on your symptoms and challenges. For sedentary people, just getting up and moving is beneficial. More active people can build up to the regular, vigorous activity. Many approaches work well to help maintain and improve mobility, flexibility, and balance to ease non-motor tremors symptoms such as depression or constipation.

    Researchers in the study did not distinguish between what type of exercise participants did and determined that all types of exercise are beneficial. The most important thing is to do the exercise regularly. We suggest finding an exercise you enjoy and stick with it.


    Challenges to Exercising

    • People in the early stages of tremors tend to be just as strong and physically fit as healthy individuals of the same age.
    • Disease progression can lead to the following physical change:
    • Loss of joint flexibility, which can affect balance.
    • Decreased muscle strength or deconditioning can affect walking and the ability to stand up from sitting.
    • The decline in cardiovascular conditioning, which affects endurance.

    Day to day living

    On a day-to-day basis, people feel stressed and frustrated, but they are not alone. People with orthostatic tremor will often struggle with:

    • standing
    • walking
    • other physical movements
    • exhaustion
    • pain

    Variability

    Orthostatic tremor varies from person to person, and sufferers find their own experiences change from time to time – sometimes due to stress or exertion, but sometimes without any reason what so ever.

    Standing

    For everyone who has an orthostatic tremor, standing, sometimes for just a few seconds, is difficult. People feel their legs buckle under them. This can result in actual falling. There may be a “freezing up” of the legs and doing day-to-day things such as queuing, or browsing in shops is difficult and quite likely impossible. People find that the pain will disappear slightly when the person sits or lies down.

    Walking

    In the early stages of orthostatic tremor, walking may not be affected too much. People may find that they walk quickly and are unable to walk slowly. However, as the condition progresses, the walking distance tends to reduce. The actual distance which can be walked will vary, and at worst people can not walk at all.

    Exhaustion

    People frequently suffer from extreme exhaustion or fatigue. Basic routines such as showering or dressing can take much longer than normal and require a period of rest for recovery. Even after a day of relatively little physical activity, they may feel unable to get out of a chair or needing sleep.

    Pain

    Some people will suffer pain when moving and over some said they have some pain when resting, usually in the legs and back.

    The effect of stress and emotion

    It is recognized that stress makes tremors worst. There is a vicious circle where the tremor gives rise to stress, and then the stress increases the tremor and so on. Feelings such as anger, annoyance, concern, frustration, and even excitement or anticipation can be a problem. The particular difficulty is caused by situations such as a crowded place – nowhere to sit, exertion involved, and the risk of falling.

    Frustration

    People experience much frustration and dependency on spouses/partners/carers and often lack of confidence when separated from them. Simple household tasks such as cleaning, cooking, and even making a cup of tea (or carrying it to another room) are either difficult or impossible.

    Mobility aids

    People often use a wheelchair, and some find that a wheelchair is essential for going out and/or moving around at home. Others use them only occasionally – such as at airports. Just over a third of respondents use a scooter. Some people often use scooters or walking sticks.

    Tips for Getting Started

    • First, be safe. Before starting an exercise program, consult your neurologist and primary care doctor about concerns and recommendations.
    • Ask your doctor or members in your support group to refer to a physical therapist (PT) who knows about tremors. Work together to identify your concerns and limitations. Target exercises to improve them. For most people, a structured exercise program will include aerobic exercise (such as brisk walking) and resistance training (using weights or bands).
    • Purchase a pedometer (step-counter) and figure out how many steps you take on average each day, then build up from there. Many smartphones or smartwatches have a built-in pedometer feature or an application that can be downloaded.
    • Exercise indoors and outdoors. Change your routine to stay interested and motivated.
    • Again, most importantly pick an exercise you enjoy.

    What research is being done?

    The mission is to seek fundamental knowledge about the brain and nervous system and to use that knowledge to reduce the burden of neurological disease.  The NINDS is a component of the National Institutes of Health (NIH), the leading supporter of biomedical research in the world.

    Researchers are working to better understand the underlying brain functions that cause tremors, identify the genetic factors that make individuals more susceptible to the disorder, and develop new and better treatment options.

    • Brain functioning – It can be difficult to distinguish between movement disorders such as Parkinson’s disease and essential tremor. These debilitating movement disorders have different prognoses and can respond very differently to available therapies. NINDS researchers are working to identify structural and functional changes in the brain using non-invasive neuroimaging techniques to develop sensitive and specific markers for each of these diseases and then track how they change as each disease progresses. Other researchers are using functional magnetic resonance imaging technology to better understand normal and diseased brain circuit functions and associated motor behaviors.  Scientists hope to design therapies that can restore normal brain circuit function in diseases such as Parkinson’s disease and tremor.
    • Genetics – Research has shown that essential tremors may have a strong genetic component affecting multiple generations of families.  NINDS researchers are building on previous genetics work to identify susceptibility genes for familial early-onset (before age 40) essential tremor.  Researchers are focusing on multigenerational, early-onset families to better detect linkages.

    Additionally, NINDS scientists are researching the impact of genetic abnormalities on the development of essential tremors.  Previous research that has shown a link between essential tremor and possible genetic variants on chromosome 6 and 11; ongoing research is targeting the impact of other genetic variations in families.

    Medications and other treatment methods

    While drugs can be effective for some people, approximately 50 percent of individuals do not respond to medication.  In order to develop assistive and rehabilitative tremor-suppressing devices for people with essential tremors, researchers are exploring where and how to minimize or suppress tremors while still allowing for voluntary movements.

    Many people with essential tremors respond to ethanol (alcohol); however, it is not clear why or how.  NINDS researchers are studying the impact of ethanol on tremors to determine the correct dosage amount and its physiological impact on the brain and whether other medications without the side effects of ethanol can be effective.

    Other NIH researchers hope to identify the source of essential tremors, study the effects of currently available tremor-suppressant drugs on the brain, and develop more targeted and effective therapies.

    FAQ

    Please answer the following questions to participate in our certified Continuing Medical Education program. Only one answer is possible per question. Please select the answer that is most appropriate.

    Question 1

    Which of the following constellations of clinical findings is typical of tremor in patients with Parkinson’s disease?

    1. bilateral postural tremor

    2. unilateral rest tremor and diminished ipsilateral arm swing while walking

    3. severe unilateral tremor while holding a cup or glass

    4. tremor that only appears when the patient writes

    5. postural tremor of both hands and ataxic gait

    Question 2

    A 25-year-old man has a mild postural tremor of both hands that improves when he drinks alcohol. His mother had the same condition. What can you advise him?

    1. He should definitely be evaluated for possible early Parkinson’s disease.

    2. He must get treatment now, as otherwise the condition could worsen.

    3. If treatment is indicated, propranolol or primidone could be given.

    4. Relaxation exercises and physiotherapy are effective treatment options.

    5. Genetic testing is needed to confirm the diagnosis of essential tremor.

    Question 3

    A man who received the diagnosis of multiple sclerosis two years ago presents to you with the new onset of tremor. What constellation of clinical findings is typical of tremor due to multiple sclerosis?

    1. rest tremor, only occasionally observable when the patient is excited

    2. a tremor that appears sometimes on the left side, sometimes on the right

    3. a tremor that is only present in the morning

    4. a swaying, broad-based gait and an intention tremor

    5. a postural tremor that is easily suppressed by voluntary effort

    Question 4

    A 55-year-old man with essential tremor says that he can no longer feed himself because of tremor, can dress himself only with great difficulty, and has not had legible handwriting for many years. Drug treatment as recommended in the relevant clinical guidelines brings only slight improvement. What can you advise the patient about the option of surgical treatment?

    1. Deep brain stimulation (DBS) might help but is not available in Germany.

    2. DBS is an experimental technique that is only performed in clinical trials.

    3. DBS is indicated only to treat Parkinson’s disease and plays no role in the treatment of essential tremor.

    4. DBS has a high chance of success in this situation; it is now established as a standard treatment for essential tremor.

    5. DBS is no more effective than pharmacotherapy for this indication.

    Question 5

    What information is most important for the diagnostic classification of a tremor syndrome?

    1. the clinical findings

    2. brain magnetic resonance imaging (MRI) with fine cerebellar sections

    3. nuclear-medical visualization of brain perfusion

    4. ultrasonography of the basal ganglia

    5. measurement of serum drug levels

    Question 6

    What findings indicate that tremor may be psychogenic?

    1. no evidence of essential tremor or Parkinson’s disease on brain MRI

    2. a longstanding marital conflict

    3. a tremor of inconstant location that diminishes on distraction and is found to be irregular on tremor analysis

    4. a clearly identifiable underlying psychological conflict

    5. remission after psychotherapy

    Question 7

    When can tremor be treated surgically?

    1. When the patient is unwilling to take drugs to treat tremor.

    2. When the patient is under 50 years old.

    3. When the tremor cannot be adequately suppressed by drugs and there is no contraindication to surgery.

    4. When the patient is willing to see a neurosurgeon once a week so that brain stimulation can be performed.

    5. When the patient is willing to assume the cost of weekly battery changes.

    Question 8

    What must be borne in mind with respect to drug treatment for various tremor syndromes?

    1. That the treatment is based on the clinical findings and not on the underlying disease causing tremor.

    2. That causally directed treatment is generally possible only for drug-induced tremors or tremors due to metabolic disturbance.

    3. That parkinsonian tremor responds best to anticholinergic drugs and does not respond at all to the classic dopamine preparations.

    4. That the cerebellar tremor of multiple sclerosis is treated in exactly the same way as essential tremor.

    5. That essential tremor is usually medically intractable.

    Question 9

    What drugs can induce tremor?

    1. lithium, valproic acid, cyclosporine A

    2. carbamazepine, propranolol, Seroxat

    3. aspirin, diclofenac, paracetamol

    4. penicillin, erythromycin, cephalosporin

    5. antilipid drugs, antidiabetic drugs

    Question 10

    What is the drug, or drug class, of first choice for the treatment of parkinsonian tremor?

    1. dopaminergic drugs

    2. propanolol

    3. primidone

    4. gabapentin

    5. ondansetron

    References

     

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    Cerebellar Tremor – Causes, Symptoms, Treatment

    Cerebellar tremor is typically a slow, high-amplitude (easily visible) tremor of the extremities (e.g., arm, leg) that occurs at the end of a purposeful movement such as trying to press a button.  It is caused by damage to the cerebellum and its pathways to other brain regions resulting from a stroke or tumor.  Damage also may be caused by diseases such as multiple sclerosis or an inherited degenerative disorder such as ataxia (in which people lose muscle control in the arms and legs) and Fragile X syndrome (a disorder marked by a range of intellectual and developmental problems).  It can also result from chronic damage to the cerebellum due to alcoholism.

    Cerebellar tremor is often used synonymously with intention tremor. However, several clinical types of action tremor are included in this category with intention tremor being the most common form. Intention tremor typically increases during the approach to a target. Action, kinetic, and titubation or stance tremors are usually regarded as being of cerebellar origin if other signs of cerebellar dysfunction are also present. According to the consensus statement of the Movement Disorder Society on tremor, cerebellar tremors can be diagnosed according to the following clinical signs: (1) pure or dominant intention tremor, either unilateral or bilateral; (2) tremor frequency usually less than 5 Hz; and (3) postural tremor present without rest tremor.

    Causes of Cerebellar Tremor

    Generally, tremor is caused by a problem in the deep parts of the brain that control movements.  Most types of tremors have no known cause, although there are some forms that appear to be inherited and run in families.

    Tremor can occur on its own or be a symptom associated with a number of neurological disorders, including

    • Multiple sclerosis
    • Stroke
    • Traumatic brain injury
    • Neurodegenerative diseases that affect parts of the brain (e.g.,  Parkinson’s disease).
    • Neurologic disorders, including multiple sclerosis, Parkinson’s disease, stroke, and traumatic brain injury
    • Certain medicines, such as asthma medicines, amphetamines, caffeine, corticosteroids, and medicines used for certain psychiatric and neurological disorders
    • Alcohol use disorder or alcohol withdrawal
    • Mercury poisoning
    • Hyperthyroidism (overactive thyroid)
    • Liver or kidney failure
    • Anxiety or panic

    Some other known causes can include

    • the use of certain medicines (particular asthma medication, amphetamines, caffeine, corticosteroids, and drugs used for certain psychiatric and neurological disorders)
    • alcohol abuse or withdrawal
    • mercury poisoning
    • overactive thyroid
    • liver or kidney failure
    • anxiety or panic.

    Common Causes of  tumors due to Medication- or Toxin-Induced Tremors

    Class of Medication or Toxin Examples
    Beta-adrenergic agonists Terbutaline, metaproterenol, isoetharine, epinephrine (adrenaline)
    Antidepressants Bupropion, lithium, tricyclic antidepressants
    Neuroleptics Haloperidol
    Anticonvulsants Valproate sodium
    Dopamine agonists Amphetamine
    Heavy metals Mercury, lead, arsenic, bismuth
    Xanthines or derivatives coffee, tea, theophylline, cyclosporine
      Additional causes are
    • Cerebellar Lesion (CVA or Tumor)
      • Lesions of lateral cerebellar nuclei
      • Lesions of cerebellar peduncle
      • Lesions of red nucleus (Causes Rubral Tremor)
        • Wing-beating type Tremor
        • Rubral Tremor also seen in Wilson’s Disease
    • Cerebellar Postural Tremor
      • Multiple Sclerosis with cerebellar Plaques (most common etiology)
      • Frequency
        1. Mild: 10 Hz
        2. Severe: 2.5-4 Hz
      • Amplitude waxes and wanes
    • Wilson’s Disease
    • Psychogenic Tremor
    • Drug-Induced Tremor
      • Lithium
      • Alcoholism
      • Dystonic Tremor (estrapyramidal side effect)
        1. Typically drug induced, with onset age <50, with abnormal wrist flexion and jerky hand or arm positions

    Symptoms of Cerebellar Tremor

    Symptoms of tremor may include

    • A tremor is involuntary, rhythmic contractions of various muscles. Shaky legs syndrome causes feelings of “vibration”, unsteadiness or imbalance in the legs.
    • A rhythmic shaking in the hands, arms, head, legs, or torso
    • Balance and muscle coordination problem
    • Spasticity and muscle spasm with wasting
    • Shaky voice
    • Difficulty writing or drawing
    • Problems holding and controlling utensils, such as a spoon.
    • Begin gradually, usually more prominently on one side of the body
    • Worsen with movement
    • Usually occur in the hands first, affecting one hand or both hands
    • Can include a “yes-yes” or “no-no” motion of the head
    • It May be aggravated by emotional stress, fatigue, caffeine, or temperature extremes
    • Tremors that get worse during emotional stress
    • Tremors that get worse when you move on purpose
    • Tremors that lessen with rest
    • Balance problems (in rare cases)

    Signs

    • Intention Tremor on the ipsilateral side of lesion
      • Exacerbated Tremor at end of goal-directed movement
      • Low to Medium frequency Tremor
      • Example: Finger-Nose-Finger
      • Midline disease causes bilateral Tremor
      • Contrast with Rest Tremor
        1. Rest Tremor improves with goal-directed movement
    • Tremor increases as extremity reach target (with secondary dysmetria or over-shooting)
      • Finger-Nose-Finger
      • Heel-Knee-Shin
    • Concurrent Cerebellar signs
      • Abnormal gait
      • Speech abnormalities
      • Ocular movement abnormalities
      • Rapid Alternating Movements abnormal
      • Abnormal tandem walk (esp. Multiple Sclerosis)
    • Other findings
      1. Hypotonia

    What we feel in both legs simultaneously is extreme straining, fatigue, unsteadiness, and a fear of falling. The muscles in our legs become hard, our ankles feel weak and our toes curl under as our legs fail to support us. We can stand for only a short period of time, in some cases only seconds. There is a feeling of panic to find a place to sit, or if possible, walk to gain some relief from our symptoms. Some tremors /shaky legs syndrome may be triggered by or become worse during times of stress or strong emotion, when an individual is physically exhausted, or when a person is in certain postures or makes certain movements.

    Diagnosis of Cerebellar Tremor

    Medical history

    During the physical evaluation, a doctor will assess the tremor based on:

    • whether the tremor occurs when the muscles are at rest or inaction
    • the location of the tremor on the body (and if it occurs on one or both sides of the body)
    • the appearance of the tremor (tremor frequency and amplitude).

    The doctor will also check other neurological findings such as impaired balance, speech abnormalities, or increased muscle stiffness.  Blood or urine tests can rule out metabolic causes such as thyroid malfunction and certain medications that can cause tremors/shaky legs syndrome.  These tests may also help to identify contributing causes such as drug interactions, chronic alcoholism, or other conditions or diseases.  Diagnostic imaging may help determine if the tremor is the result of damage to the brain.

    Clinical observations

    The diagnosis is based on a combination of a number of clinical observations and recognition of typical characteristics (phenomenology) that include, but are not necessarily limited to the following:

    • Onset of the movements is abrupt/sudden.
    • Movements are triggered by emotional or physical trauma, or by some conflict (marital, sexual, work-related).
    • Movements are episodic or appear intermittent.
    • There are spontaneous remissions of the movements.
    • Movements disappear with distraction.
    • Movements are suggestible, meaning they may disappear by making a suggestion. For example, suggesting that the application of a tuning fork to the body part affected may help relieve the movements.
    • Underlying psychiatric disturbances (depression, anxiety) are present.
    • There are multiple somatizations and undiagnosed conditions.
    • There is a lack of emotional concern about the disorder (“la belle indifference”).
    • There has been exposure to neurologic disorders during one’s occupation (e.g. nurse, physician) or while caring for someone with similar problems.
    • Slurred speech, soft voice, gibberish, foreign accent
    • Delayed and excessive startle (bizarre movements in response to sudden, unexpected noise or threatening movement)
    • Presence of additional types of abnormal movements that are not known to be part of the primary or principal movement disorder pattern that the patient manifests
    • Active resistance against passive movement
    • Fixed posture

    Physical Exam

    • Finger-to-nose and heel-to-shin tests can be useful to evaluate for end-point intention tremors, especially when the patient is asked to do the maneuver quickly.
    • Fine finger movements can be used as well to assess coordination and speed in tasks such as finger or foot tapping, buttoning/unbuttoning shirt, grabbing an object such as a cup or pencil.  The tremor will increase when the extremity is approaching the target.
    • Another characteristic of intention tremors is that the oscillating amplitude can be decreased when the eyes are closed.
    • Rapid alternating movement maneuvers can be used to identify dysdiadochokinesia.
    • Proprioception of the great toes can be impaired as well. Gait testing may reveal wide-based ataxia, with difficulties with tandem gait and a positive Romberg. The patient may have slow saccadic movements and nystagmus.
    • Depending on the etiology, patients may have increased reflexes and extensor Babinski reflexes.
    • Additional tests may be administered to determine functional limitations such as difficulty with handwriting or the ability to hold a fork or cup.  Individuals may be asked to perform a series of tasks or exercises such as placing a finger on the tip of their nose or drawing a spiral.

    Lab Test and Imaging

    • Magnetic resonance imaging (MRI) is the gold standard study to evaluate the brain and cerebellum. Many of the etiologies will be identified by this study.
    • Complete metabolic panel (CMP) – a good history and physical, complete metabolic panel (CMP), psychiatric history, nonpharmacological management, stressful situations (anxiety, fear, anger, and fatigue).
    • Echocardiogram – The doctor may order an electromyogram to diagnose muscle or nerve problems. This test measures involuntary muscle activity and muscle response to nerve stimulation. A comprehensive stroke workup including a good history and physical, screening of vascular risk factors, A1C, lipid panel, blood pressure measurements, brain and vessel imaging (head computed tomographic (CT) scan, head CT angiography, CT perfusion, brain MRI), 2D Echocardiogram with bubble study, Holter monitoring.
    • Complete blood count (CBC) – coagulation studies, head CT scan, CT angiography, brain MRI, MR venous, electromyography, or nerve conduction.
    • Neuroinflammatory, autoimmune or paraneoplastic – CMP, CBC, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), antinuclear antibodies, extractable nuclear antigen panel, Sjogren and lupus anticoagulant studies, antineutrophil cytoplasmic antibodies, angiotensin-converting enzyme test, head CT, brain and spine MRI, chest/abdomen/pelvis CT scan, and lumbar puncture with laboratory studies including cells with differential, glucose, protein, IgG index, myelin basic protein, oligoclonal bands, aquaporin four antibodies, myelin oligodendrocyte glycoprotein antibodies, paraneoplastic panel, flow cytometry/cytology.
    • Metabolic test – CBC, CMP, vitamin deficiency workup, ammonia level, liver ultrasound, abdomen/pelvis CT scan with contrast, advanced metabolic testing.
    • Toxic test –  urine toxicology, ethanol level, heavy metal testing.
    • Hereditary test – CBC, CMP, ESR, CRP, copper/ceruloplasmin, slit eye lamp examination, head CT scan, brain MRI, genetic testing.
    • EMG – measures the electrical impulses of muscles at rest and during contraction. A surface electromyogram can often rapidly establish a diagnosis of primary orthostatic tremor by reproducing the characteristic tremor in the legs. With a surface, electromyogram electrodes are placed on the skin overlying the muscles that are to be tested.

    Treatment of Cerebellar Tremor

    Non-pharmacological

    • Physical, speech-language, and occupational therapy – may help to control tremors and meet daily challenges caused by the tremor.  A physical therapist can help people improve their muscle control, functioning, and strength through coordination, balancing, and other exercises.  Some therapists recommend the use of weights, splints, other adaptive equipment, and special plates and utensils for eating.  Speech-language pathologists can evaluate and treat speech, language, communication, and swallowing disorders.  Occupational therapists can teach individuals new ways of performing activities of daily living that may be affected by tremors.
    • Eliminating or reducing tremor-inducing substances such as caffeine and other medication – (such as stimulants) can help improve tremor. Though small amounts of alcohol can improve tremors for some people, tremors can become worse once the effects of the alcohol wear off.
    • Interventional Therapy – For patients who fail pharmacologic treatment with the above drugs or are unable to tolerate the side effects, surgical options include deep brain stimulation (DBS), focused ultrasound, or radio-surgical gamma knife thalamotomy to treat persistently disabling limb tremor, and botulinum toxin injections to treat persistently disabling head or vocal cord tremor.
    • Deep-brain stimulation This is the most common surgical treatment for essential tremors. Most series report 70% to 90% hand tremor control. In deep-brain stimulation, electrical stimulation is delivered to the brain through an electrode implanted deep into the ventral intermediate nucleus (VIM) of the thalamus. This is typically done by implanting 4 electrodes in the VIM using stereotactic methods. Computerized programming of the pulse generator is most commonly done with a handheld device after the patient leaves the hospital to optimize the electrode montage, voltage, pulse frequency, and pulse width. Deep-brain stimulation can be done unilaterally or bilaterally depending on the patient’s symptoms. There is an increased risk of speech and balance difficulties with bilateral procedures. If the tremor significantly affects both hands, the dominant hand is targeted, bilateral procedures may be considered.
    • Focused ultrasound – Approved by the FDA in 2016, magnetic resonance imaging-guided, high-intensity, focused ultrasound thalamotomy is an innovative method for the treatment of essential tremors. Although it is transcranial and does not require an incision, skull penetration, or an implanted device, it is an invasive therapy that produces a permanent thalamic lesion.
    • Radio-surgical gamma knife thalamotomy Gamma-knife thalamotomy fo­cuses high-energy gamma rays on the ventral intermediate resulting in the death of neurons. It is an unproven treatment that has not generally been adopted due to concerns about potential radiation side effects, including a theoretical, long-term risk of secondary tumor formation.
    • Ultrasound Therapy – A new treatment for essential tremors uses magnetic resonance images to deliver focused ultrasound to create a lesion in tiny areas of the brain’s thalamus thought to be responsible for causing the tremors.  The treatment is approved only for those individuals with essential tremors who do not respond well to anticonvulsant or beta-blocking drugs.
    • Biofeedback – is a mind-body technique that involves using visual or auditory feedback to teach people to recognize the physical signs and symptoms of stress and anxiety, such as increased heart rate, body temperature, and muscle tension.
    • Relaxation techniques – can reduce stress symptoms and help you enjoy a better quality of life, especially if you have an illness. Explore relaxation techniques you can do by yourself.
    • Learn to relax – Stress and anxiety tend to make tremors worse, and being relaxed may improve tremors. Although you can’t eliminate all stress from your life, you can change how you react to stressful situations using a range of relaxation techniques, such as massage or meditation.
    • Noninvasive techniques – Include gait rehabilitation, visually guided techniques, tendon vibration, weighting extremities, positioning techniques, and manual techniques, all of which can be useful for the recovery of functional activities.
    • Invasive techniques – Thalamic deep brain stimulation can alleviate the tremor in MS, providing better functional performance. Stereotactic radiosurgery thalamotomy at the nucleus ventralis intermedius with a median maximum dose of 140 Gy also provides good functional outcomes in patients with MS. Radiofrequency thalamotomy had been successfully used in the past but has been replaced with the newer techniques of radiosurgery and deep brain stimulation as they had fewer adverse effects.
    • Physical therapy – can help some patients control their tremors better, as can reducing the intake of substances such as caffeine, which can induce tremors. Many patients experience an increase in the severity of their tremors when they are stressed. Therefore, trying to reduce sources of anxiety and engaging in complementary therapies (such as yoga or aromatherapy) may help some patients.
    • Speech and occupational therapy – may be useful not only in improving physical and psychological functioning, such as activities of daily living, but also to alter the abnormally learned pattern of movement – “motor reprograming.” Antidepressants and muscle relaxants may be also beneficial. Rarely, transcutaneous electrical stimulation applied to the area of spasm or involuntary movement may be helpful, analogous to the application of a tuning fork during clinic evaluation. Most importantly, however, the patient should try to understand which stress factors may be playing a role and seek the expertise of a psychologist experienced and skilled in stress management. The role of a psychiatrist is not to make the diagnosis but to provide insights into underlying psychological or psychiatric issues and to aid in the treatment of psychiatric issues such as depression or anxiety.
    • Psychogenic movement Therapy –  It may be difficult to treat, especially if the patient is diagnosed late or is not accepting of the diagnosis. Indeed, patients with the best prognosis are those who initially accept the diagnosis and work with the movement disorder neurologist, psychologist, psychiatrist and physical, speech and occupational therapists in implementing a short-term and long-term therapeutic program. The diagnosis should be disclosed to patients in a manner that is empathetic and nonjudgmental.

    For example, tremors due to thyroid hyperactivity will improve or even resolve (return to the normal state) with the treatment of thyroid malfunction.  Also, if the tremor is caused by medication, discontinuing the tremor-causing drug may reduce or eliminate this tremor.

    Medical Therapy

    The therapeutic approach to essential tremors many times follows a trial and error approach, and patients should be challenged by several medications if the first choice is ineffective or associated with debilitating adverse effects. Medical therapy can be divided into first, second, and third-line therapies.

    First-line therapy – It is either approved by the FDA or supported by double-blinded, placebo-controlled studies that meet the criteria for the class I evidence. This class of medications includes propranolol and primidone. If both primidone and propranolol are not effective alone, combinations of both may provide relief in selected patients.

    Second-line therapy – Second-line therapy is supported by double-blinded, placebo-controlled trials that do not meet other requirements for the class I evidence studies. This includes gabapentin, pregabalin, topiramate, benzodiazepines (clonazepam, alprazolam), beta-blockers (atenolol and metoprolol) and zonisamide.

    Third-line therapy These therapies are based on open-label studies or case series. Drugs in this class include nimodipine and clozapine.

    Medication

    Pharmacological Agents to Treat Tremor
    Medication Dosage Clinical Efficacy Comment
    Clonazepam 0.5–6 mg/day +++ Documented effect
    Gabapentin 300–2400 mg/day ++ Documented effect
    Levodopa 300–800 mg/day ++ Only short-term benefit
    Pramipexole 0.75 mg/day + Anecdotal effect
    Primidone 125–250 mg/day + Anecdotal effect
    Valproic acid 500–1000 mg/day +/– Anecdotal effect
    Carbamazepine 400 mg/day +/– Anecdotal effect
    Phenobarbital 100 mg/day +/– Anecdotal effect
    Intravenous immunoglobulin1 2 g/kg over 3 days + Anecdotal effect
    Propanolol 120 mg/day Without effect
    Levetiracetam 3000 mg/day Without effect
    Botulinum toxin 200 mU in the tibialis anterior bilaterally Without effect
    Alcohol Without effect
    • Beta-blocking drugs such as propranolol are normally used to treat high blood pressure but they also help treat essential tremors.  Propranolol can also be used in some people with other types of action tremors.  Other beta-blockers that may be used include atenolol, metoprolol, nadolol, and sotalol.
    • Anti-seizure medications such as primidone can be effective in people with essential tremors who do not respond to beta-blockers.  Other medications that may be prescribed include gabapentin and topiramate.  However, it is important to note that some anti-seizure medications can cause tremors.
    • Tranquilizers (also known as benzodiazepines) such as alprazolam and clonazepam may temporarily help some people with tremors.  However, their use is limited due to unwanted side effects that include sleepiness, poor concentration, and poor coordination.  This can affect the ability of people to perform daily activities such as driving, school, and work.  Also, when taken regularly, tranquilizers can cause physical dependence and when stopped abruptly can cause several withdrawal symptoms.
    • Parkinson’s disease medications (levodopa, carbidopa) are used to treat tremors associated with Parkinson’s disease.
    • Botulinum toxin – injections can treat almost all types of tremors.  It is especially useful for head tremor, which generally does not respond to medications.  Botulinum toxin is widely used to control dystonic tremors.  Although botulinum toxin injections can improve tremors for roughly three months at a time, they can also cause muscle weakness.  While this treatment is effective and usually well tolerated for head tremors, botulinum toxin treatment in the hands can cause weakness in the fingers.  It can cause a hoarse voice and difficulty swallowing when used to treat voice tremors.

    Additional drug therapies that have been used to treat individuals with primary orthostatic tremors include primidone (Mysoline), chlordiazepoxide (Librium), pregabalin (Lyrica), pramipexole (Mirapex), phenobarbital, and valproic acid (Depakote). Drugs commonly used to treat people with Parkinson’s disease (levodopa or pramipexole) may also be prescribed for individuals with primary orthostatic tremors.


    Surgery

    When people do not respond to drug therapies or have a severe tremor that significantly impacts their daily life, a doctor may recommend surgical interventions such as deep brain stimulation (DBS) or very rarely, thalamotomy.  While DBS is usually well-tolerated, the most common side effects of tremor surgery include dysarthria (trouble speaking) and balance problems.

    • Deep brain stimulation (DBS) – is the most common form of surgical treatment of tremors.  This method is preferred because it is effective, has low risk, and treats a broader range of symptoms than thalamotomy.  The treatment uses surgically implanted electrodes to send high-frequency electrical signals to the thalamus, the deep structure of the brain that coordinates and controls some involuntary movements.  A small pulse generating device placed under the skin in the upper chest (similar to a pacemaker) sends electrical stimuli to the brain and temporarily disables the tremor.  DBS is currently used to treat parkinsonian tremors, essential tremors, and dystonia.


    • Thalamotomy – is a surgical procedure that involves the precise, permanent destruction of a tiny area in the thalamus.  Currently, surgery is replaced by radiofrequency ablation to treat severe tremors when deep brain surgery is contraindicated—meaning it is unwise as a treatment option or has undesirable side effects.  Radiofrequency ablation uses a radio wave to generate an electric current that heats up a nerve and disrupts its signaling ability for typically six or more months.  It is usually performed on only one side of the brain to improve tremors on the opposite side of the body.  Surgery on both sides is not recommended as it can cause problems with speech.
    •  Stereotactic surgical techniques – can be used to create a lesion in the ventral intermediate (VIM) nucleus of the thalamus.

    Rehabilitation

    Exercise is an important part of healthy living for everyone. For people with tremors, exercise is more than healthy it is a vital component to maintaining balance, mobility, and activities of daily living. Exercise and physical activity can improve many tremors symptoms. These benefits are supported by research.

    The tremors show that people with tremors who start exercising earlier and a minimum of 2.5 hours a week, experience a slowed decline in quality of life compared to those who start later. Establishing early exercise habits is essential to overall disease management.

    What Type of Exercise Should I Do?

    To help manage the symptoms of tremors, be sure your exercise program includes a few key ingredients:

    • Aerobic activity
    • Strength training
    • Balance, agility, and multitasking
    • Flexibility

    These elements are included in many types of exercise. Biking, running, Tai chi, yoga, Pilates, dance, weight training, non-contact boxing, qi gong, and more — all have positive effects on tremors symptoms.

    There is no “exercise prescription” that is right for every person with tremors. The type of exercise you do depends on your symptoms and challenges. For sedentary people, just getting up and moving is beneficial. More active people can build up to the regular, vigorous activity. Many approaches work well to help maintain and improve mobility, flexibility, and balance to ease non-motor tremors symptoms such as depression or constipation.

    Researchers in the study did not distinguish between what type of exercise participants did and determined that all types of exercise are beneficial. The most important thing is to do the exercise regularly. We suggest finding an exercise you enjoy and stick with it.


    Challenges to Exercising

    • People in the early stages of tremors tend to be just as strong and physically fit as healthy individuals of the same age.
    • Disease progression can lead to the following physical change:
    • Loss of joint flexibility, which can affect balance.
    • Decreased muscle strength or deconditioning can affect walking and the ability to stand up from sitting.
    • The decline in cardiovascular conditioning, which affects endurance.

    Day to day living

    On a day-to-day basis, people feel stressed and frustrated, but they are not alone. People with orthostatic tremor will often struggle with:

    • standing
    • walking
    • other physical movements
    • exhaustion
    • pain

    Variability

    Orthostatic tremor varies from person to person, and sufferers find their own experiences change from time to time – sometimes due to stress or exertion, but sometimes without any reason what so ever.

    Standing

    For everyone who has an orthostatic tremor, standing, sometimes for just a few seconds, is difficult. People feel their legs buckle under them. This can result in actual falling. There may be a “freezing up” of the legs and doing day-to-day things such as queuing, or browsing in shops is difficult and quite likely impossible. People find that the pain will disappear slightly when the person sits or lies down.

    Walking

    In the early stages of orthostatic tremor, walking may not be affected too much. People may find that they walk quickly and are unable to walk slowly. However, as the condition progresses, the walking distance tends to reduce. The actual distance which can be walked will vary, and at worst people can not walk at all.

    Exhaustion

    People frequently suffer from extreme exhaustion or fatigue. Basic routines such as showering or dressing can take much longer than normal and require a period of rest for recovery. Even after a day of relatively little physical activity, they may feel unable to get out of a chair or needing sleep.

    Pain

    Some people will suffer pain when moving and over some said they have some pain when resting, usually in the legs and back.

    The effect of stress and emotion

    It is recognized that stress makes tremors worst. There is a vicious circle where the tremor gives rise to stress, and then the stress increases the tremor and so on. Feelings such as anger, annoyance, concern, frustration, and even excitement or anticipation can be a problem. The particular difficulty is caused by situations such as a crowded place – nowhere to sit, exertion involved, and the risk of falling.

    Frustration

    People experience much frustration and dependency on spouses/partners/carers and often lack of confidence when separated from them. Simple household tasks such as cleaning, cooking, and even making a cup of tea (or carrying it to another room) are either difficult or impossible.

    Mobility aids

    People often use a wheelchair, and some find that a wheelchair is essential for going out and/or moving around at home. Others use them only occasionally – such as at airports. Just over a third of respondents use a scooter. Some people often use scooters or walking sticks.

    Tips for Getting Started

    • First, be safe. Before starting an exercise program, consult your neurologist and primary care doctor about concerns and recommendations.
    • Ask your doctor or members in your support group to refer to a physical therapist (PT) who knows about tremors. Work together to identify your concerns and limitations. Target exercises to improve them. For most people, a structured exercise program will include aerobic exercise (such as brisk walking) and resistance training (using weights or bands).
    • Purchase a pedometer (step-counter) and figure out how many steps you take on average each day, then build up from there. Many smartphones or smartwatches have a built-in pedometer feature or an application that can be downloaded.
    • Exercise indoors and outdoors. Change your routine to stay interested and motivated.
    • Again, most importantly pick an exercise you enjoy.

    What research is being done?

    The mission is to seek fundamental knowledge about the brain and nervous system and to use that knowledge to reduce the burden of neurological disease.  The NINDS is a component of the National Institutes of Health (NIH), the leading supporter of biomedical research in the world.

    Researchers are working to better understand the underlying brain functions that cause tremors, identify the genetic factors that make individuals more susceptible to the disorder, and develop new and better treatment options.

    • Brain functioning – It can be difficult to distinguish between movement disorders such as Parkinson’s disease and essential tremor. These debilitating movement disorders have different prognoses and can respond very differently to available therapies. NINDS researchers are working to identify structural and functional changes in the brain using non-invasive neuroimaging techniques to develop sensitive and specific markers for each of these diseases and then track how they change as each disease progresses. Other researchers are using functional magnetic resonance imaging technology to better understand normal and diseased brain circuit functions and associated motor behaviors.  Scientists hope to design therapies that can restore normal brain circuit function in diseases such as Parkinson’s disease and tremor.
    • Genetics – Research has shown that essential tremors may have a strong genetic component affecting multiple generations of families.  NINDS researchers are building on previous genetics work to identify susceptibility genes for familial early-onset (before age 40) essential tremor.  Researchers are focusing on multigenerational, early-onset families to better detect linkages.

    Additionally, NINDS scientists are researching the impact of genetic abnormalities on the development of essential tremors.  Previous research that has shown a link between essential tremor and possible genetic variants on chromosome 6 and 11; ongoing research is targeting the impact of other genetic variations in families.

    Medications and other treatment methods

    While drugs can be effective for some people, approximately 50 percent of individuals do not respond to medication.  In order to develop assistive and rehabilitative tremor-suppressing devices for people with essential tremors, researchers are exploring where and how to minimize or suppress tremors while still allowing for voluntary movements.

    Many people with essential tremors respond to ethanol (alcohol); however, it is not clear why or how.  NINDS researchers are studying the impact of ethanol on tremors to determine the correct dosage amount and its physiological impact on the brain and whether other medications without the side effects of ethanol can be effective.

    Other NIH researchers hope to identify the source of essential tremors, study the effects of currently available tremor-suppressant drugs on the brain, and develop more targeted and effective therapies.

    FAQ

    Please answer the following questions to participate in our certified Continuing Medical Education program. Only one answer is possible per question. Please select the answer that is most appropriate.

    Question 1

    Which of the following constellations of clinical findings is typical of tremor in patients with Parkinson’s disease?

    1. bilateral postural tremor

    2. unilateral rest tremor and diminished ipsilateral arm swing while walking

    3. severe unilateral tremor while holding a cup or glass

    4. tremor that only appears when the patient writes

    5. postural tremor of both hands and ataxic gait

    Question 2

    A 25-year-old man has a mild postural tremor of both hands that improves when he drinks alcohol. His mother had the same condition. What can you advise him?

    1. He should definitely be evaluated for possible early Parkinson’s disease.

    2. He must get treatment now, as otherwise the condition could worsen.

    3. If treatment is indicated, propranolol or primidone could be given.

    4. Relaxation exercises and physiotherapy are effective treatment options.

    5. Genetic testing is needed to confirm the diagnosis of essential tremor.

    Question 3

    A man who received the diagnosis of multiple sclerosis two years ago presents to you with the new onset of tremor. What constellation of clinical findings is typical of tremor due to multiple sclerosis?

    1. rest tremor, only occasionally observable when the patient is excited

    2. a tremor that appears sometimes on the left side, sometimes on the right

    3. a tremor that is only present in the morning

    4. a swaying, broad-based gait and an intention tremor

    5. a postural tremor that is easily suppressed by voluntary effort

    Question 4

    A 55-year-old man with essential tremor says that he can no longer feed himself because of tremor, can dress himself only with great difficulty, and has not had legible handwriting for many years. Drug treatment as recommended in the relevant clinical guidelines brings only slight improvement. What can you advise the patient about the option of surgical treatment?

    1. Deep brain stimulation (DBS) might help but is not available in Germany.

    2. DBS is an experimental technique that is only performed in clinical trials.

    3. DBS is indicated only to treat Parkinson’s disease and plays no role in the treatment of essential tremor.

    4. DBS has a high chance of success in this situation; it is now established as a standard treatment for essential tremor.

    5. DBS is no more effective than pharmacotherapy for this indication.

    Question 5

    What information is most important for the diagnostic classification of a tremor syndrome?

    1. the clinical findings

    2. brain magnetic resonance imaging (MRI) with fine cerebellar sections

    3. nuclear-medical visualization of brain perfusion

    4. ultrasonography of the basal ganglia

    5. measurement of serum drug levels

    Question 6

    What findings indicate that tremor may be psychogenic?

    1. no evidence of essential tremor or Parkinson’s disease on brain MRI

    2. a longstanding marital conflict

    3. a tremor of inconstant location that diminishes on distraction and is found to be irregular on tremor analysis

    4. a clearly identifiable underlying psychological conflict

    5. remission after psychotherapy

    Question 7

    When can tremor be treated surgically?

    1. When the patient is unwilling to take drugs to treat tremor.

    2. When the patient is under 50 years old.

    3. When the tremor cannot be adequately suppressed by drugs and there is no contraindication to surgery.

    4. When the patient is willing to see a neurosurgeon once a week so that brain stimulation can be performed.

    5. When the patient is willing to assume the cost of weekly battery changes.

    Question 8

    What must be borne in mind with respect to drug treatment for various tremor syndromes?

    1. That the treatment is based on the clinical findings and not on the underlying disease causing tremor.

    2. That causally directed treatment is generally possible only for drug-induced tremors or tremors due to metabolic disturbance.

    3. That parkinsonian tremor responds best to anticholinergic drugs and does not respond at all to the classic dopamine preparations.

    4. That the cerebellar tremor of multiple sclerosis is treated in exactly the same way as essential tremor.

    5. That essential tremor is usually medically intractable.

    Question 9

    What drugs can induce tremor?

    1. lithium, valproic acid, cyclosporine A

    2. carbamazepine, propranolol, Seroxat

    3. aspirin, diclofenac, paracetamol

    4. penicillin, erythromycin, cephalosporin

    5. antilipid drugs, antidiabetic drugs

    Question 10

    What is the drug, or drug class, of first choice for the treatment of parkinsonian tremor?

    1. dopaminergic drugs

    2. propanolol

    3. primidone

    4. gabapentin

    5. ondansetron

    References

     

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    Physiologic Tremor – Causes, Symptoms, Treatment

    Physiologic tremor/ Physiologic tremor occurs in all healthy individuals.  It is rarely visible to the eye and typically involves a fine shaking of both of the hands and also the fingers.  It is not considered a disease but is a normal human phenomenon that is the result of physical properties in the body (for example, rhythmical activities such as heartbeat and muscle activation).

    Physiologic tremor is a tremor or trembling of a limb or other body part. The usual frequency is about 10 times per second. It occurs in normal individuals, especially when they are stressed by anxiety or fatigue. It is therefore common in sports such as rock-climbing where it is known by names such as Elvis leg or sewing machine leg.[rx] It may occur in an enhanced form as a pathological symptom of conditions such as hyperthyroidism or stimulants such as caffeine.[rx]

    Causes of Physiologic Tremor

    Generally, tremor is caused by a problem in the deep parts of the brain that control movements.  Most types of tremors have no known cause, although there are some forms that appear to be inherited and run in families.

    Tremor can occur on its own or be a symptom associated with a number of neurological disorders, including

    • Multiple sclerosis
    • Stroke
    • Traumatic brain injury
    • Neurodegenerative diseases that affect parts of the brain (e.g.,  Parkinson’s disease).
    • Neurologic disorders, including multiple sclerosis, Parkinson’s disease, stroke, and traumatic brain injury
    • Certain medicines, such as asthma medicines, amphetamines, caffeine, corticosteroids, and medicines used for certain psychiatric and neurological disorders
    • Alcohol use disorder or alcohol withdrawal
    • Mercury poisoning
    • Hyperthyroidism (overactive thyroid)
    • Liver or kidney failure
    • Anxiety or panic

    Some other known causes can include

    • the use of certain medicines (particular asthma medication, amphetamines, caffeine, corticosteroids, and drugs used for certain psychiatric and neurological disorders)
    • alcohol abuse or withdrawal
    • mercury poisoning
    • overactive thyroid
    • liver or kidney failure
    • anxiety or panic.

    Common Causes of  tumors due to Medication- or Toxin-Induced Tremors

    Class of Medication or Toxin Examples
    Beta-adrenergic agonists Terbutaline, metaproterenol, isoetharine, epinephrine (adrenaline)
    Antidepressants Bupropion, lithium, tricyclic antidepressants
    Neuroleptics Haloperidol
    Anticonvulsants Valproate sodium
    Dopamine agonists Amphetamine
    Heavy metals Mercury, lead, arsenic, bismuth
    Xanthines or derivatives coffee, tea, theophylline, cyclosporine

    Symptoms of Physiologic Tremor

    Symptoms of tremor may include

    • A tremor is involuntary, rhythmic contractions of various muscles. Shaky legs syndrome causes feelings of “vibration”, unsteadiness or imbalance in the legs.
    • A rhythmic shaking in the hands, arms, head, legs, or torso
    • Balance and muscle coordination problem
    • Spasticity and muscle spasm with wasting
    • Shaky voice
    • Difficulty writing or drawing
    • Problems holding and controlling utensils, such as a spoon.
    • Begin gradually, usually more prominently on one side of the body
    • Worsen with movement
    • Usually occur in the hands first, affecting one hand or both hands
    • Can include a “yes-yes” or “no-no” motion of the head
    • It May be aggravated by emotional stress, fatigue, caffeine, or temperature extremes
    • Tremors that get worse during emotional stress
    • Tremors that get worse when you move on purpose
    • Tremors that lessen with rest
    • Balance problems (in rare cases)

    What we feel in both legs simultaneously is extreme straining, fatigue, unsteadiness, and a fear of falling. The muscles in our legs become hard, our ankles feel weak and our toes curl under as our legs fail to support us. We can stand for only a short period of time, in some cases only seconds. There is a feeling of panic to find a place to sit, or if possible, walk to gain some relief from our symptoms. Some tremors /shaky legs syndrome may be triggered by or become worse during times of stress or strong emotion, when an individual is physically exhausted, or when a person is in certain postures or makes certain movements.

    Diagnosis of Physiologic Tremor

    Medical history

    During the physical evaluation, a doctor will assess the tremor based on:

    • whether the tremor occurs when the muscles are at rest or inaction
    • the location of the tremor on the body (and if it occurs on one or both sides of the body)
    • the appearance of the tremor (tremor frequency and amplitude).

    The doctor will also check other neurological findings such as impaired balance, speech abnormalities, or increased muscle stiffness.  Blood or urine tests can rule out metabolic causes such as thyroid malfunction and certain medications that can cause tremors/shaky legs syndrome.  These tests may also help to identify contributing causes such as drug interactions, chronic alcoholism, or other conditions or diseases.  Diagnostic imaging may help determine if the tremor is the result of damage to the brain.

    Physical Exam

    • Finger-to-nose and heel-to-shin tests can be useful to evaluate for end-point intention tremors, especially when the patient is asked to do the maneuver quickly.
    • Fine finger movements can be used as well to assess coordination and speed in tasks such as finger or foot tapping, buttoning/unbuttoning shirt, grabbing an object such as a cup or pencil.  The tremor will increase when the extremity is approaching the target.
    • Another characteristic of intention tremors is that the oscillating amplitude can be decreased when the eyes are closed.
    • Rapid alternating movement maneuvers can be used to identify dysdiadochokinesia.
    • Proprioception of the great toes can be impaired as well. Gait testing may reveal wide-based ataxia, with difficulties with tandem gait and a positive Romberg. The patient may have slow saccadic movements and nystagmus.
    • Depending on the etiology, patients may have increased reflexes and extensor Babinski reflexes.
    • Additional tests may be administered to determine functional limitations such as difficulty with handwriting or the ability to hold a fork or cup.  Individuals may be asked to perform a series of tasks or exercises such as placing a finger on the tip of their nose or drawing a spiral.

    Lab Test and Imaging

    • Magnetic resonance imaging (MRI) is the gold standard study to evaluate the brain and cerebellum. Many of the etiologies will be identified by this study.
    • Complete metabolic panel (CMP) – a good history and physical, complete metabolic panel (CMP), psychiatric history, nonpharmacological management, stressful situations (anxiety, fear, anger, and fatigue).
    • Echocardiogram – The doctor may order an electromyogram to diagnose muscle or nerve problems. This test measures involuntary muscle activity and muscle response to nerve stimulation. A comprehensive stroke workup including a good history and physical, screening of vascular risk factors, A1C, lipid panel, blood pressure measurements, brain and vessel imaging (head computed tomographic (CT) scan, head CT angiography, CT perfusion, brain MRI), 2D Echocardiogram with bubble study, Holter monitoring.
    • Complete blood count (CBC) – coagulation studies, head CT scan, CT angiography, brain MRI, MR venous, electromyography, or nerve conduction.
    • Neuroinflammatory, autoimmune or paraneoplastic – CMP, CBC, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), antinuclear antibodies, extractable nuclear antigen panel, Sjogren and lupus anticoagulant studies, antineutrophil cytoplasmic antibodies, angiotensin-converting enzyme test, head CT, brain and spine MRI, chest/abdomen/pelvis CT scan, and lumbar puncture with laboratory studies including cells with differential, glucose, protein, IgG index, myelin basic protein, oligoclonal bands, aquaporin four antibodies, myelin oligodendrocyte glycoprotein antibodies, paraneoplastic panel, flow cytometry/cytology.
    • Metabolic test – CBC, CMP, vitamin deficiency workup, ammonia level, liver ultrasound, abdomen/pelvis CT scan with contrast, advanced metabolic testing.
    • Toxic test –  urine toxicology, ethanol level, heavy metal testing.
    • Hereditary test – CBC, CMP, ESR, CRP, copper/ceruloplasmin, slit eye lamp examination, head CT scan, brain MRI, genetic testing.
    • EMG – measures the electrical impulses of muscles at rest and during contraction. A surface electromyogram can often rapidly establish a diagnosis of primary orthostatic tremor by reproducing the characteristic tremor in the legs. With a surface, electromyogram electrodes are placed on the skin overlying the muscles that are to be tested.

    Treatment of Physiologic Tremor

    Non-pharmacological

    • Physical, speech-language, and occupational therapy – may help to control tremors and meet daily challenges caused by the tremor.  A physical therapist can help people improve their muscle control, functioning, and strength through coordination, balancing, and other exercises.  Some therapists recommend the use of weights, splints, other adaptive equipment, and special plates and utensils for eating.  Speech-language pathologists can evaluate and treat speech, language, communication, and swallowing disorders.  Occupational therapists can teach individuals new ways of performing activities of daily living that may be affected by tremors.
    • Eliminating or reducing tremor-inducing substances such as caffeine and other medication – (such as stimulants) can help improve tremor. Though small amounts of alcohol can improve tremors for some people, tremors can become worse once the effects of the alcohol wear off.
    • Interventional Therapy – For patients who fail pharmacologic treatment with the above drugs or are unable to tolerate the side effects, surgical options include deep brain stimulation (DBS), focused ultrasound, or radio-surgical gamma knife thalamotomy to treat persistently disabling limb tremor, and botulinum toxin injections to treat persistently disabling head or vocal cord tremor.
    • Deep-brain stimulation This is the most common surgical treatment for essential tremors. Most series report 70% to 90% hand tremor control. In deep-brain stimulation, electrical stimulation is delivered to the brain through an electrode implanted deep into the ventral intermediate nucleus (VIM) of the thalamus. This is typically done by implanting 4 electrodes in the VIM using stereotactic methods. Computerized programming of the pulse generator is most commonly done with a handheld device after the patient leaves the hospital to optimize the electrode montage, voltage, pulse frequency, and pulse width. Deep-brain stimulation can be done unilaterally or bilaterally depending on the patient’s symptoms. There is an increased risk of speech and balance difficulties with bilateral procedures. If the tremor significantly affects both hands, the dominant hand is targeted, bilateral procedures may be considered.
    • Focused ultrasound – Approved by the FDA in 2016, magnetic resonance imaging-guided, high-intensity, focused ultrasound thalamotomy is an innovative method for the treatment of essential tremors. Although it is transcranial and does not require an incision, skull penetration, or an implanted device, it is an invasive therapy that produces a permanent thalamic lesion.
    • Radio-surgical gamma knife thalamotomy Gamma-knife thalamotomy fo­cuses high-energy gamma rays on the ventral intermediate resulting in the death of neurons. It is an unproven treatment that has not generally been adopted due to concerns about potential radiation side effects, including a theoretical, long-term risk of secondary tumor formation.
    • Ultrasound Therapy – A new treatment for essential tremors uses magnetic resonance images to deliver focused ultrasound to create a lesion in tiny areas of the brain’s thalamus thought to be responsible for causing the tremors.  The treatment is approved only for those individuals with essential tremors who do not respond well to anticonvulsant or beta-blocking drugs.
    • Biofeedback – is a mind-body technique that involves using visual or auditory feedback to teach people to recognize the physical signs and symptoms of stress and anxiety, such as increased heart rate, body temperature, and muscle tension.
    • Relaxation techniques – can reduce stress symptoms and help you enjoy a better quality of life, especially if you have an illness. Explore relaxation techniques you can do by yourself.
    • Learn to relax – Stress and anxiety tend to make tremors worse, and being relaxed may improve tremors. Although you can’t eliminate all stress from your life, you can change how you react to stressful situations using a range of relaxation techniques, such as massage or meditation.
    • Noninvasive techniques – Include gait rehabilitation, visually guided techniques, tendon vibration, weighting extremities, positioning techniques, and manual techniques, all of which can be useful for the recovery of functional activities.
    • Invasive techniques – Thalamic deep brain stimulation can alleviate the tremor in MS, providing better functional performance. Stereotactic radiosurgery thalamotomy at the nucleus ventralis intermedius with a median maximum dose of 140 Gy also provides good functional outcomes in patients with MS. Radiofrequency thalamotomy had been successfully used in the past but has been replaced with the newer techniques of radiosurgery and deep brain stimulation as they had fewer adverse effects.
    • Physical therapy – can help some patients control their tremors better, as can reducing the intake of substances such as caffeine, which can induce tremors. Many patients experience an increase in the severity of their tremors when they are stressed. Therefore, trying to reduce sources of anxiety and engaging in complementary therapies (such as yoga or aromatherapy) may help some patients.

    For example, tremors due to thyroid hyperactivity will improve or even resolve (return to the normal state) with the treatment of thyroid malfunction.  Also, if the tremor is caused by medication, discontinuing the tremor-causing drug may reduce or eliminate this tremor.

    Medical Therapy

    The therapeutic approach to essential tremors many times follows a trial and error approach, and patients should be challenged by several medications if the first choice is ineffective or associated with debilitating adverse effects. Medical therapy can be divided into first, second, and third-line therapies.

    First-line therapy – It is either approved by the FDA or supported by double-blinded, placebo-controlled studies that meet the criteria for the class I evidence. This class of medications includes propranolol and primidone. If both primidone and propranolol are not effective alone, combinations of both may provide relief in selected patients.

    Second-line therapy – Second-line therapy is supported by double-blinded, placebo-controlled trials that do not meet other requirements for the class I evidence studies. This includes gabapentin, pregabalin, topiramate, benzodiazepines (clonazepam, alprazolam), beta-blockers (atenolol and metoprolol) and zonisamide.

    Third-line therapy These therapies are based on open-label studies or case series. Drugs in this class include nimodipine and clozapine.

    Medication

    Pharmacological Agents to Treat Tremor
    Medication Dosage Clinical Efficacy Comment
    Clonazepam 0.5–6 mg/day +++ Documented effect
    Gabapentin 300–2400 mg/day ++ Documented effect
    Levodopa 300–800 mg/day ++ Only short-term benefit
    Pramipexole 0.75 mg/day + Anecdotal effect
    Primidone 125–250 mg/day + Anecdotal effect
    Valproic acid 500–1000 mg/day +/– Anecdotal effect
    Carbamazepine 400 mg/day +/– Anecdotal effect
    Phenobarbital 100 mg/day +/– Anecdotal effect
    Intravenous immunoglobulin1 2 g/kg over 3 days + Anecdotal effect
    Propanolol 120 mg/day Without effect
    Levetiracetam 3000 mg/day Without effect
    Botulinum toxin 200 mU in the tibialis anterior bilaterally Without effect
    Alcohol Without effect
    • Beta-blocking drugs such as propranolol are normally used to treat high blood pressure but they also help treat essential tremors.  Propranolol can also be used in some people with other types of action tremors.  Other beta-blockers that may be used include atenolol, metoprolol, nadolol, and sotalol.
    • Anti-seizure medications such as primidone can be effective in people with essential tremors who do not respond to beta-blockers.  Other medications that may be prescribed include gabapentin and topiramate.  However, it is important to note that some anti-seizure medications can cause tremors.
    • Tranquilizers (also known as benzodiazepines) such as alprazolam and clonazepam may temporarily help some people with tremors.  However, their use is limited due to unwanted side effects that include sleepiness, poor concentration, and poor coordination.  This can affect the ability of people to perform daily activities such as driving, school, and work.  Also, when taken regularly, tranquilizers can cause physical dependence and when stopped abruptly can cause several withdrawal symptoms.
    • Parkinson’s disease medications (levodopa, carbidopa) are used to treat tremors associated with Parkinson’s disease.
    • Botulinum toxin – injections can treat almost all types of tremors.  It is especially useful for head tremor, which generally does not respond to medications.  Botulinum toxin is widely used to control dystonic tremors.  Although botulinum toxin injections can improve tremors for roughly three months at a time, they can also cause muscle weakness.  While this treatment is effective and usually well tolerated for head tremors, botulinum toxin treatment in the hands can cause weakness in the fingers.  It can cause a hoarse voice and difficulty swallowing when used to treat voice tremors.

    Additional drug therapies that have been used to treat individuals with primary orthostatic tremors include primidone (Mysoline), chlordiazepoxide (Librium), pregabalin (Lyrica), pramipexole (Mirapex), phenobarbital, and valproic acid (Depakote). Drugs commonly used to treat people with Parkinson’s disease (levodopa or pramipexole) may also be prescribed for individuals with primary orthostatic tremors.


    Surgery

    When people do not respond to drug therapies or have a severe tremor that significantly impacts their daily life, a doctor may recommend surgical interventions such as deep brain stimulation (DBS) or very rarely, thalamotomy.  While DBS is usually well-tolerated, the most common side effects of tremor surgery include dysarthria (trouble speaking) and balance problems.

    • Deep brain stimulation (DBS) – is the most common form of surgical treatment of tremors.  This method is preferred because it is effective, has low risk, and treats a broader range of symptoms than thalamotomy.  The treatment uses surgically implanted electrodes to send high-frequency electrical signals to the thalamus, the deep structure of the brain that coordinates and controls some involuntary movements.  A small pulse generating device placed under the skin in the upper chest (similar to a pacemaker) sends electrical stimuli to the brain and temporarily disables the tremor.  DBS is currently used to treat parkinsonian tremors, essential tremors, and dystonia.


    • Thalamotomy – is a surgical procedure that involves the precise, permanent destruction of a tiny area in the thalamus.  Currently, surgery is replaced by radiofrequency ablation to treat severe tremors when deep brain surgery is contraindicated—meaning it is unwise as a treatment option or has undesirable side effects.  Radiofrequency ablation uses a radio wave to generate an electric current that heats up a nerve and disrupts its signaling ability for typically six or more months.  It is usually performed on only one side of the brain to improve tremors on the opposite side of the body.  Surgery on both sides is not recommended as it can cause problems with speech.
    •  Stereotactic surgical techniques – can be used to create a lesion in the ventral intermediate (VIM) nucleus of the thalamus.

    Rehabilitation

    Exercise is an important part of healthy living for everyone. For people with tremors, exercise is more than healthy it is a vital component to maintaining balance, mobility, and activities of daily living. Exercise and physical activity can improve many tremors symptoms. These benefits are supported by research.

    The tremors show that people with tremors who start exercising earlier and a minimum of 2.5 hours a week, experience a slowed decline in quality of life compared to those who start later. Establishing early exercise habits is essential to overall disease management.

    What Type of Exercise Should I Do?

    To help manage the symptoms of tremors, be sure your exercise program includes a few key ingredients:

    • Aerobic activity
    • Strength training
    • Balance, agility, and multitasking
    • Flexibility

    These elements are included in many types of exercise. Biking, running, Tai chi, yoga, Pilates, dance, weight training, non-contact boxing, qi gong, and more — all have positive effects on tremors symptoms.

    There is no “exercise prescription” that is right for every person with tremors. The type of exercise you do depends on your symptoms and challenges. For sedentary people, just getting up and moving is beneficial. More active people can build up to the regular, vigorous activity. Many approaches work well to help maintain and improve mobility, flexibility, and balance to ease non-motor tremors symptoms such as depression or constipation.

    Researchers in the study did not distinguish between what type of exercise participants did and determined that all types of exercise are beneficial. The most important thing is to do the exercise regularly. We suggest finding an exercise you enjoy and stick with it.


    Challenges to Exercising

    • People in the early stages of tremors tend to be just as strong and physically fit as healthy individuals of the same age.
    • Disease progression can lead to the following physical change:
    • Loss of joint flexibility, which can affect balance.
    • Decreased muscle strength or deconditioning can affect walking and the ability to stand up from sitting.
    • The decline in cardiovascular conditioning, which affects endurance.

    Day to day living

    On a day-to-day basis, people feel stressed and frustrated, but they are not alone. People with orthostatic tremor will often struggle with:

    • standing
    • walking
    • other physical movements
    • exhaustion
    • pain

    Variability

    Orthostatic tremor varies from person to person, and sufferers find their own experiences change from time to time – sometimes due to stress or exertion, but sometimes without any reason what so ever.

    Standing

    For everyone who has an orthostatic tremor, standing, sometimes for just a few seconds, is difficult. People feel their legs buckle under them. This can result in actual falling. There may be a “freezing up” of the legs and doing day-to-day things such as queuing, or browsing in shops is difficult and quite likely impossible. People find that the pain will disappear slightly when the person sits or lies down.

    Walking

    In the early stages of orthostatic tremor, walking may not be affected too much. People may find that they walk quickly and are unable to walk slowly. However, as the condition progresses, the walking distance tends to reduce. The actual distance which can be walked will vary, and at worst people can not walk at all.

    Exhaustion

    People frequently suffer from extreme exhaustion or fatigue. Basic routines such as showering or dressing can take much longer than normal and require a period of rest for recovery. Even after a day of relatively little physical activity, they may feel unable to get out of a chair or needing sleep.

    Pain

    Some people will suffer pain when moving and over some said they have some pain when resting, usually in the legs and back.

    The effect of stress and emotion

    It is recognized that stress makes tremors worst. There is a vicious circle where the tremor gives rise to stress, and then the stress increases the tremor and so on. Feelings such as anger, annoyance, concern, frustration, and even excitement or anticipation can be a problem. The particular difficulty is caused by situations such as a crowded place – nowhere to sit, exertion involved, and the risk of falling.

    Frustration

    People experience much frustration and dependency on spouses/partners/carers and often lack of confidence when separated from them. Simple household tasks such as cleaning, cooking, and even making a cup of tea (or carrying it to another room) are either difficult or impossible.

    Mobility aids

    People often use a wheelchair, and some find that a wheelchair is essential for going out and/or moving around at home. Others use them only occasionally – such as at airports. Just over a third of respondents use a scooter. Some people often use scooters or walking sticks.

    Tips for Getting Started

    • First, be safe. Before starting an exercise program, consult your neurologist and primary care doctor about concerns and recommendations.
    • Ask your doctor or members in your support group to refer to a physical therapist (PT) who knows about tremors. Work together to identify your concerns and limitations. Target exercises to improve them. For most people, a structured exercise program will include aerobic exercise (such as brisk walking) and resistance training (using weights or bands).
    • Purchase a pedometer (step-counter) and figure out how many steps you take on average each day, then build up from there. Many smartphones or smartwatches have a built-in pedometer feature or an application that can be downloaded.
    • Exercise indoors and outdoors. Change your routine to stay interested and motivated.
    • Again, most importantly pick an exercise you enjoy.

    What research is being done?

    The mission is to seek fundamental knowledge about the brain and nervous system and to use that knowledge to reduce the burden of neurological disease.  The NINDS is a component of the National Institutes of Health (NIH), the leading supporter of biomedical research in the world.

    Researchers are working to better understand the underlying brain functions that cause tremors, identify the genetic factors that make individuals more susceptible to the disorder, and develop new and better treatment options.

    • Brain functioning – It can be difficult to distinguish between movement disorders such as Parkinson’s disease and essential tremor. These debilitating movement disorders have different prognoses and can respond very differently to available therapies. NINDS researchers are working to identify structural and functional changes in the brain using non-invasive neuroimaging techniques to develop sensitive and specific markers for each of these diseases and then track how they change as each disease progresses. Other researchers are using functional magnetic resonance imaging technology to better understand normal and diseased brain circuit functions and associated motor behaviors.  Scientists hope to design therapies that can restore normal brain circuit function in diseases such as Parkinson’s disease and tremor.
    • Genetics – Research has shown that essential tremors may have a strong genetic component affecting multiple generations of families.  NINDS researchers are building on previous genetics work to identify susceptibility genes for familial early-onset (before age 40) essential tremor.  Researchers are focusing on multigenerational, early-onset families to better detect linkages.

    Additionally, NINDS scientists are researching the impact of genetic abnormalities on the development of essential tremors.  Previous research that has shown a link between essential tremor and possible genetic variants on chromosome 6 and 11; ongoing research is targeting the impact of other genetic variations in families.

    Medications and other treatment methods

    While drugs can be effective for some people, approximately 50 percent of individuals do not respond to medication.  In order to develop assistive and rehabilitative tremor-suppressing devices for people with essential tremors, researchers are exploring where and how to minimize or suppress tremors while still allowing for voluntary movements.

    Many people with essential tremors respond to ethanol (alcohol); however, it is not clear why or how.  NINDS researchers are studying the impact of ethanol on tremors to determine the correct dosage amount and its physiological impact on the brain and whether other medications without the side effects of ethanol can be effective.

    Other NIH researchers hope to identify the source of essential tremors, study the effects of currently available tremor-suppressant drugs on the brain, and develop more targeted and effective therapies.

    FAQ

    Please answer the following questions to participate in our certified Continuing Medical Education program. Only one answer is possible per question. Please select the answer that is most appropriate.

    Question 1

    Which of the following constellations of clinical findings is typical of tremor in patients with Parkinson’s disease?

    1. bilateral postural tremor

    2. unilateral rest tremor and diminished ipsilateral arm swing while walking

    3. severe unilateral tremor while holding a cup or glass

    4. tremor that only appears when the patient writes

    5. postural tremor of both hands and ataxic gait

    Question 2

    A 25-year-old man has a mild postural tremor of both hands that improves when he drinks alcohol. His mother had the same condition. What can you advise him?

    1. He should definitely be evaluated for possible early Parkinson’s disease.

    2. He must get treatment now, as otherwise the condition could worsen.

    3. If treatment is indicated, propranolol or primidone could be given.

    4. Relaxation exercises and physiotherapy are effective treatment options.

    5. Genetic testing is needed to confirm the diagnosis of essential tremor.

    Question 3

    A man who received the diagnosis of multiple sclerosis two years ago presents to you with the new onset of tremor. What constellation of clinical findings is typical of tremor due to multiple sclerosis?

    1. rest tremor, only occasionally observable when the patient is excited

    2. a tremor that appears sometimes on the left side, sometimes on the right

    3. a tremor that is only present in the morning

    4. a swaying, broad-based gait and an intention tremor

    5. a postural tremor that is easily suppressed by voluntary effort

    Question 4

    A 55-year-old man with essential tremor says that he can no longer feed himself because of tremor, can dress himself only with great difficulty, and has not had legible handwriting for many years. Drug treatment as recommended in the relevant clinical guidelines brings only slight improvement. What can you advise the patient about the option of surgical treatment?

    1. Deep brain stimulation (DBS) might help but is not available in Germany.

    2. DBS is an experimental technique that is only performed in clinical trials.

    3. DBS is indicated only to treat Parkinson’s disease and plays no role in the treatment of essential tremor.

    4. DBS has a high chance of success in this situation; it is now established as a standard treatment for essential tremor.

    5. DBS is no more effective than pharmacotherapy for this indication.

    Question 5

    What information is most important for the diagnostic classification of a tremor syndrome?

    1. the clinical findings

    2. brain magnetic resonance imaging (MRI) with fine cerebellar sections

    3. nuclear-medical visualization of brain perfusion

    4. ultrasonography of the basal ganglia

    5. measurement of serum drug levels

    Question 6

    What findings indicate that tremor may be psychogenic?

    1. no evidence of essential tremor or Parkinson’s disease on brain MRI

    2. a longstanding marital conflict

    3. a tremor of inconstant location that diminishes on distraction and is found to be irregular on tremor analysis

    4. a clearly identifiable underlying psychological conflict

    5. remission after psychotherapy

    Question 7

    When can tremor be treated surgically?

    1. When the patient is unwilling to take drugs to treat tremor.

    2. When the patient is under 50 years old.

    3. When the tremor cannot be adequately suppressed by drugs and there is no contraindication to surgery.

    4. When the patient is willing to see a neurosurgeon once a week so that brain stimulation can be performed.

    5. When the patient is willing to assume the cost of weekly battery changes.

    Question 8

    What must be borne in mind with respect to drug treatment for various tremor syndromes?

    1. That the treatment is based on the clinical findings and not on the underlying disease causing tremor.

    2. That causally directed treatment is generally possible only for drug-induced tremors or tremors due to metabolic disturbance.

    3. That parkinsonian tremor responds best to anticholinergic drugs and does not respond at all to the classic dopamine preparations.

    4. That the cerebellar tremor of multiple sclerosis is treated in exactly the same way as essential tremor.

    5. That essential tremor is usually medically intractable.

    Question 9

    What drugs can induce tremor?

    1. lithium, valproic acid, cyclosporine A

    2. carbamazepine, propranolol, Seroxat

    3. aspirin, diclofenac, paracetamol

    4. penicillin, erythromycin, cephalosporin

    5. antilipid drugs, antidiabetic drugs

    Question 10

    What is the drug, or drug class, of first choice for the treatment of parkinsonian tremor?

    1. dopaminergic drugs

    2. propanolol

    3. primidone

    4. gabapentin

    5. ondansetron

    References

     

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    Shaky Legs Syndrome – Causes, Symptoms, Treatment

    Shaky legs syndrome, also known as Orthostatic Tremor (OT), is a progressive neurological movement disorder, characterized by high-frequency tremors, predominantly in the legs when in a standing position, and an immediate sense of instability.

    The term “orthostatic tremor” (OT), also known as “shaky legs syndrome” was first coined in 1984 by Heilman, although the earlier descriptions of this entity date back to 1970 when Pazzaglia et al. reported on three patients with a peculiar disorder only occurring on standing.

    Orthostatic tremor (OT) is a rare disorder characterized by tremor and a feeling of unsteadiness while standing that resolves upon walking or sitting. A pathognomonic 13-18 Hz tremor is seen on surface EMG while standing. Though its clinical features have been better defined over time, much of its pathophysiology remains unknown and treatment options are limited. We review here recent developments in both of these areas.

    Another Name

    • Shaky legs syndrome
    • Idiopathic orthostatic tremor

    Causes of Shaky Legs Syndrome

    Generally, tremor is caused by a problem in the deep parts of the brain that control movements.  Most types of tremors have no known cause, although there are some forms that appear to be inherited and run in families.

    Tremor and shaky legs syndrome can occur on its own or be a symptom associated with a number of neurological disorders, including:

    • Multiple sclerosis
    • Stroke
    • Traumatic brain injury
    • Neurodegenerative diseases that affect parts of the brain (e.g.,  Parkinson’s disease).
    • Neurologic disorders, including multiple sclerosis, Parkinson’s disease, stroke, and traumatic brain injury
    • Certain medicines, such as asthma medicines, amphetamines, caffeine, corticosteroids, and medicines used for certain psychiatric and neurological disorders
    • Alcohol use disorder or alcohol withdrawal
    • Mercury poisoning
    • Hyperthyroidism (overactive thyroid)
    • Liver or kidney failure
    • Anxiety or panic

    Some other known causes can include

    • the use of certain medicines (particular asthma medication, amphetamines, caffeine, corticosteroids, and drugs used for certain psychiatric and neurological disorders)
    • alcohol abuse or withdrawal
    • mercury poisoning
    • overactive thyroid
    • liver or kidney failure
    • anxiety or panic.

    Common Causes of  tumors due to Medication- or Toxin-Induced Tremors

    Class of Medication or Toxin Examples
    Beta-adrenergic agonists Terbutaline, metaproterenol, isoetharine, epinephrine (adrenaline)
    Antidepressants Bupropion, lithium, tricyclic antidepressants
    Neuroleptics Haloperidol
    Anticonvulsants Valproate sodium
    Dopamine agonists Amphetamine
    Heavy metals Mercury, lead, arsenic, bismuth
    Xanthines or derivatives coffee, tea, theophylline, cyclosporine

    Symptoms of Shaky Legs Syndrome

    Symptoms of tremor may include

    •  A tremor is involuntary, rhythmic contractions of various muscles. Shaky legs syndrome causes feelings of “vibration”, unsteadiness or imbalance in the legs.
    • A rhythmic shaking in the hands, arms, head, legs, or torso
    • Balance and muscle coordination problem
    • Spasticity and muscle spasm with wasting
    • Shaky voice
    • Difficulty writing or drawing
    • Problems holding and controlling utensils, such as a spoon.
    • Begin gradually, usually more prominently on one side of the body
    • Worsen with movement
    • Usually occur in the hands first, affecting one hand or both hands
    • Can include a “yes-yes” or “no-no” motion of the head
    • It May be aggravated by emotional stress, fatigue, caffeine, or temperature extremes
    • Tremors that get worse during emotional stress
    • Tremors that get worse when you move on purpose
    • Tremors that lessen with rest
    • Balance problems (in rare cases)

    What we feel in both legs simultaneously is extreme straining, fatigue, unsteadiness, and a fear of falling. The muscles in our legs become hard, our ankles feel weak and our toes curl under as our legs fail to support us. We can stand for only a short period of time, in some cases only seconds. There is a feeling of panic to find a place to sit, or if possible, walk to gain some relief from our symptoms. Some tremors /shaky legs syndrome may be triggered by or become worse during times of stress or strong emotion, when an individual is physically exhausted, or when a person is in certain postures or makes certain movements.

    Diagnosis of Shaky Legs Syndrome

    Medical history

    During the physical evaluation, a doctor will assess the tremor based on:

    • whether the tremor occurs when the muscles are at rest or inaction
    • the location of the tremor on the body (and if it occurs on one or both sides of the body)
    • the appearance of the tremor (tremor frequency and amplitude).

    The doctor will also check other neurological findings such as impaired balance, speech abnormalities, or increased muscle stiffness.  Blood or urine tests can rule out metabolic causes such as thyroid malfunction and certain medications that can cause tremors/shaky legs syndrome.  These tests may also help to identify contributing causes such as drug interactions, chronic alcoholism, or other conditions or diseases.  Diagnostic imaging may help determine if the tremor is the result of damage to the brain.

    Physical Exam

    • Finger-to-nose and heel-to-shin tests can be useful to evaluate for end-point intention tremors, especially when the patient is asked to do the maneuver quickly.
    • Fine finger movements can be used as well to assess coordination and speed in tasks such as finger or foot tapping, buttoning/unbuttoning shirt, grabbing an object such as a cup or pencil.  The tremor will increase when the extremity is approaching the target.
    • Another characteristic of intention tremors is that the oscillating amplitude can be decreased when the eyes are closed.
    • Rapid alternating movement maneuvers can be used to identify dysdiadochokinesia.
    • Proprioception of the great toes can be impaired as well. Gait testing may reveal wide-based ataxia, with difficulties with tandem gait and a positive Romberg. The patient may have slow saccadic movements and nystagmus.
    • Depending on the etiology, patients may have increased reflexes and extensor Babinski reflexes.
    • Additional tests may be administered to determine functional limitations such as difficulty with handwriting or the ability to hold a fork or cup.  Individuals may be asked to perform a series of tasks or exercises such as placing a finger on the tip of their nose or drawing a spiral.

    Lab Test and Imaging

    • Magnetic resonance imaging (MRI) is the gold standard study to evaluate the brain and cerebellum. Many of the etiologies will be identified by this study.
    • Complete metabolic panel (CMP) – a good history and physical, complete metabolic panel (CMP), psychiatric history, nonpharmacological management, stressful situations (anxiety, fear, anger, and fatigue).
    • Echocardiogram – The doctor may order an electromyogram to diagnose muscle or nerve problems. This test measures involuntary muscle activity and muscle response to nerve stimulation. A comprehensive stroke workup including a good history and physical, screening of vascular risk factors, A1C, lipid panel, blood pressure measurements, brain and vessel imaging (head computed tomographic (CT) scan, head CT angiography, CT perfusion, brain MRI), 2D Echocardiogram with bubble study, Holter monitoring.
    • Complete blood count (CBC) – coagulation studies, head CT scan, CT angiography, brain MRI, MR venous, electromyography, or nerve conduction.
    • Neuroinflammatory, autoimmune or paraneoplastic – CMP, CBC, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), antinuclear antibodies, extractable nuclear antigen panel, Sjogren and lupus anticoagulant studies, antineutrophil cytoplasmic antibodies, angiotensin-converting enzyme test, head CT, brain and spine MRI, chest/abdomen/pelvis CT scan, and lumbar puncture with laboratory studies including cells with differential, glucose, protein, IgG index, myelin basic protein, oligoclonal bands, aquaporin four antibodies, myelin oligodendrocyte glycoprotein antibodies, paraneoplastic panel, flow cytometry/cytology.
    • Metabolic test – CBC, CMP, vitamin deficiency workup, ammonia level, liver ultrasound, abdomen/pelvis CT scan with contrast, advanced metabolic testing.
    • Toxic test –  urine toxicology, ethanol level, heavy metal testing.
    • Hereditary test – CBC, CMP, ESR, CRP, copper/ceruloplasmin, slit eye lamp examination, head CT scan, brain MRI, genetic testing.
    • EMG – measures the electrical impulses of muscles at rest and during contraction. A surface electromyogram can often rapidly establish a diagnosis of primary orthostatic tremor by reproducing the characteristic tremor in the legs. With a surface, electromyogram electrodes are placed on the skin overlying the muscles that are to be tested.

    Treatment of Shaky Legs Syndrome

    Non-pharmacological

    • Physical, speech-language, and occupational therapy – may help to control tremors and meet daily challenges caused by the tremor.  A physical therapist can help people improve their muscle control, functioning, and strength through coordination, balancing, and other exercises.  Some therapists recommend the use of weights, splints, other adaptive equipment, and special plates and utensils for eating.  Speech-language pathologists can evaluate and treat speech, language, communication, and swallowing disorders.  Occupational therapists can teach individuals new ways of performing activities of daily living that may be affected by tremors.
    • Eliminating or reducing tremor-inducing substances such as caffeine and other medication – (such as stimulants) can help improve tremor. Though small amounts of alcohol can improve tremors for some people, tremors can become worse once the effects of the alcohol wear off.
    • Interventional Therapy – For patients who fail pharmacologic treatment with the above drugs or are unable to tolerate the side effects, surgical options include deep brain stimulation (DBS), focused ultrasound, or radio-surgical gamma knife thalamotomy to treat persistently disabling limb tremor, and botulinum toxin injections to treat persistently disabling head or vocal cord tremor.
    • Deep-brain stimulation This is the most common surgical treatment for essential tremors. Most series report 70% to 90% hand tremor control. In deep-brain stimulation, electrical stimulation is delivered to the brain through an electrode implanted deep into the ventral intermediate nucleus (VIM) of the thalamus. This is typically done by implanting 4 electrodes in the VIM using stereotactic methods. Computerized programming of the pulse generator is most commonly done with a handheld device after the patient leaves the hospital to optimize the electrode montage, voltage, pulse frequency, and pulse width. Deep-brain stimulation can be done unilaterally or bilaterally depending on the patient’s symptoms. There is an increased risk of speech and balance difficulties with bilateral procedures. If the tremor significantly affects both hands, the dominant hand is targeted, bilateral procedures may be considered.
    • Focused ultrasound – Approved by the FDA in 2016, magnetic resonance imaging-guided, high-intensity, focused ultrasound thalamotomy is an innovative method for the treatment of essential tremors. Although it is transcranial and does not require an incision, skull penetration, or an implanted device, it is an invasive therapy that produces a permanent thalamic lesion.
    • Radio-surgical gamma knife thalamotomy Gamma-knife thalamotomy fo­cuses high-energy gamma rays on the ventral intermediate resulting in the death of neurons. It is an unproven treatment that has not generally been adopted due to concerns about potential radiation side effects, including a theoretical, long-term risk of secondary tumor formation.
    • Ultrasound Therapy – A new treatment for essential tremors uses magnetic resonance images to deliver focused ultrasound to create a lesion in tiny areas of the brain’s thalamus thought to be responsible for causing the tremors.  The treatment is approved only for those individuals with essential tremors who do not respond well to anticonvulsant or beta-blocking drugs.
    • Biofeedback – is a mind-body technique that involves using visual or auditory feedback to teach people to recognize the physical signs and symptoms of stress and anxiety, such as increased heart rate, body temperature, and muscle tension.
    • Relaxation techniques – can reduce stress symptoms and help you enjoy a better quality of life, especially if you have an illness. Explore relaxation techniques you can do by yourself.
    • Learn to relax – Stress and anxiety tend to make tremors worse, and being relaxed may improve tremors. Although you can’t eliminate all stress from your life, you can change how you react to stressful situations using a range of relaxation techniques, such as massage or meditation.
    • Noninvasive techniques – Include gait rehabilitation, visually guided techniques, tendon vibration, weighting extremities, positioning techniques, and manual techniques, all of which can be useful for the recovery of functional activities.
    • Invasive techniques – Thalamic deep brain stimulation can alleviate the tremor in MS, providing better functional performance. Stereotactic radiosurgery thalamotomy at the nucleus ventralis intermedius with a median maximum dose of 140 Gy also provides good functional outcomes in patients with MS. Radiofrequency thalamotomy had been successfully used in the past but has been replaced with the newer techniques of radiosurgery and deep brain stimulation as they had fewer adverse effects.
    • Physical therapy – Physical therapy may help strengthen your muscles and improve your coordination. The use of wrist weights and adaptive devices, such as heavier utensils, may also help relieve tremors.

    For example, tremors due to thyroid hyperactivity will improve or even resolve (return to the normal state) with the treatment of thyroid malfunction.  Also, if the tremor is caused by medication, discontinuing the tremor-causing drug may reduce or eliminate this tremor.

    Medical Therapy

    The therapeutic approach to essential tremors many times follows a trial and error approach, and patients should be challenged by several medications if the first choice is ineffective or associated with debilitating adverse effects. Medical therapy can be divided into first, second, and third-line therapies.

    First-line therapy – It is either approved by the FDA or supported by double-blinded, placebo-controlled studies that meet the criteria for the class I evidence. This class of medications includes propranolol and primidone. If both primidone and propranolol are not effective alone, combinations of both may provide relief in selected patients.

    Second-line therapy – Second-line therapy is supported by double-blinded, placebo-controlled trials that do not meet other requirements for the class I evidence studies. This includes gabapentin, pregabalin, topiramate, benzodiazepines (clonazepam, alprazolam), beta-blockers (atenolol and metoprolol) and zonisamide.

    Third-line therapy These therapies are based on open-label studies or case series. Drugs in this class include nimodipine and clozapine.

    Medication

    Pharmacological Agents to Treat Orthostatic Tremor
    Medication Dosage Clinical Efficacy Comment
    Clonazepam 0.5–6 mg/day +++ Documented effect
    Gabapentin 300–2400 mg/day ++ Documented effect
    Levodopa 300–800 mg/day ++ Only short-term benefit
    Pramipexole 0.75 mg/day + Anecdotal effect
    Primidone 125–250 mg/day + Anecdotal effect
    Valproic acid 500–1000 mg/day +/– Anecdotal effect
    Carbamazepine 400 mg/day +/– Anecdotal effect
    Phenobarbital 100 mg/day +/– Anecdotal effect
    Intravenous immunoglobulin1 2 g/kg over 3 days + Anecdotal effect
    Propanolol 120 mg/day Without effect
    Levetiracetam 3000 mg/day Without effect
    Botulinum toxin 200 mU in the tibialis anterior bilaterally Without effect
    Alcohol Without effect
    • Beta-blocking drugs such as propranolol are normally used to treat high blood pressure but they also help treat essential tremors.  Propranolol can also be used in some people with other types of action tremors.  Other beta-blockers that may be used include atenolol, metoprolol, nadolol, and sotalol.
    • Anti-seizure medications such as primidone can be effective in people with essential tremors who do not respond to beta-blockers.  Other medications that may be prescribed include gabapentin and topiramate.  However, it is important to note that some anti-seizure medications can cause tremors.
    • Tranquilizers (also known as benzodiazepines) such as alprazolam and clonazepam may temporarily help some people with tremors.  However, their use is limited due to unwanted side effects that include sleepiness, poor concentration, and poor coordination.  This can affect the ability of people to perform daily activities such as driving, school, and work.  Also, when taken regularly, tranquilizers can cause physical dependence and when stopped abruptly can cause several withdrawal symptoms.
    • Parkinson’s disease medications (levodopa, carbidopa) are used to treat tremors associated with Parkinson’s disease.
    • Botulinum toxin – injections can treat almost all types of tremors.  It is especially useful for head tremor, which generally does not respond to medications.  Botulinum toxin is widely used to control dystonic tremors.  Although botulinum toxin injections can improve tremors for roughly three months at a time, they can also cause muscle weakness.  While this treatment is effective and usually well tolerated for head tremors, botulinum toxin treatment in the hands can cause weakness in the fingers.  It can cause a hoarse voice and difficulty swallowing when used to treat voice tremors.

    Additional drug therapies that have been used to treat individuals with primary orthostatic tremors include primidone (Mysoline), chlordiazepoxide (Librium), pregabalin (Lyrica), pramipexole (Mirapex), phenobarbital, and valproic acid (Depakote). Drugs commonly used to treat people with Parkinson’s disease (levodopa or pramipexole) may also be prescribed for individuals with primary orthostatic tremors.


    Surgery

    When people do not respond to drug therapies or have a severe tremor that significantly impacts their daily life, a doctor may recommend surgical interventions such as deep brain stimulation (DBS) or very rarely, thalamotomy.  While DBS is usually well-tolerated, the most common side effects of tremor surgery include dysarthria (trouble speaking) and balance problems.

    • Deep brain stimulation (DBS) – is the most common form of surgical treatment of tremors.  This method is preferred because it is effective, has low risk, and treats a broader range of symptoms than thalamotomy.  The treatment uses surgically implanted electrodes to send high-frequency electrical signals to the thalamus, the deep structure of the brain that coordinates and controls some involuntary movements.  A small pulse generating device placed under the skin in the upper chest (similar to a pacemaker) sends electrical stimuli to the brain and temporarily disables the tremor.  DBS is currently used to treat parkinsonian tremors, essential tremors, and dystonia.


    • Thalamotomy – is a surgical procedure that involves the precise, permanent destruction of a tiny area in the thalamus.  Currently, surgery is replaced by radiofrequency ablation to treat severe tremors when deep brain surgery is contraindicated—meaning it is unwise as a treatment option or has undesirable side effects.  Radiofrequency ablation uses a radio wave to generate an electric current that heats up a nerve and disrupts its signaling ability for typically six or more months.  It is usually performed on only one side of the brain to improve tremors on the opposite side of the body.  Surgery on both sides is not recommended as it can cause problems with speech.
    •  Stereotactic surgical techniques – can be used to create a lesion in the ventral intermediate (VIM) nucleus of the thalamus.

    Rehabilitation

    Exercise is an important part of healthy living for everyone. For people with tremors, exercise is more than healthy it is a vital component to maintaining balance, mobility, and activities of daily living. Exercise and physical activity can improve many tremors symptoms. These benefits are supported by research.

    The tremors show that people with tremors who start exercising earlier and a minimum of 2.5 hours a week, experience a slowed decline in quality of life compared to those who start later. Establishing early exercise habits is essential to overall disease management.

    What Type of Exercise Should I Do?

    To help manage the symptoms of tremors, be sure your exercise program includes a few key ingredients:

    • Aerobic activity
    • Strength training
    • Balance, agility, and multitasking
    • Flexibility

    These elements are included in many types of exercise. Biking, running, Tai chi, yoga, Pilates, dance, weight training, non-contact boxing, qi gong, and more — all have positive effects on tremors symptoms.

    There is no “exercise prescription” that is right for every person with tremors. The type of exercise you do depends on your symptoms and challenges. For sedentary people, just getting up and moving is beneficial. More active people can build up to the regular, vigorous activity. Many approaches work well to help maintain and improve mobility, flexibility, and balance to ease non-motor tremors symptoms such as depression or constipation.

    Researchers in the study did not distinguish between what type of exercise participants did and determined that all types of exercise are beneficial. The most important thing is to do the exercise regularly. We suggest finding an exercise you enjoy and stick with it.


    Challenges to Exercising

    • People in the early stages of tremors tend to be just as strong and physically fit as healthy individuals of the same age.
    • Disease progression can lead to the following physical change:
    • Loss of joint flexibility, which can affect balance.
    • Decreased muscle strength or deconditioning can affect walking and the ability to stand up from sitting.
    • The decline in cardiovascular conditioning, which affects endurance.

    Day to day living

    On a day-to-day basis, people feel stressed and frustrated, but they are not alone. People with orthostatic tremor will often struggle with:

    • standing
    • walking
    • other physical movements
    • exhaustion
    • pain

    Variability

    Orthostatic tremor varies from person to person, and sufferers find their own experiences change from time to time – sometimes due to stress or exertion, but sometimes without any reason what so ever.

    Standing

    For everyone who has an orthostatic tremor, standing, sometimes for just a few seconds, is difficult. People feel their legs buckle under them. This can result in actual falling. There may be a “freezing up” of the legs and doing day-to-day things such as queuing, or browsing in shops is difficult and quite likely impossible. People find that the pain will disappear slightly when the person sits or lies down.

    Walking

    In the early stages of orthostatic tremor, walking may not be affected too much. People may find that they walk quickly and are unable to walk slowly. However, as the condition progresses, the walking distance tends to reduce. The actual distance which can be walked will vary, and at worst people can not walk at all.

    Exhaustion

    People frequently suffer from extreme exhaustion or fatigue. Basic routines such as showering or dressing can take much longer than normal and require a period of rest for recovery. Even after a day of relatively little physical activity, they may feel unable to get out of a chair or needing sleep.

    Pain

    Some people will suffer pain when moving and over some said they have some pain when resting, usually in the legs and back.

    The effect of stress and emotion

    It is recognized that stress makes tremors worst. There is a vicious circle where the tremor gives rise to stress, and then the stress increases the tremor and so on. Feelings such as anger, annoyance, concern, frustration, and even excitement or anticipation can be a problem. The particular difficulty is caused by situations such as a crowded place – nowhere to sit, exertion involved, and the risk of falling.

    Frustration

    People experience much frustration and dependency on spouses/partners/carers and often lack of confidence when separated from them. Simple household tasks such as cleaning, cooking, and even making a cup of tea (or carrying it to another room) are either difficult or impossible.

    Mobility aids

    People often use a wheelchair, and some find that a wheelchair is essential for going out and/or moving around at home. Others use them only occasionally – such as at airports. Just over a third of respondents use a scooter. Some people often use scooters or walking sticks.

    Tips for Getting Started

    • First, be safe. Before starting an exercise program, consult your neurologist and primary care doctor about concerns and recommendations.
    • Ask your doctor or members in your support group to refer to a physical therapist (PT) who knows about tremors. Work together to identify your concerns and limitations. Target exercises to improve them. For most people, a structured exercise program will include aerobic exercise (such as brisk walking) and resistance training (using weights or bands).
    • Purchase a pedometer (step-counter) and figure out how many steps you take on average each day, then build up from there. Many smartphones or smartwatches have a built-in pedometer feature or an application that can be downloaded.
    • Exercise indoors and outdoors. Change your routine to stay interested and motivated.
    • Again, most importantly pick an exercise you enjoy.

    What research is being done?

    The mission is to seek fundamental knowledge about the brain and nervous system and to use that knowledge to reduce the burden of neurological disease.  The NINDS is a component of the National Institutes of Health (NIH), the leading supporter of biomedical research in the world.

    Researchers are working to better understand the underlying brain functions that cause tremors, identify the genetic factors that make individuals more susceptible to the disorder, and develop new and better treatment options.

    • Brain functioning – It can be difficult to distinguish between movement disorders such as Parkinson’s disease and essential tremor. These debilitating movement disorders have different prognoses and can respond very differently to available therapies. NINDS researchers are working to identify structural and functional changes in the brain using non-invasive neuroimaging techniques to develop sensitive and specific markers for each of these diseases and then track how they change as each disease progresses. Other researchers are using functional magnetic resonance imaging technology to better understand normal and diseased brain circuit functions and associated motor behaviors.  Scientists hope to design therapies that can restore normal brain circuit function in diseases such as Parkinson’s disease and tremor.
    • Genetics – Research has shown that essential tremors may have a strong genetic component affecting multiple generations of families.  NINDS researchers are building on previous genetics work to identify susceptibility genes for familial early-onset (before age 40) essential tremor.  Researchers are focusing on multigenerational, early-onset families to better detect linkages.

    Additionally, NINDS scientists are researching the impact of genetic abnormalities on the development of essential tremors.  Previous research that has shown a link between essential tremor and possible genetic variants on chromosome 6 and 11; ongoing research is targeting the impact of other genetic variations in families.

    Medications and other treatment methods

    While drugs can be effective for some people, approximately 50 percent of individuals do not respond to medication.  In order to develop assistive and rehabilitative tremor-suppressing devices for people with essential tremors, researchers are exploring where and how to minimize or suppress tremors while still allowing for voluntary movements.

    Many people with essential tremors respond to ethanol (alcohol); however, it is not clear why or how.  NINDS researchers are studying the impact of ethanol on tremors to determine the correct dosage amount and its physiological impact on the brain and whether other medications without the side effects of ethanol can be effective.

    Other NIH researchers hope to identify the source of essential tremors, study the effects of currently available tremor-suppressant drugs on the brain, and develop more targeted and effective therapies.

    FAQ

    Please answer the following questions to participate in our certified Continuing Medical Education program. Only one answer is possible per question. Please select the answer that is most appropriate.

    Question 1

    Which of the following constellations of clinical findings is typical of tremor in patients with Parkinson’s disease?

    1. bilateral postural tremor

    2. unilateral rest tremor and diminished ipsilateral arm swing while walking

    3. severe unilateral tremor while holding a cup or glass

    4. tremor that only appears when the patient writes

    5. postural tremor of both hands and ataxic gait

    Question 2

    A 25-year-old man has a mild postural tremor of both hands that improves when he drinks alcohol. His mother had the same condition. What can you advise him?

    1. He should definitely be evaluated for possible early Parkinson’s disease.

    2. He must get treatment now, as otherwise the condition could worsen.

    3. If treatment is indicated, propranolol or primidone could be given.

    4. Relaxation exercises and physiotherapy are effective treatment options.

    5. Genetic testing is needed to confirm the diagnosis of essential tremor.

    Question 3

    A man who received the diagnosis of multiple sclerosis two years ago presents to you with the new onset of tremor. What constellation of clinical findings is typical of tremor due to multiple sclerosis?

    1. rest tremor, only occasionally observable when the patient is excited

    2. a tremor that appears sometimes on the left side, sometimes on the right

    3. a tremor that is only present in the morning

    4. a swaying, broad-based gait and an intention tremor

    5. a postural tremor that is easily suppressed by voluntary effort

    Question 4

    A 55-year-old man with essential tremor says that he can no longer feed himself because of tremor, can dress himself only with great difficulty, and has not had legible handwriting for many years. Drug treatment as recommended in the relevant clinical guidelines brings only slight improvement. What can you advise the patient about the option of surgical treatment?

    1. Deep brain stimulation (DBS) might help but is not available in Germany.

    2. DBS is an experimental technique that is only performed in clinical trials.

    3. DBS is indicated only to treat Parkinson’s disease and plays no role in the treatment of essential tremor.

    4. DBS has a high chance of success in this situation; it is now established as a standard treatment for essential tremor.

    5. DBS is no more effective than pharmacotherapy for this indication.

    Question 5

    What information is most important for the diagnostic classification of a tremor syndrome?

    1. the clinical findings

    2. brain magnetic resonance imaging (MRI) with fine cerebellar sections

    3. nuclear-medical visualization of brain perfusion

    4. ultrasonography of the basal ganglia

    5. measurement of serum drug levels

    Question 6

    What findings indicate that tremor may be psychogenic?

    1. no evidence of essential tremor or Parkinson’s disease on brain MRI

    2. a longstanding marital conflict

    3. a tremor of inconstant location that diminishes on distraction and is found to be irregular on tremor analysis

    4. a clearly identifiable underlying psychological conflict

    5. remission after psychotherapy

    Question 7

    When can tremor be treated surgically?

    1. When the patient is unwilling to take drugs to treat tremor.

    2. When the patient is under 50 years old.

    3. When the tremor cannot be adequately suppressed by drugs and there is no contraindication to surgery.

    4. When the patient is willing to see a neurosurgeon once a week so that brain stimulation can be performed.

    5. When the patient is willing to assume the cost of weekly battery changes.

    Question 8

    What must be borne in mind with respect to drug treatment for various tremor syndromes?

    1. That the treatment is based on the clinical findings and not on the underlying disease causing tremor.

    2. That causally directed treatment is generally possible only for drug-induced tremors or tremors due to metabolic disturbance.

    3. That parkinsonian tremor responds best to anticholinergic drugs and does not respond at all to the classic dopamine preparations.

    4. That the cerebellar tremor of multiple sclerosis is treated in exactly the same way as essential tremor.

    5. That essential tremor is usually medically intractable.

    Question 9

    What drugs can induce tremor?

    1. lithium, valproic acid, cyclosporine A

    2. carbamazepine, propranolol, Seroxat

    3. aspirin, diclofenac, paracetamol

    4. penicillin, erythromycin, cephalosporin

    5. antilipid drugs, antidiabetic drugs

    Question 10

    What is the drug, or drug class, of first choice for the treatment of parkinsonian tremor?

    1. dopaminergic drugs

    2. propanolol

    3. primidone

    4. gabapentin

    5. ondansetron

    References

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    Trigeminal Neuralgia Type 2 (TN2) – Causes, Symptoms, Treatment

    Trigeminal Neuralgia Type 2 (TN2)/Trigeminal neuralgia (TN), also called tic douloureux, is a chronic pain condition that affects the trigeminal or 5th cranial nerve, one of the most widely distributed nerves in the head. TN is a form of neuropathic pain (pain associated with nerve injury or nerve lesion.) The typical or “classic” form of the disorder (called “Type 1” or TN1) causes extreme, sporadic, sudden burning, or shock-like facial pain that lasts anywhere from a few seconds to as long as two minutes per episode.  These attacks can occur in quick succession, in volleys lasting as long as two hours.  The “atypical” form of the disorder (called “Type 2” or TN2), is characterized by constant aching, burning, stabbing pain of somewhat lower intensity than Type 1.  Both forms of pain may occur in the same person, sometimes at the same time. The intensity of pain can be physically and mentally incapacitating.

    TRIGEMINAL NEURALGIA is an extremely severe unilateral episodic facial pain that tends to come and go unpredictably in sudden shock-like attacks. The pain is normally triggered, for example by light touch, and is described as stabbing, shooting, excruciating or burning. It usually lasts for a few seconds but there can be many bursts of pain in quick succession.  There can be slight variations of trigeminal neuralgia which require different treatments.

    Synonyms of Trigeminal Neuralgia

    • Fothergill Disease
    • Tic Douloureux
    • TN
    • Trifacial Neuralgia

    Subdivisions of Trigeminal Neuralgia

    • Trigeminal neuralgia type 1 (TN1)
    • Trigeminal neuralgia type 2 (TN2)

    Types of Trigeminal Neuralgia

    The typical or “classic” form of the disorder (called TN1) causes extreme, sporadic, sudden burning or shock-like facial pain in the areas of the face where the branches of the nerve are distributed – lips, eyes, nose, scalp, forehead, upper jaw, and lower jaw. Trigeminal neuralgia can progress and cause longer, more frequent bouts of searing pain. You may feel as though your pain came out of nowhere. Some people initially think their pain is a toothache or migraine headache.

    The “atypical” form of the disorder (called TN2), is characterized by constant aching, burning, stabbing pain of somewhat lower intensity than TN1. Both forms of pain may occur in the same person, sometimes at the same time

    Primary trigeminal neuralgia

    • Evidence suggests that in up to 95% of cases, trigeminal neuralgia is caused by pressure on the trigeminal nerve close to where it enters the brain stem, the lowest part of the brain that merges with the spinal cord.\
    • This type of trigeminal neuralgia is known as primary trigeminal neuralgia. In most cases, the pressure is caused by an artery or vein squashing (compressing) the trigeminal nerve. These are normal blood vessels that happen to come into contact with the nerve at a, particularly sensitive point.
    • It’s not clear why this pressure can cause painful attacks in some people but not others, as not everyone with a compressed trigeminal nerve will experience pain.
    • It may be that, in some people, the pressure on the nerve wears away its protective outer layer (myelin sheath), which may cause pain signals to travel along the nerve. However, this does not fully explain why some people have periods without symptoms (remission), or why pain relief is immediately after a successful operation to move the blood vessels away from the nerve.

    Secondary trigeminal neuralgia

    Secondary trigeminal neuralgia is the term used when trigeminal neuralgia is caused by another medical condition or problem, including:

    • a tumor
    • a cyst – a fluid-filled sac
    • arteriovenous malformation – an abnormal tangle of arteries and veins
    • multiple sclerosis (MS) – a long-term condition that affects the nervous system
    • facial injury
    • damage caused by surgery including dental surgery

    The subtypes of TN are defined by ICHD-3 as follows

    • Classic TN: This is secondary to neuromuscular compression and fulfilling the criteria above. This requires demonstration of the compression on an MRI or during the surgery for neuromuscular compression, with associated morphological changes in the trigeminal nerve root.
    • Secondary TN: This is defined as TN secondary to an underlying disease. Some of the reported causes are multiple sclerosis, arteriovenous malformation, and cerebellopontine angle tumor.
    • Idiopathic TN: This is defined as TN with no abnormalities seen on MRI or electrophysiological tests.

    The trigeminal nerve is one of 12 pairs of nerves that are attached to the brain. The nerve has three branches that conduct sensations from the upper, middle, and lower portions of the face, as well as the oral cavity, to the brain. The ophthalmic, or upper, branch supplies sensation to most of the scalp, forehead, and front of the head. The maxillary, or middle, branch stimulates the cheek, upper jaw, top lip, teeth, and gums, and to the side of the nose. The mandibular, or lower, branch supplies nerves to the lower jaw, teeth and gums, and bottom lip. More than one nerve branch can be affected by the disorder. Rarely, both sides of the face may be affected at different times in an individual, or even more rarely at the same time (called bilateral TN).

    What causes trigeminal neuralgia?

    TN is associated with a variety of conditions. TN can be caused by a blood vessel pressing on the trigeminal nerve as it exits the brain stem. This compression causes the wearing away or damage to the protective coating around the nerve (the myelin sheath). TN symptoms can also occur in people with multiple sclerosis, a disease that causes deterioration of the trigeminal nerve’s myelin sheath. Rarely, symptoms of TN may be caused by nerve compression from a tumor, or a tangle of arteries and veins called an arteriovenous malformation. Injury to the trigeminal nerve (perhaps the result of sinus surgery, oral surgery, stroke, or facial trauma) may also produce neuropathic facial pain.

    The exact cause of trigeminal neuralgia remains unknown. The majority of cases are referred to as idiopathic, although many are associated with vascular compression of the trigeminal nerve close to its exit from the brainstem by an aberrant loop of an artery or vein. A minority of cases are due to conditions like multiple sclerosis or nerve compression by a tumor. Some rare causes of trigeminal neuralgia include focal arachnoid thickening, adhesion, traction, tethering or torsion, fibrous ring around the root, cerebellopontine angle tumors, brain stem infarction, aneurysm, and arteriovenous malformation.

    The trigeminal nerve starts at the pons. Most cases of trigeminal neuralgia are due to the compression of the trigeminal nerve root, within a few millimeters of its entry into the pons. Between 80% and 90% of the cases of TN are caused by compression by an adjacent artery or a vein. The blood vessel, which has been mostly implicated in about 75% to 80% of the cases, is the superior cerebellar artery. Other blood vessels that are known to cause TN include the anterior inferior cerebellar artery, the vertebral artery, and the petrosal vein.

    Vascular Theory

    Generally, it has been assumed that vascular contact at the root entry zone causes trigeminal neuralgia; however, TN also may be caused by contact at a transition zone between the central and peripheral myelin. Reportedly, the most common artery involved in this condition is the superior cerebellar artery, as seen in 75% to 80% of TN cases. Persistent primitive trigeminal artery variant, an anomaly that occurs between the carotid and basilar arteries or aneurysms of the persistent primitive trigeminal artery, vertebrobasilar dolichoectasia can cause TN. Sharper trigeminal-pontine angle cisterns and smaller cerebellopontine angle cisterns may facilitate neurovascular compression (NVC).

    Extracranial Causes

    The most common extracranial cause of trigeminal neuralgia is a perineural spread of head and neck malignancies, commonly squamous cell carcinoma, adenoid cystic carcinoma, lymphoma, melanoma, and sarcoma.

    What are the symptoms of trigeminal neuralgia?

    Pain varies, depending on the type of TN, and may range from sudden, severe, and stabbing to a more constant, aching, burning sensation. The intense flashes of pain can be triggered by vibration or contact with the cheek (such as when shaving, washing the face, or applying makeup), brushing teeth, eating, drinking, talking, or being exposed to the wind. The pain may affect a small area of the face or may spread. Bouts of pain rarely occur at night, when the affected individual is sleeping.

    TN is typified by attacks that stop for a period of time and then return, but the condition can be progressive. The attacks often worsen over time, with fewer and shorter pain-free periods before they recur. Eventually, the pain-free intervals disappear and medication to control the pain becomes less effective. The disorder is not fatal but can be debilitating. Due to the intensity of the pain, some individuals may avoid daily activities or social contacts because they fear an impending attack.

    The trigeminal nerve is the fifth cranial nerve. It is responsible for the sensory supply of the face and the motor and sensory supply to the muscles of mastication. The trigeminal nerve starts at the pons and divides into three branches:

    • Ophthalmic (V1): Supplies the eye, upper eyelid, and the forehead
    • Maxillary (V2): Supplies lower eyelid, cheek, nostril, upper lip, and upper gum
    • Mandibular (V3): Supplies the lower lip, lower gum, jaw and muscles of mastication

    Trigeminal neuralgia symptoms may include one or more of these patterns:

    • Episodes of severe, shooting or jabbing pain that may feel like an electric shock
    • Spontaneous attacks of pain or attacks triggered by things such as touching the face, chewing, speaking or brushing teeth
    • Bouts of pain lasting from a few seconds to several minutes
    • Episodes of several attacks lasting days, weeks, months, or longer — some people have periods when they experience no pain
    • Constant aching, burning feeling that may occur before it evolves into the spasm-like pain of trigeminal neuralgia
    • Pain in areas supplied by the trigeminal nerve, including the cheek, jaw, teeth, gums, lips, or less often the eye and forehead
    • Pain affecting one side of the face at a time though may rarely affect both sides of the face
    • Pain focused in one spot or spread in a wider pattern
    • Attacks that become more frequent and intense over time
    • The attacks happen several times a day or a week, followed by periods during which you have none at all. These pain-free periods are known as remission.
    • The pain usually affects only one side of the face.
    • The attacks happen more often over time, and the pain can worsen.
    • You feel the pain mostly in your cheek, jaw, teeth, gums, and lips. The eyes and forehead are affected less often.

    Symptom triggers

    Attacks of trigeminal neuralgia can be triggered by certain actions or movements, such as:

    • talking
    • smiling
    • chewing
    • brushing your teeth
    • washing your face
    • a light touch
    • shaving or putting on make-up
    • swallowing
    • kissing
    • a cool breeze or air conditioning
    • head movements
    • vibrations, such as walking or traveling in a car

    However, pain can happen spontaneously with no trigger whatsoever.

    The symptoms of several pain disorders are similar to those of trigeminal neuralgia. The most common mimicker of TN is trigeminal neuropathic pain (TNP). TNP results from an injury or damage to the trigeminal nerve. TNP pain is generally described as being constant, dull and burning. Attacks of sharp pain can also occur, commonly triggered by touch. Additional mimickers include:

    • Temporal tendinitis
    • Ernest syndrome (injury of the stylomandibular ligament
    • Occipital neuralgia
    • Cluster headaches/ migraines
    • Giant cell arteritis
    • Dental pain
    • Post-herpetic neuralgia
    • Glossopharyngeal neuralgia
    • Sinus infection
    • Ear infection
    • Temporomandibular joint syndrome (TMJ)

    Diagnosis of Child Trigeminal Neuralgia

    TN diagnosis is based primarily on the person’s history and description of symptoms, along with results from physical and neurological examinations. Other disorders that cause facial pain should be ruled out before TN is diagnosed. Some disorders that cause facial pain include post-herpetic neuralgia (nerve pain following an outbreak of shingles), cluster headaches, and temporomandibular joint disorder (TMJ, which causes pain and dysfunction in the jaw joint and muscles that control jaw movement).  Because of overlapping symptoms and the large number of conditions that can cause facial pain, obtaining a correct diagnosis is difficult, but finding the cause of the pain is important as the treatments for different types of pain may differ.

    Most people with TN eventually will undergo a magnetic resonance imaging (MRI) scan to rule out a tumor or multiple sclerosis as the cause of their pain. This scan may or may not clearly show a blood vessel compressing the nerve. Special MRI imaging procedures can reveal the presence and severity of compression of the nerve by a blood vessel.

    A diagnosis of classic trigeminal neuralgia may be supported by an individual’s positive response to a short course of antiseizure medication. Diagnosis of TN2 is more complex and difficult but tends to be supported by a positive response to low doses of tricyclic antidepressant medications (such as amitriptyline and nortriptyline), similar to other neuropathic pain diagnoses.

    Your doctor may conduct many tests to diagnose trigeminal neuralgia and determine underlying causes for your condition, including:

    • A neurological examination. Touching and examining parts of your face can help your doctor determine exactly where the pain is occurring and — if you appear to have trigeminal neuralgia — which branches of the trigeminal nerve may be affected. Reflex tests also can help your doctor determine if your symptoms are caused by a compressed nerve or another condition.
    • Magnetic resonance imaging (MRI). Your doctor may order an MRI scan of your head to determine if multiple sclerosis or a tumor is causing trigeminal neuralgia. In some cases, your doctor may inject a dye into a blood vessel to view the arteries and veins and highlight blood flow (magnetic resonance angiogram).
    One published a set of guidelines for diagnosing TN is from the International Headache Society.

    For classical TN

    • Paroxysmal attacks of pain lasting from a fraction of a second to two minutes, affecting one or more divisions of the trigeminal nerve, and fulfilling criteria 2 and 3.
    • Pain has at least one of the following characteristics:
      • Intense, sharp, superficial or stabbing
      • Precipitated from trigger zones or by trigger factors
    • Attacks are stereotyped in the individuals patient
    • There is no clinically evident neurologic deficit
    • Not attributed to another disorder


    For symptomatic TN

    • Paroxysmal attacks of pain lasting from a fraction of a second to two minutes, with or without persistence of aching between paroxysms, affecting one or more divisions of the trigeminal nerve, and fulfilling criteria 2 and 3.
    • Pain has at least one of the following characteristics
      • Intense, sharp, superficial or stabbing
      • Precipitated from trigger zones or by trigger factors.
    • Attacks are stereotyped in the individual patient
    • A causative lesion, other than vascular compression, has been demonstrated by special investigations and/or posterior fossa exploration.

    Treatment of Child Trigeminal Neuralgia

    Treatment options include medicines, surgery, and complementary approaches.

    Pharmacologic Therapy

    • The first-line treatment – for patients with classic TN and idiopathic TN is pharmacologic therapy. The most commonly used medication is the anticonvulsant drug, carbamazepine. It is usually started at a low dose, and the dose is gradually increased until it controls the pain. It controls pain for most people in the early stages of the disease. However, in some patients, the effectiveness of carbamazepine decreases over time. Possible side effects of carbamazepine include drowsiness, dizziness, double vision, and nausea. In patients with Asian ancestry, before starting carbamazepine, testing for the HLA-B allele is recommended, as its presence increases the risk of development of toxic epidermal necrolysis or Stevens-Johnson syndrome.
    • Oxcarbazepine – is a newer drug and is being increasingly used as first-line therapy for TN in patients who do not respond to or who cannot tolerate carbamazepine (200 to 1200 mg/day) and oxcarbazepine (600 to 1800 mg/day). Possible side effects include double vision and dizziness. It can also cause hyponatremia. It should also be avoided in patients with the HLA-B 15:02 allele.
    • Muscle relaxant – Baclofen is a muscle relaxant that can be used to treat TN. Baclofen, lamotrigine, clonazepam, topiramate, phenytoin, gabapentin, pregabalin, and sodium valproate can be used. Side effects include dizziness, sedation, and dyspepsia.
    • Seizures, anticonvulsant medication – used to treat epilepsy and to delay or prevent the recurrence of depressive episodes in bipolar disorder. For epilepsy, this includes focal seizures, tonic-clonic seizures, and seizures in Lennox-Gastaut syndrome and medication lamotrigine, phenytoin, gabapentin, clonazepam, and valproic acid. Lamotrigine (200 to 400 mg/day), pregabalin (150 to 600 mg/day), gabapentin (1800 to 4200 mg/day), or topiramate (100 to 400 mg/day) may be considered. If the combination therapy fails, a switch to baclofen (40 to 80 mg/day) may be considered.
    • Eslicarbazepine – an active metabolite of oxcarbazepine, and the new Nav1.7 blocker, vixotrigine, are being explored for pain relief in TN.

    • Anticonvulsant medicines—used to block nerve firing—are generally effective in treating TN1 but often less effective in TN2. These drugs include carbamazepine, oxcarbazepine, topiramate, gabapentin, pregabalin, clonazepam, phenytoin, lamotrigine, and valproic acid.

    • Tricyclic antidepressants – such as amitriptyline or nortriptyline can be used to treat pain. Common analgesics and opioids are not usually helpful in treating the sharp, recurring pain caused by TN1, although some individuals with TN2 do respond to opioids.  Eventually, if medication fails to relieve pain or produces intolerable side effects such as cognitive disturbances, memory loss, excess fatigue, bone marrow suppression, or allergy, then surgical treatment may be indicated. Since TN is a progressive disorder that often becomes resistant to medication over time, individuals often seek surgical treatment.

    • Botulinum Toxin Injections – This can be beneficial for some patients, particularly the middle-aged and the elderly, who are refractory to medical therapy or who cannot tolerate medical therapy due to their side effects.

    • Tetracaine nerve block – may be used as an additional treatment after carbamazepine, as can acupuncture and/or peripheral nerve stimulation. Patients with secondary TN also can respond well to pharmacotherapy. However, it is recommended to treat the underlying lesion or disease.

    • There is controversy around opiate use such as morphine and oxycodone for treatment of TN, with varying evidence on its effectiveness for neuropathic pain. Generally, opioids are considered ineffective against TN and thus should not be prescribed.[rx]

    Surgical Therapy

    Patients who are refractory to medical therapy can be considered for surgery.
    • Microvascular decompression – This is one of the most common procedures used to treat trigeminal neuralgia. This is beneficial for patients with TN, where compression of the nerve root is the cause. This involves craniotomy and posterior fossa exploration for identifying and moving the blood vessel that is compressing the trigeminal nerve. A soft cushion is then inserted between the nerve and the vessel, to allow the nerve to recover, which eventually relieves the pain. In some patients, this procedure can result in sustained pain relief for greater than 10 years. Though this is the most effective procedure, it is also the most invasive one. Some of the complications associated with it are decreased hearing, cerebellar hematoma, CSF leaks, infarction, and facial weakness. It is believed to be the most effective long-term surgical treatment available currently for patients with TN.
    • Ablative procedures include rhizotomy–  with thermocoagulation, chemical injection, or mechanical balloon compression. These procedures involve damaging the trigeminal nerve root, thereby interrupting the pain transmission signals to the brain. Rhizotomy with thermocoagulation uses an electrode to apply heat to damage the nerve fibers. Chemical rhizotomy involves injecting the chemical, glycerol to the trigeminal nerve, thereby damaging it. Balloon compression involves inserting a tiny balloon to the point of location of nerve fibers. This balloon, on inflation, damages the nerve fibers. Some of the associated complications are postoperative dysesthesia, corneal numbness, sensory loss in trigeminal nerve distribution, and anesthesia Dolorosa.
    • Radiosurgery – This procedure involves using radiosurgery instrumentation. This is a non-invasive procedure, wherein, a highly concentrated dose of ionizing radiation is delivered to a precise target at the trigeminal nerve root. The radiation creates a lesion near the nerve root, thereby interrupting the pain signals from transmission to the brain. The formation of the lesion can be slow, and hence the pain relief using this procedure is delayed by up to several weeks or months. As this is one of the least invasive procedures, it can be repeated in patients who have a recurrence of pain. Some of the associated complications can be facial sensory loss and paresthesias.
    • Peripheral neurectomy and nerve block – The neurectomy can be performed on peripheral branches of the trigeminal nerve like the supraorbital, infraorbital, lingual, and alveolar nerves. This can be accomplished by alcohol injection, incision, cryotherapy, or radiofrequency lesioning. Peripheral neurectomy can be safe in elderly patients in remote and rural areas, where neurosurgical facilities are not readily available. However, the evidence regarding these peripheral techniques for trigeminal neuralgia is inconclusive.
    • A rhizotomy (rhizolysis)–  is a procedure in which nerve fibers are damaged to block pain. A rhizotomy for TN always causes some degree of sensory loss and facial numbness. Several forms of rhizotomy are available to treat trigeminal neuralgia:
    • Balloon compression – works by injuring the insulation on nerves that are involved with the sensation of light touch on the face. The procedure is performed in an operating room under general anesthesia. A tube called a cannula is inserted through the cheek and guided to where one branch of the trigeminal nerve passes through the base of the skull. A soft catheter with a balloon tip is threaded through the cannula and the balloon is inflated to squeeze part of the nerve against the hard edge of the brain covering (the dura) and the skull. After about a minute the balloon is deflated and removed, along with the catheter and cannula. Balloon compression is generally an outpatient procedure, although sometimes the patient may be kept in the hospital overnight. Pain relief usually lasts one to two years.
    • Glycerol injection is also generally an outpatient procedure in which the individual is sedated with intravenous medication. A thin needle is passed through the cheek, next to the mouth, and guided through the opening in the base of the skull where the third division of the trigeminal nerve (mandibular) exits. The needle is moved into the pocket of spinal fluid (cistern) that surrounds the trigeminal nerve center (or ganglion, the central part of the nerve from which the nerve impulses are transmitted to the brain). The procedure is performed with the person sitting up, since glycerol is heavier than spinal fluid and will then remain in the spinal fluid around the ganglion. The glycerol injection bathes the ganglion and damages the insulation of trigeminal nerve fibers. This form of rhizotomy is likely to result in the recurrence of pain within a year to two years. However, the procedure can be repeated multiple times.
    • Radiofrequency thermal lesioning – (also known as “RF Ablation” or “RF Lesion”) is most often performed on an outpatient basis. The individual is anesthetized and a hollow needle is passed through the cheek through the same opening at the base of the skull where the balloon compression and glycerol injections are performed. The individual is briefly awakened and a small electrical current is passed through the needle, causing tingling in the area of the nerve where the needle tips rest. When the needle is positioned so that the tingling occurs in the area of TN pain, the person is then sedated and the nerve area is gradually heated with an electrode, injuring the nerve fibers.  The electrode and needle are then removed and the person is awakened. The procedure can be repeated until the desired amount of sensory loss is obtained; usually a blunting of sharp sensation, with preservation of touch. Approximately half of the people have symptoms that reoccur three to four years following RF lesioning. Production of more numbness can extend the pain relief even longer, but the risks of anesthesia dolorosa also increase.
    • Stereotactic radiosurgery – (Gamma Knife, CyberKnife) uses computer imaging to direct highly focused beams of radiation at the site where the trigeminal nerve exits the brain stem. This causes the slow formation of a lesion on the nerve that disrupts the transmission of sensory signals to the brain. People usually leave the hospital the same day or the next day following treatment but won’t typically experience relief from pain for several weeks (or sometimes several months) following the procedure.  The International Radiosurgery Association reports that between 50 and 78 percent of people with TN who are treated with Gamma Knife radiosurgery experience “excellent” pain relief within a few weeks following the procedure. For individuals who were treated successfully, almost half have a recurrence of pain within three years.
    • Decompression Surgery –  is the most invasive of all surgeries for TN, but also offers the lowest probability that pain will return. About half of individuals undergoing MVD for TN will experience recurrent pain within 12 to 15 years.  This inpatient procedure, which is performed under general anesthesia, requires that a small opening be made through the mastoid bone behind the ear. While viewing the trigeminal nerve through a microscope or endoscope, the surgeon moves away from the vessel (usually an artery) that is compressing the nerve and places a soft cushion between the nerve and the vessel. Unlike rhizotomies, the goal is not to produce numbness in the face after this surgery. Individuals generally recuperate for several days in the hospital following the procedure, and will generally need to recover for several weeks after the procedure.
    • A neurectomy (also called partial nerve section) – which involves cutting part of the nerve, may be performed near the entrance point of the nerve at the brain stem during an attempted microvascular decompression if no vessel is found to be pressing on the trigeminal nerve. Neurectomies also may be performed by cutting superficial branches of the trigeminal nerve in the face. When done during microvascular decompression, a neurectomy will cause more long-lasting numbness in the area of the face that is supplied by the nerve or nerve branch that is cut. However, when the operation is performed in the face, the nerve may grow back and in time sensation may return.  With neurectomy, there is risk of creating anesthesia Dolorosa.

    Surgical treatment for TN2 is usually more problematic than for TN1, particularly where vascular compression is not detected in brain imaging prior to a proposed procedure. Many neurosurgeons advise against the use of MVD or rhizotomy in individuals for whom TN2 symptoms predominate over TN1, unless vascular compression has been confirmed. MVD for TN2 is also less successful than for TN1.

    Some individuals manage trigeminal neuralgia using complementary techniques, usually in combination with drug treatment. These therapies offer varying degrees of success. Some people find that low-impact exercise, yoga, creative visualization, aromatherapy, or meditation may be useful in promoting well-being. Other options include acupuncture, upper cervical chiropractic, biofeedback, vitamin therapy, and nutritional therapy. Some people report modest pain relief after injections of botulinum toxin to block the activity of sensory nerves.


    Chronic pain from TN is frequently very isolating and depressing for the individual. Conversely, depression and sleep disturbance may render individuals more vulnerable to pain and suffering. Some individuals benefit from supportive counseling or therapy by a psychiatrist or psychologist. However, there is no evidence that TN is psychogenic in origin or caused by depression, and persons with TN require effective medical or surgical treatment for their pain.

    References

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    Trigeminal Neuralgia Type 1 (TN1) – Symptoms, Treatment

    Trigeminal Neuralgia Type 1 (TN1)/Trigeminal neuralgia (TN), also called tic douloureux, is a chronic pain condition that affects the trigeminal or 5th cranial nerve, one of the most widely distributed nerves in the head. TN is a form of neuropathic pain (pain associated with nerve injury or nerve lesion.) The typical or “classic” form of the disorder (called “Type 1” or TN1) causes extreme, sporadic, sudden burning, or shock-like facial pain that lasts anywhere from a few seconds to as long as two minutes per episode.  These attacks can occur in quick succession, in volleys lasting as long as two hours.  The “atypical” form of the disorder (called “Type 2” or TN2), is characterized by constant aching, burning, stabbing pain of somewhat lower intensity than Type 1.  Both forms of pain may occur in the same person, sometimes at the same time. The intensity of pain can be physically and mentally incapacitating.

    TRIGEMINAL NEURALGIA is an extremely severe unilateral episodic facial pain that tends to come and go unpredictably in sudden shock-like attacks. The pain is normally triggered, for example by light touch, and is described as stabbing, shooting, excruciating or burning. It usually lasts for a few seconds but there can be many bursts of pain in quick succession.  There can be slight variations of trigeminal neuralgia which require different treatments.

    Synonyms of Trigeminal Neuralgia

    • Fothergill Disease
    • Tic Douloureux
    • TN
    • Trifacial Neuralgia

    Subdivisions of Trigeminal Neuralgia

    • Trigeminal neuralgia type 1 (TN1)
    • Trigeminal neuralgia type 2 (TN2)

    Types of Trigeminal Neuralgia

    The typical or “classic” form of the disorder (called TN1) causes extreme, sporadic, sudden burning or shock-like facial pain in the areas of the face where the branches of the nerve are distributed – lips, eyes, nose, scalp, forehead, upper jaw, and lower jaw. Trigeminal neuralgia can progress and cause longer, more frequent bouts of searing pain. You may feel as though your pain came out of nowhere. Some people initially think their pain is a toothache or migraine headache.

    The “atypical” form of the disorder (called TN2), is characterized by constant aching, burning, stabbing pain of somewhat lower intensity than TN1. Both forms of pain may occur in the same person, sometimes at the same time

    Primary trigeminal neuralgia

    • Evidence suggests that in up to 95% of cases, trigeminal neuralgia is caused by pressure on the trigeminal nerve close to where it enters the brain stem, the lowest part of the brain that merges with the spinal cord.\
    • This type of trigeminal neuralgia is known as primary trigeminal neuralgia. In most cases, the pressure is caused by an artery or vein squashing (compressing) the trigeminal nerve. These are normal blood vessels that happen to come into contact with the nerve at a, particularly sensitive point.
    • It’s not clear why this pressure can cause painful attacks in some people but not others, as not everyone with a compressed trigeminal nerve will experience pain.
    • It may be that, in some people, the pressure on the nerve wears away its protective outer layer (myelin sheath), which may cause pain signals to travel along the nerve. However, this does not fully explain why some people have periods without symptoms (remission), or why pain relief is immediately after a successful operation to move the blood vessels away from the nerve.

    Secondary trigeminal neuralgia

    Secondary trigeminal neuralgia is the term used when trigeminal neuralgia is caused by another medical condition or problem, including:

    • a tumor
    • a cyst – a fluid-filled sac
    • arteriovenous malformation – an abnormal tangle of arteries and veins
    • multiple sclerosis (MS) – a long-term condition that affects the nervous system
    • facial injury
    • damage caused by surgery including dental surgery

    The subtypes of TN are defined by ICHD-3 as follows

    • Classic TN: This is secondary to neuromuscular compression and fulfilling the criteria above. This requires demonstration of the compression on an MRI or during the surgery for neuromuscular compression, with associated morphological changes in the trigeminal nerve root.
    • Secondary TN: This is defined as TN secondary to an underlying disease. Some of the reported causes are multiple sclerosis, arteriovenous malformation, and cerebellopontine angle tumor.
    • Idiopathic TN: This is defined as TN with no abnormalities seen on MRI or electrophysiological tests.

    The trigeminal nerve is one of 12 pairs of nerves that are attached to the brain. The nerve has three branches that conduct sensations from the upper, middle, and lower portions of the face, as well as the oral cavity, to the brain. The ophthalmic, or upper, branch supplies sensation to most of the scalp, forehead, and front of the head. The maxillary, or middle, branch stimulates the cheek, upper jaw, top lip, teeth, and gums, and to the side of the nose. The mandibular, or lower, branch supplies nerves to the lower jaw, teeth and gums, and bottom lip. More than one nerve branch can be affected by the disorder. Rarely, both sides of the face may be affected at different times in an individual, or even more rarely at the same time (called bilateral TN).

    What causes trigeminal neuralgia?

    TN is associated with a variety of conditions. TN can be caused by a blood vessel pressing on the trigeminal nerve as it exits the brain stem. This compression causes the wearing away or damage to the protective coating around the nerve (the myelin sheath). TN symptoms can also occur in people with multiple sclerosis, a disease that causes deterioration of the trigeminal nerve’s myelin sheath. Rarely, symptoms of TN may be caused by nerve compression from a tumor, or a tangle of arteries and veins called an arteriovenous malformation. Injury to the trigeminal nerve (perhaps the result of sinus surgery, oral surgery, stroke, or facial trauma) may also produce neuropathic facial pain.

    The exact cause of trigeminal neuralgia remains unknown. The majority of cases are referred to as idiopathic, although many are associated with vascular compression of the trigeminal nerve close to its exit from the brainstem by an aberrant loop of an artery or vein. A minority of cases are due to conditions like multiple sclerosis or nerve compression by a tumor. Some rare causes of trigeminal neuralgia include focal arachnoid thickening, adhesion, traction, tethering or torsion, fibrous ring around the root, cerebellopontine angle tumors, brain stem infarction, aneurysm, and arteriovenous malformation.

    The trigeminal nerve starts at the pons. Most cases of trigeminal neuralgia are due to the compression of the trigeminal nerve root, within a few millimeters of its entry into the pons. Between 80% and 90% of the cases of TN are caused by compression by an adjacent artery or a vein. The blood vessel, which has been mostly implicated in about 75% to 80% of the cases, is the superior cerebellar artery. Other blood vessels that are known to cause TN include the anterior inferior cerebellar artery, the vertebral artery, and the petrosal vein.

    Vascular Theory

    Generally, it has been assumed that vascular contact at the root entry zone causes trigeminal neuralgia; however, TN also may be caused by contact at a transition zone between the central and peripheral myelin. Reportedly, the most common artery involved in this condition is the superior cerebellar artery, as seen in 75% to 80% of TN cases. Persistent primitive trigeminal artery variant, an anomaly that occurs between the carotid and basilar arteries or aneurysms of the persistent primitive trigeminal artery, vertebrobasilar dolichoectasia can cause TN. Sharper trigeminal-pontine angle cisterns and smaller cerebellopontine angle cisterns may facilitate neurovascular compression (NVC).

    Extracranial Causes

    The most common extracranial cause of trigeminal neuralgia is a perineural spread of head and neck malignancies, commonly squamous cell carcinoma, adenoid cystic carcinoma, lymphoma, melanoma, and sarcoma.

    What are the symptoms of trigeminal neuralgia?

    Pain varies, depending on the type of TN, and may range from sudden, severe, and stabbing to a more constant, aching, burning sensation. The intense flashes of pain can be triggered by vibration or contact with the cheek (such as when shaving, washing the face, or applying makeup), brushing teeth, eating, drinking, talking, or being exposed to the wind. The pain may affect a small area of the face or may spread. Bouts of pain rarely occur at night, when the affected individual is sleeping.

    TN is typified by attacks that stop for a period of time and then return, but the condition can be progressive. The attacks often worsen over time, with fewer and shorter pain-free periods before they recur. Eventually, the pain-free intervals disappear and medication to control the pain becomes less effective. The disorder is not fatal but can be debilitating. Due to the intensity of the pain, some individuals may avoid daily activities or social contacts because they fear an impending attack.

    The trigeminal nerve is the fifth cranial nerve. It is responsible for the sensory supply of the face and the motor and sensory supply to the muscles of mastication. The trigeminal nerve starts at the pons and divides into three branches:

    • Ophthalmic (V1): Supplies the eye, upper eyelid, and the forehead
    • Maxillary (V2): Supplies lower eyelid, cheek, nostril, upper lip, and upper gum
    • Mandibular (V3): Supplies the lower lip, lower gum, jaw and muscles of mastication

    Trigeminal neuralgia symptoms may include one or more of these patterns:

    • Episodes of severe, shooting or jabbing pain that may feel like an electric shock
    • Spontaneous attacks of pain or attacks triggered by things such as touching the face, chewing, speaking or brushing teeth
    • Bouts of pain lasting from a few seconds to several minutes
    • Episodes of several attacks lasting days, weeks, months, or longer — some people have periods when they experience no pain
    • Constant aching, burning feeling that may occur before it evolves into the spasm-like pain of trigeminal neuralgia
    • Pain in areas supplied by the trigeminal nerve, including the cheek, jaw, teeth, gums, lips, or less often the eye and forehead
    • Pain affecting one side of the face at a time though may rarely affect both sides of the face
    • Pain focused in one spot or spread in a wider pattern
    • Attacks that become more frequent and intense over time
    • The attacks happen several times a day or a week, followed by periods during which you have none at all. These pain-free periods are known as remission.
    • The pain usually affects only one side of the face.
    • The attacks happen more often over time, and the pain can worsen.
    • You feel the pain mostly in your cheek, jaw, teeth, gums, and lips. The eyes and forehead are affected less often.

    Symptom triggers

    Attacks of trigeminal neuralgia can be triggered by certain actions or movements, such as:

    • talking
    • smiling
    • chewing
    • brushing your teeth
    • washing your face
    • a light touch
    • shaving or putting on make-up
    • swallowing
    • kissing
    • a cool breeze or air conditioning
    • head movements
    • vibrations, such as walking or traveling in a car

    However, pain can happen spontaneously with no trigger whatsoever.

    The symptoms of several pain disorders are similar to those of trigeminal neuralgia. The most common mimicker of TN is trigeminal neuropathic pain (TNP). TNP results from an injury or damage to the trigeminal nerve. TNP pain is generally described as being constant, dull and burning. Attacks of sharp pain can also occur, commonly triggered by touch. Additional mimickers include:

    • Temporal tendinitis
    • Ernest syndrome (injury of the stylomandibular ligament
    • Occipital neuralgia
    • Cluster headaches/ migraines
    • Giant cell arteritis
    • Dental pain
    • Post-herpetic neuralgia
    • Glossopharyngeal neuralgia
    • Sinus infection
    • Ear infection
    • Temporomandibular joint syndrome (TMJ)

    Diagnosis of Child Trigeminal Neuralgia

    TN diagnosis is based primarily on the person’s history and description of symptoms, along with results from physical and neurological examinations. Other disorders that cause facial pain should be ruled out before TN is diagnosed. Some disorders that cause facial pain include post-herpetic neuralgia (nerve pain following an outbreak of shingles), cluster headaches, and temporomandibular joint disorder (TMJ, which causes pain and dysfunction in the jaw joint and muscles that control jaw movement).  Because of overlapping symptoms and the large number of conditions that can cause facial pain, obtaining a correct diagnosis is difficult, but finding the cause of the pain is important as the treatments for different types of pain may differ.

    Most people with TN eventually will undergo a magnetic resonance imaging (MRI) scan to rule out a tumor or multiple sclerosis as the cause of their pain. This scan may or may not clearly show a blood vessel compressing the nerve. Special MRI imaging procedures can reveal the presence and severity of compression of the nerve by a blood vessel.

    A diagnosis of classic trigeminal neuralgia may be supported by an individual’s positive response to a short course of antiseizure medication. Diagnosis of TN2 is more complex and difficult but tends to be supported by a positive response to low doses of tricyclic antidepressant medications (such as amitriptyline and nortriptyline), similar to other neuropathic pain diagnoses.

    Your doctor may conduct many tests to diagnose trigeminal neuralgia and determine underlying causes for your condition, including:

    • A neurological examination. Touching and examining parts of your face can help your doctor determine exactly where the pain is occurring and — if you appear to have trigeminal neuralgia — which branches of the trigeminal nerve may be affected. Reflex tests also can help your doctor determine if your symptoms are caused by a compressed nerve or another condition.
    • Magnetic resonance imaging (MRI). Your doctor may order an MRI scan of your head to determine if multiple sclerosis or a tumor is causing trigeminal neuralgia. In some cases, your doctor may inject a dye into a blood vessel to view the arteries and veins and highlight blood flow (magnetic resonance angiogram).
    One published a set of guidelines for diagnosing TN is from the International Headache Society.

    For classical TN

    • Paroxysmal attacks of pain lasting from a fraction of a second to two minutes, affecting one or more divisions of the trigeminal nerve, and fulfilling criteria 2 and 3.
    • Pain has at least one of the following characteristics:
      • Intense, sharp, superficial or stabbing
      • Precipitated from trigger zones or by trigger factors
    • Attacks are stereotyped in the individuals patient
    • There is no clinically evident neurologic deficit
    • Not attributed to another disorder


    For symptomatic TN

    • Paroxysmal attacks of pain lasting from a fraction of a second to two minutes, with or without persistence of aching between paroxysms, affecting one or more divisions of the trigeminal nerve, and fulfilling criteria 2 and 3.
    • Pain has at least one of the following characteristics
      • Intense, sharp, superficial or stabbing
      • Precipitated from trigger zones or by trigger factors.
    • Attacks are stereotyped in the individual patient
    • A causative lesion, other than vascular compression, has been demonstrated by special investigations and/or posterior fossa exploration.

    Treatment of Child Trigeminal Neuralgia

    Treatment options include medicines, surgery, and complementary approaches.

    Pharmacologic Therapy

    • The first-line treatment – for patients with classic TN and idiopathic TN is pharmacologic therapy. The most commonly used medication is the anticonvulsant drug, carbamazepine. It is usually started at a low dose, and the dose is gradually increased until it controls the pain. It controls pain for most people in the early stages of the disease. However, in some patients, the effectiveness of carbamazepine decreases over time. Possible side effects of carbamazepine include drowsiness, dizziness, double vision, and nausea. In patients with Asian ancestry, before starting carbamazepine, testing for the HLA-B allele is recommended, as its presence increases the risk of development of toxic epidermal necrolysis or Stevens-Johnson syndrome.
    • Oxcarbazepine – is a newer drug and is being increasingly used as first-line therapy for TN in patients who do not respond to or who cannot tolerate carbamazepine (200 to 1200 mg/day) and oxcarbazepine (600 to 1800 mg/day). Possible side effects include double vision and dizziness. It can also cause hyponatremia. It should also be avoided in patients with the HLA-B 15:02 allele.
    • Muscle relaxant – Baclofen is a muscle relaxant that can be used to treat TN. Baclofen, lamotrigine, clonazepam, topiramate, phenytoin, gabapentin, pregabalin, and sodium valproate can be used. Side effects include dizziness, sedation, and dyspepsia.
    • Seizures, anticonvulsant medication – used to treat epilepsy and to delay or prevent the recurrence of depressive episodes in bipolar disorder. For epilepsy, this includes focal seizures, tonic-clonic seizures, and seizures in Lennox-Gastaut syndrome and medication lamotrigine, phenytoin, gabapentin, clonazepam, and valproic acid. Lamotrigine (200 to 400 mg/day), pregabalin (150 to 600 mg/day), gabapentin (1800 to 4200 mg/day), or topiramate (100 to 400 mg/day) may be considered. If the combination therapy fails, a switch to baclofen (40 to 80 mg/day) may be considered.
    • Eslicarbazepine – an active metabolite of oxcarbazepine, and the new Nav1.7 blocker, vixotrigine, are being explored for pain relief in TN.

    • Anticonvulsant medicines—used to block nerve firing—are generally effective in treating TN1 but often less effective in TN2. These drugs include carbamazepine, oxcarbazepine, topiramate, gabapentin, pregabalin, clonazepam, phenytoin, lamotrigine, and valproic acid.

    • Tricyclic antidepressants – such as amitriptyline or nortriptyline can be used to treat pain. Common analgesics and opioids are not usually helpful in treating the sharp, recurring pain caused by TN1, although some individuals with TN2 do respond to opioids.  Eventually, if medication fails to relieve pain or produces intolerable side effects such as cognitive disturbances, memory loss, excess fatigue, bone marrow suppression, or allergy, then surgical treatment may be indicated. Since TN is a progressive disorder that often becomes resistant to medication over time, individuals often seek surgical treatment.

    • Botulinum Toxin Injections – This can be beneficial for some patients, particularly the middle-aged and the elderly, who are refractory to medical therapy or who cannot tolerate medical therapy due to their side effects.

    • Tetracaine nerve block – may be used as an additional treatment after carbamazepine, as can acupuncture and/or peripheral nerve stimulation. Patients with secondary TN also can respond well to pharmacotherapy. However, it is recommended to treat the underlying lesion or disease.

    • There is controversy around opiate use such as morphine and oxycodone for treatment of TN, with varying evidence on its effectiveness for neuropathic pain. Generally, opioids are considered ineffective against TN and thus should not be prescribed.[rx]

    Surgical Therapy

    Patients who are refractory to medical therapy can be considered for surgery.
    • Microvascular decompression – This is one of the most common procedures used to treat trigeminal neuralgia. This is beneficial for patients with TN, where compression of the nerve root is the cause. This involves craniotomy and posterior fossa exploration for identifying and moving the blood vessel that is compressing the trigeminal nerve. A soft cushion is then inserted between the nerve and the vessel, to allow the nerve to recover, which eventually relieves the pain. In some patients, this procedure can result in sustained pain relief for greater than 10 years. Though this is the most effective procedure, it is also the most invasive one. Some of the complications associated with it are decreased hearing, cerebellar hematoma, CSF leaks, infarction, and facial weakness. It is believed to be the most effective long-term surgical treatment available currently for patients with TN.
    • Ablative procedures include rhizotomy–  with thermocoagulation, chemical injection, or mechanical balloon compression. These procedures involve damaging the trigeminal nerve root, thereby interrupting the pain transmission signals to the brain. Rhizotomy with thermocoagulation uses an electrode to apply heat to damage the nerve fibers. Chemical rhizotomy involves injecting the chemical, glycerol to the trigeminal nerve, thereby damaging it. Balloon compression involves inserting a tiny balloon to the point of location of nerve fibers. This balloon, on inflation, damages the nerve fibers. Some of the associated complications are postoperative dysesthesia, corneal numbness, sensory loss in trigeminal nerve distribution, and anesthesia Dolorosa.
    • Radiosurgery – This procedure involves using radiosurgery instrumentation. This is a non-invasive procedure, wherein, a highly concentrated dose of ionizing radiation is delivered to a precise target at the trigeminal nerve root. The radiation creates a lesion near the nerve root, thereby interrupting the pain signals from transmission to the brain. The formation of the lesion can be slow, and hence the pain relief using this procedure is delayed by up to several weeks or months. As this is one of the least invasive procedures, it can be repeated in patients who have a recurrence of pain. Some of the associated complications can be facial sensory loss and paresthesias.
    • Peripheral neurectomy and nerve block – The neurectomy can be performed on peripheral branches of the trigeminal nerve like the supraorbital, infraorbital, lingual, and alveolar nerves. This can be accomplished by alcohol injection, incision, cryotherapy, or radiofrequency lesioning. Peripheral neurectomy can be safe in elderly patients in remote and rural areas, where neurosurgical facilities are not readily available. However, the evidence regarding these peripheral techniques for trigeminal neuralgia is inconclusive.
    • A rhizotomy (rhizolysis)–  is a procedure in which nerve fibers are damaged to block pain. A rhizotomy for TN always causes some degree of sensory loss and facial numbness. Several forms of rhizotomy are available to treat trigeminal neuralgia:
    • Balloon compression – works by injuring the insulation on nerves that are involved with the sensation of light touch on the face. The procedure is performed in an operating room under general anesthesia. A tube called a cannula is inserted through the cheek and guided to where one branch of the trigeminal nerve passes through the base of the skull. A soft catheter with a balloon tip is threaded through the cannula and the balloon is inflated to squeeze part of the nerve against the hard edge of the brain covering (the dura) and the skull. After about a minute the balloon is deflated and removed, along with the catheter and cannula. Balloon compression is generally an outpatient procedure, although sometimes the patient may be kept in the hospital overnight. Pain relief usually lasts one to two years.
    • Glycerol injection is also generally an outpatient procedure in which the individual is sedated with intravenous medication. A thin needle is passed through the cheek, next to the mouth, and guided through the opening in the base of the skull where the third division of the trigeminal nerve (mandibular) exits. The needle is moved into the pocket of spinal fluid (cistern) that surrounds the trigeminal nerve center (or ganglion, the central part of the nerve from which the nerve impulses are transmitted to the brain). The procedure is performed with the person sitting up, since glycerol is heavier than spinal fluid and will then remain in the spinal fluid around the ganglion. The glycerol injection bathes the ganglion and damages the insulation of trigeminal nerve fibers. This form of rhizotomy is likely to result in the recurrence of pain within a year to two years. However, the procedure can be repeated multiple times.
    • Radiofrequency thermal lesioning – (also known as “RF Ablation” or “RF Lesion”) is most often performed on an outpatient basis. The individual is anesthetized and a hollow needle is passed through the cheek through the same opening at the base of the skull where the balloon compression and glycerol injections are performed. The individual is briefly awakened and a small electrical current is passed through the needle, causing tingling in the area of the nerve where the needle tips rest. When the needle is positioned so that the tingling occurs in the area of TN pain, the person is then sedated and the nerve area is gradually heated with an electrode, injuring the nerve fibers.  The electrode and needle are then removed and the person is awakened. The procedure can be repeated until the desired amount of sensory loss is obtained; usually a blunting of sharp sensation, with preservation of touch. Approximately half of the people have symptoms that reoccur three to four years following RF lesioning. Production of more numbness can extend the pain relief even longer, but the risks of anesthesia dolorosa also increase.
    • Stereotactic radiosurgery – (Gamma Knife, CyberKnife) uses computer imaging to direct highly focused beams of radiation at the site where the trigeminal nerve exits the brain stem. This causes the slow formation of a lesion on the nerve that disrupts the transmission of sensory signals to the brain. People usually leave the hospital the same day or the next day following treatment but won’t typically experience relief from pain for several weeks (or sometimes several months) following the procedure.  The International Radiosurgery Association reports that between 50 and 78 percent of people with TN who are treated with Gamma Knife radiosurgery experience “excellent” pain relief within a few weeks following the procedure. For individuals who were treated successfully, almost half have a recurrence of pain within three years.
    • Decompression Surgery –  is the most invasive of all surgeries for TN, but also offers the lowest probability that pain will return. About half of individuals undergoing MVD for TN will experience recurrent pain within 12 to 15 years.  This inpatient procedure, which is performed under general anesthesia, requires that a small opening be made through the mastoid bone behind the ear. While viewing the trigeminal nerve through a microscope or endoscope, the surgeon moves away from the vessel (usually an artery) that is compressing the nerve and places a soft cushion between the nerve and the vessel. Unlike rhizotomies, the goal is not to produce numbness in the face after this surgery. Individuals generally recuperate for several days in the hospital following the procedure, and will generally need to recover for several weeks after the procedure.
    • A neurectomy (also called partial nerve section) – which involves cutting part of the nerve, may be performed near the entrance point of the nerve at the brain stem during an attempted microvascular decompression if no vessel is found to be pressing on the trigeminal nerve. Neurectomies also may be performed by cutting superficial branches of the trigeminal nerve in the face. When done during microvascular decompression, a neurectomy will cause more long-lasting numbness in the area of the face that is supplied by the nerve or nerve branch that is cut. However, when the operation is performed in the face, the nerve may grow back and in time sensation may return.  With neurectomy, there is risk of creating anesthesia Dolorosa.

    Surgical treatment for TN2 is usually more problematic than for TN1, particularly where vascular compression is not detected in brain imaging prior to a proposed procedure. Many neurosurgeons advise against the use of MVD or rhizotomy in individuals for whom TN2 symptoms predominate over TN1, unless vascular compression has been confirmed. MVD for TN2 is also less successful than for TN1.

    Some individuals manage trigeminal neuralgia using complementary techniques, usually in combination with drug treatment. These therapies offer varying degrees of success. Some people find that low-impact exercise, yoga, creative visualization, aromatherapy, or meditation may be useful in promoting well-being. Other options include acupuncture, upper cervical chiropractic, biofeedback, vitamin therapy, and nutritional therapy. Some people report modest pain relief after injections of botulinum toxin to block the activity of sensory nerves.


    Chronic pain from TN is frequently very isolating and depressing for the individual. Conversely, depression and sleep disturbance may render individuals more vulnerable to pain and suffering. Some individuals benefit from supportive counseling or therapy by a psychiatrist or psychologist. However, there is no evidence that TN is psychogenic in origin or caused by depression, and persons with TN require effective medical or surgical treatment for their pain.

    References

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